Neurologic complications of vaccination …

Douglas J Lanska MD MS MSPH

Neuropharmacology & Neurotherapeutics

Updated 04.30.2024
Released 07.04.2018
Expires For CME 04.30.2027

Neurologic complications of vaccination

Author: Douglas J Lanska MD MS MSPH

See Contributor Disclosures

Neurologic complications of vaccination

In This Article

Quick Link

Introduction

Overview

Serious neurologic complications of vaccination are rare. Unfortunately, many associations between vaccination and putative neurologic complications have been asserted without sufficient objective data to establish a causal relationship. Most patients with vaccine-associated neurologic complications recover fully, although rare poor outcomes are recognized. Reported neurologic complications of vaccination have included headache, postvaccination (“needle-stick”) syncope, febrile seizures, encephalomyelitis, transverse myelitis, meningitis, polyneuritis, and macrophagic myofasciitis. This article reviews the neurologic complications of vaccines in general, as well as specific vaccines in particular, and also addresses special situations (eg, vaccination of patients with multiple sclerosis). Because it is generally impossible to determine causality from anecdotal reports of adverse events occurring after a vaccine, the emphasis in this chapter is on epidemiologic studies that establish an association between events that occur after vaccination beyond what would be expected by chance.

Key points

	• Serious neurologic complications of vaccination are rare.
	• Unfortunately, many associations between vaccination and putative neurologic complications have been asserted without sufficient objective data to establish a causal relationship.
	• Most patients with vaccine-associated neurologic complications recover fully, although rare poor outcomes are recognized.
	• Reported neurologic complications of vaccination have included headache, postvaccination (“needle-stick”) syncope, febrile seizures, encephalomyelitis, transverse myelitis, meningitis, and polyneuritis.
	• Postvaccination encephalomyelitis usually occurs 10 to 14 days after vaccination, but it may occur from 7 to 21 days after vaccination.
	• Headache, vomiting, drowsiness, and fever are often the first symptoms observed in postvaccination encephalomyelitis, with severe cases progressing to include disorientation, confusion, stupor or coma, paralysis, incontinence, urinary retention, and seizures.
	• Case-fatality rates for postvaccination encephalomyelitis vary considerably, from approximately 10% to 50%. Death can occur suddenly, usually within a week of onset of symptoms.
	• Approximately 25% to 30% of all survivors of postvaccination encephalomyelitis have some residual neurologic defect.
	• Vaccination-proximate febrile seizures represent only a small proportion of all febrile seizure hospital presentations, and vaccination-proximate febrile seizures have the same outcomes as other febrile seizures.

Historical note and terminology

Vaccines are dead or inactivated organisms or purified products derived from them that are administered to a person (or livestock or pet animal) to induce a beneficial immune response that will provide protection against infection with corresponding virulent organisms.

Several types of vaccine have been employed, including different types of whole-agent and partial-agent (subunit) vaccines and live-recombinant vector vaccines.

Whole-agent vaccines were the first vaccine types employed against communicable diseases, and these include inactivated and live-attenuated vaccines. Inactivated vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, or radiation. Live-attenuated vaccines contain live, attenuated microorganisms; many of these are active viruses (or less commonly, bacteria) that have been cultivated under conditions that disable their virulent properties or that use closely related but less dangerous organisms (eg, vaccinia virus for smallpox vaccination) to produce a broad immune response. Attenuated vaccines typically provoke more durable immunological responses than inactivated vaccines and are the preferred type for healthy adults. However, live-attenuated vaccines may not be safe in immunocompromised individuals and may on rare occasions mutate to a virulent form (reversal of attenuation) and cause disease.

In contrast to whole-agent vaccines, partial-agent (or subunit) vaccines are derived from some fraction of the microorganism, such as acellular protein components, inactivated toxic compounds produced by the microorganism (toxoid vaccines), capsular polysaccharides, or capsular polysaccharides covalently bound to a protein carrier to increase immunogenicity (conjugate vaccines).

More recently, live-recombinant vector vaccines have been introduced. These occupy a middle category, in that subunits of the target pathogen are made using recombinant DNA technology, reproduced using another viral backbone.

Table 1a. Whole-Organism Vaccines by Type, Organism Category, and Disease

Vaccine subtype	Organism category	Disease	Notes and comments

Inactivated	Virus	Hepatitis A
		Influenza	“Flu shot” made from highly purified, egg-grown viruses In most countries, since the 1970s, whole-virus vaccines have been replaced by less reactogenic split-virus vaccines and subunit vaccines.
		Japanese encephalitis	Vero cell-derived vaccine; licensed in the United States, Europe, Australia, and New Zealand
		Polio	Salk vaccine (injection)
		Rabies	Nerve tissue vaccines (Semple and Fuenzalida) can induce severe adverse reactions and are less immunogenic; now outdated they are still used in a limited and decreasing number of developing countries. Cell culture vaccines include human diploid cell vaccine that contains inactivated Pitman-Moore L503 or Flury strain of rabies virus grown on MRC-5 human diploid cell culture. Other cell culture vaccines include purified chick embryo cell vaccine, purified Vero cell rabies vaccine, and primary hamster kidney cell vaccine. Embryonated egg vaccines: Purified duck embryo vaccine uses duck embryo cells as a substrate. This vaccine contains thiomersal.
		Tick-borne encephalitis	FSME-Immun (Austria), Encepur (Germany), TBE-Moscow (Russian Federation), EnceVir (Russian Federation)
		SARS-CoV-2	CoronaVac (Chinese)
	Bacteria	Cholera	WC-rBS, killed whole-cell monovalent (O1) vaccine with a recombinant B subunit of cholera toxin 37 WC, killed modified whole-cell bivalent (O1 and O139) vaccine
		Pertussis
		Typhoid
Live-attenuated	Virus	Influenza	Seasonal flu nasal spray and 2009 H1N1 flu nasal spray
		Japanese encephalitis	Licensed in China
		Measles	Monovalent
		Mumps	Monovalent
		Measles, mumps, rubella	MMR combined vaccine
		Measles, rubella	MR combined vaccine
		Measles, mumps, rubella, varicella	MMRV combined vaccine
		Polio	Sabin vaccine (oral)
		Rotavirus	Rotarix and RotaTeq
		Rubella	Monovalent
		Smallpox	ACAM2000 has replaced Dryvax smallpox vaccine
		Shingles or zoster (varicella zoster virus)	Lyophilized preparation of live-attenuated Oka/Merck strain (Zostavax)
		Varicella (Chickenpox, varicella zoster virus)	Zoster Vaccine Live (ZVL) - Live-attenuated Oka strain, propagated in MRC-5 human diploid cells (Varilix and Varivax vaccines)
		Yellow fever	Two 17D substrain vaccines are manufactured today: 17DD (manufactured in Brazil and used in South America) and 17D-204 (YF-VAX; Manufactured outside of Brazil, including the US)
	Bacteria	Anthrax	Russian vaccine containing spores from attenuated strains of B. anthracis
		Typhoid	Oral
		Tuberculosis	BCG vaccine
Note: Some diseases have multiple vaccines of different types that are currently being used.

Table 1b. Partial-Organism (Subunit) Vaccines by Type, Organism Category, and Disease

Vaccine subtype	Organism category	Disease	Notes and comments
	Virus
Split virus		Influenza	The split-virus vaccine uses detergent to dissociate the viral lipid envelope, exposing all viral proteins and subviral elements
Protein subunit		Hepatitis B	Hepatitis B surface antigen
Protein subunit		Hepatitis E	Licensed in China Based on a recombinant 239-amino-acid-long peptide (a portion of the capsid protein), which is expressed in E. coli, and purified.
Protein subunit		Human papillomavirus	Highly purified virus-like particles (VLPs) that are the protein shells of the human papillomavirus virus (major capsid protein L1). VLPs contain no viral DNA, so cannot infect cells, reproduce, or cause disease. Gardasil 4v and 9v are produced using recombinant Saccharomyces cerevisiae (bacteria), and Cervarix 2v are produced in a recombinant Baculovirus expression vector system.
Protein subunit		Influenza	Hemagglutinin and neuraminidase antigens have been purified by removal of other viral components.
Protein subunit		Meningococcal disease	MenB-FHbp is a bivalent vaccine consisting of two different recombinant lipidated factor H binding protein (FHbp) antigens. MenB-4C is a multicomponent vaccine consisting of three recombinant proteins.
Protein subunit		Shingles or zoster (herpes zoster virus)	Zoster vaccine recombinant, adjuvanted (Shingrix)
Protein subunit		SARS-CoV-2	Novavax
Live-recombinant vector		SARS-CoV-2	Astra-Zeneca recombinant vaccine uses a replication-deficient adenoviral vector vaccine against SARS-CoV-2. The vaccine expresses the SARS-CoV-2 spike protein gene.
	Bacteria
Acellular fraction		Anthrax	Anthrax vaccine adsorbed licensed in United States, and Anthrax vaccine precipitated licensed in United Kingdom
Acellular fraction		Pertussis
Toxoid		Diphtheria	Monovalent
Toxoid		Tetanus	Monovalent
Toxoid		Diphtheria and tetanus	Combination toxoid vaccines: DT, used for primary immunization and boosting in children; Td, used for boosting and primary immunization in adolescents/adults
Toxoid (DandT), Acellular fraction (P)		Diphtheria, pertussis, and tetanus	DTP combinations: Initial DTP combinations contained whole-cell pertussis antigens. Frequent occurrence of minor local reactions and less common severe reactions of whole-cell pertussis vaccine led to the development of acellular vaccines.
Polysaccharide		Meningococcal disease	Monovalent (A or C), bivalent (A, C), trivalent (A, C, W135), and quadrivalent (A, C, W135, Y) formulations. The quadrivalent MPSV4 vaccine is used in the United States.
Polysaccharide		Pneumococcal disease	PPSV, 23-valent vaccine
Conjugate		Haemophilus influenzae type b	Hib
Conjugate		Meningococcal disease	MenACWY-D, MenACWY-CRM, Hib-MenCY-TT
Conjugate		Pneumococcal disease	PCV, 7-, 10-, and 13-valent vaccines
Live-recombinant vector	Virus	Dengue	CYD-TDV is a live attenuated tetravalent chimeric vaccine made using recombinant DNA technology using a yellow fever vaccine virus backbone vector that expresses envelope proteins of dengue viruses
Live-recombinant vector		Japanese encephalitis	Genetically engineered chimeric vaccine that combines protective antigenic determinants of attenuated SA14-14-2 JE strain with yellow fever vaccine strain 17D (YF 17D) virus as a vector backbone. Licensed in Australia and some Asian countries
Note: Some diseases have multiple vaccines of different types that are currently being used.

Table 1c. mRNA Vaccine, Type, Organism Category, and Disease

Vaccine subtype	Organism category	Disease	Notes and comments
	Virus	SARS-CoV-2	Pfizer-BioNTech COVID-19 vaccine; Moderna’s COVID-19 vaccine
Note: Some diseases have multiple vaccines of different types that are currently being used.

Clinical manifestations

Presentation and course

	• A variety of neurologic complications of vaccination have been reported, including headache, dizziness or vertigo, paresthesias, postvaccination (“needle-stick”) syncope, seizures, encephalomyelitis, transverse myelitis, meningitis, Bell palsy, and polyneuritis or Guillain-Barré syndrome.
	• Almost all serious complications occur within 12 days of vaccination.
	• Postvaccination encephalomyelitis usually occurs 10 to 14 days after vaccination but may occur from 7 to 21 days after vaccination.
	• Headache, vomiting, drowsiness, and fever are often the first symptoms observed with postvaccination encephalomyelitis.
	• Acute disseminated encephalomyelitis usually has an abrupt onset 7 to 14 days after vaccination with fever, altered consciousness, focal neurologic findings, and possibly seizures; neurologic sequelae occur in 25% to 30% and include personality changes, seizures, dysarthria, paresis, ataxia, and other cerebellar dysfunction.

A variety of neurologic complications of vaccination have been reported, including headache, dizziness or vertigo, paresthesias, postvaccination (“needle-stick”) syncope, seizures, encephalomyelitis, transverse myelitis, meningitis, Bell palsy, and polyneuritis or Guillain-Barré syndrome (129; 63; 64; 302; 225; 196). Almost all serious complications occur within 12 days of vaccination (302). Table 2 shows one method of categorizing neurologic adverse reactions to vaccination.

Table 2. Categorization of Neurologic Adverse Reactions to Vaccination

(1) Feature of systemic reaction to vaccination (applies to all vaccines, but frequency may vary; typically mild and transient, without sequelae)
	(A) Headache
	(B) Febrile seizures
	(C) Postvaccination (or “needle-stick”) syncope
(2) CNS infection (encephalomyelitis) from vaccine organism (high rates of serious sequelae, including major permanent disability and death)
	(A) Live-attenuated virus vaccine use in young infants or immunosuppressed individuals (eg, yellow fever vaccine, smallpox vaccine, measles vaccines)
	(B) Induction of herpes zoster with the HZV vaccine organism rather than naturally acquired wild-type virus (in early clinical trials)
	(C) Mutation of live-attenuated vaccine virus with development of neurotropism (historically, with yellow fever vaccines during serial passage) or reversion to wild-type virulent organism (eg, oral polio vaccine)
	(D) Mishap in manufacture of inactivated vaccine so that vaccine virus inactivation is incomplete, resulting in outbreak of clinical disease due to vaccination (eg, Cutter incident with Salk polio vaccine)
(3) Autoimmune or inflammatory reaction precipitated by vaccination, causing central or peripheral nervous system disease (ie, presumably autoimmune reactions in which vaccine-induced antibodies or T-cells cross-react with the host’s neuronal epitopes [eg, myelin basic protein], leading to central-nervous-system or peripheral-nerve damage). Often associated with excellent recovery and minimal sequelae, but severe permanent sequelae are possible.
	(A) Postvaccination encephalomyelitis
	(B) Acute disseminated encephalomyelitis
	(C) Autoimmune narcolepsy (2009 pandemic H1N1 influenza vaccine and sporadic postvaccination cases for various viruses)
	(D) Transverse myelitis
	(E) Cranial neuritis (eg, optic neuritis, Bell palsy, sudden deafness)
	(F) Aseptic meningitis (eg, mumps vaccine)
	(G) Guillain-Barré syndrome
	(H) Brachial neuritis
	(I) Mononeuritis multiplex
(4) Developmental, including adverse neurologic outcome of fetus (no clear examples) and childhood developmental disorders. (The only historical example was fraudulent and has since been entirely discredited [ie, supposed autism spectrum disorders after MMR vaccine administration].)
(5) Exacerbates (or induces relapse of) existing neurologic disease (typically raised as potential issue with immunologically mediated neurologic diseases but is controversial)
	(A) Multiple sclerosis
	(B) Guillain-Barré syndrome
(6) Other
(7) Unknown

Postvaccination encephalomyelitis usually occurs 10 to 14 days after vaccination but may occur from 7 to 21 days after vaccination (302). Headache, vomiting, drowsiness, and fever are often the first symptoms observed (156; 129; 281; 55; 80; 196). In mild cases, these may be the only symptoms, and in such cases, recovery is often rapid and complete. In more severe cases, symptoms progress to include disorientation, confusion, stupor or coma, paralysis, incontinence, urinary retention, and seizures (156; 129; 281; 55; 80; 196). Cerebral, midbrain, medullary, and spinal cord lesions have been observed clinically.

Acute disseminated encephalomyelitis usually has an abrupt onset 7 to 14 days after vaccination, with fever, altered consciousness, focal neurologic findings, and possibly seizures. Neurologic sequelae occur in 25% to 30% and include personality changes, seizures, dysarthria, paresis, ataxia, and other cerebellar dysfunction.

Clinical vignette

Suspected postvaccinial encephalomyelitis. A 38-year-old man with a history of heavy cigarette usage was hospitalized with acute respiratory distress and hypoxia 10 days after primary smallpox vaccination (68). He was treated for acute epiglottitis with corticosteroids, bronchodilators, antibiotics, and intermittent lorazepam. He was discharged 1 week later on a steroid taper and bupropion (for smoking cessation) but was again readmitted after several days because of agitation, emotional lability, and confusion. He had difficulty concentrating but was afebrile and well-oriented and had no focal neurologic deficits. Head CT showed several punctate areas of hypointensity in the deep white matter. MRI with and without gadolinium contrast showed multiple nonspecific nonenhancing punctate areas of increased signal in the deep white matter on fluid attenuation inversion recovery (FLAIR) images. Laboratory studies were significant for an elevated creatine phosphokinase level in the serum (3000 u/L) and a urine toxicology screen positive for marijuana and benzodiazepines. CSF studies were normal, including cell counts, protein, glucose, and IgG indices, with no oligoclonal bands. Polymerase chain reaction studies of CSF for herpes simplex virus and vaccinia virus were also negative. EEG was normal with the exception of findings consistent with ingestion of benzodiazepines. He improved and was discharged several days later with a diagnosis of steroid-induced psychosis. Four days later (25 days after vaccination) he had a generalized tonic-clonic seizure. A repeat MRI was unchanged from the previous scan. He was treated with phenytoin, and his steroid dose was increased. He was discharged the following day with a diagnosis of postinfectious encephalomyelitis. A month after his vaccination he had mild residual confusion and emotional lability.

The Centers for Disease Control and Prevention (CDC) categorize this case as “suspected” (based apparently on the diagnosis of clinicians involved in the patient’s care) rather than “probable” or “confirmed.” Several other factors could have caused or contributed to the patient’s neurologic presentation, including the acute infection and hypoxia, steroids, lorazepam, and bupropion. Features that are not typical of postvaccinial encephalomyelitis include the absence of fever or focal neurologic deficits, normal CSF cell counts and protein, normal EEG, and absence of enhancing white matter lesions on MRI. The reported CT and MRI findings are not specific. As noted by the Centers for Disease Control and Prevention, “a temporal association with vaccination does not necessarily indicate causality” (68).

Macrophagic myofasciitis. A previously healthy 25-year-old man was admitted for generalized muscle pain with an insidious onset that began 3 years prior to admission (313). He had exercise intolerance and a significant decrease in muscle strength, requiring gait support. He was on no chronic medications and had no recent history of illicit drug use or exposure to recognized toxin. Hepatitis B and tetanus vaccines were administered, respectively, 10 and 2 years before symptom onset. No analytical, imaging, or electromyography changes were found. Muscle biopsy revealed a predominantly macrophagic inflammatory infiltrate with aluminium deposits suggestive of macrophagic myofasciitis, which was attributed to previously administered vaccines.

Biological basis

	• Many reported neurologic events following vaccination are not caused by the vaccine in question but, rather, are part of the background occurrence of such events; consequently, well-conducted epidemiological studies are necessary to establish causality.
	• Postvaccination febrile seizures do not differ from febrile seizures occurring in other contexts and generally have no worse outcome or prognostic implications.
	• In most cases, genetic or structural defects are the underlying cause of epilepsy with onset after vaccination, including cases with either preexistent encephalopathy or benign epilepsy with good outcome.
	• Postvaccination encephalomyelitis likely represents an autoimmune demyelinating process.
	• In rare cases, live-attenuated viruses may spread directly to the central nervous system, an occurrence that is most likely in young infants and immunocompromised individuals.

Etiology and pathogenesis

Many reported neurologic events following vaccination are not caused by the vaccine in question but, rather, are part of the background occurrence of such events. Well-conducted epidemiological studies are necessary to establish causality.

The etiology of true neurologic complications of vaccination may be mixed or multiple; these include vasovagal or anxiety reactions induced by the needle-stick of vaccination, febrile seizures induced by postvaccination fever, direct spread of the vaccine virus to the central nervous system (with live-attenuated vaccines), and induction of immune-mediated demyelination.

Postvaccination febrile seizures do not differ from febrile seizures occurring in other contexts and generally have no worse outcome or prognostic implications (66). The only recognized exception is vaccination-triggered occurrence of febrile seizures in Dravet syndrome; vaccine-induced fever may trigger an earlier manifest onset of this genetic disorder, but this does not alter the course of the disease (222; 382; 347).

Postvaccination encephalomyelitis likely represents an autoimmune demyelinating process (334). In immunologically normal adults, most cases probably result from induction of autoimmune demyelination, ie, acute disseminated encephalomyelitis, as can occur with other viral exanthems or several vaccines (eg, smallpox, chickenpox, rabies). Limited pathologic studies have demonstrated perivenous demyelination, mononuclear cell perivascular inflammation, and diffuse cortical petechial hemorrhages (298; 314; 280; 281; 55; 80; 196). With the smallpox vaccine, postvaccination encephalomyelitis occurred much more frequently after primary vaccination than after revaccination (298; 55; 172; 196).

Experimental allergic encephalomyelitis has been an informative animal model for postvaccination encephalomyelitis (279; 261; 204), although its utility as a model for multiple sclerosis has been highly contested (316; 85; 155).

With some vaccines, there appears to be variation in individual susceptibility to development of adverse events after vaccination. For example, genetic polymorphisms in the methylenetetrahydrofolate reductase gene and interferon regulatory factor 1, an immunological transcription factor, have been associated with an increased susceptibility to adverse events after smallpox vaccination (275).

In rare cases, live-attenuated viruses may spread directly to the central nervous system. This is most likely in young infants and immunocompromised individuals. This may occur with reactivation of live-attenuated (Sabin) poliovirus and with the vaccinia virus used in smallpox vaccination. In a few cases, vaccinia virus has been recovered from cerebrospinal fluid and blood (137; 136; 138; 196; 198), but the significance of this is not entirely clear in the absence of similar studies on healthy vaccinees. Animal models suggest that vaccinia virus can migrate across the blood-brain barrier but that encephalitis only occurs when additional factors are operative, such as during co-infection by bacteria (117).

Neurologic complications have also resulted from manufacturing defects, as with the Cutter incident in 1955 in which some lots of the Salk inactivated poliovirus vaccine manufactured by Cutter Laboratories contained live polio virus (see further discussion below) (264; 250; 251).

Aluminium oxyhydroxide (alum), a nano-crystaline compound forming agglomerates, was first introduced in vaccines as an immunologic adjuvant effect in 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines. Although generally well tolerated, alum may rarely cause disabling health problems in susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue, and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at sites of previous intramuscular immunization, forming a granulomatous lesion called macrophagic myofasciitis (127; 128; 125; 126; 313). Macrophagic myofasciitis should be regarded as pathological only if detected at least 18 months after last aluminum-containing immunization (313). Macrophagic myofasciitis is considered part of the spectrum of the so-called autoimmune/inflammatory syndrome induced by adjuvants (“ASIA”) (308).

Epidemiology

	• The United States Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system for reporting adverse events that occur after administration of United States-licensed vaccines, is important for detecting rare adverse events and assessing reporting trends but cannot be used to assess incidence rates or causality.
	• Because reports to VAERS are submitted voluntarily by individuals with different professional backgrounds and personal interests (eg, manufacturers, health-care providers, patients, and family members), reports vary in quality and completeness, often lack detail, and frequently include inaccurate information.
	• Actual rates for adverse events reported to VAERS cannot be calculated because (1) the cases reported are influenced by both underreporting and differential reporting, and (2) the corresponding number of doses administered is unknown.
	• Unfortunately, many associations between vaccination and putative neurologic complications have been asserted without sufficient objective data to establish a causal relationship.
	• Neurologic complications of vaccination are rare.
	• Most patients with vaccine-associated neurologic complications recover fully, although rare poor outcomes are recognized.
	• Multiple vaccines have been associated with an increased risk of febrile seizures.
	• Children receiving vaccinations associated with an increased risk of febrile seizure should not receive prophylactic antipyretics because no significant reduction in the rate of febrile seizures has been documented and because prophylactic antipyretic use can potentially decrease the immune response to certain vaccines.
	• Vaccination-proximate febrile seizures have the same outcomes as other febrile seizures: febrile seizures after vaccination do not increase the likelihood that epilepsy or other neurologic disorders will develop in these children.
	• Postvaccination syncope is an uncommon but recognized complication of vaccination (and other needle-stick-related medical procedures).
	• Postvaccination acute disseminated encephalomyelitis has been associated with several vaccines, including those for rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese encephalitis, pertussis, influenza, and hepatitis B.
	• Vaccination is not associated with an increased risk of multiple sclerosis or optic neuritis for the following vaccines: BCG, diphtheria, influenza, measles, MMR, polio, rubella, tetanus, and typhoid.
	• In general, immunization of patients with multiple sclerosis has been effective and relatively safe, such that benefits of vaccination outweigh the risks.
	• There is (1) strong evidence against an increased risk of multiple sclerosis exacerbation after influenza immunization, (2) no evidence that hepatitis B, varicella, tetanus, or BCG vaccines increase the risk of multiple sclerosis exacerbations, and (3) insufficient evidence for other vaccines, particularly live-virus vaccines.
	• Patients with multiple sclerosis are at a significantly heightened risk of severe adverse outcomes (including death) following infectious diseases for which vaccinations are now available; therefore, such patients should not be denied the benefits of protective vaccinations because of potential undocumented risks of disease exacerbation.
	• Decision-making regarding immunization may be complicated in multiple sclerosis patients who are receiving immunosuppressive or immunomodulatory therapy that might impair their ability to generate an appropriate protective response to immunization.
	• Live-virus vaccines are contraindicated in patients on immunosuppressant therapy.

The United States Vaccine Adverse Event Reporting System (VAERS). The United States Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system for reporting adverse events that occur after administration of United States-licensed vaccines, is important for detecting rare adverse events and assessing reporting trends but cannot be used to assess incidence rates or causality. Because reports to VAERS are submitted voluntarily by individuals with different professional backgrounds and personal interests (eg, manufacturers, health-care providers, patients, and family members), reports vary in quality and completeness, often lack detail, and frequently include inaccurate information. Actual rates for adverse events reported to VAERS cannot be calculated because (1) the cases reported are influenced by both underreporting and differential reporting, and (2) the corresponding number of doses administered is unknown. Differential reporting is often manifest by increased reporting for specific vaccines or specific adverse events, particularly for more serious and unexpected events, events occurring soon after vaccination, events surrounded by publicity, and reports related to litigation proceedings (376).

Standard case definitions for (some) adverse neurologic events. The Brighton Collaboration was inaugurated in 2000 as a voluntary international organization to facilitate the development, evaluation, and dissemination of high-quality information about the safety of human vaccines (53; 54). The Collaboration subsequently developed standardized case definitions of adverse events following immunizations (AEFI). Standardized case definitions of adverse events following immunizations are an essential element in the assessment of immunization safety because they establish a common “vocabulary” and understanding of adverse events following immunizations that facilitates the comparability of data from clinical trials and surveillance (54). In particular, Brighton Collaboration case definitions were developed for encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM) (301); aseptic meningitis (330); and facial nerve palsy including Bell palsy (274). In later work from the Brighton Collaboration, 45 maternal and 62 fetal/neonatal events were prioritized, and key terms and concept definitions were endorsed, including various adverse outcomes of pregnancy, microcephaly and macrocephaly, neonatal encephalopathy, hypoxic ischemic encephalopathy, neonatal seizure, hypotonia/hypertonia, hyporeflexia/hyperreflexia, meningitis, meningoencephalitis, intraventricular hemorrhage, and periventricular leukomalacia (238).

Assessment of a causal relationship ("causality"). Unfortunately, many associations between vaccination and putative neurologic complications have been asserted without sufficient objective data to establish a causal relationship (234; 65). As Gellin and Schaffner noted in 2001, events that occur after vaccination are likely to be attributed to vaccination, regardless of whether or not the vaccine actually caused the events (123). Many patients and some physicians interpret the temporal sequence of vaccination-followed-by-a-neurologic-event as sufficient evidence to support an interpretation of causality—ie, that the vaccine actually caused the neurologic event (post hoc ergo prompter hoc fallacy; “after this, therefore, because of this”). The consideration of a causal association is supported by apparent biological plausibility: for example, because hepatitis B vaccination stimulates the immune system and because multiple sclerosis has an immunologic basis, several authors have suggested that hepatitis B vaccination may trigger a paradoxical response that triggers the onset of (ie, causes) multiple sclerosis. Furthermore, published case reports and inadequately performed epidemiologic studies suggesting increased risk instill “the persuasive power of immediacy” to public policy development and medicolegal decision-making. However, these considerations are not sufficient to establish causality.

English epidemiologist and statistician Sir Austin Bradford Hill CBE FRS (1897-1991) pioneered the randomized clinical trial and, together with British physician epidemiologist Sir William Richard Doll CH OBE FRS (1912-2005), demonstrated the connection between cigarette smoking and lung cancer.

English epidemiologist and statistician Sir Austin Bradford Hill CBE FRS (1897-1991)

(Courtesy of the Wellcome Collection, London, England. Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/deed.en.)

Hill is widely known for pioneering the "Bradford Hill" criteria for determining a causal association.

Braford Hill "considerations" to assess causality (presented in the original order):

	• Strength of association (effect size): Although a small association does not exclude causality, support for causality is increased with stronger associations (in part because stronger associations are less likely to occur from unrecognized biases or random events).
	• Consistency (reproducibility): Consistent findings observed by different investigators in different places with different samples support a causal arrangement and give confidence that the effects are not due to unrecognized bias in a single study. However, this is difficult to operationalize, though this concept is incorporated into the concept of statistical heterogeneity in meta-analyses.
	• Specificity: Causation is likely if there is a very specific disease produced by an exposure that is unlikely to otherwise occur, but this consideration cannot be considered a necessary criterion of causality, as Hill himself recognized and acknowledged: "Milk as a carrier of infection and, in that sense, the cause of disease can produce such a disparate galaxy as scarlet fever, diphtheria, tuberculosis, undulant fever, sore throat, dysentery and typhoid fever. Before the discovery of the underlying factor, the bacterial origin of disease, harm would have been done by pushing too firmly the need for specificity as a necessary feature before convicting the dairy" (150). Very specific causal relationships of drugs and adverse reactions are rare (eg, clear cell adenocarcinoma, a rare form of cancer of the vagina and cervix, in daughters of women who used diethylstilbestrol during pregnancy; or phocomelia in offspring of mothers who used thalidomide during a critical period of pregnancy).
	• Temporality: The effect must occur after the putative cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). Obviously, though, just having something happen after something else can occur by chance. Separating causal temporal sequences from noncausal/chance occurrences simply cannot be done with a case report or even a case series (219). Moreover, even presenting case reports as possibly causal without doing a necessary study to assess more formally whether there is a causal relationship can have very negative results if less critical colleagues and the public interpret such reports as proof of causality, which happened all too frequently during the COVID-19 pandemic.
	• Biological gradient (dose-response or dose-effect relationship): Greater exposure should generally lead to a greater incidence of a causal effect, although a true causal effect can work the other way and produce a smaller effect (as in something that produces/causes a protective effect). In some cases, however, the mere presence of a truly causal factor can trigger the effect without a progressively larger effect with increasing exposures—a threshold effect (like the all-or-none firing of a neuron). More problematically, apparent dose-effect relationships may arise from confounding (ie, a third variable that influences both the independent and dependent variables).
	• Coherence: Coherence between epidemiological and laboratory findings could possibly increase the likelihood of a causal effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations." Coherence is also like beauty, something that is in the eye of the beholder. Circumstances where such coherence would sway a decision about causality are difficult to imagine. Others have similarly found this difficult to apply and lacking in utility (307).
	• Experiment: "Occasionally it is possible to appeal to experimental evidence." When considering the possible adverse effects of vaccinations, the first experimental evidence is the results of the randomized controlled trials that were done to support licensing the vaccines in the first place. The problem is that the sample size of such trials is only sufficient to detect relatively common adverse effects. Rare effects may only come to attention during postmarketing surveillance. Testing whether rare events are associated with a given exposure usually requires other study designs (eg, case-control studies).
	• Analogy: The use of analogies or similarities between the observed association and any other associations. Circumstances where analogy would sway a decision about causality are difficult to imagine. Others have similarly found this difficult to apply and lacking in utility (307).

The influential Bradford Hill "viewpoints" (often referred to by others as "criteria," although he did not see them as such) are still commonly used to assess causality within epidemiology (150). Bradford Hill's considerations or viewpoints can be misapplied and misinterpreted, and some of the viewpoints may even be misleading, for example, if studies reporting similar effects are similarly biased (which is not uncommon) (65).

Hill's approach also served as a stimulus for later causal frameworks, including some that tried to incorporate multicausal networks: (1) directed acyclic graphs (DAGs); (2) sufficient-component cause models ("causal pies"); and (3) the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology (286; 327; 303; 130; 87; 01; 03; 56; 345; 377; 31; 30; 99; 42; 51; 77; 296; 344; 381).

Directed acyclic graph

(Illustration by Lyonsam/Dmitry Dzhus August 23, 2007. Public domain.)

The GRADE approach, used to assess the quality of evidence for a specific outcome across studies, is most directly applicable to a meta-analysis undertaken in the context of a systematic review (but can also be applied to individual studies or nonquantitative syntheses). The different causal frameworks have substantial overlap, particularly for four of Hill's viewpoints: "strength of association (including analysis of plausible confounding); temporality; plausibility (encoded by DAGs or SCC models to articulate mediation and interaction, respectively); and experiments (including implications of study design on exchangeability)" (307).

The Clinical Immunization Safety Assessment (CISA) network in the United States developed a thoughtful and very detailed algorithm to assist in collecting and interpreting data, and to help assess causality after individual adverse events following immunizations (AEFI) (200; 141).

In 2019, the World Health Organization published an updated manual on causality assessment of an adverse event following immunization (AEFI) (375). WHO categorized adverse events following immunizations into five categories: (1) vaccine product-related reaction; (2) vaccine quality defect-related reaction; (3) immunization error-related reaction (ie, caused by inappropriate vaccine handling, prescribing or administration); (4) immunization anxiety-related reaction/Immunization stress related response (ISRR); and (5) coincidental event (375). For causality assessment, the WHO relied heavily on the Bradford Hill viewpoints. WHO developed a causality assessment checklist with five major sections: (1) Is there strong evidence for other causes? (2) Is there a known causal association with the vaccine or vaccination? (3) Was the event in section II within the time window of increased risk? (4) Is there strong evidence against a causal association? and (5) Other qualifying factors for classification (eg, history of prior similar response to a similar vaccine, or in the absence of vaccination) (375).

Butler and colleagues in 2021 provided another excellent resource from the United Kingdom that provided criteria for defining causality in vaccine-related adverse events adapted from WHO criteria and Bradford Hill viewpoints (150; 375; 60). Butler and colleagues also presented suggested criteria for labelling causality in neurologic adverse events following immunization as probable, possible, or unlikely (60).

Reference to these guides by clinicians, authors, and editors would greatly improve the reporting of adverse events following immunization (150; 141; World Heath Organization 2019; 60).

Criteria for labelling causality in neurologic adverse events following immunization (60):

• Probable (all are required):
	- Typical time frame (eg, for immune-associated adverse events following immunization, less than 6 weeks from vaccination).
	- No indication of an alternative etiology.
	- No risk factors for an alternate etiology.
• Possible (either is required):
	- Plausible time frame, but outside of typical (eg, for immune-associated adverse events following immunization, 6 to 12 weeks from vaccination).
	- There may be an indication of an alternative etiology and/or risk factors for an alternate etiology, but these are unlikely to explain the event.
• Unlikely
	- Timeline not in keeping with prior established temporal associations (eg, for immune-associated adverse events following immunization, less than 24 hours or greater than 12 weeks from vaccination).
	- Alternative etiology and/or risk factors fully explain the event.

In a review of 154 postmarketing individual case safety reports (ICSRs) reporting immunization errors and a fatal outcome that were submitted to EudraVigilance from 2001 to 2016, 20 cases were classified as consistent with causal association of which 12 had a large error contribution, two had a moderate error contribution, and the remainder had small or no error contributions or were unclassifiable; two general issues were responsible for the 12 cases with a large error contribution: (1) incorrect handling of the multidose vial after opening of the vial; and (2) administration of live-attenuated vaccines to immunocompromised patients (154).

Neurologic complications of vaccination: general considerations. Neurologic complications of vaccination are in fact rare (234). Most patients with vaccine-associated neurologic complications recover fully, although rare poor outcomes are recognized (234).

Febrile seizures. Multiple vaccines have been associated with an increased risk of febrile seizure: (1) measles; (2) measles-mumps-rubella (MMR); (3) measles-mumps-rubella-varicella (MMRV); (4) combined diphtheria, tetanus, acellular pertussis, polio, and Haemophilus influenzae type b vaccine; (5) whole-cell pertussis vaccine; (6) 7-valent pneumococcal conjugate vaccine; and (7) concomitant administration of the trivalent inactivated influenza vaccine with either the 7-valent pneumococcal conjugate vaccine or the diphtheria, tetanus, and acellular pertussis vaccine (369; 236). Children receiving these vaccinations should not receive prophylactic antipyretics because no significant reduction in the rate of febrile seizures has been documented and because prophylactic antipyretic use can potentially decrease the immune response to certain vaccines (236).

Vaccination-proximate febrile seizures represent only a small proportion of all febrile seizure hospital presentations, and vaccination-proximate febrile seizures have the same outcomes as other febrile seizures (91). Specifically, febrile seizures after vaccination do not increase the likelihood that epilepsy or other neurologic disorders will develop in these children (369). Children with a history of convulsions may be at increased risk for febrile convulsions after vaccination (particularly MMR or MMRV vaccination), but the risk appears to be minimal (369).

Postvaccination syncope. Postvaccination syncope is an uncommon but recognized complication of vaccination (and other needle-stick-related medical procedures) (72; 194; 315). From 0.28 to 0.54 episodes of syncope are reported per million doses of vaccine distributed, although for various methodological reasons these figures may not reflect the true rate of postvaccination syncope. Postvaccination syncope occurs primarily among girls aged 11 to 18 years. Syncope is most commonly reported after three vaccines given to adolescents: human papilloma virus, MCV4 (meningococcal disease), and Tdap (tetanus, diphtheria, and pertussis). Because the ingredients of these three vaccines are different, syncope is most likely due to the vaccination process and not to the vaccines themselves. Only about 6% of postvaccination syncopal cases are considered "serious" (including those with secondary injuries), and three fourths of these occurred in females. Rare serious outcomes with secondary injury include skull fracture, other head injury, subarachnoid and other intracranial hemorrhage, motor vehicle accident, and death. One half of "serious" cases of postvaccination syncope occur within 5 minutes of vaccination, and more than two thirds occur within 15 minutes.

Vaccination and CNS demyelinating disorders. In one study, vaccination (of any type) was associated with an increased risk of acquired central nervous system demyelinating syndromes within the first 30 days after vaccination only in younger (less than 50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57), but there was no longer-term association of vaccines with multiple sclerosis or any other CNS demyelinating syndrome (191); the authors concluded that the apparent short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity. Postvaccination acute disseminated encephalomyelitis has been associated with several vaccines, including those for rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese encephalitis, pertussis, influenza, and hepatitis B (162). However, vaccination is not associated with an increased risk of multiple sclerosis or optic neuritis for the following vaccines: BCG, diphtheria, influenza, measles, MMR, polio, rubella, tetanus, and typhoid (93; 94; 95; 148; 105).

Although several studies suggested a slightly increased risk of multiple sclerosis onset with hepatitis B vaccination, most studies have not found such an association (338; 32; 93; 94; 265; 310; 153; 105; 207). This consideration has largely been dismissed (see further discussion in section on hepatitis B vaccination below).

In general, immunization of patients with multiple sclerosis has been effective and relatively safe, such that benefits of vaccination outweigh the risks. In particular, vaccination does not appear to increase the short-term risk of relapse in multiple sclerosis (83). A review in 2002 for the American Academy of Neurology found (1) strong evidence against an increased risk of multiple sclerosis exacerbation after influenza immunization, (2) no evidence that hepatitis B, varicella, tetanus, or BCG vaccines increase the risk of multiple sclerosis exacerbations, and (3) insufficient evidence for other vaccines, particularly live-virus vaccines (288). In addition, patients with multiple sclerosis are at a significantly heightened risk of severe adverse outcomes (including death) following infectious diseases for which vaccinations are now available. Therefore, such patients should not be denied the benefits of protective vaccinations because of potential undocumented risks of disease exacerbation. Decision-making regarding immunization may be complicated in multiple sclerosis patients who are receiving immunosuppressive or immunomodulatory therapy that might impair their ability to generate an appropriate protective response to immunization. Also, live-virus vaccines are contraindicated in patients on immunosuppressant therapy.

Selected vaccines

Anthrax vaccine (AVA). Fatigue and headache were the most commonly reported systemic adverse events following anthrax vaccine administration among clinical trial participants, but they were reported by fewer than 11% of participants (376). Serious disorders of the nervous system were infrequently reported after anthrax vaccine vaccination, and none have been fatal (376; 366). None of the studies found that the risk for adverse health effects or chronic diseases was higher after anthrax vaccination (376). There is no evidence that anthrax vaccine recipients had a higher risk than the general population for life-threatening or permanently disabling adverse events immediately after receiving anthrax vaccine (171; 376). In addition, in a matched case-control study, Vaccine Analytic Unit (VAU) investigators found no significant associations between optic neuritis and previous receipt of anthrax vaccine (259).

Hepatitis B vaccine. In general, there are minimal adverse reactions (eg, myalgias) after receipt of hepatitis B vaccine, and these are transient, mostly limited to within 24 hours. Serious side effects of hepatitis B virus vaccine are rare.

During early post-licensure surveillance, several types of neurologic adverse events following hepatitis B vaccination were reported, including Guillain-Barré syndrome, chronic fatigue syndrome, sudden infant death syndrome, optic neuritis, and multiple sclerosis. Guillain-Barré syndrome was reported rarely following immunization with the plasma-derived vaccine, but Guillain-Barré syndrome has not been associated with the newer recombinant hepatitis vaccines. In addition, in the late 1990s, there were reports of onset or relapse of multiple sclerosis following hepatitis B immunization, particularly following an extensive immunization program in France; consequently, in 1998, the French government suspended the school-based vaccination program because of fears that hepatitis B vaccination caused neurologic disorders, including multiple sclerosis. Some considered a causal explanation to be biologically plausible (a viewpoint in Bradford Hill's list of causality considerations) because immune stimulation from vaccination might precipitate the onset of multiple sclerosis in susceptible persons or could lead to relapses, possibly through molecular mimicry between vaccine antigens and human proteins (emphasizing the limitations of biological plausibility as a consideration of causality) (220). Critically, infection with wild-type hepatitis B virus (HBV) has not been identified as a risk factor for multiple sclerosis, and there is no evidence that hepatitis B virus protein may trigger an attack on nerve tissue (220).

However, since then, multiple epidemiological studies have demonstrated no causal association between receipt of hepatitis B vaccine and any of these conditions (140; 386; 293; 32; 322; 323; 95; 227; 228; 229; 29; 294). The well-designed and conducted study by Ascherio and colleagues identified no association between hepatitis B vaccination and the development of multiple sclerosis (32); the strengths of this study included careful selection of control groups, a high prevalence of hepatitis B virus immunization among study subjects, and validation of vaccination status. Furthermore, the lack of an association between hepatitis B virus vaccination and development of multiple sclerosis is supported by other studies, including a Canadian study of children vaccinated as part of a school-based program (293) and a retrospective cohort study in the United States (386).

In addition, no evidence of a causal association between Bell palsy (287), Guillain-Barré syndrome (44), optic neuritis (259; 45), sudden-onset sensorineural hearing loss (46), or other chronic illnesses and receipt of hepatitis B vaccine has been demonstrated through analysis of the CDC’s Vaccine Safety Datalink (VSD) data.

In fact, there are no well-conducted studies demonstrating a statistically significant association between hepatitis B virus vaccination and the subsequent development of multiple sclerosis. Therefore, prior concerns about the development of multiple sclerosis should not interfere with vaccination of individuals at increased risk of hepatitis B virus infection, nor does available evidence justify changes in national vaccination policy for hepatitis B virus (192).

Human papilloma virus (HPV) vaccines. Available evidence has not suggested any significant safety concern regarding the use of HPV vaccines, and in particular it has not identified any serious neurologic adverse effects of the vaccine (28; 372). The proportions of persons reporting a serious adverse event were similar in the vaccine and placebo groups, as were the types of serious adverse event reported. Among nonserious adverse events in postlicensure data, the most commonly reported generalized symptoms included syncope, dizziness, headache, and myalgias (81; 28). In a VSD collaborative study between the Centers for Disease Control and Prevention and nine integrated health-care organizations, there were no statistically significant increased risks observed for any of the prespecified endpoints including Guillain-Barré syndrome, stroke, seizures, or syncope (122; 81). In a general safety assessment evaluating outcomes diagnosed in emergency room visits and hospitalizations among 189,000 females receiving at least one dose of HPV4, same-day syncope was associated with HPV4 (81). In France, a case-control study to evaluate autoimmune disorders following HPV4 (among 211 cases and 875 controls) found no increased risk for central demyelination disease, multiple sclerosis, or Guillain-Barré syndrome (81; 134). Another study in England similarly found no increased risk for Guillain-Barré syndrome (13). A review of post-licensure safety surveillance during more than 4 years of routine use of the bivalent vaccine found no patterns or trends for potential immune-mediated diseases after vaccination, and in particular the observed incidences of Bell palsy and (confirmed) Guillain-Barré syndrome were within the expected range in the general population (14). Although anecdotal concerns have been raised about complex regional pain syndrome and postural orthostatic tachycardia syndrome following HPV vaccination, reviews of pre- and postlicensure data provide no evidence that these syndromes are caused by the HPV vaccines (28; 372).

Herpes zoster (shingles) vaccines. Overall, with the live-attenuated vaccine Zostavax (Zoster Vaccine Live, ZVL), serious adverse events occurred at similar rates in vaccinated and placebo groups (04; 101). In rare instances, the ZVL vaccine strain may cause disseminated rash and herpes zoster in immunocompetent recipients (Food and Drug Administration, 2006; 04; 101), and life-threatening and fatal complications in immunocompromised recipients (101). In the Shingles Prevention Study, the number and types of serious adverse events during the 42 days after receipt of vaccine or placebo were similar (1.4%) (254). However, rates of serious adverse events in the safety substudy were higher in vaccine recipients than in placebo recipients (1.9% vs. 1.3%, respectively, with a relative risk of 1.5 and 95% CI of 1.0-2.3), but no temporal or clinical patterns of adverse events were observed in vaccine recipients to suggest a causal relation. Zoster-like rashes were less common in vaccine versus placebo recipients during this 42-day period (p< 0.05) and the Oka/Merck strain of VZV was not detected in any of 10 lesion specimens from vaccine recipients available for PCR testing (indicating that these cases had zoster from reactivation of previously acquired VZV). In contrast, in early studies conducted during vaccine development, samples from rashes in two vaccinated persons were confirmed to be Oka/Merck-strain VZV; both experienced noninjection-site varicella-like rashes (72). (Note: Zostavax is no longer available for use in the United States, as of November 18, 2020.)

With the new subunit vaccine Shingrix (Zoster Vaccine Recombinant, Adjuvanted; RZV), overall rates of serious adverse events over the study periods were similar in the RZV and placebo groups (101).

Zoster vaccines and Guillain-Barré syndrome. In a cohort study and self-controlled case series analyses, Goud and colleagues assessed the risk of Guillain-Barré syndrome after administration of the zoster vaccines (131). This study utilized Medicare claims data on beneficiaries aged 65 years or older. The cohort study compared approximately 849,000 individuals vaccinated with Shingrix and approximately 1,817,000 individuals vaccinated with Zostavax. Self-controlled analyses included events identified from approximately 2,114,000 eligible beneficiaries 65 years or older vaccinated with Shingrix. The authors compared the relative risk of Guillain-Barré syndrome after Shingrix versus Zostavax, followed by claims-based and medical record-based self-controlled case series analyses to assess the risk of Guillain-Barré syndrome during a postvaccination risk window (from days 1 to 42) compared with a control window (from days 43 to 183).

In the cohort analysis, the risk of Guillain-Barré syndrome was significantly increased among those receiving Shingrix compared with those receiving Zostavax, with a rate ratio point estimate of 2.3. In the self-controlled case series analyses, there was a significantly increased risk of Guillain-Barré syndrome in the risk window following Shingrix compared with the control window, with a corresponding rate ratio of 4.3, and an adjusted attributable risk of 5.1 excess cases of Guillain-Barré syndrome per million vaccinations. Secondary analysis included approximately 951,000 first doses of Shingrix and identified a significantly increased risk of Guillain-Barré syndrome with a rate ratio of 9.3, and an adjusted attributable risk of 9.5 excess cases for every million vaccinations administered. The medical record-based analysis confirmed this significantly increased risk, finding a rate ratio of 5.0, and an adjusted attributable risk of 5.2 excess cases for every million vaccinations administered. The extended study period self-controlled case series decreased the observed rate ratio to 2.8 and the adjusted attributable risk to 3.1 excess cases for every million vaccinations administered.

The authors concluded that there is a slightly increased risk of Guillain-Barré syndrome during the 42 days following Shingrix vaccination in the Medicare population, with approximately three excess Guillain-Barré syndrome cases per million vaccinations administered.

Vaccination against shingles in patients with multiple sclerosis. In 1997, Ross and colleagues conducted an uncontrolled longitudinal pilot trial of vaccination of 50 multiple sclerosis patients with a live-attenuated VZV vaccine (N.B., not ZVL/Zostavax) as a possible therapeutic agent (285). All of the patients were seropositive for VZV before the vaccination and all of them developed a rise in antibody titers following vaccination. The patients were followed for 1 year. There were no major adverse effects identified. Overall, at the end of the trial, of 47 patients for whom such information was available, 14 were reported to be improved, four were reported to be worse, and 29 were unchanged. Although not a controlled trial, these results suggest that live-attenuated VZV vaccines are not necessarily harmful to patients with multiple sclerosis and could possibly be helpful.

In general, despite the results of Ross and colleagues (285), live-virus vaccines are not recommended for people with multiple sclerosis because live-virus vaccines can potentially precipitate an increase in disease activity (195). However, most people have had chickenpox earlier in their lives, so the virus is already in their bodies, undercutting the need for avoidance of live-virus vaccines for prevention of shingles in patients with multiple sclerosis. The use of ZVL (Zostavax) was not addressed in the 2002 American Academy of Neurology guideline on vaccine use in multiple sclerosis (288), prescribing information from the manufacturer (Merck), the CDC recommendations (143), or the FDA licensing of Zostavax. Regardless of these considerations, ZVL (Zostavax) is contraindicated for patients with multiple sclerosis who are on immunosuppressant medications: “For patients on immunosuppressant medications, live attenuated vaccines should be avoided while patients are on therapy and for 3 months after treatment” (61).

However, now that there is a subunit vaccine for prevention of shingles (Zoster Vaccine Recombinant, Adjuvanted; RZV; Shingrix), the evidence gap and the potential risks of the live-attenuated vaccine in this population group have been largely obviated: pending new information that would indicate an unsuspected risk in this population group with the subunit vaccine, the subunit vaccine is strongly preferred for patients with multiple sclerosis.

Influenza vaccines (inactivated). A matched case-control study found no significant associations between optic neuritis and previous receipt of influenza vaccines (259).

Influenza vaccines and Guillain-Barré syndrome. The 1976 swine influenza vaccine was associated with an increased risk of Guillain-Barré syndrome (161), with a rate of Guillain-Barré syndrome among vaccine recipients exceeding the background rate by approximately 10 cases per million vaccinated (20; 368). Multiple subsequent controlled studies did not identify a significant association between influenza vaccination and Guillain-Barré syndrome (161; 174; 282; 160; 173; 328; 319; 57; 58; 132; 368). However, during some influenza seasons since the 1976/77 influenza season, inactivated influenza vaccines have been associated with a slight increase in the risk of Guillain-Barré syndrome in some population groups (17; 173; 24; 268). For example, there was a small, but significantly increased, risk for hospitalization because of Guillain-Barré syndrome in Ontario, Canada, in the period from 1992 to 2004, although a separate time-series analysis from the same population found no statistically significant increase in hospital admissions because of Guillain-Barré syndrome after the introduction of the universal influenza immunization program (173). In the United States, there was a small excess risk of Guillain-Barré syndrome in vaccine recipients aged 18 to 64 years in the 1990/91 vaccine season (17), and a small excess risk of Guillain-Barré syndrome among the Medicare population after monovalent H1N1 influenza vaccination in 2009/10 vaccine season (268), but no such increase was found in some other years since 1976 (201). For comparison, influenza-related Guillain-Barré syndrome is four to seven times more frequent than influenza-vaccine-associated Guillain-Barré syndrome (368). The weight of epidemiologic evidence over the last 40 years does not support a major causal relationship between influenza vaccinations and Guillain-Barré syndrome (368). Nevertheless, given the experience with the 1976 swine influenza vaccine, and some intermittent small increased risks with some subsequent influenza vaccines, a significant association cannot be confidently excluded for future vaccine strains (165). A history of Guillain-Barré syndrome within 6 weeks following a previous dose of any type of influenza vaccine is a relative contraindication to further influenza vaccination (135).

Influenza A (H1N1) vaccines and narcolepsy etc. A sudden increase in the incidence of childhood narcolepsy was observed in Finland in 2009 (257); among 54 cases of incident childhood narcolepsy, 93% had received the AS03-adjuvanted pandemic H1N1 influenza A vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) made using the European inactivation/purification protocol and used in Europe during the 2009 H1N1 influenza A pandemic. The incidence of narcolepsy was 9.0 per 100,000 person-years in vaccinated individuals compared with only 0.7 per 100,000 person-years in the unvaccinated individuals (rate ratio 12.7 with 95% confidence interval 6.1-30.8) (248). The vaccine-attributable risk of developing narcolepsy was 1 per 16,000 vaccinated 4- to 19-year-olds (95% confidence interval 1:13,000-1:21,000) (248). Similar, but less marked, increases in narcolepsy occurred in association with this vaccine in other European countries (86; 231; 360; 252; 263), with some studies also demonstrating an increased risk of lower magnitude in adults (320). Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2, a hypothalamic neuropeptide that is involved in the regulation of sleep and arousal states, and that was previously shown to be deficient in narcolepsy (05). In contrast, influenza vaccines containing the A(H1N1)pdm09 virus strain used in the United States, Saudi Arabia, and Korea were not associated with an increased risk of narcolepsy (79; 103; 271). Results were inconsistent in Canadian studies (144; 237). There are still many unanswered questions regarding this novel vaccine-related adverse effect, particularly given reports that narcolepsy developed in some nonvaccinated children infected with wild A(H1N1) pandemic influenza (suggesting a role for viral antigens in disease development, although this apparently did not occur in Finland) (226) and different rates observed in different countries, particularly using different inactivation or purification protocols (suggesting that the AS03 adjuvant alone was not sufficient for disease development).

Postvaccination narcolepsy with cataplexy has also since been reported with tick-borne encephalitis vaccine (149) and yellow fever vaccine (283).

Relative risks were significantly increased for Bell palsy, paraesthesia, and inflammatory bowel disease after vaccination, predominantly in the early phase of the A(H1N1) vaccination campaign, but there was no change in the risk of Guillain-Barré syndrome or multiple sclerosis (40).

Japanese encephalitis virus vaccines.

Mouse-brain-derived inactivated vaccines. Most mouse-brain-derived inactivated vaccines have been discontinued (371) because of serious, but rare, allergic and neurologic adverse events (376). Although these vaccines contained no myelin basic protein at the detection threshold of the assay, use of mouse brains as the substrate for virus growth raised concerns about potential neurologic side effects associated with the vaccine. Moderate-to-severe neurologic symptoms (eg, encephalitis, seizures, gait disturbances, and parkinsonism) were reported at a rate of 0.1 to 2 cases per 100,000 vaccine recipients (with variation noted by country, case definition, and surveillance method) (376). In addition, cases of severe or fatal acute disseminated encephalomyelitis were reported that were temporally associated with vaccination of children in Japan and Korea (110; 371). In 2005, in response to these cases, Japan suspended routine vaccination with mouse-brain-derived Japanese encephalitis vaccines (110). However, the WHO Global Advisory Committee on Vaccine Safety determined that no evidence existed of an increased risk for acute disseminated encephalomyelitis associated with the mouse-brain-derived Japanese encephalitis vaccine and that a causal link had not been demonstrated. Nevertheless, the committee recommended that the inactivated mouse brain-derived vaccine be gradually replaced by new-generation Japanese encephalitis vaccines (110).

Vero-cell-derived inactivated vaccine. Neurologic events (encephalitis, encephalopathy, convulsions, peripheral neuropathy, transverse myelitis, and aseptic meningitis) have been reported at a rate of 1 per 1,000,000 doses (371). Two cases with serious neurologic events after vaccination (neuritis and oropharyngeal spasm) were reported from 12-month postmarketing-surveillance data for 10 phase-III trials in adults; however, on review they were considered unrelated to vaccination, and both subsequently recovered (297).

Live-attenuated vaccine. In a randomized trial of the safety of Japanese encephalitis vaccine (SA14-14-2) in 26,239 children, no cases of encephalitis or meningitis or severe reaction consistent with anaphylaxis occurred in either group within 30 days of vaccination (371). No cases of vaccine-associated Japanese encephalitis were reported in a review of data covering a 20-year period as of 2005 (371).

Meningococcal vaccines.

Polysaccharide vaccines. Adverse reactions to polysaccharide meningococcal vaccines are usually mild (26). Neurologic adverse effects (eg, seizures, anesthesias, and paresthesias) have been observed infrequently (22).

Conjugate vaccines. The most frequently reported adverse events following vaccination with MenACWY-D include headache (16%), dizziness (13%), and syncope (10%) (223). Among the 6.6% of reports coded as serious, the most frequent adverse events reported included headache (38%) and Guillain-Barré Syndrome (15%), although the diagnosis was not validated by medical records for all reports (223).

In 2005, shortly after licensure of MenACWY-D, several cases of Guillain-Barré syndrome were reported to VAERS (69; 70). Symptom onset clustered approximately 14 days after vaccination. No deaths were reported, and most persons recovered fully. The Advisory Committee on Immunization Practices reviewed the data and concluded that vaccine-induced protection against meningococcal disease outweighed the potential small increased risk for Guillain-Barré syndrome (78). However, because the risk for recurrence of Guillain-Barré syndrome after meningococcal vaccination was unknown, the FDA considered a prior history of Guillain-Barré syndrome to be a contraindication for use of this vaccine (71). The attributable risk for Guillain-Barré syndrome ranged from 0 to 1.5 additional cases of Guillain-Barré syndrome per 1 million vaccines administered within the 6-week period following vaccination, based on a large retrospective cohort study conducted from 2005- to 2008 and involving approximately 1.4 million adolescents aged 11 through 21 years (346). No cases of Guillain-Barré syndrome were identified within 1 to 42 days following 889,684 vaccine doses of MenACWY-D administered from January 2005 to March 2010 (223). In June 2010, after reviewing the two safety studies, the Advisory Committee on Immunization Practices removed the precaution for persons with a history of Guillain-Barré syndrome because the benefits of meningococcal vaccination were felt to outweigh the risk for recurrent Guillain-Barré syndrome in these people (223). Although a history of Guillain-Barré syndrome continues to be listed as a precaution in the package inserts for MenACWY-D, no specific concerns have since been raised about the risk for Guillain-Barré syndrome in persons who have a history of this condition and have been vaccinated with meningococcal conjugate vaccine (43; 223).

Among approximately 5000 infants studied through 6 months postvaccination in five clinical trials of MenACWY-CRM, local and systemic adverse events after administration and routine vaccinations were similar to those observed after routine vaccination alone (213); 11 serious adverse events were considered possibly related to MenACWY-CRM, including acute encephalomyelitis (n=1), complex partial seizure (n=1), epilepsy (n=1), and febrile seizure (n=3) (213). No deaths were considered related to MenACWY-CRM (213). During the 20-month period from February 2010 to September 2011, there were 284 reports of adverse events reported to VAERS following receipt of MenACWY-CRM in the United States: syncope was reported in 9%, but Guillain-Barré syndrome was not reported (223).

Serogroup B protein subunit vaccines. In clinical trials, both MenB vaccines (MenB-4C and MenB-FHbp) were generally well tolerated, with few serious adverse events that all resolved without sequelae (111; 214; 82; 258).

In three controlled clinical trials of MenB-4C, serious adverse events were assessed through 6 months postvaccination in 2716 participants who received at least one dose of MenB-4C (111; 214). One patient developed a tremor, which was considered by the study investigator to be a serious adverse event possibly related to the vaccine (111; 214); the administration of the investigational vaccine and onset of tremor were considered reasonably related in time, and the serious adverse event could not be attributed to other causes.

In addition, information about serious adverse events after MenB-4C vaccination was collected during three prelicensure vaccination campaigns in response to three outbreaks of serogroup B meningococcal disease at universities in the United States and Canada (111; 214). A total of 59,091 participants received at least one dose of MenB-4C. Rates of serious adverse events were similar in the vaccine and the control groups. One patient developed rhabdomyolysis (that resolved with no sequelae), which was considered by the study investigator to be a serious adverse event possibly related to the vaccine (111; 214).

In seven clinical trials, a total of 9808 subjects received at least one dose of MenB-FHbp, the most common adverse reactions in the 7 days after vaccination included fatigue (at least 40%), headache (at least 35%), and myalgias (at least 30%) (111; 214; 258). Four subjects reported seven serious adverse events that were considered by the study investigator to be possibly related to the vaccine, including one report each of headache and vertigo (111; 214). All vaccine-related serious adverse events resolved without sequelae. No increased risk for any specific serious adverse event considered to be clinically significant was identified in any of the studies. No deaths were considered to be related to MenB-FHbp (111; 214).

Measles vaccine. Adverse reactions following measles vaccination are generally mild and transient (373). Measles vaccines can cause febrile seizures (see discussion under MMR/MMRV below), and there has been (unrealized) concern that it would impose a significant risk of postvaccination encephalomyelitis, Guillain-Barré syndrome, or subacute sclerosing panencephalitis (SSPE).

Although natural measles infection can cause an immunologically mediated postinfectious encephalomyelitis with perivenular demyelination in approximately 1 per 1000 infected persons (369a), the Institute of Medicine did not find convincing evidence to establish a causal relationship between administration of live-attenuated measles vaccine and development of postvaccination encephalomyelitis (324). Furthermore, the British National Childhood Encephalopathy Study (NCES) did not identify an increased risk of permanent neurologic abnormality following measles vaccination after 10 years of follow-up (230). Analysis of claims for encephalitis following measles vaccination in the United States found clustering of reported adverse events at 8 to 9 days after immunization, which is consistent with, but does not prove, the possibility that the vaccine causes encephalitis (102; 359); however, the reported risk was less than 1 per million doses, or roughly 1000 times less than the risk from measles infection (369a).

Another late adverse outcome of natural measles infection is the development of subacute sclerosing panencephalitis (SSPE), a progressive, disabling, and deadly brain disease caused by recrudescence of latent measles virus, typically years after the primary infection. Naturally, there was concern initially that a live-virus measles vaccine would pose a significant risk of later development of SSPE. However, the live-attenuated measles vaccine does not increase the risk for subacute sclerosing panencephalitis, even among individuals with a prior history of measles or measles vaccination (158; 102). Furthermore, vaccine-strain measles virus has never been identified in patients with SSPE.

Guillain-Barré syndrome has been reported following vaccination with MMR and its component vaccines; however, the United States Institute of Medicine found insufficient evidence to accept or reject a causal relationship (324). Subsequent studies also found no evidence to support a causal association between measles vaccination and Guillain-Barré syndrome (159; 311; 369a).

Measles inclusion body encephalitis. Measles inclusion body encephalitis has been reported in persons with immune deficiencies following measles vaccination and was documented by demonstration of intranuclear inclusions corresponding to measles virus (39; 269) or by isolation of measles virus from the brain among vaccinated persons (50). The interval from vaccination to development of measles inclusion body encephalitis ranged from 4 to 9 months, consistent with development of measles inclusion body encephalitis after infection with wild measles virus (239).

Mumps vaccine and aseptic meningitis. Adverse reactions to mumps vaccination are generally rare and mild, although sensorineural deafness (242; 318), acute myositis (284), and particularly aseptic meningitis have been reported after mumps vaccination (21; 369a).

Aseptic meningitis. Aseptic meningitis has been reported over a wide incidence range from one case per 400 vaccinations to 1/1,500,000 vaccinations, with the extremely wide range apparently reflecting differences in vaccine strains and their preparation as well as variation in study design and diagnostic criteria (21). The onset of aseptic meningitis usually occurs 2 to 3 weeks after vaccine administration with a median of 23 days (range, 18 to 34 days) (221; 21; 369a). In November 2006, the Global Advisory Committee on Vaccine Safety (GACVS) reviewed adverse events following mumps vaccination with special reference to the risk of vaccine-associated aseptic meningitis; GACVS concluded that all available mumps vaccine preparations are acceptable for use in immunization programs but recommended implementing appropriate strategies for risk communication and case management if higher-risk strains of mumps vaccine are being used in mass vaccination campaigns (21).

Rubella vaccines. Adverse reactions following vaccination with the RA27/3 rubella vaccine, whether monovalent or in fixed combinations, are generally mild, particularly in children (23). Common adverse reactions include irritability, myalgia, and paresthesias. Other reported neurologic side effects in fixed combination vaccines that include rubella vaccine appear to reflect the other components (eg, aseptic meningitis with mumps vaccine, and febrile convulsions with MMR/MMRV) (23).

Measles-Mumps-Rubella (MMR) and Measles-Mumps-Rubella-Varicella combination vaccines. The MMR vaccine is well-tolerated and rarely associated with serious adverse events (223). Headache is more common with the first vaccination than with revaccination (223). Expert committees at the Institute of Medicine concluded that the available evidence supports a causal relation between MMR vaccination and febrile seizures, and between MMR vaccination and measles inclusion body encephalitis in persons with demonstrated immunodeficiencies (223). Numerous studies in different countries have demonstrated no increased risk of permanent neurologic sequelae and no evidence to support an increased risk of Guillain-Barré syndrome or autism following administration of measles-containing combination vaccines (373).

MMR/MMRV vaccines and febrile convulsions. MMR vaccine is associated with an increased risk for febrile seizures during the first 2 weeks after vaccination when the peak in replication of the live-attenuated measles virus occurs (6 to 12 days) (41; 218; 210), but monovalent varicella vaccine at age 18 months was not associated with increased risk of febrile seizures (210). Among 12- to 23-month-olds who received their first dose of measles-containing combination vaccine, fever and seizure were elevated 7 to 10 days after vaccination (185). Across a range of studies, febrile seizures typically occurred 6 to 14 days after vaccination and were not associated with any recognized long-term sequelae (133; 106; 76; 41). The risk for febrile seizures is approximately one case for every 1,150 to 4,000 doses of MMR vaccine administered, with most studies in the range of one case for every 3000 to 4000 doses of MMR vaccine administered (106; 41; 369a). Children with a personal or family history of febrile seizures or family history of epilepsy might be at increased risk for febrile seizures after MMR vaccination (48; 350).

For unclear reasons, a first MMRV vaccine dose in children aged 10 to 24 months is associated with an elevated risk of seizure or febrile seizure beyond that of the component vaccines (185; 212; 337; 295; 209). Indeed, the risk of febrile seizures is more than two times higher in children aged 12 to 60 months who were given a first dose of MMRV than those given separate MMR and varicella vaccinations (168) and approximately 2 to 3.5 times higher in children aged 11 to 23 months who were given MMRV than those given separate MMR and varicella vaccinations (185; 295). Nevertheless, the absolute level of risk is small (185; 212). Among 12- to 23-month-olds who received their first dose of measles-containing combination vaccine, vaccination with MMRV resulted in one additional febrile seizure for every 2300 to 2600 doses given compared with vaccination with separate MMR and varicella vaccines (168; 185). Given the low number of MMRV-specific febrile seizure cases, their transient and benign nature, and the benefits of vaccination (including improved vaccine coverage), the MMRV vaccine continues to be recommended, although some now include the option to separately immunize with MMR and varicella vaccines (185; 218; 121; 212). MMRV as the second dose of measles-containing vaccine did not carry an increased risk of febrile seizures in children aged 11 to 23 months (211). MMRV administration to older children does not appear to carry the same excess risk: MMRV and the combination of separate MMR and varicella vaccines were not associated with increased risk of febrile seizures among 4- to 6-year-olds (186).

In 2010, the Advisory Committee on Immunization Practices adopted new recommendations regarding use of MMRV vaccine and identified a personal or family (sibling or parent) history of seizure as a precaution for use of the MMRV vaccine. For the first dose of measles, mumps, rubella, and varicella vaccines at age 12 to 47 months, either MMRV vaccine or the combination of MMR vaccine and varicella vaccine may be used. However, in the absence of a parental preference for MMRV vaccine, the CDC recommends that the MMR and varicella vaccines should be administered for the first dose in this age group. For the second dose of measles, mumps, rubella, and varicella vaccines at any age (from 15 months to 12 years) and for the first dose administered at age of 48 months or older, MMRV vaccine is preferred over separate injections of its component vaccines (218).

The MMR vaccine and autism controversy. In 1998 the Lancet published a paper by British surgeon Andrew Wakefield and colleagues that suggested a temporal connection between the measles, mumps, and rubella vaccine and subsequent development of nonspecific colitis and behavioral symptoms consistent with autism spectrum disorder and "possible postviral or vaccinal encephalitis" (353). Despite uncontrolled observations in a small number of cases (n=12), the authors suggested that the MMR vaccine can serve as a trigger for the development of autism, a claim that garnered extensive media attention and resulted in widespread public anxiety over vaccine safety. Wakefield reiterated this claim in 1999 (353).

Attempts to evaluate the Wakefield hypothesis produced uniformly negative results (245; 163; 164; 321; 325; 215; 265; 332; 361; 312; 157; 341; 223; 369a). Indeed, an early review of national data from the United Kingdom showed that the incidence of autism started rising over a decade before the introduction of the MMR vaccine into the country, and furthermore the trend in autism incidence did not change on introduction of the MMR vaccine (245). In 2001, the US Institute of Medicine, at the request of the CDC and the National Institutes of Health, convened an independent committee to critically review available information; the committee concluded that available evidence "favors rejection of the causal relationship at the population level between MMR vaccination and ASD [autism spectrum disorder]" (321). Subsequent systematic reviews of epidemiological evidence also found no support for a causal relationship between MMR vaccine and autism (325; 361). An independent review commissioned by the World Health Organization also concluded that “existing studies do not show evidence of an association between the risk of autism or autistic disorders and MMR vaccine”; based on the extensive review presented, the Global Advisory Committee on Vaccine concluded that “no evidence exists of a causal association between MMR vaccine and autism or autistic disorders” (364). The Institute of Medicine concluded that available evidence favors rejection of a causal association between MMR vaccine and autistic spectrum disorders/autism (163; Institute of Medicine 2003; 223).

In 2004, investigative journalist Brian Deer published compelling evidence that raised the possibility of research fraud, unethical treatment of children, and financial conflict of interest by Wakefield (196). Despite a rebuttal from Wakefield (354; 355), Deer’s report prompted an official inquiry by the UK General Medical Council, which ultimately (in 2010) found Wakefield "irresponsible" and guilty of unethical behavior involving study participant selection criteria, accepting funding from the Legal Aid Board, and misrepresenting key facts about the study. Wakefield was stricken from the United Kingdom medical register, and his 1998 paper was retracted by the Lancet because it was shown to be fraudulent. Nevertheless, for more than a decade after its publication (and since), Wakefield’s paper severely damaged public acceptance of important health-promoting disease-prevention efforts, undermined faith in medical research, and resulted in huge expenditures for litigation and reparative health promotion efforts (196). Deer later published further information concerning the extent of Wakefield’s fraudulent claims and his brazen efforts to use his self-generated fraud for financial gain (88; 89; 90).

Polio vaccines.

Inactivated polio vaccine. Beginning around 1951, Jonas Salk and his team of researchers in Pittsburgh utilized the Enders-Weller-Robbins method to grow poliovirus for development of an inactivated-virus polio vaccine.

Jonas Salk (1914-1995)

American virologist Jonas Salk (1914-1995) in 1988. Salk developed the first effective trivalent killed-virus poliovirus vaccine. (Contributed by Dr. Douglas Lanska. Courtesy of the U.S. Public Health Image Library.)

They initially focused on optimizing the virus cultivation process, including selecting the optimal nonneural monkey tissue for growing large quantities of virus, which proved to be monkey kidney tissue. By 1952, Salk’s team had begun immunization experiments in monkeys using polioviruses inactivated with formalin to identify the viral strains that would induce the optimal antibody response and to determine the optimal use of formalin to inactivate the virus without compromising its ability to stimulate production of protective antibodies. In 1952, after a year of trials with animal immunizations, Salk began human studies of the antibody response to inactivated poliovirus immunization among children; the results from the first 161 subjects were published in 1953. Then, in anticipation of a large national trial, Salk conducted community-based pilot trials in 1953 and 1954. The Salk vaccine was field tested in 1954 in a huge clinical trial funded by the National Foundation for Infantile Paralysis, through the “March of Dimes” public fundraising campaign developed by President Franklin Delano Roosevelt and his law partner, D. Basil O’Connor (193; 197). The 1954 Field Trial of the Salk vaccine was the largest public health experiment ever conducted, involving 1.8 million children (labeled "polio pioneers") who were inoculated with either vaccine or placebo or were simply observed. On April 12, 1955, at a press conference in Ann Arbor, epidemiologist and virologist Thomas Francis Jr. declared that the Salk inactivated polio vaccine was both safe and effective. That same afternoon, an advisory committee to the Laboratory of Biologics Control, the federal agency that was responsible for licensing biological products, recommended that vaccine licenses be granted to five pharmaceutical companies.

The "Cutter incident". Shortly after the 1954 field trial of the Salk inactivated polio vaccine, manufacturing difficulties with clumping of material and inadequate formaldehyde inactivation of virus during large-scale processing resulted in a large outbreak of iatrogenic paralytic poliomyelitis (the so-called "Cutter incident") (264; 243; 151; 250; 251; 193; 197). Within 2 weeks of the 1955 report that the Salk vaccine was safe and effective, five cases of paralytic polio were reported in the inoculated arms of patients receiving vaccine manufactured by Cutter Laboratories of Berkeley, California. All unused Cutter vaccine was promptly recalled, but by then at least 220,000 people were infected with live poliovirus: approximately 70,000 developed muscle weakness, 164 developed severe paralysis, and 10 died. Subsequent investigation found that small-scale manufacture of inactivated polio vaccine produced predictable inactivation of poliovirus, but large-scale production produced inconsistent inactivation at all five companies producing the vaccine. Furthermore, the test procedures that had been used to ensure that vaccine had been inactivated were found to be insensitive to residual live virus. Clumping of cellular debris had prevented adequate exposure of the virus to formaldehyde. Federal requirements for the manufacture of poliovirus vaccine were revised to require a filtration step to ensure complete inactivation of virus.

Vaccine-associated poliomyelitis. In 1957, Albert Sabin developed a trivalent live-attenuated polio vaccine using the time-consuming process of infecting monkeys with the poliovirus (193; 198).

Albert Sabin (1906-1993)

Polish-American virologist Albert Sabin (1906-1993) developed the first effective trivalent live-attenuated (oral) poliovirus vaccine. (Contributed by Dr. Douglas Lanska. Source: Woodward T. The Armed Forces Epidemiological Boa...

Because the inactivated-virus vaccine developed by Salk and colleagues in Pittsburgh had already been successfully introduced in the United States in 1954, Sabin’s oral vaccine was tested in Russia and was ultimately licensed in the United States in 1963. The live-attenuated vaccine soon thereafter became the polio vaccine of choice because it was less costly, required minimal training to administer (ie, orally rather than by injection), prevented the disease carrier state, and helped prevent the spread of wild poliovirus. However, by then rates of polio in the United States had already dropped from tens of thousands per year to just 50 to 100 cases per year because of the Salk vaccine; consequently, the Sabin oral polio vaccine had a relatively limited impact on overall polio incidence in the United States, although it did have an important role in other countries. By the early 1970s, remaining incident cases of paralytic poliomyelitis in the United States were almost exclusively either imported cases or caused by the vaccine itself. The Sabin oral polio vaccine was discontinued in the United States in 2000 because by then the continued risk of vaccine-associated paralytic poliomyelitis outweighed the potential benefits of a live-virus vaccine (270).

Following oral polio vaccine, the vaccine strains of poliovirus replicate in the gut of vaccine recipients and may be excreted for 4 to 6 weeks after vaccination. During this time, the few attenuating mutations in the vaccine strains may revert so that the virus reacquires its previous virulence. Reversion of attenuating mutations is the underlying cause of vaccine-associated paralytic poliomyelitis (VAPP) in oral polio vaccine recipients and their close contacts. Symptoms of VAPP usually develop 4 to 30 days after oral polio vaccine or within 4 to 75 days after contact with an recipient of the vaccine (370).

VAPP incidence is higher with the first dose of oral polio vaccine than with subsequent doses (370). The first-dose risk of VAPP among recipients of the vaccine was estimated at one case per 1.4 million children in the United States and one case per 2.8 million children in India (370). VAPP is more common in individuals who are immunocompromised (370). In industrialized countries, VAPP occurs mainly in early infancy associated with the first dose of oral polio vaccine, and incidence decreases sharply (more than 10-fold) with subsequent doses, whereas in low-income countries VAPP may occur with second or subsequent doses of oral polio vaccine, with cases concentrated among children aged 1 to 4 years (27). Transmission from one VAPP case resulting in secondary VAPP cases has not been demonstrated (370).

Vaccine-derived poliovirus (VDPV). The attenuated viruses in oral polio vaccine may, through replication (in an individual or a community), reacquire the neurovirulence and transmissibility characteristics of wild-type polioviruses (27). A vaccine-derived poliovirus is an oral polio vaccine strain that has reverted to a virulent form and has developed the capacity for sustained circulation. VDPVs differ from the parental Sabin strains found in oral polio vaccine by 1% to 15% of their nucleotides, a measure of genetic change. VDPVs are categorized as circulating (cVDPV), immunodeficiency-associated (iVDPV), or ambiguous (aVDPV) when isolated from people with no known immunodeficiency or sewage isolates of unknown origin (27). cVDPVs were first recognized in 2000 during an outbreak in Hispaniola (179). In under-immunized populations, VDPVs can circulate and can cause paralysis (27). cVDPVs can be imported and spread in any under-vaccinated community within an otherwise well-vaccinated developed country, as occurred in an Amish community in Minnesota in 2005 (after oral polio vaccine had been discontinued in the United States in 2000) (09). Most cVDPVs (more than 90%) are type 2 poliovirus (27). Persistent cVDPVs, or VDPVs that continue to circulate for more than 6 months following detection, represent programmatic failures to contain an outbreak (27). Oral polio vaccine protects against VDPVs and is used to contain outbreaks. A fully immunized population will be protected against both vaccine-derived and wild polioviruses.

Aseptic meningitis and encephalitis. Aseptic meningitis and encephalitis have been reported rarely after oral polio vaccine, particularly in immunodeficient infants (370).

Guillain-Barré syndrome. In the 1980s, studies in Finland suggested an increased incidence of Guillain-Barré syndrome following mass oral polio vaccine vaccination (182; 342; 19). Other factors were later found to have contributed to the increase in Guillain-Barré syndrome incidence in Finland at that time, including an influenza epidemic (183). Subsequent data do not indicate an increased risk of Guillain-Barré syndrome following receipt of oral polio vaccine (273; 18; 67; 183).

Provocation poliomyelitis. In persons incubating wild poliovirus infection, intramuscular injections (eg, other vaccines) may provoke paralysis in the injected limb (326).

Siman papovavirus 40. From 1954 to 1962, both the inactivated and live-attenuated forms of polio vaccine were prepared in primary cultures of rhesus monkey kidney cells, some of which were derived from monkeys that were naturally infected with simian papovavirus 40 (SV40) (370). SV40 is an oncogenic DNA virus that can induce primary brain cancers in animals, and viruses from the same family are oncogenic in humans. However, long-term follow-up studies did not support a causal association between the receipt of oral polio vaccine and the subsequent development of malignancies in humans (59). Oral polio vaccine is now tested for SV40, and none has been found positive (370).

Rabies vaccines. There are three main types of rabies vaccine: (1) nerve-tissue vaccines (now outdated), (2) cell-culture vaccines, and (3) embryonated-egg vaccines. Cell-culture and embryonated-egg vaccines have replaced nerve tissue vaccines in industrialized countries and are the ones recommended by the World Health Organization; they are considered safe and well tolerated (367).

Earlier inactivated nerve-tissue rabies vaccines frequently induced severe adverse reactions (eg, encephalitis, encephalomyelitis, and myelitis) and were less immunogenic than modern, concentrated, purified cell culture and embryonated egg-based rabies vaccines (CCEEVs) (202; 367; 374). Nevertheless, they are still used in a limited and decreasing number of developing countries (367). Severe adverse events with nerve-tissue vaccines were mainly neurologic, typically occurred about 2 weeks after vaccination, and were caused by an autoimmune response (possibly triggered by myelin basic protein contained in the vaccine) (146; 147; 266). These included: (1) meningoencephalomyelitis, (2) meningomyelitis or transverse myelitis (which results in lower limb paralysis, decreased sensation and sphincter disturbance), (3) meningoradiculitis, (4) mononeuritis multiplex (which may affect cranial nerves, particularly II, III, VII, IX, or X), and (5) ascending paralysis of the Landry type (ie, sudden onset of flaccid paralysis of the legs, followed by paralysis of the arms, usually developing between 1 to 2 weeks after the first injection). Historically, with the Semple nerve-tissue vaccine (prepared from rabies virus-infected goat or sheep brain tissue), the incidence of neurologic complications varied from 0.14 to 7 per 1,000 cases per vaccine recipient with a case fatality rate of up to 10% (38; 367). The Fuenzalida-type vaccine (prepared from suckling mouse brain tissue with a decreased myelin content compared with the Semple vaccine) was reported to cause neurologic complications in 0.12 to 0.037 per 1000 courses (Noguiera 1998; 367) with a case fatality rate of 22% (367). In one study of 18 patients with neurologic complications after administration of the Fuenzalida vaccine, only one had Guillain-Barré syndrome, one had meningoradiculitis, four had myelitis, and 12 had diffuse involvement of the nervous system, especially of the spinal cord and meninges (meningomyelitis and meningoencephalomyelitis) (34).

Because of the problems with inactivated nerve-tissue rabies vaccines, the World Health Organization has since 1984 strongly recommended their replacement by inactivated CCEEVs (374). Mild systemic adverse events following rabies immunization with inactivated CCEEV vaccines, such as transient headache and dizziness, have been observed in 5% to 15% of vaccine recipients (365; 374). In general, rabies vaccines with smaller doses and more advanced processing techniques are relatively safer, especially for young children (262). From October 1997 through December 2005, the United States Vaccine Adverse Event Reporting System (VAERS) received 336 reports of adverse events after vaccination with the Purified Chick Embryo Cell vaccine against rabies: among these there were 13 neurologic events, representing 4% of reports, without a clear pattern to suggest a plausible relationship to vaccination (100). Although serious neuroparalytic reactions during and after the administration of CCEEV rabies vaccines are rare (49; 169; 100; 217; 365; 374), such reactions, when they occur, pose a serious dilemma for the patient and the attending physician because a decision to discontinue the vaccination series must be weighed against the risk for acquiring rabies (217).

Smallpox vaccine. Encephalitis as a complication of smallpox vaccination was initially recognized in 1905 (281), more than a century after Edward Jenner performed his first smallpox vaccination (on 8-year-old James Phipps) on 14 May 14, 1796.

Edward Jenner (1749-1823)

English physician and scientist Edward Jenner (1749-1823) was pioneer of the smallpox vaccine. Drawing by Vigneron Pierre Roch, circa 1824. (Contributed by Dr. Douglas Lanska. Public domain. Courtesy of BIU Health Medicine Collect...

Since then, the estimated incidence of encephalitis and other neurologic complications of smallpox vaccination has varied considerably over time and across countries (187). Some of the variation reflects use of different strains of virus in the vaccines: vaccination with the New York City Board of Health strain is associated with a low rate of postvaccination encephalitis (three cases per 1 million vaccinations) whereas the Lister and Copenhagen strains are associated with intermediate rates (26 and 33 cases per 1 million vaccinations, respectively), and the Bern strain is associated with very high rates (45 cases per 1 million vaccinations). Some additional variation in reported rates over time is explained by changes in vaccine production methods, quality control, vaccination procedures, health care, and case ascertainment (eg, better ascertainment procedures may have reduced the number of adverse events misdiagnosed as postvaccination encephalitis) (187). Vaccine postmarketing surveillance has suggested no association between optic neuritis and receipt of smallpox vaccinations in the United States military (259), although this continues to be intermittently raised as a potential issue (260).

Yellow fever vaccines. A French neurotropic yellow fever vaccine was discontinued in 1982 due to the high frequency of neurologic adverse effects (317).

Modern yellow fever vaccines are usually fairly well tolerated. In clinical trials, headache and myalgia were among the mild clinical symptoms that were commonly reported post vaccination (25). With the 17D-204 strain vaccine, YF-VAX (manufactured outside of Brazil, including in the United States), there were 4.7 serious adverse effects reported per 100,000 doses in the period from 2000 to 2006 (317). Reporting rates of serious adverse effects were highest among persons aged 60 years and older (8.3 per 100,000 doses) (317; 25). YEL-AND (YELlow fever vaccine-Associated Neurologic Disease) is one of the most common, well-characterized categories of serious adverse effects of vaccination with the vaccine (317). All reported cases of YEL-AND have been in primary vaccine recipients (ie, first dose of vaccine), possibly due to viremia that occurs after the first dose of vaccine (which has not been documented in persons receiving a booster dose of vaccine) (25).

YEL-AND encompasses several distinct clinical syndromes: (1) meningoencephalitis (neurotropic disease), (2) Guillain-Barré syndrome, (3) acute disseminated encephalomyelitis, and (4) bulbar palsy (184; 224; 317; 25). Meningoencephalitis develops from direct viral invasion of the central nervous system by the vaccine virus, with infection of the meninges or the brain. The other neurologic syndromes encompassed by YEL-AND represent autoimmune reactions in which vaccine-induced antibodies or T-cells cross-react with the host’s neuronal epitopes, leading to central-nervous-system or peripheral-nerve damage.

The viral strains used to develop yellow fever vaccines can develop neurovirulence, either with too few or too many passages during the attenuation process (116; 244). To minimize this risk, a vaccine seed lot system was developed in 1945 to clearly define the number of passages allowed for particular strains, but still additional cases of vaccine-associated encephalitis continued to be reported (317). In addition, studies in the 1950s found that vaccine-associated encephalitis occurred at extremely high rates in infants younger than 6 months of age (ie, four cases per 1000 children vaccinated in this age group), so in the 1960s use of yellow fever vaccine was restricted to individuals who were at least 6 months old (16; 317). Subsequently, the number of cases of vaccine-associated encephalitis diminished in infants. Now, age less than 6 months continues to be a contraindication for yellow fever vaccination; additionally, vaccination is discouraged for infants aged 6 to 8 months except during epidemics when the risk of yellow fever virus transmission may be very high (25).

The reported rate for YEL-AND with the 17D-204 strain vaccine are generally 0.25 to 0.8 per 100,000 vaccine doses (181; 205; 206; 25). From VAERS data, the reporting rate for YEL-AND is 0.4 to 0.8 cases per 100,000 doses distributed (181; 205; 206; 317). Higher rates were reported in the elderly: 1.6 cases per 100,000 doses distributed among persons aged 60 to 69 years and 1.1 to 2.3 cases per 100,000 doses distributed among persons aged 70 years and older. These values are likely underestimates, given underreporting to VAERS. Reported rates of YEL-AND with postmarketing surveillance reports in Brazil using the 17DD YF strain vaccine were somewhat higher, at 1.1 per 100,000 doses distributed (25) whereas rates during preventive mass vaccination campaigns in West African countries were extremely low, only 0.016 cases per 100,000 doses of vaccine administered (25), likely indicating incomplete ascertainment.

Among 29 YEL-AND cases that occurred from 1990 to 2006 were nine of meningoencephalitis, eight of Guillain-Barré syndrome, three of acute disseminated encephalomyelitis, one of bulbar palsy, and eight cases with insufficient data to classify (178; 184; 224; 317). The cases had a varied period from vaccination to symptom onset (range: 3 to 28 days) and a varied age range (6 to 78 years). All of the cases occurred in first-time vaccine recipients.

Fifty cases of YEL-AND were reported from three tertiary referral centers in São Paulo, Brazil, during 2017 to 2018: 32 had meningoencephalitis (14 with reactive yellow fever IgM in cerebrospinal fluid), two died, and one may have transmitted infection to an infant through breast milk (278). Of seven cases of autoimmune neurologic disease after yellow fever vaccination, three had Guillain-Barre syndrome, two had ADEM, and two had myelitis. Novel potential vaccine-associated syndromes identified include autoimmune encephalitis, opsoclonus-myoclonus-ataxia syndrome, optic neuritis, and ataxia.

Cases continue to reveal novel or diagnostically confusing presentations. For example, a case of longitudinal myelitis with onset 45 days after yellow fever vaccination was reported in a 56-year-old man who received no other vaccines (74). Yellow fever virus IgM antibodies were detected in his cerebrospinal fluid and serologic testing for other regional flaviviruses was negative. However, the case is atypical because the time to symptom onset was considerably longer than that reported for other YEL-AND cases. Another case was a 23-year-old man who was diagnosed originally with meningoencephalitis but was later determined to have acute disseminated encephalomyelitis based on magnetic resonance imaging of the brain (233).

YEL-AND is rarely fatal (15; 317). In one fatal case of encephalitis in a 3-year-old girl who was vaccinated against yellow fever in 1965, molecular studies of the virus isolated from the brain later demonstrated that the vaccine virus had mutated, and monkey studies demonstrated that the virus had become more neurovirulent (15; 170); this is the only documented case in which a mutation of the yellow fever vaccine virus has been linked to an adverse outcome in a recipient (although this has been reported numerous times with the live-attenuated polio vaccine). Another fatal case was reported in a 53-year-old man who had unrecognized asymptomatic human immunodeficiency virus (HIV) infection and a CD4 count of less than 200/mm3 (178); the man developed fever and malaise 3 days after vaccination, became encephalopathic by day 5, and died 9 days after vaccination.

During the 2001 yellow fever mass vaccination campaign in Juiz de Fora, Brazil, 12 cases of aseptic meningitis were temporally associated with yellow fever vaccination, but a causal relationship with the vaccine was never established because "clinical and laboratory data were not available to confirm nor deny causality" (108).

SARS-CoV-2 vaccines. The safety of the various SARS-CoV-2 vaccines in use around the world (eg, mRNA vaccines, subunit protein vaccine, inactivated virus vaccines, DNA vaccine, recombinant adenovirus type-5-vectored vaccine, recombinant spike protein nanoparticle vaccine) has generally been excellent (12; 112; 167; 176; 177; 190; 208; 267; 335; 357; 378; 384; 385; 37; 47; 52; 75; 272; 289; 331; 333; 352; 379; 383; 35; 97; 166; 203; 247). A systematic review and metaanalysis found that significantly more adverse events were reported in vaccine groups compared with placebo groups of various COVID-19 vaccine trials, but the rates of reported adverse events in the placebo arms were still substantial; headache and fatigue were the most common adverse effects in this study (139). In general, the most common adverse reactions after COVID-19 vaccination are injection site pain, fever, headache, fatigue or malaise, and myalgias, which were mild and self-limiting. A prospective study in Mexico identified very low frequency of potential adverse neurologic events after the Pfizer COVID-19 vaccination (119).

An Italian population-based study aimed to evaluate the neurologic complications after the first and/or second dose of COVID-19 vaccines and factors potentially associated with these adverse effects (290). The study included adults aged 18 years and older who received two vaccine doses in Milan between 7 and 16 July 2021. A questionnaire was used to capture neurologic events, onset, and duration. The cohort included 19,108 vaccinated people: 15,368 with the Pfizer BioNTech mRNA vaccine (BNT162b2), 2077 with the Moderna mRNA vaccine (mRNA-1273), 1651 with AstraZeneca recombinant, replication-deficient, adenoviral vector vaccine (ChAdOx1nCov-19), and 12 with the Johnson and Johnson recombinant, replication-deficient, adenoviral vector vaccine (Ad26.COV2.S) who were subsequently excluded. Approximately 31.2% of the sample developed minor post-vaccination neurologic complications, particularly with the AstraZeneca vaccine. Over 40% of the symptomatic people showed comorbidities in their clinical histories. With the AstraZeneca vaccine, a significantly increased risk was observed for tremors (vs. the Pfizer mRNA vaccine, odds ratio: 5.12); insomnia (vs. Moderna mRNA vaccine, odds ratio: 1.87); muscle spasms (vs. the Pfizer mRNA vaccine, odds ratio: 1.62); and headaches (vs. the Pfizer mRNA vaccine, odds ratio: 1.49). For the Moderna mRNA vaccine, there were increased risks of paresthesia (vs. the AstraZeneca recombinant vaccine, odds ratio: 2.37); vertigo (vs. the AstraZeneca recombinant vaccine, odds ratio: 1.68); diplopia (vs. the AstraZeneca recombinant vaccine, odds ratio: 1.55); and sleepiness (vs. the AstraZeneca recombinant vaccine, odds ratio: 1.28). In the period that ranged from March to August 2021, no one was hospitalized and/or died of severe complications related to COVID-19 vaccinations.

The dozens of anecdotal reports of supposed "complications" of COVID-19 vaccination, and narrative, systemic, or other reviews of such case reports that do not properly consider causation from an epidemiologic standpoint (10; 11; 96; 109; 73) do not withstand scrutiny; these include reviews labeled "systematic" that tabulate case reports and have no control group (11; 96; 235; 241; 253; 336; 73). Some case reports present caveats that the complication in question occurred after vaccination but cannot be proven to be caused by vaccination, or alternatively that " a coincidental relationship with this inactivated vaccine cannot be excluded." Others, despite such caveats, inappropriately proffer their respective cases as a "possible rare side effect," a "possible complication," a "possible neurological side effect," a "possible causal link," or an event "that may have been triggered by" or "possible [sic] caused by" vaccination. Rare events in an appropriate time window for vaccines can be used for hypothesis generation, but except in very unusual circumstances the causality of side effects cannot be established from individual events. Most published reviews of supposed neurologic complications have been of low methodological quality, have failed to consider standard criteria for vaccine complications or causality, and have accepted anecdotal reports as prima facie evidence of causality (10; 11; 96; 109; 120; 253; 336; 73). In addition, some anecdotal reports of supposed "complications" of vaccination represent functional or somatoform neurologic disorders (08; 124). Unfortunately, such dubious reports have nevertheless been widely reported in mainstream and social media, leading to public confusion and doubt, and adding to vaccine resistance or avoidance. Such anecdotal reports of vaccine complications are intentionally not cited in this chapter. Two key points are worth emphasizing: (1) the incidence of most of these side effects is not different between vaccinated and unvaccinated populations; and (2) the mortality and morbidity risks of COVID-19 infection far outweigh the risks associated with vaccination (104).

It is also essential to recognize and distinguish cases of supposed complications attributed to vaccination that are instead functional neurologic disorders (eg, functional movement disorders, functional protracted limb weakness, and sensory dysfunction) (92).

Currently, four vaccines are authorized and recommended in the United States to prevent COVID-19:

	(1) Pfizer or Pfizer-BioNTech COVID-19 vaccine (BNT162b2 mRNA; international non-proprietary name "tozinameran”; sold under the brand name Comirnaty—a mashup of Community, mRNA and Immunity). The primary series of the Pfizer COVID-19 vaccine is administered as two shots 3 to 8 weeks apart. In children, age 6 months to 4 years, a booster can be given at least 8 weeks after the second dose of the primary series. In older children and adults, a booster can be given at least 5 months after the second dose of the primary series. In adults, the booster can be either Pfizer-BioNTech or Moderna.
	(2) Moderna COVID-19 vaccine (international non-proprietary name "elasomeran"; codenamed mRNA-1273; sold under the brand name Spikevax).
	(3) Novavax COVID-19 vaccine, a subunit protein vaccine.
	(4) Johnson and Johnson COVID-19 vaccine (Ad26.COV2; tradename "Janssen COVID-19 vaccine," so-named because it was developed by Janssen Vaccines in Leiden, Netherlands, and its Belgian parent company Janssen Pharmaceuticals, a subsidiary of the American company Johnson and Johnson).

The Pfizer and Moderna vaccines are mRNA vaccines that give cells genetic instructions to make a harmless piece of the SARS-CoV-2 spike protein. After the protein piece is made, the cell breaks down the mRNA but displays the protein piece on its surface. The protein fragment is recognized as foreign by the immune system, which triggers an immune response and an antibody response like what happens in natural infection with COVID-19. For all four authorized vaccines, the most common side effects locally were pain, swelling, and redness, and systemically were chills, tiredness, and headache. Reactogenicity symptoms (side effects that happen within 7 days of getting vaccinated) are common but are mostly mild to moderate in severity. Systemic side effects (eg, fever, chills, tiredness, and headache) are more common after the second dose of the vaccine. Most side effects are mild to moderate.

The Johnson & Johnson vaccine uses a disabled adenovirus to deliver the instructions. However, according to the CDC, "In most situations, Pfizer-BioNTech, Moderna, or Novavax COVID-19 vaccines are recommended over the J&J/Janssen COVID-19 vaccine." This is because the Johnson & Johnson COVID-19 vaccine is less protective and has been associated with greater risks. Novavax COVID-19 vaccine is a subunit protein vaccine.

Selected other COVID-19 vaccines in use in other countries. The AstraZeneca or Oxford-AstraZeneca recombinant vaccine (ChAdOx1-S/nCoV-19; AZD1222; trade name "Vaxzevria," previously "COVID-19 Vaccine AstraZeneca") is not an mRNA vaccine, but instead uses a replication-deficient adenoviral vector vaccine against SARS-CoV-2. The vaccine expresses the SARS-CoV-2 spike protein gene, which instructs the host cells to produce the protein of the S-antigen unique to SARS-CoV-2, which stimulates the body to generate an immune response and to retain that information in memory immune cells. Although this vaccine is not approved for use in the United States, it has been used by numerous countries in Europe (eg, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, etc.), Asia (eg, Indonesia, South Korea, Thailand), as well as Canada and Australia; some have suspended its use due to concerns about clotting disorders, however.

CoronaVac, also known as the Sinovac COVID-19 vaccine, is an inactivated virus COVID-19 vaccine developed by the Chinese company Sinovac Biotech. Unlike the mRNA vaccines approved in the United States, CoronaVac relies on traditional technology.

Cerebral venous sinus thrombosis with thrombocytopenia. Cerebral venous sinus thrombosis (CVST) with “vaccine-induced immune thrombotic thrombocytopenia” (VITT) was described in Europe following receipt of the AstraZeneca COVID-19 vaccine, which uses a chimpanzee adenoviral vector. Some have since employed the term thrombosis and thrombocytopenia syndrome (TTS) instead of vaccine-induced immune thrombotic thrombocytopenia because thrombosis and thrombocytopenia syndrome does not assume that the temporal sequence is necessarily causal.

In the United States, after six cases of cerebral venous sinus thrombosis with vaccine-induced immune thrombotic thrombocytopenia were recognized among approximately 7 million vaccine recipients of the Johnson and Johnson COVID-19 vaccine, there was a temporary national pause in United States vaccination with this product on April 13, 2021.

In a summary of reports of cerebral venous sinus thrombosis with vaccine-induced immune thrombotic thrombocytopenia after vaccination with the Johnson and Johnson COVID-19 vaccine in the United States, 12 U.S. patients were reported to the Vaccine Adverse Event Reporting System from March 2, 2021 to April 21, 2021, with follow-up through April 21, 2021 (300). All the cases were adult women, with 11 patients younger than 50 years of age and the remaining cases younger than 60 years of age. Seven cases had at least one risk factor for cerebral venous sinus thrombosis, including obesity (n=6), hypothyroidism (n=1), and oral contraceptive use (n=1). None had documented prior heparin exposure. Time from vaccination to symptom onset ranged from 6 to 15 days. Eleven cases initially presented with headache, whereas the remaining case initially presented with back pain and later developed headache. Seven of the 12 cases also had intracerebral hemorrhage; eight had other venous thromboses, including portal vein thrombosis, internal jugular vein thrombosis, lower extremity deep venous thrombosis, and pulmonary emboli. After diagnosis of cerebral venous sinus thrombosis, six patients initially received heparin treatment. The platelet nadir ranged from 9,000/μL to 127,000/μL, with normal platelet levels typically considered between 150,000 and 450,000 per microliter of blood. All 11 patients tested for the platelet factor 4 antibody (as occurs in heparin-induced thrombocytopenia or HIT) by ELIZA screening had positive results, although functional platelet HIT antibody test results were positive in only one of nine (11%) U.S. cases with results available. All patients were hospitalized, including 10 in an intensive care unit. As of April 21, 2021, three of the patients had died with intracerebral hemorrhage.

In a later systematic review and metaanalysis of cerebral venous sinus thrombosis after vector-based COVID-19 vaccines (ie, Johnson & Johnson vaccine available in the United States and the AstraZeneca vaccine available in Europe), Palaiodimou and colleagues identified 69 studies comprising 370 patients with cerebral venous sinus thrombosis among 4182 patients with any thrombotic event temporally associated with COVID-19 vector-based vaccine administration (256); 23 of these studies were included in the quantitative metaanalysis. Among thrombosis and thrombocytopenia syndrome cases, the pooled proportion of cerebral venous sinus thrombosis was 51%. Thrombosis and thrombocytopenia syndrome was independently associated with a higher likelihood of cerebral venous sinus thrombosis when compared to patients with thrombotic events but without thrombosis and thrombocytopenia syndrome after vaccination (odds ratio 13.8). The pooled mortality rate of thrombosis and thrombocytopenia syndrome was 28%, whereas the pooled mortality rate of thrombosis and thrombocytopenia syndrome-associated cerebral venous sinus thrombosis was 38%. Thrombotic complications developed within 2 weeks of exposure to vector-based SARS-CoV-2 vaccines with a mean interval of 10 days. Thrombotic complications affected predominantly women under age 45, even in the absence of prothrombotic risk factors (eg, birth control pills). Women comprised 71% of the cases with thrombosis and thrombocytopenia syndrome, 75% of the cases with cerebral venous sinus thrombosis, 75% of the cases with thrombosis and thrombocytopenia syndrome-associated cerebral venous sinus thrombosis, and 69% of all cases with thrombotic events. Women are apparently disproportionately susceptible to these complications following vaccination with adenovirus vector-based COVID-19 vaccines; however, the pre-pandemic incidence rates of cerebral venous sinus thrombosis show only a slight female preponderance: women comprise three quarters of the cases following vaccination with adenovirus vector-based COVID-19 vaccines.

In a population-based cohort study, Ashrani and colleagues compared incidence rates of cerebral venous sinus thrombosis after Johnson & Johnson COVID-19 vaccination with the pre-pandemic incidence rate (33). Incident cases of cerebral venous sinus thrombosis were identified in Olmsted County, Minnesota, from January 2001 through December 2015. Sex-and age-adjusted incidence rates were adjusted to the 2010 United States census population. Then, VAERS data from February 28 to May 7, 2021 were used to estimate the incidence of cerebral venous sinus thrombosis after Johnson & Johnson COVID-19 vaccination. Estimates were calculated separately for three plausible periods during which individuals might be at risk: 15, 30, and 92 days. From 2001 through 2015, 39 Olmsted County residents developed cerebral venous sinus thrombosis: 74% had a predisposing risk factor, such as infection, cancer, or oral contraceptives. The median age at diagnosis was 41 years (range 22 to 84 years). There was only a slight female predominance, with women comprising 56% of the cases. The overall age- and sex-adjusted incidence rate was 2.3. Age-adjusted incidence rates were similar for women and men (2.5 and 2.3, respectively). As of May 7, 2021, approximately 8.7 million Johnson & Johnson vaccine doses had been administered in the United States. After excluding potentially duplicate reports and cases that were not objectively diagnosed, there were 38 objectively diagnosed cases within 92 days after vaccination (71% women). The median age was 45 years (range 19 to 75 years). The median time from vaccination to cerebral venous sinus thrombosis was 9 days (range 1 to 51 days); 82% occurred within 15 days and 95% within 30 days. The overall postvaccination incidence rate was 8.7 per 100,000 person-years at 15 days, 5.0 per 100,000 person-years at 30 days, and 1.7 per 100,000 person-years at 92 days. The 15-day postvaccination incidence rate for women was 13.0 per 100,000 person-years, approximately three times higher than the rate of 4.4 per 100,000 person-years for men. The postvaccination incidence rate among women was 5.1-fold higher than the pre-COVID-19 pandemic rate. This risk was highest among women aged 30 to 49 years. The authors concluded that in this population, the incidence rate of cerebral venous sinus thrombosis 15 days after Johnson & Johnson COVID-19 vaccination was significantly higher than the pre-pandemic rate. The higher rate of this rare adverse effect must be considered against the effectiveness of the vaccine in preventing COVID-19, with an absolute reduction of severe or critical COVID-19 of 940 per 100,000 person-years. However, the mRNA vaccines are even more effective and do not appear to carry the same excess risk of cerebral venous sinus thrombosis.

A self-controlled case series study using national data on COVID-19 vaccination and hospital admissions was conducted in England from December 1, 2020 to April 24, 2021 (152). Among approximately 30 million people vaccinated during this period, about two out of three were vaccinated with the AstraZeneca vaccine and one out of three were vaccinated with the Pfizer vaccine. The risk of cerebral venous sinus thrombosis was increased 4-fold after the AstraZeneca vaccine (incidence rate ratio 4.0, 95% confidence interval 2.1 to 7.7), 3.6 fold after the Pfizer vaccine (incidence rate ratio 3.6, 95% confidence interval 1.49 to 9.3 at 15 to 21 days), and after a positive SARS-CoV-2 test (1 to 7 days: incidence rate ratio 12.9, 95% confidence interval 1.9 to 89.6; 8 to 14 days: incidence rate ratio 13.4, 95% confidence interval 2.0 to 90.6).

A systematic review subsequently identified 41 cases of cerebral venous sinus thrombosis and vaccine-induced immune thrombotic thrombocytopenia after the AstraZeneca vaccine and 13 cases after the Johnson and Johnson vaccine (305). Most of the patients were women (72% of 32 cases after the AstraZeneza vaccine for whom gender information was reported, and all 13 of the cases after the Johnson and Johnson vaccine). Symptom onset occurred within one week after the first dose of vaccination (range 4 to 19 days). Headache was the most common presenting symptom. Intracerebral hemorrhage and/or subarachnoid hemorrhage were reported in half (49%) of the patients. The platelet count of the patients ranged from 5 to 127 cells×109/L. Anti-PF4 IgG assay and d-dimer were positive in most of the reported cases. At least 19 patients (39%) died due to complications of cerebral venous sinus thrombosis and vaccine-induced immune thrombotic thrombocytopenia.

In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia (HIT) and anti-PF4/heparin antibodies were rare (291).

A large international consortium (from 81 hospitals in 19 countries) conducted a cohort study of consecutive cases with cerebral venous sinus thrombosis within 28 days of SARS-CoV-2 vaccination between March 29, 2021 and June 18, 2021 (292). For reference, cases with cerebral venous sinus thrombosis between 2015 and 2018 were identified from an existing international registry. Cases were classified as having thrombosis with thrombocytopenia syndrome (TTS) if they had new-onset thrombocytopenia without recent exposure to heparin. Of 116 cases with cerebral venous sinus thrombosis after SARS-CoV-2 vaccination, 78 (67%) had thrombocytopenia syndrome, of whom 76 (97%) had been vaccinated with the AstraZeneca vaccine (and one each with the Johnson and Johnson vaccine and the Pfizer vaccines), whereas 38 (33%) had no indication of thrombocytopenia syndrome (53% with the AstraZeneca vaccine, 40% with the Pfizer vaccine, 5% with the Chinese CoronaVac vaccine, and 3% with the Moderna vaccine). The cases of cerebral venous sinus thrombosis after SARS-CoV-2 vaccination were predominantly women (80%) and the mean age was 48 years. The control group included 207 patients with cerebral venous sinus thrombosis before the COVID-19 pandemic (70% women; mean age 42 years). In-hospital mortality rates were 47% (95% CI, 37% to 58%) for cerebral venous sinus thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination, 5% (95% CI, 1% to 18%) for cerebral venous sinus thrombosis without thrombocytopenia syndrome after SARS-CoV-2 vaccination, and 4% (95% CI, 2% to 7%) after other vaccinations in the pre-pandemic control group. The mortality rate was 61% among patients in the thrombocytopenia syndrome group diagnosed before the condition garnered attention and 42% among patients diagnosed later.

As of 9 June 2021, 390 thrombosis and thrombocytopenia syndrome cases (140 CVST, 250 other major thromboembolic events with concurrent thrombocytopenia) occurred within 28 days following vaccination with the AstraZeneca vaccine in the United Kingdom where there has been a high early uptake: 67 were fatal after an estimated 24.6 million first doses (2.7 deaths/million first-dose vaccinations) (65).

Cerebral venous sinus thrombosis with thrombosis and thrombocytopenia syndrome after SARS-CoV-2 vaccination has a distinct clinical profile and a high case-fatality rate (292). Moreover, the FDA has determined cerebral venous sinus thrombosis with vaccine-induced immune thrombotic thrombocytopenia to be a plausible complication of COVID-19 vaccination (ie, plausibly caused by COVID-19 vaccination). Although many cases occur in women under 40 years of age, very few have been identified as taking birth control pills. Cases have occurred predominantly with the AstraZeneca vaccine, but significant numbers have occurred following both the Johnson and Johnson and the Pfizer mRNA vaccines (175; 292). A mechanism like that of autoimmune heparin-induced thrombocytopenia has been proposed. If clinicians identify such cases, diagnostic laboratories should be notified that thrombosis with thrombocytopenia syndrome is being considered to optimize testing methods. Anti-PF4 antibodies and functional platelet HIT antibody testing should be obtained (300; 309). Early recognition of this complication should prompt acute treatment that addresses the autoimmune and prothrombotic processes (309). Intravenous immunoglobulin (1 g/kg for 2 days), consideration of plasma exchange, and nonheparin anticoagulation (argatroban, fondaparinux) are recommended (309).

Using an observational study with a case-control design, Garcia-Azorin and colleagues assessed whether a headache following COVID-19 vaccine-related cerebral venous sinus thrombosis is associated with a higher probability of death or intracranial hemorrhage (118). The study population was individuals vaccinated with nonreplicant adenovirus vector-based vaccines (ie, the Johnson & Johnson vaccine available in the United States, and the AstraZeneca vaccine available in Europe). The authors reviewed (1) all the published cases and case series during March and April 2021, and (2) reports from the CDC and the European Medicines Agency providing patient-level data. Controls were identified from cases of “headache” following COVID-19 vaccination reported to the VAERS up to April 30, 2021. The statistical analysis assessed whether the presence of headache in patients with cerebral venous sinus thrombosis was associated with a higher probability of intracranial hemorrhage of death. Of the 77 identified cases, 90% were women. Headache was described in 49 and intracranial hemorrhage in 43%, and 25% died. The median time between vaccination and onset of cerebral venous sinus thrombosis-related headache was 8 days (interquartile range 7 to 10 days). The presence of headache was associated with a significantly higher odds of intracranial hemorrhage (odds ratio of 7.4), but not of death. Therefore, patients with a new-onset headache 7 to 10 days after vaccination with an adenovirus vector-based vaccine should be carefully evaluated to identify or exclude cerebral venous sinus thrombosis.

Krzywicka and colleagues estimated the absolute risk of cerebral venous sinus thrombosis with and without thrombocytopenia within 28 days of a first dose of four SARS-CoV-2 vaccinations using data from the European Medicines Agency’s EudraVigilance database and data on vaccine delivery from 31 European countries (189); the risk of cerebral venous sinus thrombosis with thrombocytopenia was considerably increased in patients receiving the AstraZeneca and slightly increased in patients receiving the Johnson & Johnson vaccine compared with the estimated background risk, but the risk was not increased in recipients of SARS-CoV-2 mRNA vaccines. The absolute risk of cerebral venous sinus thrombosis within 28 days of first-dose vaccination was 7.5 per million of first doses for the AstraZeneca vaccine (95% CI 6.9-8.3), 0.7 per million of first doses for the Johnson & Johnson vaccine (95% CI 0.2-2.4), 0.6 per million of first doses for the Pfizer vaccine (95% CI 0.5-0.7), and 0.6 for the Moderna vaccine (95% CI 0.3-1.1). The risk of cerebral venous sinus thrombosis with thrombocytopenia within 28 days of first-dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups.

In Singapore, Tu and colleagues found cerebral venous sinus thrombosis was rare after mRNA-based SARS-CoV-2 vaccines, and the incidence rate of cerebral venous sinus thrombosis after SARS-CoV-2 infection was significantly higher than with mRNA-based SARS-CoV-2 vaccination (340).

In an ongoing international registry on cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT), women were much more likely to be affected and women were more severely affected at presentation, but clinical course and outcome did not differ between women and men (299). Among 133 patients with possible, probable, or definite CVST-VITT, 77% were women. Women presented more often with coma (26% vs. 10%) and had a lower platelet count at presentation (median 50 x 109/L vs. 68 x109/L) than men. The nadir platelet count was lower in women (median 34 x109/L vs. 53 x109/L). New venous thromboembolic events (14% vs. 14%) and major bleeding complications (30% vs. 20%) were similar in men and women. Rates of treatment with intravenous immunoglobulins were similar (63% vs. 66%), but more women received endovascular treatment than men (15% vs. 6%). Rates of good functional outcome (modified Rankin Scale 0 to 2, 42% vs. 45%) and in-hospital death (39% vs. 41%) did not differ.

Facial paralysis (Bell palsy). Data from the Pfizer-BioNTech and Moderna vaccine trials suggested an imbalance in the incidence of Bell palsy following vaccination compared with the placebo arm of each trial: among nearly 40,000 participants who received a vaccine, there were seven Bell palsy cases, compared with only one among participants receiving placebo, a difference though that was not statistically significant (p=0·07) (255). However, because the 40,000 vaccine-arm participants were followed for a median of 2 months (roughly 6700 person-years of observation time), only one or two cases would be expected based on the estimated incidence rate of Bell palsy in the general population of from 15 to 30 cases per 100 000 person-years (255). Notably, the number observed in the placebo arms of the trials was consistent with what would be expected. Thus, the observed incidence of Bell palsy in the vaccine arms is between 3.5 and 7 times higher than would be expected in the general population.

Peripheral facial nerve palsy has been widely suggested as a possible complication of the Pfizer vaccine. In the original efficacy trial published in December 2019, Bell palsy was reported in four cases among vaccinated participants but in none of the controls. Subsequent case reports and commentaries fostered speculation that the Pfizer vaccine is associated with an increased risk of Bell palsy. However, a case-control study in Israel found no association between recent vaccination with the Pfizer vaccine and risk of Bell palsy (306). Several factors made Israel an ideal place to conduct this study: (1) Israel exclusively uses the Pfizer vaccine; (2) all residents of Israel are obligatory members of a national digital health registry system; (3) in Israel it is standard practice to refer all new-onset cases of Bell palsy for evaluation in the emergency department. Patients with Bell palsy admitted in January and February of 2021 at the emergency department of a tertiary referral center in Israel were matched by age, sex, and date of admission with control patients admitted for other reasons (306). Thirty-seven patients were admitted to the emergency department for Bell palsy during the study period: two of three were male, and the mean age was 51 years. Fifty seven percent of cases with Bell palsy had been recently vaccinated compared with 60% of matched controls with identical age, sex, and admittance date. The mean time from vaccination to occurrence of Bell palsy among cases was 9.3 days with a range of 3 to 14 days from the first dose and 14.0 days with a range of 1 to 23 days from the second dose. The adjusted odds ratio for exposure was 0.84 with a 95% confidence interval of 0.37 to 1.90; this was not statistically significant. For comparison, the number of admissions for Bell palsy during the months of January and February in preceding years from 2015 to 2020 ranged from 17 to 35 cases with a mean of 26.8 cases, a median of 27.5 cases, and with 35 cases in the immediately preceding year.

In a retrospective study, data were collected from 41 health care organizations worldwide to identify patients diagnosed with COVID-19 with or without a diagnosis code of Bell palsy within 8 weeks of the COVID-19 diagnosis (329). To account for vaccination, the queries were restricted to the period from January 1, 2021 to March 31, 2021. The authors matched 63,551 nonvaccinated patients with COVID-19 to those who were vaccinated against the disease and had no history of COVID-19 infection. Among these patients, the authors identified those with a history of Bell palsy. Approximately 348,000 patients with COVID-19 were identified. Of these patients, 284 (or 82 per 100,000 cases) were diagnosed with Bell palsy within 8 weeks of the initial COVID-19 diagnosis. One hundred fifty three (54%) of these had no prior history of Bell palsy, whereas 131 or 46% did have a prior history of Bell palsy. Among the 1525 patients with a prior history of Bell palsy before developing COVID-19, there was an 8.6% recurrence rate within 8 weeks of COVID-19 diagnosis. There was a statistically significant increased relative risk of 6.8 for a diagnosis of Bell palsy in those with COVID-19 compared with those who were vaccinated. The observed incidence of Bell palsy temporally associated with COVID-19 infection is 2.7 to 5.5 times higher than the baseline annual incidence of Bell palsy, which ranges from 15 to 30 per 100,000 people.

To assess whether COVID-19 vaccination is associated with development of postvaccination facial paresis, Renoud and colleagues used data from the World Health Organization pharmacovigilance database (276). The authors employed disproportionality analyses, which are hypothesis-generating methods that quantify the extent to which a drug-event combination occurs disproportionally compared with what would be expected in the absence of any association. They do not quantify risk because the population that is exposed to the drugs is unknown. The authors performed four analyses with two control groups and two facial paralysis definitions (broad and narrow); the first control group was comprised of individuals exposed to all other viral vaccines and the second was restricted to influenza vaccines. Analyses were adjusted for sex and age. When compared with other viral vaccines, mRNA COVID-19 vaccines did not show a signal of facial paralysis (276). The incidence of facial paralysis after mRNA COVID-19 vaccination was not higher than that observed with other viral vaccines (276). Therefore, any association between facial paralysis and mRNA COVID-19 vaccines is likely comparable to other viral vaccines.

In summary, data so far suggest that the rate of Bell palsy is 2.7 to 7 times more likely following mRNA vaccination than the baseline incidence of Bell palsy in the population, but these values are nevertheless comparable to rates occurring with other viral vaccines. The U.S. Food and Drug Administration has recommended monitoring vaccine recipients for facial paralysis.

In a case series and nested case-control study completed in Hong Kong, the age-standardized incidence of clinically confirmed Bell palsy was 66.9 cases per 100,000 person-years (95% CI 37.2 to 96.6) following CoronaVac (inactivated virus) vaccination and 42.8 per 100,000 person-years (95% CI 19.4 to 66.1) following the Pfizer vaccination (358). The age-standardized difference in incidence compared with the background population was 41·5 (95% CI 11.7 to 71.4) for CoronaVac and 17.0 (95% CI -6.6 to 40.6) for the Pfizer vaccine, equivalent to an additional 4.8 cases per 100,000 people vaccinated for CoronaVac and 2.0 cases per 100,000 people vaccinated with the Pfizer vaccine. In the nested case-control analysis, 298 cases were matched to 1181 controls, and the adjusted odds ratios were 2.4 (95% CI 1.4 to 4.0) for CoronaVac and 1.8 (95% CI 0.9 to 3.5) for the Pfizer vaccine. Only the Chinese CoronaVac vaccine was associated with a significantly increased risk of Bell palsy (358).

Using data from more than 17 million patients in England in a self-controlled case series design, Walker and colleagues found an increased rate of Bell palsy in the period from 4 to 28 days after receiving the first dose of AztraZeneca vaccine (7,783,441 vaccinees; incidence rate ratio 1.39; 95% CI 1.27-1.53), corresponding to 17.9 cases of Bell palsy per 1 million vaccinees if causal (356); as the authors noted, "The absolute risk, assuming a causal effect attributable to vaccination, was low." In contrast, among vaccinees who received the Pfizer and Moderna vaccines, there was no evidence of any association with Bell palsy (Pfizer: 5,729,152 vaccinees; incidence rate ratio 1.09; 95% CI 0.75-1.57; Moderna 255,446 vaccinees; rate ratio 0.88, 95% CI 0.32-2.42).

Sudden sensorineural hearing loss. Preliminary analyses of VAERS data in the early phase of societal COVID-19 vaccination using two messenger RNA vaccines (Pfizer and Moderna) found no association between inoculation with a SARS-CoV-2 messenger RNA vaccine and incident sudden hearing loss (114).

In a subsequent cross-sectional study, an updated analysis of VAERS data and a case series of patients who experienced sudden sensorineural hearing loss after COVID-19 vaccination did not suggest an association between COVID-19 vaccination (Pfizer, Moderna, or Johnson & Johnson) and an increased incidence of hearing loss compared with the expected incidence in the general population (115). An annualized incidence estimate of the post-vaccination incidence of sudden sensorineural hearing loss was 0.6 to 28.0 cases per 100,000 people per year, which is comparable to the annual incidence of idiopathic sudden sensorineural hearing loss (11 to 77 cases per 100 000 people per year, depending on age). The rate of incident reports of sudden sensorineural hearing loss was similar across all three vaccines (0.16 cases per 100,000 doses for both Pfizer-BioNTech and Moderna vaccines, and 0.22 cases per 100,000 doses for the Johnson & Johnson vaccine).

In a population-based, retrospective, cohort study using data from the largest health care organization in Israel, Yanir and colleagues found a small increased risk of sudden sensorineural hearing loss in individuals who received the Pfizer vaccine (380). The age- and sex-weighted standardized incidence ratios were 1.35 (95% CI, 1.09-1.65) after the first vaccine dose and 1.23 (95% CI, 0.98-1.53) after the second vaccine dose. The attributable risks were generally small, and the results were similar when 2019 was used as a reference to estimate the expected number of cases.

The analysis of United States VAERS data found that the incidence of sudden sensorineural hearing loss after vaccination with either mRNA vaccine (Pfizer or Moderna) or the Johnson & Johnson vaccine did not exceed the background rate observed in the general United States population, but data from Israel revealed a slightly higher risk of sudden sensorineural hearing loss after vaccination with the Pfizer mRNA vaccine compared with expected rates (115; 343; 380). However, in the Israeli study, sudden sensorineural hearing loss occurred in fewer than one per 100,000 vaccinated individuals. Neither study reported the severity and duration of hearing loss or the clinical outcomes after treatment (343).

In a register-based country-wide retrospective cohort study of 5.5 million Finnish residents conducted from January 1, 2019 to April 20, 2022, the incidence of sudden sensorineural hearing loss following COVID-19 vaccination was compared with the incidence before the COVID-19 epidemic in Finland (246). Before the COVID-19 epidemic, 18.7 out of 100,000 people received a diagnosis of sudden sensorineural hearing loss annually. There was no increased risk for sudden sensorineural hearing loss following any COVID-19 vaccination. In particular, adjusted incidence rate ratios with 95% confidence intervals for the three doses of the Pfizer vaccine were 0.8 (95% CI, 0.6-1.0), 0.9 (95% CI, 0.6-1.2), and 1.0 (95% CI, 0.7-1.4), respectively.

Guillain-Barré syndrome. Guillain-Barré syndrome (GBS) has been recognized in anecdotal reports following vaccination for COVID-19, but such anecdotal reports cannot distinguish sporadic cases from those that are precipitated by vaccination. A significant increased risk of Guillain-Barré syndrome has been demonstrated following administration of the Johnson & Johnson COVID-19 vaccine, but not after administration of mRNA vaccines.

In the Johnson and Johnson COVID-19 vaccine trial, two subjects developed Guillain-Barré syndrome: one each in the placebo and active vaccine arms. Consequently, the incidence of Guillain-Barré syndrome was identical in both arms of the trial (219). From available evidence it is not possible to infer that this case was (or was not) caused by the coronavirus vaccine she received. The main reason for publishing this case was precisely because of its causally indeterminate nature, which is certainly an unusual reason for a case report. In the present circumstances, though, the authors were trying to raise awareness of the possibility of misattributing postvaccination cases of Guillain-Barré syndrome to vaccination. An increased risk of postvaccination complications can only be determined with comparative trials, meta-analyses of such trials, or large-scale epidemiologic studies. The authors pointed out that as countries collectively move closer to vaccinating 1 billion people, some 8000 to 19,000 cases of Guillain-Barré syndrome can be expected per year based on the background incidence of Guillain-Barré syndrome. Accounting for single- or dual-dose vaccine strategies, perhaps 1000 to 4000 cases might be anticipated in the weeks after vaccination, but not caused by the vaccination. Misattributing these cases to vaccination could undermine global efforts at combatting COVID-19.

A systematic review summarized anecdotal reports of Guillain-Barré syndrome after COVID-19 vaccination and concluded that "COVID-19-associated Guillain-Barré syndrome seems to share most features of classic post-infectious Guillain-Barré syndrome and possibly the same immune-mediated pathogenetic mechanisms," which could arise if the association is causal but which would certainly be the case if the observed association was not causal (02). Interestingly, another systematic review summarized anecdotal reports of Guillain-Barré syndrome after COVID-19 itself (ie, SARS-CoV-2 infection) (07). Neither anecdotal reports, nor case series, nor aggregated systematic reviews of such anecdotal reports can establish causality for Guillain-Barré syndrome caused by either the virus or the vaccine.

As part of postauthorization safety surveillance, the U.S. Food and Drug Administration identified a potential safety concern for Guillain-Barré syndrome following receipt of the Johnson & Johnson COVID-19 vaccine. To assess the risk of Guillain-Barré syndrome following the Johnson & Johnson COVID-19 vaccine, Woo and colleagues examined reports of presumptive Guillain-Barre syndrome from February 2021 to July 2021 in the U.S. VAERS passive reporting system (363). The observed-to-expected ratio of Guillain-Barré syndrome was calculated based on background rates and vaccine administration data. The comparator was the background rate of Guillain-Barré syndrome in the general (unvaccinated) population that had been estimated and published based on a standardized case definition. Because of limited availability of medical records, cases were not assessed according to the Brighton criteria for Guillain-Barré syndrome. As of July 24, 2021, 130 reports of presumptive Guillain-Barre syndrome were identified following vaccination with the Johnson & Johnson COVID-19 vaccine. With approximately 13,210,000 doses of vaccine administered to adults in the United States to this point, the estimated crude reporting rate of Guillain-Barré syndrome was one case per 100,000 doses administered. The overall estimated observed-to-expected rate ratio was 4.2 for the 42-day window. For both risk windows, the observed-to-expected rate ratio was elevated in all age groups, except for the age group from 18 to 29 years. The authors concluded that there is a small but statistically significant increased risk of Guillain-Barré syndrome following receipt of the Johnson & Johnson COVID-19 vaccine. Following availability of these results, the FDA warned in July 2021 that the Johnson & Johnson COVID-19 vaccine is associated with an increased risk of Guillain-Barré syndrome. This, and the lower preventive efficacy of the Johnson & Johnson vaccine against COVID-19, greatly curtailed use of this vaccine in the United States.

In a cohort study of COVID-19 vaccines in the Unites States, the incidence of Guillain-Barré syndrome was elevated after receiving the Johnson & Johnson vaccine (142). Hanson and colleagues used surveillance data on 10,158,003 participants aged at least 12 years from the Vaccine Safety Datalink at eight integrated health care systems in the United States. The unadjusted incidence rate of Guillain-Barré syndrome was 32.4 per 100,000 person-years in the 1 to 21 days after vaccination with the Johnson & Johnson vaccine (95% CI, 14.8-61.5), significantly higher than the background rate of one to two per 100 000 person-years. The unadjusted incidence rate of Guillain-Barré syndrome was 1.3 per 100,000 person-years in the 1 to 21 days after mRNA vaccines (95% CI, 0.7-2.4). In a comparison of the Johnson & Johnson vaccine with mRNA vaccines, the adjusted rate ratio was 20.6 (95% CI, 7.0-64.7).

In a cohort study of 702 patients with a prior history of Guillain-Barré syndrome, only one needed short medical care for postvaccination relapse, which was considered a minimal risk (304).

Using data from more than 17 million patients in England in a self-controlled case series design, Walker and colleagues found an increased rate of Guillain-Barré syndrome in the period from 4 to 42 days after receiving the first (but not the second) dose of AztraZeneca vaccine (7,783,441 vaccinees; incidence rate ratio 2.85; 95% CI 2.33-3.47), corresponding to 11.0 additional cases of Guillain-Barré syndrome per 1 million vaccinees if causal (356). As the authors noted, "The absolute risk, assuming a causal effect attributable to vaccination, was low." In contrast, among vaccinees who received the Pfizer vaccine, there was no evidence of any association with Guillain-Barré syndrome (5,729,152 vaccinees; incidence rate ratio 1.09; 95% CI 0.75-1.57). Among the 255,446 recipients of Moderna vaccine, there were too few outcomes to investigate Guillain-Barré syndrome.

CNS demyelination. Various anecdotal reports of central nervous system demyelination after SARS-CoV-2 vaccination have appeared, most of which followed receipt of the AstraZeneca vaccine. So far, none of the studies have established an increased risk of CNS demyelination following any vaccine for SARS-CoV-2 (240).

Using data from more than 17 million patients in England in a self-controlled case series design, Walker and colleagues found no evidence of a significant association with transverse myelitis for either the AztraZeneca vaccine (7,783,441 vaccinees; incidence rate ratio 1·51; 95% CI 0.96-2.37) or the Pfizer vaccine (5,729,152 vaccinees; incidence rate ratio 1.62; 95% CI 0.86-3·03). Among the 255,446 recipients of Moderna vaccine, there were too few outcomes to investigate transverse myelitis.

In a prospective, self-controlled, multicentric observational study, involving 25 Italian tertiary multiple sclerosis centers, Di Filippo and colleagues assessed whether mRNA COVID-19 vaccines increase the short-term risk of clinical relapses in multiple sclerosis (98). Individuals with multiple sclerosis (n=324; 84% with relapsing-remitting multiple sclerosis), diagnosed according to the 2017 McDonald criteria, who underwent the first dose of an mRNA COVID-19 vaccine in January 2021, were recruited from each participating center in Italy. Based on vaccine availability in Italy at that time, all of them received the Pfizer vaccine. The investigators recorded the presence, characteristics, and number of relapses in the 60 days after the first dose of the vaccine. In the 2 months before vaccination, six clinical relapses were reported in six of the 324 patients, giving a relapse rate of 1.9%. In the 2 months after vaccination, seven clinical relapses occurred in seven of the 324 patients, giving a relapse rate of 2.2%. The mean interval from the first dose of vaccination to the clinical relapse was 44 days. The relapse rates in the 2 months before and after vaccination were not significantly different. Age, gender, disease duration, and disability status had no effect on relapses. The authors concluded that the Pfizer COVID-19 vaccine does not increase the short-term risk of clinical reactivation in people with multiple sclerosis.

Herpes zoster. Multiple anecdotal reports of herpes zoster after the first and second doses of a COVID-19 vaccine have appeared in the medical literature in the United States and abroad.

In a cohort study using a self-controlled risk interval (SCRI) design applied to 1451 people who had herpes zoster during either a risk or control interval (among 2,039,854 vaccinated individuals), Akpandak and colleagues found no significant association between COVID-19 vaccination and herpes zoster (incidence rate ratio, 0.91; 95% CI, 0.82-1.01; P = .08) (06). In the supplementary cohort analysis, COVID-19 vaccination was not associated with a higher risk of herpes zoster compared with influenza vaccination in the prepandemic period (first dose of COVID-19 vaccine: hazard ratio, 0.78; 95% CI, 0.70-0.86; p < .001); second dose of COVID-19 vaccine: hazard ratio, 0.79; 95% CI, 0.71-0.88; p < .001]) or the early pandemic period (first dose of COVID-19 vaccine: hazard ratio, 0.89; 95% CI, 0.80-1.00; P = .05; second dose: hazard ratio, 0.91; 95% CI, 0.81-1.02; p = .09) (06).

Adverse pregnancy outcomes. Vaccination with mRNA vaccines administered during the second and third trimesters of pregnancy is not associated with an increased risk of adverse pregnancy outcomes (107; 180; 216). In a population-based retrospective cohort study of 157,521 pregnant women with singleton pregnancies in Sweden and Norway, COVID-19 vaccination against SARS-CoV-2 during pregnancy was not significantly associated with an increased risk of adverse pregnancy outcomes (216). Similarly, in a population-based retrospective cohort study of 97,590 of pregnant women in Ontario, Canada, COVID-19 vaccination during pregnancy was not significantly associated with an increased risk of adverse peripartum outcomes (107).

Anxiety-related adverse event clusters. On April 7, 2021, after 5 weeks of use of the Johnson and Johnson vaccine, the U.S. Centers for Disease Control and Prevention (CDC) received reports of clusters of anxiety-related events from five mass vaccination sites, all in different states (145). An anxiety-related event was defined as any of the following occurring in a person during the 15-minute postvaccination observation period: tachycardia, hyperventilation, dyspnea, chest pain, paresthesia, light-headedness, hypotension, headache, pallor, or syncope. Four of the five sites temporarily closed while an investigation took place. Overall, 64 anxiety-related events, including 17 reports of syncope, among 8624 vaccine recipients, were reported from these sites for vaccines administered during April 7 to 9, 2021. Approximately one quarter of the syncopal and other anxiety-related events occurred in persons who reported a history of similar events after prior vaccinations. Approximately half of the reports to the Vaccine Adverse Event Reporting System (VAERS) concerning syncope after the Johnson and Johnson vaccination were for persons in the youngest age group (18 to 29 years) recommended for vaccination, an age group prone to vasovagal reactions to needlesticks and vaccinations. Based on reports to VAERS, syncope occurred at a rate of 8.2 episodes per 100,000 doses following the Johnson and Johnson vaccine compared with 0.05 episodes per 100,000 doses after influenza vaccination.

Prevention

	• Among the vaccines available today, the cost-benefit analysis of vaccinations and complications strongly argues in favor of vaccination.
	• With mass vaccinations, significant numbers of adverse events can be anticipated (only some of which are directly attributable to the vaccine in question whereas many represent cases that would have occurred regardless of vaccination).
	• All potential vaccine recipients need to be screened for contraindications to vaccination, including prior allergic reactions to the vaccine or its components.
	• Any person with an evolving central nervous system disorder should generally not receive vaccination until the condition has resolved or stabilized.
	• Individuals who are immunosuppressed or have an immunological disorder should generally not receive live-attenuated vaccines.
	• The Advisory Committee on Immunization Practices and the Centers for Disease Control and Prevention recommend observing patients (keeping them sitting or lying down) for 15 minutes after they are vaccinated, and if syncope develops, patients should be observed until symptoms resolve.

Among the vaccines available today, the cost-benefit analysis of vaccinations and complications strongly argues in favor of vaccination (234). Sadly, the perception of significant risk associated with vaccinations has limited the success of disease-eradication measures. Evaluating whether there is causal relationship between vaccinations and putative neurologic complications is essential if we are to confront the widespread public misperception of vaccination risk.

With mass vaccinations, significant numbers of adverse events can be anticipated (only some of which are directly attributable to the vaccine in question whereas many represent cases that would have occurred regardless of vaccination). All potential vaccine recipients need to be screened for contraindications to vaccination, including prior allergic reactions to the vaccine or its components. Any person with an evolving central nervous system disorder should generally not receive vaccination until the condition has resolved or stabilized. Individuals who are immunosuppressed or have an immunological disorder should generally not receive live-attenuated vaccines.

Because half of "serious" cases of postvaccination syncope occur within 5 minutes of vaccination, and more than two thirds occur within 15 minutes, the Advisory Committee on Immunization Practices and the Centers for Disease Control and Prevention recommend observing patients (keeping them sitting or lying down) for 15 minutes after they are vaccinated, and if syncope develops, patients should be observed until symptoms resolve (188; 72; 194).

In some cases, where neuroparalytic adverse reactions to vaccines are particularly common within a specific age group, or where one type of vaccine has a relatively higher incidence of such serious adverse reactions, CDC’s Advisory Committee on Immunization Practices and the WHO’s Global Advisory Committee on Vaccine Safety (GACVS) will provide guidance on vaccine selection or age-specific restrictions. For example, when it became clear that yellow fever vaccines produced an unacceptably high rate of vaccine-associated encephalitis in infants younger than 6 months of age, the vaccine was restricted to individuals at least 6 months old or older. Similarly, when alternatives to nerve-tissue rabies vaccines became available, the World Health Organization strongly recommended their replacement with safer inactivated CCEEV rabies vaccines.

Differential diagnosis

Confusing conditions

It remains unclear how many cases of reported encephalitis or meningoencephalitis following vaccination are simply coincidental in time but not due to the vaccination itself. A number of different infectious agents and noninfectious processes can be responsible for encephalitis, and it is often impossible to establish the etiology.

A variety of encephalitic syndromes can mimic those attributed to vaccination. The possible causes are numerous and include, but are not limited to, Epstein-Barr virus, herpes viruses, enteroviruses, measles, mumps, Mycoplasma pneumoniae, varicella-zoster virus, and arboviruses (including West Nile virus). A variety of toxic encephalopathies can produce identical symptoms.

In most cases, genetic or structural defects are the underlying cause of epilepsy with onset after vaccination, including cases with either preexistent encephalopathy or benign epilepsy with good outcome (348). Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies, in more than 10% of cases (351). Genetic conditions, such as Dravet syndrome (a severe epileptic encephalopathy starting in the first year of life resulting from mutations in SCN1A) and Angelman syndrome (a complex genetic disorder that primarily affects the nervous system, due to a deletion or mutation of the UBE3A gene on chromosome 15), can cause vaccine-associated encephalopathies (typically precipitated by vaccine-induced fever) that are misinterpreted as vaccine complications (62; 249); numerous alleged cases of vaccine encephalopathy were reevaluated, sometimes years later, and diagnosed as having Dravet syndrome (277), and in one case intellectual disability and epilepsy attributed to a vaccine encephalopathy following smallpox vaccination were later recognized as resulting from Angelman syndrome (249). Seizures following vaccinations were reported in about one quarter to one half of patients diagnosed with Dravet syndrome, and in more than half (58%), vaccination-related seizures represented the first clinical manifestation (66; 339; 362; 36); the majority of seizures occurred after DPT vaccinations and within 72 hours after vaccination, and two thirds occurred in the context of fever (339). Even though Dravet syndrome is a rare disorder, 2.5% of reported seizures following vaccinations in the first year of life in our cohort occur in children with this disorder (349). Importantly, although vaccination might trigger an earlier onset of Dravet syndrome in children who, because of a SCN1A mutation, are destined to ultimately develop the disease, vaccination-associated earlier seizure onset in Dravet syndrome does not alter the disease course (222; 382; 347). Consequently, vaccination should not be withheld from children with SCN1A mutations (222).

Diagnostic workup

	• For cases with vaccine-associated meningitis or encephalitis due to vaccination with live-attenuated vaccines (eg, oral polio vaccine, smallpox [vaccinia] vaccine, yellow fever vaccine), detection of the vaccine virus in CSF either by culture or nucleic acid amplification is diagnostic; in addition, because virus-specific IgM antibodies do not normally cross the blood-brain barrier, their presence in CSF is considered indicative of local CNS infection.
	• No confirmatory vaccine-specific laboratory tests exist for vaccine-induced autoimmune syndromes.
	• No clinical, radiological, or laboratory findings are specific for a diagnosis of postvaccination encephalomyelitis.
	• Temporal association with vaccination (10 to 14 days from vaccination to onset of symptoms on average) and meningoencephalitic symptoms suggest a diagnosis of postvaccination encephalomyelitis.
	• Because vaccine-associated paralytic poliomyelitis (VAPP) is clinically indistinguishable from poliomyelitis caused by wild-type polioviruses, diagnosis of VAPP requires demonstration of acute flaccid paralysis with residual weakness present 60 days after symptom onset and confirmation with a stool sample that is negative for wild-type poliovirus but positive for vaccine virus.

For cases with vaccine-associated meningitis or encephalitis due to CNS of the vaccine virus with live-attenuated vaccines (eg, oral polio vaccine, smallpox [vaccinia] vaccine, yellow fever vaccine), detection of the vaccine virus in CSF either by culture or nucleic acid amplification is diagnostic. The detection of virus-specific IgM and specific neutralizing antibodies in the CSF also supports the diagnosis (317): because virus-specific IgM antibodies do not normally cross the blood-brain barrier, their presence in CSF is considered indicative of local CNS infection (317).

For autoimmune-mediated events (eg, acute disseminated encephalomyelitis, Guillain-Barré syndrome), diagnosis should be made using appropriate studies (eg, neuroimaging, electromyography, and nerve conduction studies). No confirmatory vaccine-specific laboratory tests exist for vaccine-induced autoimmune syndromes.

No clinical, radiological, or laboratory findings are specific for a diagnosis of postvaccination encephalomyelitis. Temporal association with vaccination (10 to 14 days from vaccination to onset of symptoms on average) and meningoencephalitic symptoms suggest a diagnosis of postvaccination encephalomyelitis. In such cases with suspected postvaccination encephalitis, enhanced MRI and spinal fluid studies (including myelin basic protein studies) should be obtained (55). CSF findings are nonspecific but include an increase in opening pressure, a modest mononuclear pleocytosis (less than 500 cells/cc), and elevated protein concentration (156; 281; 55; 84). CSF glucose concentration is normal. EEG may show high-voltage slow-waves (55). Bacterial infection should be ruled out by examination and culture of CSF as well as other appropriate cultures, including blood. Polymerase chain reaction testing of CSF should be performed for agents commonly associated with meningoencephalitis.

Because VAPP is clinically indistinguishable from poliomyelitis caused by wild-type polioviruses (27), diagnosis of VAPP requires demonstration of acute flaccid paralysis with residual weakness present 60 days after symptom onset and confirmation with a stool sample that is negative for wild-type poliovirus but positive for vaccine virus (370).

Management

	• For vaccine-associated autoimmune-mediated neurologic manifestations, treatment typically includes intravenous immunoglobulin or plasmapheresis for Guillain-Barré syndrome and corticosteroids, intravenous immunoglobulin, or plasmapheresis for acute disseminated encephalomyelitis.
	• There is no specific therapy for encephalitis following vaccination; no treatment is recognized to alter the clinical course, although some authors advocate intravenous methylprednisolone and consideration of intravenous immunoglobulin and plasmapheresis.
	• Healthcare providers who need clinical consultation for potential vaccine adverse reactions should contact their state or local health department or the CDC Clinician Information Line at (877) 554-4625. Military healthcare providers (or civilian providers treating a military healthcare beneficiary) should call (866) 210-6469 for clinical consultation.
	• Healthcare providers should report vaccine adverse events to their state or local health department and to the Vaccine Adverse Event Reporting System.

Treatment for vaccine-associated neurologic disorders depends on the particular clinical syndrome.

For vaccine-associated autoimmune-mediated neurologic manifestations, treatment typically includes intravenous immunoglobulin or plasmapheresis for Guillain-Barré syndrome and corticosteroids, intravenous immunoglobulin, or plasmapheresis for acute disseminated encephalomyelitis (317).

There is no specific therapy for encephalitis following vaccination (84). Supportive care, anticonvulsants, and intensive care may be required in individual cases (317). No treatment is recognized to alter the clinical course, although some authors advocate intravenous methylprednisolone and consideration of intravenous immunoglobulin and plasmapheresis (232).

For postvaccination encephalitis following smallpox vaccination, vaccinia immune globulin is not effective, and the antiviral cidofovir is not indicated (129; 281; 55; 80; 84; 232).

Healthcare providers who need clinical consultation for potential vaccine adverse reactions should contact their state or local health department or the CDC Clinician Information Line at (877) 554-4625. Military healthcare providers (or civilian providers treating a military healthcare beneficiary) should call (866) 210-6469 for clinical consultation.

Healthcare providers should report vaccine adverse events to their state or local health department and to the Vaccine Adverse Event Reporting System at the VAERS Web site or (800) 822-7967. The Vaccine Adverse Event Reporting System (VAERS) and the National Vaccine Injury Compensation Program track vaccine-associated adverse events and allow compensation for documented vaccine-related injury.

Outcomes

Encephalomyelitis following vaccination is a severe disease with a relatively high mortality and morbidity (55). Reported case-fatality rates for postvaccination encephalomyelitis vary considerably over different studies from approximately 10% to 50%. Some of the variation may be due to different levels of supportive care and to different vaccine strains. In the United States in 1968, mortality from postvaccination encephalomyelitis was approximately 10% (80). Death can occur suddenly, usually within a week of onset of symptoms. Approximately 25% to 30% of all survivors have some residual neurologic defect.

Media

References

01: Aalen OO, Røysland K, Gran JM, Kouyos R, Lange T. Can we believe the DAGs? A comment on the relationship between causal DAGs and mechanisms. Stat Methods Med Res 2016;25(5):2294-314. PMID 24463886
02: Abu-Rumeileh S, Abdelhak A, Foschi M, Tumani H, Otto M. Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. J Neurol 2021;268(4):1133-70. PMID 32840686
03: Ackley SF, Mayeda ER, Worden L, Enanoria WTA, Glymour MM, Porco TC. Compartmental model diagrams as causal representations in relation to DAGs. Epidemiol Methods 2017;6(1):20060007. PMID 30555771
04: Advisory Committee on Immunization Practices (ACIP). Grading of recommendations, assessment, development, and evaluation (GRADE): recombinant zoster vaccine (RZV) and herpes zoster live-attenuated vaccine (ZVL). Atlanta, GA: US Department of Health and Human Services, CDC, Advisory Committee on Immunization Practices; 2017.
05: Ahmed SS, Volkmuth W, Duca J, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med 2015;7(294):294ra105. PMID 26136476
06: Akpandak I, Miller DC, Sun Y, Arnold BF, Kelly JD, Acharya NR. Assessment of herpes zoster risk among recipients of COVID-19 vaccine. JAMA Netw Open 2022;5(11):e2242240. PMID 36383382
07: Aladawi M, Elfil M, Abu-Esheh B, et al. Guillain Barre syndrome as a complication of COVID-19: a systematic review. Can J Neurol Sci 2022;49(1):38-48. PMID 33949300
08: Albu S, Vallès M, Kumru H. Diagnostic challenges of functional neurological disorders after covid-19 disease or vaccination: case series and review of the literature. Acta Neurol Belg 2022;1-12. PMID 36413270
09: Alexander JP, Ehresmann K, Seward J, et al. Transmission of imported vaccine-derived poliovirus in an undervaccinated community in Minnesota. J Infect Dis. 2009;199(3):391-7. PMID 19090774
10: Aliasin MM, Yazdanpanah N, Rezaei N. Neurological and neuropsychological adverse effects of SARS-CoV-2 vaccines - where do we stand? Rev Neurosci 2022;33(7):721-43. PMID 35334195
11: Allahyari F, Molaee H, Hosseini Nejad J. Covid-19 vaccines and neurological complications: a systematic review. Z Naturforsch C J Biosci 2022;78(1-2):1-8. PMID 36087300
12: Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020;383(25):2427-38. PMID 32991794
13: Andrews N, Stowe J, Miller E. No increased risk of Guillain-Barré syndrome after human papilloma virus vaccine: A self-controlled case-series study in England. Vaccine 2017;35(13):1729-32. PMID 28245941
14: Angelo MG, Zima J, Tavares Da Silva F, Baril L, Arellano F. Post-licensure safety surveillance for human papillomavirus-16/18-AS04-adjuvanted vaccine: more than 4 years of experience. Pharmacoepidemiol Drug Saf 2014;23(5):456-65. PMID 24644078
15: Anonymous. Fatal viral encephalitis following 17D yellow fever vaccine inoculation. Report of a case in a 3-year-old child. JAMA 1966;198(6):671-2. PMID 4380787
16: Anonymous. Yellow fever vaccine: recommendation of the U.S. Public Health Service Advisory Committee on Immunization Practices. Ann Intern Med 1969;71:365-7. PMID 5800300
17: Anonymous. Prevention and control of influenza: Part I, Vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1993;42(RR-6):1-14. PMID 8145709
18: Anonymous. Update: vaccine side effects, adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Weekly Rep 1996;45(RR-12):1-35. PMID 8801442
19: Anonymous. Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(RR-3):1-25. PMID 9026708
20: Anonymous. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention. MMWR Morb Mortal Weekly Rep 1998;47(No.RR-6):1-26. PMID 9590726
21: Anonymous. Mumps virus vaccines. Wkly Epidemiol Rec 2007;82(7):51-60. [French]. PMID 17304707
22: Anonymous. Meningococcal vaccines: WHO position paper, November 2011. [French]. Wkly Epidemiol Rec 2011a;86(47):521-39. PMID 22128384
23: Anonymous. Rubella vaccines: WHO position paper. [French]. Wkly Epidemiol Rec 2011b;86(29):301-16. PMID 21766537
24: Anonymous. Vaccines against influenza WHO position paper - November 2012. [French]. Wkly Epidemiol Rec 2012;87(47):461-76. PMID 23210147
25: Anonymous. Vaccines and vaccination against yellow fever: WHO Position Paper - June 2013. [French]. Wkly Epidemiol Rec 2013;88(27):269-83. PMID 23909008
26: Anonymous. Meningococcal A conjugate vaccine: updated guidance, February 2015. [French]. Wkly Epidemiol Rec 2015;90(8):57-62. PMID 25702330
27: Anonymous. Polio vaccines: WHO position paper - March, 2016. [French]. Wkly Epidemiol Rec 2016;91(12):145-68. PMID 27039410
28: Anonymous. Human papillomavirus vaccines: WHO position paper, May 2017. [French]. Wkly Epidemiol Rec 2017a;92(19):241-68. PMID 28530369
29: Anonymous. Hepatitis B vaccines: WHO position paper - July 2017. Wkly Epidemiol Rec 2017b;92(27):369-92.
30: Arnold KF, Berrie L, Tennant PWG, Gilthorpe MS. A causal inference perspective on the analysis of compositional data. Int J Epidemiol 2020;49(4):1307-13. PMID 32154892
31: Arnold KF, Harrison WJ, Heppenstall AJ, Gilthorpe MS. DAG-informed regression modelling, agent-based modelling and microsimulation modelling: a critical comparison of methods for causal inference. Int J Epidemiol 2019;48(1):243-53. PMID 30520989
32: Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344(5):327-32. PMID 11172163
33: Ashrani AA, Crusan DJ, Petterson T, Bailey K, Heit JA. Age- and sex-specific incidence of cerebral venous sinus thrombosis associated with Ad26.COV2.S COVID-19 vaccination. JAMA Intern Med 2022;182(1):80-3. PMID 34724036
34: Assis JL. Neurological complication of antirabies vaccination in São Paulo, Brazil. Clinical and therapeutical aspects. J Neurol Sci 1975;26(4):593-8. PMID 173809
35: Auster O, Finkel U, Dagan N, et al. Short-term adverse events after the third dose of the BNT162b2 mRNA COVID-19 vaccine in adults 60 years or older. JAMA Netw Open 2022;5(4):e227657. PMID 35435973
36: Auvin S, Jeljeli M, Desnous B, Soussi-Yanicostas N, Dournaud P, Sterkers G. Altered vaccine-induced immunity in children with Dravet syndrome. Epilepsia 2018;59(4):e45-50. PMID 29512885
37: Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;384(5):403-16. PMID 33378609
38: Bahri F, Letaief A, Ernez M, et al. Neurological complications in adults following rabies vaccine prepared from animal brains. Press Med 1996;25(10):491-3. PMID 8685108
39: Baram TZ, Gonzalez-Gomez I, Xie ZD, et al. Subacute sclerosing panencephalitis in an infant: diagnostic role of viral genome analysis. Ann Neurol 1994;36(1):103-8. PMID 8024248
40: Bardage C, Persson I, Ortqvist A, Bergman U, Ludvigsson JF, Granath F. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. BMJ 2011;343:d5956. PMID 21994316
41: Barlow WE, Davis RL, Glasser JW, et al. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med 2001;345(9):656-61. PMID 11547719
42: Barnard-Mayers R, Kouser H, Cohen JA, et al. A case study and proposal for publishing directed acyclic graphs: The effectiveness of the quadrivalent human papillomavirus vaccine in perinatally HIV Infected girls. J Clin Epidemiol 2022;144:127-35. PMID 34998951
43: Baxter R, Lewis N, Bakshi N, Vellozzi C, Klein NP, Network C. Recurrent Guillain-Barré syndrome following vaccination. Clin Infect Dis 2012;54(6):800-4. PMID 22267712
44: Baxter R, Bakshi N, Fireman B, et al. Lack of association of Guillain- Barré syndrome with vaccinations. Clin Infect Dis 2013;57(2):197-204. PMID 23580737
45: Baxter R, Lewis E, Fireman B, DeStefano F, Gee J, Klein NP. Case- centered analysis of optic neuritis after vaccines. Clin Infect Dis 2016a;63(1):79-81. PMID 27069066
46: Baxter R, Lewis N, Bohrer P, Harrington T, Aukes L, Klein NP. Sudden- onset sensorineural hearing loss after immunization: a case-centered analysis. Otolaryngol Head Neck Surg 2016b;155(1):81-6. PMID 27026733
47: Beatty AL, Peyser ND, Butcher XE, et al. Analysis of COVID-19 vaccine type and adverse effects following vaccination. JAMA Netw Open 2021;4(12):e2140364. PMID 34935921
48: Berg AT, Shinnar S, Shapiro ED, Salomon ME, Crain EF, Hauser WA. Risk factors for a first febrile seizure: a matched case-control study. Epilepsia 1995;36(4):334-41. PMID 7541745
49: Bernard KW, Roberts MA, Sumner J, et al. Human diploid cell rabies vaccine. Effectiveness of immunization with small intradermal or subcutaneous doses. JAMA 1982;247(8):1138-42. PMID 7057603
50: Bitnun A, Shannon P, Durward A, et al. Measles inclusion-body encephalitis caused by the vaccine strain of measles virus. Clin Infect Dis 1999(4);29:855-61. PMID 10589903
51: Blersch R, Franchuk N, Lucas M, Nord CM, Varsanyi S, Bonnell TR. Causal analysis as a bridge between qualitative and quantitative research. Behav Brain Sci 2022;45:e4. PMID 35139974
52: Blumenthal KG, Phadke NA, Bates DW. Safety surveillance of COVID-19 mRNA vaccines through the vaccine safety datalink. JAMA 2021;326(14):1375-7. PMID 34477809
53: Bonhoeffer J, Kohl K, Chen R, et al. The Brighton Collaboration: addressing the need for standardized case definitions of adverse events following immunization (AEFI). Vaccine 2002;21(3-4):298-302. PMID 12450705
54: Bonhoeffer J, Heininger U, Kohl K, et al. Standardized case definitions of adverse events following immunization (AEFI). Vaccine 2004;22(5-6):547-50. PMID 14741142
55: Booss J, Davis LE. Smallpox and smallpox vaccination: neurological implications. Neurology 2003;60(8):1241-5.** PMID 12707424
56: Brewer LE, Wright JM, Rice G, Neas L, Teuschler L. Causal inference in cumulative risk assessment: The roles of directed acyclic graphs. Environ Int 2017;102:30-41. PMID 27988137
57: Burwen DR, Ball R, Bryan WW, et al. Evaluation of Guillain-Barré Syndrome among recipients of influenza vaccine in 2000 and 2001. Am J Prev Med 2010;39(4):296-304. PMID 20837279
58: Burwen DR, Sandhu SK, MaCurdy TE, et al. Surveillance for Guillain-Barré syndrome after influenza vaccination among the Medicare population, 2009-2010. Am J Public Health 2012;102(10):1921-7. PMID: PMID 22970693
59: Butel J, Lednicky JA. Cell and molecular biology of Simian virus 40: implications for human infections and disease. J Natl Cancer Inst 1999;91(2):119-34. PMID 9923853
60: Butler M, Tamborska A, Wood GK, et al. Considerations for causality assessment of neurological and neuropsychiatric complications of SARS-CoV-2 vaccines: from cerebral venous sinus thrombosis to functional neurological disorder. J Neurol Neurosurg Psychiatry 2021;92(11):1144-51.** PMID 34362855
61: Cahill JF, Izzo A, Garg N. Immunization in patients with multiple sclerosis. Neurol Bull 2010;2:17-21.
62: Caraballo RH, Fejerman N. Dravet syndrome: a study of 53 patients. Epilepsy Res 2006;70 Suppl 1:S231-8. PMID 16893627
63: Casey CG, Iskander JK, Roper MH, et al. Adverse events associated with smallpox vaccination in the United States, January-October 2003. JAMA 2005;294(21):2734-43. PMID 16333009
64: Casey C, Vellozzi C, Mootrey GT, et al. Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. MMWR Recomm Rep 2006;55(RR-1):1-16. PMID 16456528
65: Cauchi M, Ball H, Ben-Shlomo Y, Robertson N. Interpretation of vaccine associated neurological adverse events: a methodological and historical review. J Neurol 2022;269(1):493-503.** PMID 34398270
66: Cendes F, Sankar R. Vaccinations and febrile seizures. Epilepsia 2011;52 Suppl 3:23-5. PMID 21542842
67: Centers for Disease Control and Prevention. Paralytic poliomyelitis 1980-94. MMWR Morb Mortal Weekly Rep 1997;46:79-83. PMID 9048844
68: Centers for Disease Control and Prevention. Update: adverse events following civilian smallpox vaccination--United States, 2003. MMWR Morb Mortal Weekly Rep 2003;52(20):475-7. PMID 12807082
69: Centers for Disease Control and Prevention. Guillain-Barré syndrome among recipients of Menactra meningococcal conjugate vaccine--United States, June-July 2005. MMWR Morb Mortal Wkly Rep 2005;54(40):1023-5. PMID 16224452
70: Centers for Disease Control and Prevention. Update: Guillain-Barré syndrome among recipients of Menactra meningococcal conjugate vaccine--United States, June 2005-September 2006. Morb Mortal Wkly Rep 2006a;55(43):1177. PMID 17060898
71: Centers for Disease Control and Prevention. Update: Guillain-Barré syndrome among recipients of Menactra meningococcal conjugate vaccine--United States, October 2005-February 2006. MMWR Morb Mortal Wkly Rep 2006b;55:364-6. PMID 16601664
72: Centers for Disease Control and Prevention. Syncope after vaccination--United States, January 2005-July 2007. MMWR Morb Mortal Wkly Rep 2008a;57(17):457-60. PMID 18451756
73: Chatterjee A, Chakravarty A. Neurological complications following COVID-19 vaccination. Curr Neurol Neurosci Rep 2023;23(1):1-14. PMID 36445631
74: Chaves M, Riccio P, Patrucco L, Rojas J, Cristiano E. Longitudinal myelitis associated with yellow fever vaccination. J Neurovirol 2009;15(4):348-50. PMID 19579072
75: Che Y, Liu X, Pu Y, et al. Randomized, double-blinded and placebo-controlled phase II trial of an inactivated SARS-CoV-2 vaccine in healthy adults. Clin Infect Dis 2021;73(11):e3949-55. PMID 33165503
76: Chen RT, Glasser JW, Rhodes PH, et al. Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team. Pediatrics 1997;99(6):765-73. PMID 9164767
77: Chen Z, He L, Liu S, Liu H, Yu J, Li Y. The grading of recommendations, assessment, development, and evaluation approach was rarely followed and inconsistently applied in pressure injury prevention guidelines development: A cross-sectional survey. J Tissue Viability 2022;31(3):438-43. PMID 35760719
78: Cho B, Clark TA, Messonnier NE. MCV vaccination in the presence of vaccine-associated Guillain-Barré Syndrome risk: a decision analysis approach. Vaccine 2010;28(3):817-22. PMID 19879992
79: Choe YJ, Bae GR, Lee DH. No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. Vaccine 2012;30(52):7439-42. PMID 23088885
80: Cleri DJ, Villota FJ, Porwancher RB. Smallpox, bioterrorism, and the neurologist. Arch Neurol 2003;60(4):489-94.** PMID 12707060
81: Cohn AC, MacNeil JR, Clark TA, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013;62(RR-2):1-28. PMID 23515099
82: Committee on Infectious Diseases. Recommendations for Serogroup B Meningococcal Vaccine for Persons 10 Years and Older. Pediatrics 2016;138(3):pii:e20161890. PMID 27573083
83: Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med 2001;344(5):319-26. PMID 11172162
84: Cono J, Casey CG, Bell DM. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep 2003;52(RR-4):1-28. PMID 12617510
85: Constantinescu CS, Farooqi N, O'Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 2011;164(4):1079-106. PMID 21371012
86: Dauvilliers Y, Montplaisir J, Cochen V, et al. Post-H1N1 narcolepsy-cataplexy. Sleep 2010;33(11):1428-30. PMID 21102981
87: Davoli M, Amato L, Clark N, et al. The role of Cochrane reviews in informing international guidelines: a case study of using the grading of recommendations, assessment, development and evaluation system to develop World Health Organization guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Addiction 2015;110(6):891-8. PMID 25490943
88: Deer B. How the case against the MMR vaccine was fixed. BMJ 2011a;342:c5347. PMID 21209059
89: Deer B. Secrets of the MMR scare. The Lancet's two days to bury bad news. BMJ 2011b;342:c7001. PMID 21245118
90: Deer B. Secrets of the MMR scare. How the vaccine crisis was meant to make money. BMJ 2011c;342:c5258. PMID 21224310
91: Deng L, Gidding H, Macartney K, et al. Postvaccination febrile seizure severity and outcome. Pediatrics 2019;143(5). PMID 31004046
92: de Souza A, Jacques R, Mohan S. Vaccine-induced functional neurological disorders in the Covid-19 era. Can J Neurol Sci 2023;50(3):346-50. PMID 35466898
93: DeStefano F, Verstraeten T, Chen RT. Hepatitis B vaccine and risk of multiple sclerosis. Expert Rev Vaccines 2002;1(4):461-6. PMID 12901584
94: DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003;60(4):504-9. PMID 12707063
95: DeStefano F, Weintraub ES, Chen RT. Hepatitis B vaccine and risk of multiple sclerosis. Pharmacoepidemiol Drug Saf 2007;16:705-7, author reply 707-8. PMID 17549685
96: Devaraj R, Shafi P, Nagesh C, Naidu A, Satishchandra P. Spectrum of neurological complications following COVID-19 vaccination in India. J Clin Neurol 2022;18(6):681-91. PMID 36367066
97: Dickerman BA, Madenci AL, Gerlovin H, et al. Comparative safety of BNT162b2 and mRNA-1273 vaccines in a nationwide cohort of US veterans. JAMA Intern Med 2022;182(7):739-46. PMID 35696161
98: Di Filippo M, Cordioli C, Malucchi S, et al. mRNA COVID-19 vaccines do not increase the short-term risk of clinical relapses in multiple sclerosis. J Neurol Neurosurg Psychiatry 2022;93(4):448-50. PMID 34408003
99: Dixon C, Dixon PE, Sultan S, et al. Guideline developers in the United States were inconsistent in applying criteria for appropriate grading of recommendations, assessment, development and evaluation use. J Clin Epidemiol 2020;124:193-9. PMID 32145368
100: Dobardzic A, Izurieta H, Woo EJ, et al. Safety review of the purified chick embryo cell rabies vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS), 1997-2005. Vaccine 2007;25(21):4244-51. PMID 17382435
101: Dooling KL, Guo A, Patel M, Lee GM, Moore K, Belongia EA, Harpaz R. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep 2018;67(3):103-8. PMID 29370152
102: Duclos P, Ward BJ. Measles vaccines: a review of adverse events. Drug Saf 1998;19(6):435-54. PMID 9880088
103: Duffy J, Weintraub E, Vellozzi C, DeStefano F; Vaccine Safety Datalink. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology 2014;83(20):1823-30. PMID 25320099
104: Esmaeilzadeh A, Maleki AJ, Moradi A, et al. Major severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccine-associated adverse effects; benefits outweigh the risks. Expert Rev Vaccines 2022;21(10):1377-94. PMID 35986451
105: Farez MF, Correale J. Immunizations and risk of multiple sclerosis: systematic review and meta-analysis. J Neurol 2011;258(7):1197-206. PMID 21431896
106: Farrington P, Pugh S, Colville A, et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 1995;345(8949):567-9. PMID 7619183
107: Fell DB, Dhinsa T, Alton GD, et al. Association of COVID-19 vaccination in pregnancy with adverse peripartum outcomes. JAMA 2022;327(15):1478-87. PMID 35323842
108: Fernandes GC, Camacho LA, Sá Carvalho M, Batista M, de Almeida SM. Neurological adverse events temporally associated to mass vaccination against yellow fever in Juiz de Fora, Brazil, 1999-2005. Vaccine 2007;25(16):3124-8. PMID 17316927
109: Finsterer J. Neurological side effects of SARS-CoV-2 vaccinations. Acta Neurol Scand 2022;145(1):5-9. PMID 34750810
110: Fischer M, Lindsey N, Staples JE, Hills S; Centers for Disease Control and Prevention (CDC). Japanese Encephalitis Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59(RR-1):1-27. PMID 20224546
111: Folaranmi T, Rubin L, Martin SW, Patel M, MacNeil JR. Use of Serogroup B Meningococcal Vaccines in Persons Aged ≥10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep 2015;64(22):608-12. Erratum in: MMWR Morb Mortal Wkly Rep 2015;64(29):806. PMID 26068564
112: Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020;396(10249):467-78. PMID 32702298
113: Food and Drug Administration. Zostavax [package insert]. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, 2006.
114: Formeister EJ, Chien W, Agrawal Y, Carey JP, Stewart CM, Sun DQ. Preliminary analysis of association between COVID-19 vaccination and sudden hearing loss using US Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System Data. JAMA Otolaryngol Head Neck Surg 2021;147(7):674-6. PMID 34014263
115: Formeister EJ, Wu MJ, Chari DA, et al. Assessment of sudden sensorineural hearing loss after COVID-19 vaccination. JAMA Otolaryngol Head Neck Surg 2022;148(4):307-15. PMID 35201274
116: Fox JP, Penna HA. Behavior of 17D yellow fever virus in Rhesus monkeys: relation to substrain, dose, and neural, or extraneural innoculaton. Am J Hyg 1943;38:152-72.
117: Garcel A, Fauquette W, Dehouck MP, Crance JM, Favier AL. Vaccinia virus-induced smallpox postvaccinal encephalitis in case of blood-brain barrier damage. Vaccine 2012;30(7):1397-405. PMID 22227123
118: Garcia-Azorin D, Do TP, Gantenbein AR, et al. Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis. J Headache Pain 2021;22(1):108. PMID 34535076
119: Garcia-Grimshaw M, Ceballos-Liceaga SE, Hernández-Vanegas LE, et al. Neurologic adverse events among 704,003 first-dose recipients of the BNT162b2 mRNA COVID-19 vaccine in Mexico: a nationwide descriptive study. Clin Immunol 2021;229:108786. PMID 34147649
120: Garg RK, Paliwal VK. Spectrum of neurological complications following COVID-19 vaccination. Neurol Sci 2022;43(1):3-40. PMID 34719776
121: Gavrielov-Yusim N, Hoshen M, Singer SR, Neumann L, Balicer RD. The weight of MMRV-related febrile convulsions among other clinical factors contributing to febrile convulsions in children. Vaccine 2014;32(39):4954-9. PMID 25075803
122: Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29(46):8279-84. PMID 21907257
123: Gellin BG, Schaffner W. The risk of vaccination--the importance of “negative” studies. N Engl J Med 2001;344(5):372-3. PMID 11172170
124: Gerb J, Becker-Bense S, Zwergal A, Huppert D. Vestibular syndromes after COVID-19 vaccination: A prospective cohort study. Eur J Neurol 2022;29(12):3693-700. PMID 36056895
125: Gherardi RK, Authier FJ. Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Immunol Allergy Clin North Am 2003;23(4):699-712. PMID 14753387
126: Gherardi RK, Authier FJ. Macrophagic myofasciitis: characterization and pathophysiology. Lupus 2012;21(2):184-9. PMID 22235051
127: Gherardi RK, Coquet M, Chérin P, et al. Macrophagic myofasciitis: an emerging entity. Groupe d'Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l'Association Française contre les Myopathies (AFM). Lancet 1998;352(9125):347-52. PMID 9717921
128: Gherardi RK, Coquet M, Chérin P, et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminum hydroxide in muscle. Brain 2001;124(Pt 9):1821-31. PMID 11522584
129: Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics 1975;55(3):342-7. PMID 238178
130: Gopalakrishna G, Mustafa RA, Davenport C, et al. Applying grading of recommendations assessment, development and evaluation (GRADE) to diagnostic tests was challenging but doable. J Clin Epidemiol 2014;67(7):760-8. PMID 24725643
131: Goud R, Lufkin B, Duffy J, et al. Risk of Guillain-Barré syndrome following recombinant zoster vaccine in medicare beneficiaries. JAMA Intern Med 2021;181(12):1623-30. PMID 34724025
132: Greene SK, Kulldorff M, Lewis EM, et al. Near real-time surveillance for influenza vaccine safety: proof-of-concept in the Vaccine Safety Datalink Project. Am J Epidemiol 2010;171(2):177-88. PMID 19965887
133: Griffin MR, Ray WA, Mortimer EA, Fenichel GM, Schaffner W. Risk of seizures after measles-mumps-rubella immunization. Pediatrics 1991;88:881-5. PMID 1945626
134: Grimaldi-Bensouda L, Guillemot D, Godeau B, et al. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. J Intern Med 2014;275:398-408. PMID 24206418
135: Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2017-18 Influenza Season. MMWR Recomm Rep 2017;66(2):1-20. PMID 28841201
136: Gurvich EB. Comparative analysis of the degree of specific humoral immunity, content of serum immunoglobulins and isolation of vaccinia virus in children with post-vaccinal encephalitis after smallpox vaccination. J Hyg Epidemiol Microbiol Immunol 1981;25(3):311-20. PMID 6117594
137: Gurvich EB, Movsesyants AA, Stepenenkova LP. Isolation of vaccinia virus from children with postvaccinal encephalitis at late intervals after vaccination. Acta Virol 1975;19(1):92. PMID 235206
138: Gurvich EB, Vilesova IS. Vaccinia virus in postvaccinal encephalitis. Acta Virol 1983;27(2):154-9. PMID 6135334
139: Haas JW, Bender FL, Ballou S, et al. Frequency of adverse events in the placebo arms of COVID-19 vaccine trials: a systematic review and meta-analysis. JAMA Netw Open 2022;5(1):e2143955. Erratum in: JAMA Netw Open 2022;5(2):e221277. PMID 35040967
140: Halsey NA, Duclos P, Van Damme P, Margolis H. Hepatitis B vaccine and central nervous system demyelinating diseases. Viral Hepatitis Prevention Board. Pediatr Infect Dis J 1999;18:23-4. PMID 9951975
141: Halsey NA, Edwards KM, Dekker CL, et al. Algorithm to assess causality after individual adverse events following immunizations. Vaccine 2012;30(39):5791-8.** PMID 22507656
142: Hanson KE, Goddard K, Lewis N, et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the vaccine safety datalink. JAMA Netw Open 2022;5(4):e228879. PMID 35471572
143: Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008;57(RR-5):1-30. PMID 18528318
144: Harris T, Wong K, Stanford L, Fediurek J, Crowcroft N, Deeks S. Did narcolepsy occur following administration of AS03-adjuvanted A(H1N1) pandemic vaccine in Ontario, Canada? A review of post-marketing safety surveillance data. Euro Surveill 2014;19(36):pii:20900. PMID 25232921
145: Hause AM, Gee J, Johnson T, et al. Anxiety-related adverse event clusters after Janssen COVID-19 vaccination - five U.S. mass vaccination sites, April 2021. MMWR Morb Mortal Wkly Rep 2021;70(18):685-8. PMID 33956781
146: Hemachudha T, Griffin DE, Chen WW, Johnson RT. Immunologic studies of rabies vaccination-induced Guillain-Barré syndrome. Neurology 1988a;38(3):375-8. PMID 2450302
147: Hemachudha T, Griffin DE, Johnson RT, Giffels JJ. Immunologic studies of patients with chronic encephalitis induced by post-exposure Semple rabies vaccine. Neurology 1988b;38(1):42-4. PMID 2447520
148: Hernan MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004;63(5):838-42. PMID 15365133
149: Hidalgo H, Kallweit U, Mathis J, Bassetti CL. Post tick-borne encephalitis virus vaccination narcolepsy with cataplexy. Sleep 2016;39(10):1811-4. PMID 27397572
150: Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58(5):295-300.** PMID 14283879
151: Hinman AR, Thacker SB. Invited commentary on "The Cutter incident: poliomyelitis following formaldehyde-inactivated poliovirus vaccination in the United States during the spring of 1955. II. Relationship of poliomyelitis to Cutter vaccine." Am J Epidemiol 1995;142:107-40.
152: Hippisley-Cox J, Patone M, Mei XW, et al. Risk of thrombocytopenia and thromboembolism after COVID-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study. BMJ 2021;374:n1931. PMID 34446426
153: Hocine MN, Farrington CP, Touzé E, et al. Hepatitis B vaccination and first central nervous system demyelinating events: reanalysis of a case-control study using the self-controlled case series method. Vaccine 2007;25(31):5938-43. PMID 17597263
154: Hoeve CE, Gadroen K, Kwa MSG, van Haren A, Sturkenboom MCJM, Straus SMJM. Fatal outcomes following immunization errors as reported to the EudraVigilance: A case series. Vaccine 2020;38(15):3086-95. PMID 32147297
155: Hoftberger R, Leisser M, Bauer J, Lassmann H. Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis ? Acta Neuropathol Commun 2015;3:80. PMID 26637427
156: Holmgren B, Lindblom U. Neurological complications after smallpox vaccination. Acta Med Scand Suppl 1966;464:105-12. PMID 5229006
157: Honda H, Shimizu Y, Rutter M. No effect of MMR withdrawal on the incidence of autism: a total population study. J Child Psychol Psychiatry 2005;46(6):572-9. PMID 15877763
158: Howson CP, Howe CJ, Fineberg HV, editors. Adverse effects of pertussis and rubella vaccines. Washington, DC, National Academy Press, 1991:86-124.
159: Hughes R, Rees J, Smeeton N, Winer J. Vaccines and Guillain-Barré syndrome. Lancet 1996;312:1475-6. PMID 8664637
160: Hughes RA, Charlton J, Latinovic R, Gulliford MC. No association between immunization and Guillain-Barré syndrome in the United Kingdom, 1992 to 2000. Arch Intern Med 2006;166(12):1301-4. PMID 16801513
161: Hurwitz ES, Schonberger LB, Nelson DB, Holman RC. Guillain-Barré syndrome and the 1978-1979 influenza vaccine. N Engl J Med 1981;304(26):1557-61. PMID 7231501
162: Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C. Post-vaccination encephalomyelitis: literature review and illustrative case. J Clin Neurosci 2008;15(12):1315-22. PMID 18976924
163: Institute of Medicine. Immunization Safety Review: Measles-mumps-rubella vaccine and autism. Stratton K, Gable A, Shetty P, McCormick M, editors. Washington, DC: National Academy Press; 2001. PMID 25057557
164: Institute of Medicine. Immunization safety review: vaccines and autism. Washington, DC: National Academy Press, 2004. PMID 20669467
165: Institute of Medicine. Adverse effects of vaccines: evidence and causality. Washington, DC: National Academies Press, 2011:390-2. PMID 24624471
166: Jabagi MJ, Botton J, Bertrand M, et al. Myocardial infarction, stroke, and pulmonary embolism after BNT162b2 mRNA COVID-19 vaccine in people aged 75 years or older. JAMA 2022;327(1):80-2. PMID 34807248
167: Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2 - preliminary report. N Engl J Med 2020;383(20):1920-31. PMID 32663912
168: Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine 2009;27(34):4656-61. PMID 19520201
169: Jaiiaroensup W, Lang J, Thipkong P, et al. Safety and efficacy of purified vero cell rabies vaccine given intramuscularly and intradermally. (Results of a prospective randomized trial). Vaccine 1998;16(16):1559-62. PMID 9711804
170: Jennings AD, Gibson CA, Miller BR, et al. Analysis of a yellow fever virus isolated from a fatal case of vaccine-associated human encephalitis. J Infect Dis 1994;169(3):512-8. PMID 7908925
171: Joellenbeck L, Zwanziger LL, Durch JS, Strom BL, editors. The anthrax vaccine: Is it safe? Does it work? Washington, DC: National Academy Press, 2002.
172: Johnson R. Smallpox: The threat of bioterrorism and the risk of the vaccine. Neurology 2003;60(8):1228-9. PMID 12707420
173: Juurlink DN, Stukel TA, Kwong J, et al. Guillain-Barré syndrome after influenza vaccination in adults: a population-based study. Arch Intern Med 2006;13;166(20):2217-21. PMID 17101939
174: Kaplan JF, Katona P, Hurwitz ES, Schonberger LB. Guillain-Barré syndrome in the United States, 1979-1980 and 1980-1981. Lack of an association with influenza vaccination. JAMA 1982;248(6):698-700. PMID 7097920
175: Karron RA, Key NS, Sharfstein JM. Assessing a Rare and Serious Adverse Event Following Administration of the Ad26.COV2.S Vaccine. JAMA 2021;325(24):2445-7. PMID 33929484
176: Kaur SP, Gupta V. COVID-19 vaccine: a comprehensive status report. Virus Res 2020;288:198114. PMID 32800805
177: Keech C, Albert G, Cho I, et al. Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med 2020;383(24):2320-32. PMID 32877576
178: Kengsakul K, Sathirapongsasuti K, Punyagupta S. Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection. J Med Assoc Thai 2002;85:131-4. PMID 12075714
179: Kew O, Morris-Glasgow V, Landaverde M, Burns C, et al. Outbreak of poliomyelitis inHispaniola associated with circulating type 1 vaccine-derived poliovirus. Science 2002;296(5566):356-9. PMID 11896235
180: Kharbanda EO, Vazquez-Benitez G. COVID-19 mRNA vaccines during pregnancy: new evidence to help address vaccine hesitancy. JAMA 2022;327(15):1451-3. PMID 35325030
181: Khromava AY, Eidex RB, Weld LH, et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005;23(25):3256-63. PMID 15837230
182: Kinnunen E, Farkkila M, Hovi T, et al. Incidence of Guillain-Barré syndrome during a nationwide oral poliovirus vaccine campaign. Neurology 1989;39(8):1034-6. PMID 2788248
183: Kinnunen E, Junttila O, Haukka J, Hovi T. Nationwide oral poliovirus vaccination campaign and the incidence of Guillain-Barré syndrome. Am J Epidemiol 1998;147(1):69-73. PMID 9440401
184: Kitchener S. Viscerotropic and neurotropic disease following vaccination with the 17D yellow fever vaccine, ARILVAX. Vaccine 2004;22(17-18):2103-5. PMID 15149765
185: Klein NP, Fireman B, Yih WK, et al. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics 2010;126(1):e1-8. PMID 20587679
186: Klein NP, Lewis E, Baxter R, et al. Measles-containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics 2012;129(5):809-14. PMID 22473362
187: Kretzschmar M, Wallinga J, Teunis P, Xing S, Mikolajczyk R. Frequency of adverse events after vaccination with different vaccinia strains. PLoS Medicine 2006;3(8):e272. PMID 16933957
188: Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-15):1-48. PMID 17136024
189: Krzywicka K, van de Munckhof A, Sánchez van Kammen M, et al. Age-stratified risk of cerebral venous sinus thrombosis after SARS-CoV-2 vaccination. Neurology 2022;98(7):e759-68. PMID 34921101
190: Kuo TY, Lin MY, Coffman RL, et al. Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19. Sci Rep 2020;10(1):20085. PMID 33208827
191: Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol 2014;71(12):1506-13. PMID 25329096
192: Lanska DJ. Journal Club: Hepatitis B vaccination and the risk of multiple sclerosis. In: Gilman S, editor. MedLink Neurology. San Diego, CA: MedLink Corporation, 2001.
193: Lanska DJ. Grand Rounds: Aspects of the history of poliomyelitis in the United States. In: Gilman S, editor. MedLink Neurology. San Diego, CA: MedLink Corporation, 2007.
194: Lanska DJ. Grand Rounds: Needle-stick syncope. In: Gilman S, editor. MedLink Neurology. San Diego, CA: MedLink Corporation, 2010.
195: Lanska DJ. Grand Rounds: In patients with multiple sclerosis, what is the etiopathogenic role of varicella zoster virus, and can Zostavax be used safely? In: Gilman S, editor. MedLink Neurology. San Diego, CA: MedLink Corporation, 2012.
196: Lanska DJ. Neurologic complications of smallpox vaccination. In: Greenamyre T, editor. MedLink Neurology. San Diego, CA: MedLink Corporation, 2014a.
197: Lanska DJ. Jonas Salk. In: Aminoff MJ, Daroff RB, editors. Encyclopedia of the Neurological Sciences. 2nd ed. Oxford: Academic Press/Elsevier, 2014b;4:85-7.
198: Lanska DJ. Albert Sabin. In: Aminoff MJ, Daroff RB, edtiors. Encyclopedia of the Neurological Sciences. 2nd ed. Oxford: Academic Press/Elsevier, 2014c;4:82-3.
199: Lanska JR, Lanska MJ. Grand rounds: MMR vaccine and autism: 15 years later. In: Greenamyre T, editor. MedLink Neurology. San Diego, CA: MedLink Corporation, 2014.
200: LaRussa PS, Edwards KM, Dekker CL, et al. Understanding the role of human variation in vaccine adverse events: the Clinical Immunization Safety Assessment Network. Pediatrics 2011;127 Suppl 1:S65-73. PMID 21502239
201: Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998;339(25):1797-802. PMID 9854114
202: Latimer FR, Webster JE, Gurdjian ES. Neurological complications of rabies vaccine: Report of Two Cases. AMA Arch Neur Psych 1951;65(1):16-28. PMID 14782764
203: Li X, Raventós B, Roel E, et al. Association between COVID-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis. BMJ 2022;376:e068373. PMID 35296468
204: Libbey JE, Fujinami RS. Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. Vaccine 2011;29(17):3356-62. PMID 20850537
205: Lindsey NP, Schroeder BA, Miller ER, Braun MM, et al. Adverse event reports following yellow fever vaccination. Vaccine 2008;26(48):6077-82. PMID 18809449
206: Lindsey NP, Rabe IB, Miller ER, Fischer M, Staples JE. Adverse event reports following yellow fever vaccination, 2007-13. J Travel Med 2016;23(5). PMID 27378369
207: Loebermann M, Winkelmann A, Hartung HP, Hengel H, Reisinger EC, Zettl UK. Vaccination against infection in patients with multiple sclerosis. Nat Rev Neurol 2012;8(3):143-51. PMID 22270022
208: Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 2020;396(10255):887-97. PMID 32896291
209: Ma SJ, Xiong YQ, Jiang LN, Chen Q. Risk of febrile seizure after measles-mumps-rubella-varicella vaccine: A systematic review and meta-analysis. Vaccine 2015;33(31):3636-49. PMID 26073015
210: Macartney KK, Gidding HF, Trinh L, et al. Febrile seizures following measles and varicella vaccines in young children in Australia. Vaccine 2015;33(11):1412-7. PMID 25444797
211: Macartney K, Gidding HF, Trinh L, et al. Evaluation of combination measles-mumps-rubella-varicella vaccine introduction in Australia. JAMA Pediatr 2017;171(10):992-8. PMID 28806450
212: MacDonald SE, Dover DC, Simmonds KA, Svenson LW. Risk of febrile seizures after first dose of measles-mumps-rubella-varicella vaccine: a population-based cohort study. CMAJ 2014;186(11):824-9. PMID 24914115
213: MacNeil JR, Rubin L, McNamara L, Briere EC, Clark TA, Cohn AC. Use of MenACWY-CRM vaccine in children aged 2 through 23 months at increased risk for meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, 2013. MMWR Morb Mortal Wkly Rep 2014;63(24):527-30. PMID 24941332
214: MacNeil JR, Rubin L, Folaranmi T, Ortega-Sanchez IR, Patel M, Martin SW. Use of serogroup B meningococcal vaccines in adolescents and young adults: recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep 2015;64(41):1171-6. PMID 26492381
215: Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347(19):1477-82. PMID 12421889
216: Magnus MC, Örtqvist AK, Dahlqwist E, et al. Association of SARS-CoV-2 vaccination during pregnancy with pregnancy outcomes. JAMA 2022;327(15):1469-77. PMID 35323851
217: Manning SE, Rupprecht CE, Fishbein D, et al. Human Rabies Prevention — United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2008;57(RR-3):1-28. PMID 18496505
218: Marin M, Broder KR, Temte JL, Snider DE, Seward JF; Centers for Disease Control and Prevention (CDC). Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59(RR-3):1-12. PMID 20448530
219: Marquez Loza AM, Holroyd KB, Johnson SA, Pilgrim DM, Amato AA. Guillain-Barré syndrome in the placebo and active arms of a COVID-19 vaccine clinical trial: temporal associations do not imply causality. Neurology 2021;96(22):1052-4. PMID 33824169
220: Marshall E. A shadow falls on hepatitis B vaccination effort. Science 1998;281(5377):630-1. PMID 9714670
221: McDonald JC, Moore DL, Quennec P. Clinical and epidemiological features of mumps meningoencephalitis and possible vaccine-related disease. Pediatr Infect Dis J 1989;8(11):751-5. PMID 2594449
222: McIntosh AM, McMahon J, Dibbens LM, et al. Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study. Lancet Neurol 2010;9(6):592-8. PMID 20447868
223: McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention. Prevention of Measles, Rubella, Congenital Rubella Syndrome, and Mumps, 2013: Summary Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013;62(RR-04):1-34. PMID 23760231
224: McMahon AW, Eidex RB, Marfin AA, et al. Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 2007;25:1727-34. PMID 17240001
225: Melekhin VV, Karem KL, Damon IK, Bloch KC. Encephalitis after secondary smallpox vaccination. Clin Infect Dis 2009;48(1):e1-2. PMID 19025490
226: Melen K, Partinen M, Tynell J, et al. No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland. PLoS One 2013;8(8):e68402. PMID 23950869
227: Mikaeloff Y, Caridade G, Assi S, Tardieu M, Suissa S; KIDSEP study group of the French Neuropaediatric Society. Hepatitis B vaccine and risk of relapse after a first childhood episode of CNS inflammatory demyelination. Brain 2007a;130:1105-10. PMID 17276994
228: Mikaeloff Y, Caridade G, Rossier M, Suissa S, Tardieu M. Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis. Arch Pediatr Adolesc Med 2007b;161(12):1176-82. PMID 18056563
229: Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2009;72(10):873-80. PMID 18843097
230: Miller E, Andrews N, Stowe J, Grant A, Waight P, Taylor B. Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United Kingdom. Am J Epidemiol 2007;165(6):704-9. PMID 17204517
231: Miller E, Andrews N, Stellitano L, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013;346:f794. PMID 23444425
232: Miravalle A, Roos KL. Encephalitis complicating smallpox vaccination. Arch Neurol 2003;60:925-8.** PMID 12873847
233: Miravalle A, Biller J, Silva E, Conneely M, O’Keefe P. Acute disseminated encephalomyelitis: yellow fever vaccination. Arq Neuro Psiquiatr 2009;67:710-1. PMID 19722058
234: Miravalle AA, Schreiner T. Neurologic complications of vaccinations. Handb Clin Neurol 2014;121:1549-57. PMID 24365435
235: Mohseni Afshar Z, Sharma A, Babazadeh A, et al. A review of the potential neurological adverse events of COVID-19 vaccines. Acta Neurol Belg 2022;1-36. PMID 36385246
236: Monfries N, Goldman RD. Prophylactic antipyretics for prevention of febrile seizures following vaccination. Can Fam Physician 2017;63(2):128-30. PMID 28209678
237: Montplaisir J, Petit D, Quinn MJ, et al. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS One 2014;9(9):e108489. PMID 25264897
238: Munoz FM, Eckert LO, Katz MA, et al. Key terms for the assessment of the safety of vaccines in pregnancy: results of a global consultative process to initiate harmonization of adverse event definitions. Vaccine 2015;33(47):6441-52.** PMID 26387433
239: Mustafa MM, Weitman SD, Winick NJ, Bellini WJ, Timmons CF, Siegel JD. Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature. Clin Infect Dis 1993;16:654-60. PMID 8323578
240: Nabizadeh F, Noori M, Rahmani S, Hosseini H. Acute disseminated encephalomyelitis (ADEM) following COVID-19 vaccination: A systematic review. J Clin Neurosci 2023;111:57-70. PMID 36963124
241: Naeem FN, Hasan SFS, Ram MD, Waseem S, Ahmed SH, Shaikh TG. The association between SARS-CoV-2 vaccines and transverse myelitis: a review. Ann Med Surg (Lond) 2022;79:103870. PMID 35702684
242: Nabe-Nielsen J, Walter B. Unilateral total deafness as a complication of the measles-mumps-rubella vaccination. Scand Audiol Suppl 1988;30:69-70. PMID 3227284
243: Nathanson N, Langmuir AD. The Cutter incident: poliomyelitis following formaldehyde-inactivated poliovirus vaccination in the United States during the spring of 1955. I. Background, and II. Relationship of poliomyelitis to Cutter vaccine. Am J Hyg 1963;78:16-60. PMID 14043543
244: Nickells J, Cannella M, Droll DA, Liang Y, Wold WS, Chambers TJ. Neuroadapted yellow fever virus strain 17D: a charged locus in domain III of the E protein governs heparin binding activity and neuroinvasiveness in the SCID mouse model. J Virol 2008;82(24):12510-9. PMID 18842715
245: Nicoll A, Elliman D, Ross E. MMR vaccination and autism 1998. BMJ 1998;316(7133):715-6. Erratum in: BMJ 1998;316(7134):796. PMID 9529392
246: Nieminen TA, Kivekäs I, Artama M, Nohynek H, Kujansivu J, Hovi P. Sudden hearing loss following vaccination against COVID-19. JAMA Otolaryngol Head Neck Surg 2023;149(2):133-40. PMID 36520464
247: Niesen MJM, Pawlowski C, O'Horo JC, et al. Surveillance of safety of 3 doses of COVID-19 mRNA vaccination using electronic health records. JAMA Netw Open 2022;5(4):e227038. PMID 35420661
248: Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One 2012;7(3):e33536. PMID 22470453
249: Novy J, Catarino CB, Chinthapalli K, et al. Another cause of vaccine encephalopathy: a case of Angelman syndrome. Eur J Med Genet 2012;55(5):338-41. PMID 22342448
250: Offit PA. The Cutter incident, 50 years after. N Engl J Med 2005a;352:1411-2. PMID 15814877
251: Offit PA. The Cutter incident: how America's first polio vaccine led to the growing vaccine crisis. New Haven: Yale University Press, 2005b.**
252: O'Flanagan D, Barret AS, Foley M, et al. Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro Surveill 2014;19(17):15-25. PMID 24821121
253: Ostovan VR, Sahraian MA, Karazhian N, Rostamihosseinkhani M, Salimi M, Marbooti H. Clinical characteristics, radiological features and prognostic factors of transverse myelitis following COVID-19 vaccination: a systematic review. Mult Scler Relat Disord 2022;66:104032. PMID 35858499
254: Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-84. PMID 15930418
255: Ozonoff A, Nanishi E, Levy O. Bell's palsy and SARS-CoV-2 vaccines. Lancet Infect Dis 2021;21(4):450-2. PMID 33639103
256: Palaiodimou L, Stefano MI, Katsanos AH, et al. Cerebral venous sinus thrombosis and thrombotic events after vector-based COVID-19 vaccines: a systematic review and meta-analysis. Neurology 2021;97(21):e2136-47. PMID 34610990
257: Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3):e33723. PMID 22470463
258: Patton ME, Stephens D, Moore K, MacNeil JR. Updated Recommendations for Use of MenB-FHbp Serogroup B Meningococcal Vaccine - Advisory Committee on Immunization Practices, 2016. MMWR Morb Mortal Wkly Rep 2017;66(19):509-13. PMID 28520709
259: Payne DC, Rose CE Jr, Kerrison J, Aranas A, Duderstadt S, MacNeil MM. Anthrax vaccination and risk of optic neuritis in the United States military, 1998-2003. Arch Neurol 2006;63:871-5. PMID 16769869
260: Peate WF. Prevention of vaccinia infection in a laboratory worker. Mil Med 2007;172(10):1117-8. PMID 17985778
261: Peers JH. Allergic encephalitis and its possible relationship to human disease. Am J Clin Pathol 1950;20(6):503-14. PMID 15432347
262: Peng J, Lu S, Zhu Z, Zhang M, Hu Q, Fang Y. Safety comparison of four types of rabies vaccines in patients with WHO category II animal exposure: an observation based on different age groups. Medicine (Baltimore) 2016;95(47):e5049. PMID 27893654
263: Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N. Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. J Intern Med 2014;275(2):172-90. PMID 24134219
264: Peterson LJ, Benson WW, Graebe FO. Vaccination-induced poliomyelitis in Idaho: preliminary report of experience with Salk poliomyelitis vaccine. JAMA 1955;159(4):241-4. PMID 13251869
265: Piyasirisilp S, Hemachudha T. Neurological adverse events associated with vaccination. Curr Opin Neurol 2002;15(3):333-8. PMID 12045734
266: Piyasirisilp S, Hemachudha T, Griffin DE. B-cell responses to myelin basic protein and its epitopes in autoimmune encephalomyelitis induced by Semple rabies vaccine. J Neuroimmunol 1999;98:96-104. PMID 10430042
267: Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020;383(27):2603-15. PMID 33301246
268: Polakowski LL, Sandhu SK, Martin DB, et al. Chart-confirmed guillain-barre syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010. Am J Epidemiol 2013;178(6):962-73. PMID 23652165
269: Poon TP, Tchertkoff V, Win H. Subacute measles encephalitis with AIDS diagnosed by fine needle aspiration biopsy. A case report. Acta Cytol 1998;42:729-33. PMID 9622696
270: Prevots DR, Burr RK, Sutter RW, Murphy TV; Advisory Committee on Immunization Practices. Poliomyelitis Prevention in the United States: Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Weekly Rep 2000;49(RR-5):1-22. PMID 15580728
271: Qasrawi SQ, Albarrak AM, Alharbi AS, et al. Narcolepsy in Saudi patients before and after the 2009 H1N1 vaccination. The experience of 2 referral centers. Saudi Med J 2017;38(12):1196-200. PMID 29209667
272: Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 2021;396(10267):1979-93. PMID 33220855
273: Rantala H, Cherry JD, Shields WD, Uhari M. Epidemiology of Guillain-Barré syndrome in children: relationship of oral polio vaccine administration to occurrence. J Pediatr 1994;124(2):220-3. PMID 8301426
274: Rath B, Gidudu JF, Anyoti H, et al. Facial nerve palsy including Bell's palsy: Case definitions and guidelines for collection, analysis, and presentation of immunisation safety data. Vaccine 2017;35(15):1972-83.** PMID 27235092
275: Reif DM, McKinney BA, Motsinger AA, et al. Genetic basis for adverse events after smallpox vaccination. J Infect Dis 2008;198(1):16-22. Erratum in: J Infect Dis 2008;198(5):796. PMID 18454680
276: Renoud L, Khouri C, Revol B, et al. Association of facial paralysis with mRNA COVID-19 vaccines: a disproportionality analysis using the World Health Organization Pharmacovigilance Database. JAMA Intern Med 2021;181(9):1243-5. PMID 33904857
277: Reyes IS, Hsieh DT, Laux LC, Wilfong AA. Alleged cases of vaccine encephalopathy rediagnosed years later as Dravet syndrome. Pediatrics 2011;128(3):e699-702. PMID 21844054
278: Ribeiro AF, Guedes BF, Sulleiman JMAH, et al. Neurologic disease after Yellow Fever vaccination, São Paulo, Brazil, 2017-2018. Emerg Infect Dis 2021;27(6):1577-87. PMID 34014156
279: Rivers TM, Schwentker FF. Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. J Exp Med 1935;61(5):689-702. PMID 19870385
280: Rockoff A, Spigland I, Lorenstein B, Rose AL. Postvaccinal encephalomyelitis without cutaneous vaccination reaction. Ann Neurol 1979;5(1):99-101. PMID 34358
281: Roos KL, Eckerman NL. The smallpox vaccine and postvaccinal encephalitis. Semin Neurol 2002;22(1):95-8. PMID 12170398
282: Roscelli JD, Bass JW, Pang L. Guillain-Barré syndrome and influenza vaccination in the US Army, 1980-1988. Am J Epidemiol 1991;133(9):952-5. PMID 2028981
283: Rosch RE, Farquhar M, Gringras P, Pal DK. Narcolepsy following yellow fever vaccination: a case report. Front Neurol 2016;7:130. PMID 27559330
284: Rose C, Viget N, Copin MC, et al. Myosite aiquë sévère et transitoire après vaccination ourlienne (Imovax-Oreillons). [Article in French]. Therapie 1996;51:87. PMID 8762226
285: Ross RT, Nicolle LE, Cheang M. The varicella zoster virus: a pilot trial of a potential therapeutic agent in multiple sclerosis. J Clin Epidemiol 1997;50(1):63-8. PMID 9048691
286: Rothman KJ. Causes. Am J Epidemiol 1976;104(6):587-92. PMID 998606
287: Rowhani-Rahbar A, Klein NP, Lewis N, et al. Immunization and Bell’s palsy in children: a case-centered analysis. Am J Epidemiol 2012;175:878-85. PMID 22411861
288: Rutschmann OT, McCrory DC, Matchar DB; Immunization Panel of the Multiple Sclerosis Council for Clinical Practice Guidelines. Immunization and MS: a summary of published evidence and recommendations. Neurology 2002;59:1837-43. PMID 12499473
289: Sadoff J, Le Gars M, Shukarev G, et al. Interim results of a phase 1-2a trial of Ad26.COV2.S Covid-19 vaccine. N Engl J Med 2021;384(19):1824-35. PMID 33440088
290: Salsone M, Signorelli C, Oldani A, et al. NEURO-COVAX: An Italian population-based study of neurological complications after COVID-19 vaccinations. Vaccines (Basel) 2023;11(10):1621. PMID 37897023
291: Sanchez van Kammen M, Heldner MR, Brodard J, et al. Frequency of thrombocytopenia and platelet factor 4/heparin antibodies in patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic. JAMA 2021a;326(4):332-8. PMID 34213527
292: Sanchez van Kammen M, Aguiar de Sousa D, Poli S, et al. Characteristics and outcomes of patients with cerebral venous sinus thrombosis in SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia. JAMA Neurol 2021b;78(11):1314-23. PMID 34581763
293: Sandovnick AD, Scheifele DW. School-based hepatitis B vaccination programme and adolescent multiple sclerosis. Lancet 2000;355:549-50. PMID 10683009
294: Schillie S, Vellozzi C, Reingold A, et al. Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2018;67(1):1-31. PMID 29939980
295: Schink T, Holstiege J, Kowalzik F, Zepp F, Garbe E. Risk of febrile convulsions after MMRV vaccination in comparison to MMR or MMR+V vaccination. Vaccine 2014;32(6):645-50. PMID 24374498
296: Schnitzer ME. Estimands and estimation of COVID-19 vaccine effectiveness under the test-negative design: connections to causal inference. Epidemiology 2022;33(3):325-33. PMID 35239518
297: Schuller E, Klingler A, Dubischar-Kastner K, Dewasthaly S, Müller Z. Safety profile of the Vero cell-derived Japanese encephalitis virus (JEV) vaccine IXIARO®. Vaccine 2011;29(47):8669-76. PMID 21907747
298: Scott TF. Postinfectious and vaccinal encephalitis. Med Clin North Am 1967;51(3):701-17. PMID 4381565
299: Scutelnic A, van de Munckhof A, Krzywicka K, et al. Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19. Eur Stroke J 2023;8(4):1001-10. PMID 37434312
300: See I, Su JR, Lale A, et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA 2021;325(24):2448-56. PMID 33929487
301: Sejvar JJ, Kohl KS, Bilynsky R, et al. Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2007;25(31):5771-92.** PMID 17570566
302: Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, Lane JM. Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004. JAMA 2005;294(21):2744-50.** PMID 16333010
303: Shakouri A, Compalati E, Lang DM, Khan DA. Effectiveness of Helicobacter pylori eradication in chronic urticaria: evidence-based analysis using the Grading of Recommendations Assessment, Development, and Evaluation system. Curr Opin Allergy Clin Immunol 2010;10(4):362-9. PMID 20610979
304: Shapiro Ben David S, Potasman I, Rahamim-Cohen D. Rate of recurrent Guillain- Barré syndrome after mRNA COVID-19 vaccine BNT162b2. JAMA Neurol 2021;78(11):1409-11. PMID 34468703
305: Sharifian-Dorche M, Bahmanyar M, Sharifian-Dorche A, Mohammadi P, Nomovi M, Mowla A. Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review. J Neurol Sci 2021;428:117607. PMID 34365148
306: Shemer A, Pras E, Einan-Lifshitz A, Dubinsky-Pertzov B, Hecht I. Association of COVID-19 vaccination and facial nerve palsy: a case-control study. JAMA Otolaryngol Head Neck Surg 2021;147(8):739-43. PMID 34165512
307: Shimonovich M, Pearce A, Thomson H, Keyes K, Katikireddi SV. Assessing causality in epidemiology: revisiting Bradford Hill to incorporate developments in causal thinking. Eur J Epidemiol 2021;36(9):873-87.** PMID 33324996
308: Shoenfeld Y, Agmon-Levin N. ‘ASIA’ - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 2011;36(1):4-8. PMID 20708902
309: Siegler JE, Klein P, Yaghi S, et al. Cerebral vein thrombosis with vaccine-induced immune thrombotic thrombocytopenia. Stroke 2021;52(9):3045-53. PMID 34304601
310: Sievers EJ, Heyneman CA. Relationship between vaccinations and multiple sclerosis. Ann Pharmacother. 2002;36(1):160-2. PMID 11816245
311: Silveira CM, Salisbury DM, de Quadros CA. Measles vaccination and Guillain-Barré syndrome. Lancet 1997;349:14-6. PMID 8988116
312: Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues LC, Smith PG, Hall AJ. MMR vaccination and pervasive developmental disorders: a case-control study. Lancet 2004;364(9438):963-9. PMID 15364187
313: Soares Santos D, Santos A, Rebelo O, Santos RM. Macrophagic myofasciitis: a challenging diagnosis. BMJ Case Rep 2018;2018. PMID 29973411
314: Sood SC, Singh H. Acute disseminated encephalo-myelitis complicating smallpox. Indian Pediatr 1967;4(9):361-3. PMID 5589489
315: Spencer JP, Trondsen Pawlowski RH, Thomas S. Vaccine adverse events: separating myth from reality. Am Fam Physician 2017;95(12):786-94. PMID 28671426
316: Sriram S, Steiner I. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 2005;58(6):939-45. PMID 16315280
317: Staples JE, Gershman M, Fischer M; Centers for Disease Control and Prevention (CDC). Yellow Fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59(RR-7):1-27. PMID 20671663
318: Stewart BJ, Prabhu PU. Reports of sensorineural deafness after measles-mumps-rubella immunization. Arch Dis Child 1993;69(1):153-4. PMID 8024302
319: Stowe J, Andrews N, Wise L, Miller E. Investigation of the temporal association between Guillain-Barré syndrome and influenza vaccine and influenza-like illness using the UK General Practice Research Database. Am J Epidemiol 2009;169(3):382-8. PMID 19033158
320: Stowe J, Andrews N, Kosky C, et al. Risk of narcolepsy after AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in adults: a case-coverage study in England. Sleep 2016;39(5):1051-7. PMID 26856903
321: Stratton K, Gable A, Shetty P, McCormick M, editors. Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention, Institute of Medicine. Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism. Washington, DC: National Academy Press, 2001.
322: Stratton K, Almario D, McCormick MC, editors. Immunization safety review: hepatitis B vaccine and demyelinating neurological disorders. Washington, DC: National Academies Press, 2002.
323: Stratton K, Ford A, Rusch E, Clayton EW, editors. Adverse effects of vaccines: evidence and causality. Washington, DC: National Academy Press, 2012.
324: Stratton KR, Howe CJ, Johnston RB Jr. Adverse events associated with childhood vaccines other than pertussis and rubella. Summary of a report from the Institute of Medicine. JAMA 1994;271(20):1602-5. PMID 8182813
325: Strauss B, Bigham M. Does measles-mumps-rubella (MMR) vaccination cause inflammatory bowel disease and autism? Can Commun Dis Rep 2001;27(8):65-72. PMID 11338656
326: Sutter RW, Patriaca PA, Suleman AJ, Brogan S, Cochi SL, El-Bualy MS. Attributable risk of DTP (diphtheria and tetanus toxoids and pertussis vaccine) injection in provoking paralytic poliomyelitis during a large outbreak in Oman. J Infect Dis 1992;165(3):444-9. PMID 1538150
327: Swiglo BA, Murad MH, Schünemann HJ, et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 2008;93(3):666-73. PMID 18171699
328: Tam JS, Capeding MR, Lum LC, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr Infect Dis J 2007;26(7):619-28. PMID 17596805
329: Tamaki A, Cabrera CI, Li S, et al. Incidence of Bell palsy in patients with COVID-19. JAMA Otolaryngol Head Neck Surg 2021;147(8):767-8. PMID 34165518
330: Tapiainen T, Prevots R, Izurieta HS, et al. Aseptic meningitis: case definition and guidelines for collection, analysis and presentation of immunization safety data. Vaccine 2007;25(31):5793-802.** PMID 17574313
331: Tau N, Yahav D, Shepshelovich D. Vaccine safety - is the SARS-CoV-2 vaccine any different? Hum Vaccin Immunother 2021;17(5):1322-5. PMID 33270474
332: Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ. 2002;324(7334):393-6. PMID 11850369
333: Tebas P, Yang S, Boyer JD, et al. Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: a preliminary report of an open-label, Phase 1 clinical trial. EClinicalMedicine 2021;31:100689. PMID 33392485
334: Terzin AL, Masic M, Vukovic B, Mudric V. A virological study of post-vaccinal encephalitis. J Hyg (Lond) 1974;72(2):169-72. PMID 4150692
335: Thames AH, Wolniak KL, Stupp SI, Jewett MC. Principles learned from the international race to develop a safe and effective COVID-19 vaccine. ACS Cent Sci 2020;6(8):1341-7. PMID 32868999
336: Tondo G, Virgilio E, Naldi A, Bianchi A, Comi C. Safety of COVID-19 Vaccines: Spotlight on Neurological Complications. Life (Basel) 2022;12(9):1338. PMID 36143376
337: Top KA, MacDonald NE. Combination measles-mumps-rubella-varicella vaccination and the risk of febrile seizure. CMAJ 2014;186(11):812-3. PMID 24982299
338: Tosti ME, Traversa G, Bianco E, Mele A. Multiple sclerosis and vaccination against hepatitis B: analysis of risk benefit profile. Ital J Gastroenterol Hepatol 1999;31(5):388-91. PMID 10470598
339: Tro-Baumann B, von Spiczak S, Lotte J, et al. A retrospective study of the relation between vaccination and occurrence of seizures in Dravet syndrome. Epilepsia 2011;52(1):175-8. PMID 21219303
340: Tu TM, Yi SJ, Koh JS, et al. Incidence of cerebral venous thrombosis following SARS-CoV-2 infection vs mRNA SARS-CoV-2 vaccination in Singapore. JAMA Netw Open 2022;5(3):e222940. PMID 35297971
341: Uchiyama T, Kurosawa M, Inaba Y. MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 2007;37(2):210-7. PMID 16865547
342: Uhari M, Rantala H, Niemelä M. Cluster of childhood Guillain-Barré cases after an oral poliovaccine campaign. Lancet 1989;2:440-1. PMID 2569613
343: Ulrich AK, Sundaram ME, Osterholm MT. Rare sudden sensorineural hearing loss potentially associated with COVID-19 vaccination does not outweigh the benefit of COVID-19 vaccines. JAMA Otolaryngol Head Neck Surg 2022;148(4):315-6. PMID 35201285
344: Van Goethem N, Vandromme M, Van Oyen H, et al. Severity of infection with the SARS-CoV-2 B.1.1.7 lineage among hospitalized COVID-19 patients in Belgium. PLoS One 2022;17(6):e0269138. PMID 35657787
345: VanderWeele TJ. Invited commentary: the continuing need for the sufficient cause model today. Am J Epidemiol 2017;185(11):1041-3. PMID 28535245
346: Velentgas P, Amato AA, Bohn RL, et al. Risk of Guillain-Barré syndrome after meningococcal conjugate vaccination. Pharmacoepidemiol Drug Saf 2012;21(12):1350-8. PMID 22807266
347: Verbeek NE, van der Maas NA, Sonsma AC, et al. Effect of vaccinations on seizure risk and disease course in Dravet syndrome. Neurology 2015;85(7):596-603. PMID 26203087
348: Verbeek NE, Jansen FE, Vermeer-de Bondt PE, et al. Etiologies for seizures around the time of vaccination. Pediatrics 2014;134(4):658-66. PMID 25225143
349: Verbeek NE, van der Maas NA, Jansen FE, van Kempen MJ, Lindhout D, Brilstra EH. Prevalence of SCN1A-related dravet syndrome among children reported with seizures following vaccination: a population-based ten-year cohort study. PLoS One 2013;8(6):e65758. PMID 23762420
350: Vestergaard M, Hviid A, Madsen KM, et al. MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis. JAMA 2004;292(3):351-7. PMID 15265850
351: von Spiczak S, Helbig I, Drechsel-Baeuerle U, et al. A retrospective population-based study on seizures related to childhood vaccination. Epilepsia 2011;52(8):1506-12. PMID 21692791
352: Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397(10269):99-111. PMID 33306989
353: Wakefield AJ. MMR vaccination and autism. Lancet 1999;354(9182):949-50. PMID 10489978
354: Wakefield AJ, Murch SH, Anthony A. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet 1998;351:637-41. Retraction in: Lancet 2010;375:445. Partial retraction in: Murch SH, Anthony A, Casson DH, Malik M, et al. Lancet 2004a;363:750. PMID 9500320
355: Wakefield AJ, Harvey P, Linnell J. MMR--responding to retraction. Lancet 2004b;363(9417):1327-8. PMID 15094289
356: Walker JL, Schultze A, Tazare J, et al Safety of COVID-19 vaccination and acute neurological events: A self-controlled case series in England using the OpenSAFELY platform. Vaccine 2022;40(32):4479-87. PMID 35715350
357: Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med 2020;383(25):2439-50. PMID 33053279
358: Wan EYF, Chui CSL, Lai FTT, et al. Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study. Lancet Infect Dis 2021;22(1):64-72. PMID 34411532
359: Weibel RE, Caserta V, Benor DE, Evans G. Acute encephalopathy followed by permenant brain injury or death associated with further-attenuated measles vaccines: a review of claims submitted to the National Vaccine Injury Compensation Program. Pediatrics 1998;101:383-7. PMID 9481001
360: Wijnans L, Lecomte C, de Vries C, Weibel D, et al. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine 2013;31(8):1246-54. PMID 23246544
361: Wilson K, Mills E, Ross C, McGowan J, Jadad A. Association of autistic spectrum disorder and the measles, mumps, and rubella vaccine: a systematic review of current epidemiological evidence. Arch Pediatr Adolesc Med 2003;157(7):628-34. PMID 12860782
362: Wong PT, Wong VC. Prevalence and characteristics of vaccination triggered seizures in Dravet Syndrome in Hong Kong: a retrospective study. Pediatr Neurol 2016;58:41-7. PMID 26995069
363: Woo EJ, Mba-Jonas A, Dimova RB, Alimchandani M, Zinderman CE, Nair N. Association of receipt of the Ad26.COV2.S COVID-19 vaccine with presumptive Guillain-Barré syndrome, February-July 2021. JAMA 2021;326(16):1606-13. PMID 34617967
364: World Health Organization. MMR and autism. Wkly Epidemiol Rec 2003;78(4):18.
365: World Health Organization. Rabies vaccines: WHO position paper. Wkly Epidemiol Rec 2010;85(32):309-20.
366: World Health Organization. Information sheet: Observed rate of vaccine reactions: Anthrax vaccines to humans. Geneva: World Health Organization, 2012a.
367: World Health Organization. Information sheet: Observed rate of vaccine reactions: Rabies vaccine. Geneva: World Health Organization, 2012b.
368: World Health Organization. Information sheet: Observed rate of vaccine reactions: Influenza vaccine. Geneva: World Health Organization, 2012c.
369: World Health Organization. Information sheet: Observed rate of vaccine reactions: Measles, mumps and rubella vaccines. Geneva: World Health Organization, 2014a.
370: World Health Organization. Information sheet: Observed rate of vaccine reactions: Polio vaccines. Geneva: World Health Organization, 2014b.
371: World Health Organization. Information sheet: Observed rate of vaccine reactions: Japanese encephalitis vaccine. January 2016. Geneva: World Health Organization, 2016.
372: World Health Organization (WHO). Information sheet: Observed rate of vaccine reactions: Human papilloma virus vaccine. December 2017. Geneva: World Health Organization, 2017a.
373: World Health Organization (WHO). Measles vaccines: WHO position paper - April 2017. Wkly Epidemiol Rec 2017b;92(17): 205-28.
374: World Health Organization (WHO). Rabies vaccines: WHO position paper - April 2018. Wkly Epidemiol Rec 2018;93(16):201-20.
375: World Health Organization. Causality assessment of an adverse event following immunization (AEFI): updated user manual for the revised WHO classification. Second edition. Geneva: World Health Organization, 2019.**
376: Wright JG, Quinn CP, Shadomy S, et al. Use of Anthrax Vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2010;59(RR-6):1-30. PMID 20651644
377: Wyer PC. From MARS to MAGIC: The remarkable journey through time and space of the Grading of Recommendations Assessment, Development and Evaluation initiative. J Eval Clin Pract 2018;24(5):1191-202. PMID 30109760
378: Xia S, Duan K, Zhang Y, et al. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials. JAMA 2020;324(10):951-60. PMID 32789505
379: Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021;21(1):39-51. PMID 33069281
380: Yanir Y, Doweck I, Shibli R, Najjar-Debbiny R, Saliba W. Association between the BNT162b2 messenger RNA COVID-19 vaccine and the risk of sudden sensorineural hearing loss. JAMA Otolaryngol Head Neck Surg 2022;148(4):299-306. PMID 35201275
381: Yuan H, Reynolds C, Ng S, Yang W. Factors affecting the transmission of SARS-CoV-2 in school settings. Influenza Other Respir Viruses 2022;16(4):643-52. PMID 35146922
382: Zamponi N, Passamonti C, Petrelli C, et al. Vaccination and occurrence of seizures in SCN1A mutation-positive patients: a multicenter Italian study. Pediatr Neurol 2014;50(3):228-32. PMID 24405698
383: Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021;21(2):181-92. PMID 33217362
384: Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020a;395(10240):1845-54. PMID: PMID 32450106
385: Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020b;396(10249):479-88. PMID 32702299
386: Zipp F, Weil JG, Einhäupl KM. No increase in demyelinating diseases after hepatitis B vaccination. Nat Med 1999;5:964-5. PMID 10470051

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: Female = male
Heredity: Heredity may be a factor
Population groups selectively affected: None
Occupation groups selectively affected: None

ICD & OMIM codes

ICD-10: Postimmunization acute disseminated encephalitis, myelitis and encephalomyelitis: G04.02

Poisoning by, adverse effect of and underdosing of bacterial vaccines: T50.A

Poisoning by, adverse effect of and underdosing of viral vaccines: T50.B

Poisoning by, adverse effect of and underdosing of other vaccines and biological substances: T50.Z
ICD-11: Harmful effects of drugs, medicaments or biological substances, not elsewhere classified: NE60

Other serum reactions: NE80.3

Infectious meningitis, unspecified: 1D01.Z

Other specified acute disseminated encephalomyelitis: 8A42.Y

Myelitis: 8B41

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Neurologic complications of vaccination

Associated Disorders

Acute disseminated encephalomyelitis
Acute inflammatory demyelinating polyradiculoneuropathy
Autism spectrum disorder
Bell palsy
chronic fatigue syndrome
- Dizziness
- Febrile seizures
- Guillain-Barre syndrome in children
- Measles: neurologic complications
- Optic neuritis
- Poliomyelitis
- sudden infant death syndrome
- Syncope
- Transverse myelitis
- tremors
- Varicella-zoster virus infections of the nervous system
- Vertigo

Differential Diagnosis

encephalitis
meningoencephalitis
Epstein-Barr virus
herpes viruses
enteroviruses
- measles
- mumps
- Mycoplasma pneumoniae
- varicella-zoster virus
- arboviruses
- epilepsy
- Dravet syndrome
- Angelman syndrome

Also Relevant

Acute disseminated encephalomyelitis
Acute inflammatory demyelinating polyradiculoneuropathy
Anthrax meningoencephalitis
Arboviral encephalitis
Autism spectrum disorder
- Bell palsy
- Chronic fatigue syndrome
- Congenital rubella
- Diphtheritic neuropathy
- Dizziness
- Febrile seizures
- Guillain-Barre syndrome in children
- Haemophilus influenzae meningitis
- Hepatitis viruses: neurologic complications
- Herpes zoster oticus
- Japanese encephalitis
- Measles: neurologic complications
- Meningococcal meningitis
- Multiple sclerosis: neuroimmunology
- Neurologic disorders related to chemical warfare nerve agents
- Optic neuritis
- Pertussis encephalopathy
- Pneumococcal meningitis
- Poliomyelitis
- Rabies
- sudden infant death syndrome
- Syncope
- Tetanus
- Transverse myelitis
- Tremors
- Tuberculosis of the CNS
- Varicella-zoster virus infections of the nervous system
- Vertigo
- Viral hemorrhagic fevers: neurologic complications

Neurologic complications of vaccination …

Neurologic complications of vaccination

Introduction

Overview

Key points

Historical note and terminology

Table 1a. Whole-Organism Vaccines by Type, Organism Category, and Disease

Table 1b. Partial-Organism (Subunit) Vaccines by Type, Organism Category, and Disease

Table 1c. mRNA Vaccine, Type, Organism Category, and Disease

Clinical manifestations

Presentation and course

Table 2. Categorization of Neurologic Adverse Reactions to Vaccination

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Selected vaccines

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Breath-holding spells

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Neurologic complications of vaccination

Introduction

Overview

Key points

Historical note and terminology

Table 1a. Whole-Organism Vaccines by Type, Organism Category, and Disease

Table 1b. Partial-Organism (Subunit) Vaccines by Type, Organism Category, and Disease

Table 1c. mRNA Vaccine, Type, Organism Category, and Disease

Clinical manifestations

Presentation and course

Table 2. Categorization of Neurologic Adverse Reactions to Vaccination

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Selected vaccines

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Breath-holding spells

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

This is an article preview.
Start a Free Account
to access the full version.