Vaccines and Neurologic Disease

James J. Sejvar, M.D.

Disclosures

Semin Neurol. 2011;31(3):338-355. 

In This Article

Vaccines and Specific Neurologic Adverse Events

Various vaccines have been associated with optic neuritis, myasthenia gravis, transverse myelitis, Bell palsy, limbic encephalitis, seizures, isolated cranial nerve palsies, and a long list of others.[82,83] However, in all such instances, these associations are based on a temporal association only, and any measure of causality is unable to be ascertained. There are, however, several neurologic conditions that have been reported with relative consistency and frequency with several vaccines, and warrant closer evaluation.

There have been rare situations in which a causal association of a particular vaccine with neurologic illness appears probable, based upon biologic/laboratory evidence, or in some cases, epidemiologic evidence. These have included the demonstration of cross-reactive antibodies and T cells to CNS and PNS neural epitopes in some recipients of the Semple rabies vaccine and other animal brain-derived vaccines,[84,85,86,87] leading to neurologic illness.[88] Vaccine-strain smallpox vaccine (vaccinia, a live orthopoxvirus closely related to variola, the virus causing smallpox) had historically been rarely isolated from cerebrospinal fluid (CSF) of patients suffering from postvaccination encephalopathy during large smallpox vaccine campaigns.[82,89,90,91] In rare instances, vaccine-strain live-attenuated yellow fever virus derived from the 1-D yellow fever virus strain has been detected in CSF or brain tissue, or yellow fever virus-specific IgM detected in CSF of vaccine recipients, suggesting a neurotropic effect of this normally nonneurotropic virus.[92,93] Several strains of mumps vaccine have been epidemiologically associated with aseptic meningitis. In the case of the Urabe strain, sequencing of isolates of this strain from the CSF of Italian military recruits with aseptic meningitis suggested a causal association.[94] Vaccination with tetanus toxoid has been associated with recurrent episodes of Guillain-Barré syndrome (GBS) and brachial neuritis in some individuals, supporting a "rechallenge" line of evidence for causality.[82] The most compelling line of epidemiologic evidence for an association of an antecedent vaccine with a neurologic adverse event came from assessments of GBS following the 1976 formulation of the swine influenza vaccine (below). It may be argued, however, that the rare situations in which particular vaccines appear to be causally associated with specific neurologic illnesses essentially serve as the exceptions that have proven the rule; it is singularly unusual for a person to experience a serious health event following a vaccination, and even more uncommon to find biologic or epidemiologic evidence substantiating a causal association between a vaccine and an event.

Vaccines and Guillain-Barré Syndrome

In the fall of 1976, a new swine-origin H1N1 influenza virus was detected among personnel on a United States military base. Given the new nature of this virus and the possibility of an influenza pandemic, vaccination of the entire U.S. population was undertaken on an urgent basis.[95] Beginning in October 1976, large numbers of persons were vaccinated in a short period. Although the feared pandemic never materialized, several months after initiation of the campaign, two clusters of cases of GBS occurring after vaccination were reported to the surveillance system established to monitor the safety of the vaccine. A follow-up investigation and case-control study was initiated, which found a small, but significant increase in risk of GBS following vaccination, with an attributable risk of just under one additional case of GBS per 100,000 adult vaccinations.[96] It appeared that the greatest period of risk following immunization was between 1 and 6 weeks, clustering at weeks 2 to 4. Ultimately, the vaccine campaign was discontinued in January of 1977. Over ensuing years, reanalyses of the original national GBS surveillance data confirmed the findings of increased risk of GBS in the original study.[97–99]

Following this episode, there were continuing concerns about an association of GBS with subsequent formulations of seasonal influenza vaccine. The influenza vaccine is reformulated each year to cover what are anticipated to be the most prominent circulating strains of influenza in a given year. Several assessments were conducted, with equivocal results.[100–108] Of these nine assessments of the risk of GBS following various seasonal influenza vaccine formulations conducted between 1977 and 2009, only two suggested an increased risk, of approximately one additional GBS case among adult vaccinees within a 6-week period per million vaccinations.[105,108] A biologic assessment of the immunogenicity of the 1976 vaccine strain found that archived swine flu vaccine induced antimyelin ganglioside antibodies in mice, suggesting a biologic substrate.[109] However, the study also found that several formulations that had not been associated with an increased risk of GBS were also able to induce these antibodies, leaving the significance of the results unclear. Thus, although the reason for the association of the 1976 H1N1 vaccination with GBS is unclear, there is no consistent evidence of an increased risk of GBS with subsequent seasonal influenza vaccinations.

Numerous other vaccines have been temporally associated with GBS, but causal association has been less clear. Neuroparalytic accidents associated with formulations of animal-derived rabies vaccine have been reported to occur in up to 1 in 7,500 vaccinees.[110] Tetanus toxoid vaccine, in the form of tetanus-diphtheria (Td) vaccine, has been associated with one apparent case of challenge-rechallenge clinical events in which a 42-year-old man developed GBS following Td vaccine on three separate occasions over a 13-year period, raising the possibility of causality in this individual.[111] However, larger assessments of GBS following tetanus toxoid-containing vaccines have failed to substantiate an increased risk.[112] Although case reports of GBS following several other vaccines, including hepatitis A, Japanese encephalitis virus, smallpox, yellow fever, and meningococcal vaccines, have appeared, any inference on causality cannot be drawn.[82,113]

Vaccinations and Multiple Sclerosis

Another neurologic disorder that has repeatedly been hypothesized to be associated with vaccination is MS, with hepatitis B vaccine among the most frequently cited. The overwhelming evidence, however, from these various studies, would suggest that the risk of new-onset MS in children and adults following hepatitis B vaccination, if it exists at all, is extremely low. The Institute of Medicine, after review of available evidence, has favored a rejection of a causal association.[114–116] An association between MS and other vaccines exists almost entirely in case reports or small case series. Additionally, pharmacovigilance data from large passive databases such as the U.S. Vaccine Adverse Event Reporting System (VAERS) database have not suggested any clear associations between vaccines and MS.[117]

Vaccinations and Acute Disseminated Encephalomyelitis

A related CNS demyelinating disease that has been associated with immunizations is acute disseminated encephalomyelitis (ADEM). ADEM lies within the continuum of primary inflammatory demyelinating disorders of the CNS, which include MS, acute transverse myelitis, neuromyelitis optica, and other variants. ADEM may be distinguished from these other inflammatory CNS disorders by the (generally) monophasic nature of the illness: relatively rapid onset, progression, and remission of illness; and the characteristic pattern and distribution of brain lesions on magnetic resonance imaging (MRI).[118,119,120] However, none of these features are pathognomonic of ADEM, and the absence of a definitive biologic marker for the disease further complicates the diagnostic picture. Thus, ADEM remains a clinical diagnosis, which limits the strength of much of the existing data regarding vaccines. In general, ADEM may occur in any age group, but is thought to be more common in the pediatric population.[120–122]

Although ADEM has rarely been associated with organ transplantation or toxin exposure, it has usually been temporally associated with various antecedent viral infections; up to 90% of patients report an infectious illness or immunization in the weeks prior to the onset of an ADEM illness.[81,123] A few specific immunizations have been temporally associated with subsequent ADEM, including Japanese encephalitis, yellow fever, measles, influenza, smallpox, anthrax, and a host of others.[82,124] However, with very rare exceptions, these associations have been based entirely upon temporal proximity of the antecedent vaccine to subsequent ADEM, and have appeared as case reports or very small case series. Thus, a causal association of most vaccines with ADEM has not been substantiated.

Of the more commonly associated vaccines, the Semple rabies vaccine and earlier strains of vaccinia (smallpox) vaccine have been the strongest. The only epidemiologically and pathologically proven association has been with the Semple rabies vaccine. Elevated levels of antimyelin basic protein (MBP) antibody titers have been observed, and lymphocytic proliferation in the presence of myelin has been demonstrated in patients following rabies vaccination, suggesting that MBP is the encephalitic antigen in postrabies vaccine ADEM.[86] Historically, the most widely used and available vaccine for JEV was derived from neural tissue (suckling mouse brain). Reporting rates of ADEM following these formulations of JEV vaccine have been estimated to be 0.2/100,000.[88] New cell culture-based formulations of JEV vaccine are licensed in the United States, Europe, Australia, and Japan, and a new live-attenuated vaccine is currently licensed in Australia.[125]

Historically, strains of vaccinia virus, used as the vaccine against variola (smallpox), have been associated with a condition referred to as postvaccinial encephalopathy (PVE), and a particular pathologic subtype historically termed "microglial encephalomyelitis,"[126] which clinically and pathologically appears consistent with ADEM. Reporting rates of postvaccinal microglial encephalitis ranged anywhere from 2 per million vaccinees in the United States in 1968 to 1.2/100,000 vaccinees during an assessment in Austria from 1948–1953.[127,128] These findings generally attest, however, to the extremely low rate of development of ADEM following the use of carefully selected strains of vaccinia for the vaccine.

Vaccines and Encephalopathy

Various vaccines have been temporally associated with acute neurologic disease, primarily in children. Among the most frequently cited among these neurologic conditions is acute encephalopathy, with resultant altered mental status and in some cases ongoing neurologic sequelae. Perhaps the most notable of these has been the association of whole-cell pertussis vaccine and acute encephalopathy. A study conducted in Great Britain between 1976 and 1979 evaluated the frequency of DTP vaccination in children with encephalopathy.[129] Based upon 35 children out of 1000 cases reported to the study who had received pertussis vaccine with 7 days of developing neurologic illness, the estimated relative risk of encephalopathy with 7 days of pertussis vaccine was 2.4 (p < 0.0001). However, the diagnoses among some of these cases were subsequently subject to criticism. The results of this study have been analyzed, reanalyzed, and continue to be challenged and debated.[130,131] The subsequent results of these reanalyses have been interpreted, cautiously, that the data suggest, but certainly do not prove, a causal association between pertussis vaccine and acute neurologic illness. However, subsequent studies have failed to demonstrate an association between pertussis vaccine and acute encephalopathy.[132]

Based upon available data, in 1994 the Institute of Medicine concluded that the "balance of evidence is consistent with a causal relation between DTP and chronic nervous system dysfunction in children whose serious acute neurologic illness occurred within seven days of DTP vaccination."[133] However, this conclusion did not determine whether DTP vaccine actually increased the number of children with chronic neurologic illness, or was possibly a precipitating factor or event in children who would have developed neurologic dysfunction as a result of underlying neurologic or metabolic abnormalities.

Vaccines and Autism

Autism is a developmental disorder beginning in early childhood and characterized by severe impairments with social interaction and communication, stereotypic and/or compulsive behaviors, and significant functional impairment. Autism has been described as encompassing a range of disorders of varying severity, thus the term autism spectrum disorder. There may be several causes, and a strong genetic influence has been described.[134] As the initial manifestations may be insidious, and because children may be initially developmentally normal before onset of signs, autism in some cases may be difficult to diagnose, and may not be identified until later in life.

Concern about a vaccine link to autism was originally generated by a much-publicized study published in The Lancet in 1998;[135] this report described 12 children with inflammatory bowel disease and regressive developmental disorders diagnosed as autism. In eight of these 12 cases, the children's caregivers or pediatricians felt that the onset of illness occurred shortly after receiving MMR, and that the vaccine contributed to the illness. The authors of the study suggested that support for the link between MMR and autism was the identification of measles virus nucleic acid in blood cells and intestinal tissue in some children. It was not determined whether this genetic material was from wild or vaccine-strain measles virus.

Subsequent assessments of a link between MMR and autism were performed, and did not support this association. Larger, population-based studies as well as controlled epidemiologic and ecologic studies have found no correlation between the introduction of the MMR vaccine and autism.[136–139] More recently, in January 2010 the Lancet article was retracted on the basis of charges against the authors of dishonesty and flouting of ethics protocols by the United Kingdom's General Medical Council. In January 2011, the British medical journal stated that the study was in fact fraudulent and that the data were falsified.[140] This unfortunate situation provides valuable lessons on the impact that scientific findings may have on the medical perceptions of patients and clinicians alike.

A similar concern was raised about the possible link between thimerosal and autism. Thimerosal has been used as a vaccine preservative since the 1930s; it is mercury-based and is metabolized into ethylmercury and thiosalicylate. Because of concerns about ill-health effects from exposure to environmental mercury, the U.S. Food and Drug Administration (FDA) conducted a risk assessment of the use of thimerosal in vaccines. The assessment suggested that between 1989 and 1998, more thimerosal-containing vaccines were being added to the recommended childhood immunization schedule, leading to increased exposure of children to ethylmercury, and that this exposure could result in received doses of ethylmercury in excess of the U.S. Environmental Protection Agency's exposure limit for related methylmercury.[141] Although no health effects were detected, out of precaution the U.S. Public Health Service and the American Academy of Pediatrics recommended removal of thimerosal from vaccine formulations.[141]

Following this, concerns were raised about the possible association of thimerosal-containing vaccines and autism. The suspicion for this was indirect; it rested on the neurotoxic effects of mercury compounds demonstrated in animal models, and the secular trend of an increasing number of children receiving diagnoses of autism spectrum disorder. However, there are various other factors possibly contributory to the apparent increase in autism spectrum disorder diagnoses, including changes in case definitions, and several large, population-based studies have failed to demonstrate an association of thimerosal-containing vaccines and autism,[142,143] leading the Institute of Medicine to reject a causal association between either MMR or thimerosal with autism.[144]

Vaccines and the Risk of Relapse of Neurologic Disease

A related question that often arises is the risk of relapse of particular immune-mediated neurologic illnesses, such as GBS and MS, following vaccination in an individual with a prior history. Currently, there is very little empiric evidence to provide guidance for this issue. For GBS, persons with a history of GBS have a greater likelihood of subsequently experiencing GBS than persons without a history; as such, as to whether or not a vaccination might trigger GBS in such patients, it would be expected that their likelihood of coincidentally experiencing GBS following vaccination is inherently greater. Data on this possibility are extremely limited. Two studies have audited the risk of self-reported recurrence of symptoms suggestive of GBS and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) among patient groups in the United Kingdom and the Netherlands.[145,146] In the United Kingdom, of 927 members of a GBS patient organization, 311 reported vaccinations subsequent to their initial illness, and 11 (3.5%) reported recurrence of symptoms such as weakness and fatigue. All but one of these cases had symptom onset within the first week of vaccination; none required hospitalization or treatment. The authors concluded that the risk of a relapse severe enough to result in a change in Rankin scale score was 0.3%, but could be as high as 1.78% (95% CL). Although 9% of 245 GBS patients in the Dutch study reported vaccination in the 8 weeks preceding their first GBS episode, none of the 106 patients receiving subsequent influenza vaccinations reported relapse.

Similarly, data are limited for the risk of exacerbation of MS following vaccination. After careful assessment and weighing of all the evidence, an expert panel of the American Academy of Neurology came to the conclusion that (1) the risk of MS exacerbation is high in the setting of acute infectious illness, based upon six cohort and two case-control studies; and (2) the risk of MS exacerbation following several specific vaccinations was absent in all of the controlled studies that it reviewed.[147] Thus, strategies to minimize infectious illnesses in patients with MS that have a high likelihood of triggering an exacerbation should be used. In other words, there is probably much more risk of relapse in an MS patient from getting ill from a vaccine-preventable infectious disease than from immunizing that person against the disease.

Current Centers for Disease Control and Prevention (CDC) recommendations for influenza vaccine state the precaution of "avoiding vaccinating persons who are not at high risk for severe influenza illness complications and who are known to have experienced GBS within six weeks after a previous influenza vaccination is prudent,"[148] and similar recommendations are made for tetanus toxoid vaccine;[149] However, this is largely based upon theoretical concerns.

Surveillance and Monitoring for Vaccine-Associated Adverse Events

Vigilance for potential adverse events following immunization is needed, as demonstrated by prior situations, such as the 1976 swine influenza vaccine incident. The fact that vaccines are administered to otherwise healthy people demands that proper surveillance mechanisms for adverse events be present. Monitoring for vaccine adverse events depends upon a combination of passive surveillance, which relies upon spontaneous reports of suspected adverse events following immunization from health care workers, parents, patients, or drug companies; and active surveillance, in which studies are conducted to seek out and identify suspected adverse events.

In the United States, the cornerstone of vaccine adverse events surveillance is the VAERS, a passive surveillance system operated by the CDC and the FDA.[150,151] The system essentially serves as an early warning system for adverse events following immunization. People, including health care workers and the public, are encouraged to submit reports of suspected cases of adverse events following immunization. This database is regularly analyzed to determine whether an unusually large number of cases of a particular adverse health outcome after administration of a specific vaccine are being reported. VAERS has succeeded in providing signals for potential problems with specific lots of vaccines and has served as a very useful surveillance tool for adverse events following immunization. There are limitations, including reporting biases (both underreporting—reporting depends upon the knowledge of the system, and potential overreporting—most of the illnesses reported will have nothing to do with the vaccine), no incidence data, limited or missing clinical information, and a lack of standardization of reported data. VAERS continues to serve, however, as an extremely sensitive and valuable signal detector.

To circumvent some of the limitations of VAERS and passive surveillance, other mechanisms are available. These include the use of large linked databases, in which the vaccination status of all persons in a defined population is linked to clinical features or outcomes, and controlled studies assessing possible risk from specific vaccines.[152,153]

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