Conclusion
Varicella vaccine in routine use in the United States28F* can very rarely cause viral meningitis. Measles-containing vaccines can very rarely cause measles inclusion body encephalitis (MIBE). Mumps vaccines used in other countries have caused meningitis and encephalitis. However, the mumps vaccine in routine use in the United States* is made from a different strain of vaccine virus and has not been shown to cause meningitis or encephalitis. The benefit of vaccination in preventing neurologic diseases such as meningitis and encephalitis greatly outweighs the minimal risk of vaccine complications.
Natural infections with measles, mumps, rubella and varicella viruses can cause encephalitis and meningitis. Thus, measles, mumps, rubella and varicella vaccines protect against encephalitis and meningitis caused by these agents. These vaccines are made from attenuated versions of the wild-type viruses, and do not cause central nervous system infections in normal hosts. However, these attenuated vaccine viruses can cause disease in persons with certain immune deficiencies, and are therefore contraindicated in these populations. For instance, varicella vaccine virus can persist and cause reactivation zoster, which has been very rarely associated with viral meningitis, although affected patients without immune deficiencies recover fully without any lasting effects. In addition, very rare cases of measles inclusion body encephalitis (MIBE) have occurred following administration of measles-containing vaccines.
Natural infections with Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) can cause severe bacterial meningitis. Pneumococcal, Hib, and meningococcal vaccines protect against meningitis caused by these agents. The vaccines that protect against these infections do not cause meningitis; the vaccines are made from only the outer capsule and/or bacterial proteins so they cannot cause infections like the naturally occurring bacteria 1-7.
Epidemiological Evidence
The 2012 report by the Institute of Medicine (IOM) 8, now called the National Academy of Medicine (NAM), described three studies with sufficient validity and precision that reported null associations between MMR vaccine and meningitis 9-11. The report also described several studies assessing meningitis, encephalitis or encephalopathy and MMR 9,12,13, DTaP 14,15 or meningococcal 13 vaccines, but these studies did not provide convincing evidence due to a lack of validity and precision. The IOM found no relevant studies of quality in the literature assessing encephalitis or encephalopathy and varicella, influenza or hepatitis B vaccines, since the only applicable studies available either had serious methodological limitations or used passive surveillance systems and therefore lacked an unvaccinated comparison group 8.
Shortly after publication of the 2012 IOM report, a large post-licensure study found no association between herpes zoster vaccination and meningitis, encephalitis or encephalopathy 16, and a case-centered analysis of 110 childhood encephalitis cases from California found no association between vaccination and encephalitis 17. Large Vaccine Safety Datalink studies also found no association between meningitis/encephalitis and either 2012-2013 influenza vaccines 18, the DTaP-IPV combination vaccine (Kinrix®) 19, or MMR, MMRV (ProQuad®) and varicella vaccine (Varivax®) 20. A 2016 retrospective observational study of California infants found no cases of encephalitis or meningitis during the 30-day risk interval after 46,486 doses of DTaP-IPV/Hib vaccine administered 21. A 2017 Norwegian registry study found no increased risk of encephalitis following pH1N1 vaccine 22. A 2020 self-controlled risk interval analysis of Taiwanese children using nationwide data found no increased risk of meningitis or encephalitis after varicella vaccination 23. A 2021 Cochrane review determined that although evidence supports an association between aseptic meningitis and MMR vaccines containing the Urabe and Leningrad-Zagreb mumps strains, no evidence supports such an association for MMR vaccines containing the Jeryl Lynn mumps strain (such as those used in the US), and no evidence supports an association between MMR and encephalitis or encephalopathy 24.
Analyses of safety surveillance data from the Vaccine Safety Datalink found no significant associations between mRNA COVID-19 vaccines and 23 serious health outcomes (including encephalitis/myelitis/encephalomyelitis) 25.
The IOM found no relevant epidemiologic studies of quality in the literature assessing an association between vaccination and MIBE 8.
Proposed Biological Mechanism
An estimated 1-10% of persons naturally infected with wild-type mumps virus develop meningitis. Natural infection with wild-type measles, mumps or rubella viruses occasionally leads to development of encephalitis, at estimated rates of one case per 1000-2000 patients infected with measles, 400-6000 patients infected with mumps, or 5000 patients infected with rubella, respectively 8. Measles can also cause a persistent infection of the brain resulting in subacute sclerosing panencephalitis (SSPE), which occurs at a rate of approximately 22 cases of SSPE per 100,000 reported cases of measles 26. Natural infection with wild-type influenza has also been associated with encephalitis, albeit rarely 8,27-29.
In early-onset encephalitis after infection with mumps virus, neuronal damage is suspected to result from direct viral invasion. Natural viral infection can cause meningitis or encephalitis via either direct viral invasion or a viral-induced autoimmune reaction. Mechanisms proposed for the development of meningitis or encephalitis after viral vaccination include direct viral infection, autoimmune mechanisms resulting in post-infectious encephalitis (such as ADEM), varicella vaccine-strain viral reactivation, and persistent viral infection 8. For more information, see the Do Vaccines Cause Acute Disseminated Encephalomyelitis (ADEM)? and the Do Vaccines Cause Herpes Zoster? summaries.
Encephalitis and encephalopathy have even been reported as complications of some bacterial infections such as diphtheria andpertussis. There is also some evidence that pertussis-specific antigens can traverse the blood-brain barrier and thereby directly affect the central nervous system 8. Historically, the whole cell pertussis vaccine (no longer used in the US) was associated with encephalopathy within 7 days of vaccination by the IOM in 1994. However, subsequent studies have failed to show such an association 12,30, and a landmark study from 2006 showed that 11 of 14 children with alleged vaccine encephalopathy actually had a specific de novo mutation explaining their encephalopathy (SCN1A encephalopathy, also known as Dravet Syndrome) 31.
The IOM also concluded that there was no mechanistic evidence of quality showing an association between encephalitis or encephalopathy and varicella, hepatitis b and meningococcal vaccines, nor for an association between meningitis and measles or rubella vaccines, as the publications reviewed provided no evidence beyond a temporal association 8. The 2012 IOM report described several cases of encephalitis or encephalopathy after MMR 32-34, influenza 35 and DTaP 36 vaccines, and four cases of meningitis after mumps vaccine 32,37,38, but when considering knowledge about the natural infection the IOM concluded this mechanistic evidence was weak 8. However, there is one well documented case of measles vaccine virus isolated from the cerebrospinal fluid of a patient with encephalitis in Canada 39, as well as documented cases of meningitis following reactivation of vaccine-type varicella zoster virus 40-42.
MMR and varicella vaccines are live attenuated viral vaccines which replicate in the body. Severe immunosuppression is a contraindication for MMR, MMRV, and varicella vaccine 7. For more information, see the Measles, Mumps and Rubella and Varicella summaries.
In immunodeficient persons, persistent infection with live vaccine viruses is possible. Measles vaccine virus can lead to central nervous system infection and MIBE 8. The 2012 IOM report described several cases of MIBE after measles vaccination in immunodeficient persons 39,43,44, and concluded that these cases together presented strong mechanistic evidence supporting an association 8.
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.
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