Varicella vaccine in routine use in the United States 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 generally 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].
The 2012 report by the Institute of Medicine (IOM) , 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  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 .
Since the publication of the 2012 IOM report, one large post-licensure study found no association between herpes zoster vaccination and meningitis, encephalitis or encephalopathy . A case-centered analysis of 110 childhood encephalitis cases from California found no association between vaccination and encephalitis . Large Vaccine Safety Datalink studies found no association between meningitis/encephalitis and either 2012-2013 influenza vaccines , the DTaP-IPV combination vaccine (Kinrix®) , or MMR, MMRV (ProQuad®) and varicella vaccine (Varivax®) . A 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 . A 2017 Norwegian registry study found no increased risk of encephalitis following pH1N1 vaccine .
The IOM found no relevant epidemiologic studies of quality in the literature assessing an association between vaccination and MIBE .
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 . 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 . Natural infection with wild-type influenza has also been associated with encephalitis, albeit very rarely .
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 . For more information, see the Do Vaccines Cause Acute Disseminated Encephalomyelitis (ADEM)? and the Do Vaccines Cause Herpes Zoster? summaries.
Encephalitis and/or encephalopathy have even been reported as complications of bacterial infection such as diphtheria and pertussis. There is also some evidence that pertussis-specific antigens can traverse the blood-brain barrier and thereby directly affect the central nervous system .
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 . The 2012 IOM report described several cases of encephalitis or encephalopathy after MMR [22-24], influenza  and DTaP  vaccines, and four cases of meningitis after mumps vaccine [22, 27, 28], but when considering knowledge about the natural infection the IOM concluded this mechanistic evidence was weak . However, there is one well documented case of measles vaccine virus isolated from the cerebrospinal fluid of a patient with encephalitis in Canada , as well as documented cases of meningitis following reactivation of vaccine-type varicella zoster virus [30-32].
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 . 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 . The 2012 IOM report described several cases of MIBE after measles vaccination in immunodeficient persons [29, 33, 34], and concluded that these cases together presented strong mechanistic evidence supporting an association .
1. Buchanan R, Bonthius DJ. Measles Virus and Associated Central Nervous System Sequelae. Seminars in Pediatric Neurology 2012;19:107-14.
2. Studahl M, Lindquist L, Eriksson BM, et al. Acute viral infections of the central nervous system in immunocompetent adults: diagnosis and management. Drugs 2013;73:131-58.
3. Gilden D, Nagel MA, Cohrs RJ. Chapter 12 – Varicella-zoster. In: Alex CT, John B, eds. Handbook of clinical neurology: Elsevier; 2014:265-83.
4. Griffin DE. Chapter 27 – Measles virus and the nervous system. In: Alex CT, John B, eds. Handbook of clinical neurology: Elsevier; 2014:577-90.
5. Tyor W, Harrison T. Chapter 28 – Mumps and rubella. In: Alex CT, John B, eds. Handbook of clinical neurology: Elsevier; 2014:591-600.
6. Rubin S, Eckhaus M, Rennick LJ, Bamford CG, Duprex WP. Molecular biology, pathogenesis and pathology of mumps virus. The Journal of pathology 2015;235:242-52.
7. Epidemiology and Prevention of Vaccine-Preventable Diseases. Washington D.C.: Centers for Disease Control and Prevention; 2015.
8. Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.
9. Makela A, Nuorti JP, Peltola H. Neurologic disorders after measles-mumps-rubella vaccination. Pediatrics 2002;110:957-63.
10. Ki M, Park T, Yi SG, Oh JK, Choi B. Risk analysis of aseptic meningitis after measles-mumps-rubella vaccination in Korean children by using a case-crossover design. Am J Epidemiol 2003;157:158-65.
11. Black S, Shinefield H, Ray P, et al. Risk of hospitalization because of aseptic meningitis after measles-mumps-rubella vaccination in one- to two-year-old children: an analysis of the Vaccine Safety Datalink (VSD) Project. The Pediatric infectious disease journal 1997;16:500-3.
12. Ray P, Hayward J, Michelson D, et al. Encephalopathy after whole-cell pertussis or measles vaccination: lack of evidence for a causal association in a retrospective case-control study. The Pediatric infectious disease journal 2006;25:768-73.
13. Ward KN, Bryant NJ, Andrews NJ, et al. Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Pediatrics 2007;120:314-21.
14. Greco D. Case-control study on encephalopathy associated with diphtheria-tetanus immunization in Campania, Italy. Bulletin of the World Health Organization 1985;63:919-25.
15. Yih WK, Nordin JD, Kulldorff M, et al. An assessment of the safety of adolescent and adult tetanus-diphtheria-acellular pertussis (Tdap) vaccine, using active surveillance for adverse events in the Vaccine Safety Datalink. Vaccine 2009;27:4257-62.
16. Tseng HF, Liu A, Sy L, et al. Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study. J Intern Med 2012;271:510-20.
17. Pahud BA, Rowhani-Rahbar A, Glaser C, et al. Lack of association between childhood immunizations and encephalitis in California, 1998-2008. Vaccine 2012;30:247-53.
18. Kawai AT, Li L, Kulldorff M, et al. Absence of associations between influenza vaccines and increased risks of seizures, Guillain-Barre syndrome, encephalitis, or anaphylaxis in the 2012-2013 season. Pharmacoepidemiology and Drug Safety 2014;23:548-53.
19. Daley MF, Yih WK, Glanz JM, et al. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine. Vaccine 2014;32:3019-24.
20. Klein NP, Lewis E, Fireman B, et al. Safety of measles-containing vaccines in 1-year-old children. Pediatrics 2015;135:e321-9.
21. Hansen, J., et al., Safety of DTaP-IPV/Hib vaccine administered routinely to infants and toddlers. Vaccine, 2016. 34(35): p. 4172-4179.
22. Ghaderi, S., et al., Encephalitis after influenza and vaccination: a nationwide population-based registry study from Norway. Int J Epidemiol, 2017. 46(5): p. 1618-1626.
23. Bellini WJ, Rota JS, Lowe LE, et al. Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized. The Journal of infectious diseases 2005;192:1686-93.
24. Goenka, A., et al., Neurological manifestations of influenza infection in children and adults: results of a National British Surveillance Study. Clin Infect Dis, 2014. 58(6): p. 775-84.
25. Britton, P.N., et al., Influenza-associated Encephalitis/Encephalopathy Identified by the Australian Childhood Encephalitis Study 2013-2015. Pediatr Infect Dis J, 2017. 36(11): p. 1021-1026.
26. Hoshino, A., et al., Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes. Brain Dev, 2012. 34(5): p. 337-43.
27. Moore, D.L., et al., Lack of evidence of encephalopathy related to pertussis vaccine: active surveillance by IMPACT, Canada, 1993-2002. Pediatr Infect Dis J, 2004. 23(6): p. 568-71.
28. Berkovic, S.F., et al., De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol, 2006. 5(6): p. 488-92.
29. Bakshi N, Lawson J, Hanson R, Ames C, Vinters HV. Fatal mumps meningoencephalitis in a child with severe combined immunodeficiency after bone marrow transplantation. J Child Neurol 1996;11:159-62.
30. Lacroix C, Blanche S, Dussaix E, Tardieu M. Acute necrotizing measles encephalitis in a child with AIDS. J Neurol 1995;242:249-51.
31. Valmari P, Lanning M, Tuokko H, Kouvalainen K. Measles virus in the cerebrospinal fluid in postvaccination immunosuppressive measles encephalopathy. The Pediatric infectious disease journal 1987;6:59-63.
32. Froissart M, Mizon JP, Leroux JL. [Acute meningoencephalitis immediately after an influenza vaccination]. Lille Med 1978;23:548-51.
33. Schwarz G, Lanzer G, List WF. Acute midbrain syndrome as an adverse reaction to tetanus immunization. Intensive Care Med 1988;15:53-4.
34. Ehrengut W, Zastrow K. [Complications after preventive mumps vaccination in West Germany (including multiple preventive vaccinations)]. Monatsschr Kinderheilkd 1989;137:398-402.
35. Fescharek R, Quast U, Maass G, Merkle W, Schwarz S. Measles-mumps vaccination in the FRG: an empirical analysis after 14 years of use. II. Tolerability and analysis of spontaneously reported side effects. Vaccine 1990;8:446-56.
36. Bitnun A, Shannon P, Durward A, et al. Measles inclusion-body encephalitis caused by the vaccine strain of measles virus. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1999;29:855-61.
37. Iyer S, Mittal MK, Hodinka RL. Herpes zoster and meningitis resulting from reactivation of varicella vaccine virus in an immunocompetent child. Annals of emergency medicine 2009;53:792-5.
38. Han JY, Hanson DC, Way SS. Herpes zoster and meningitis due to reactivation of varicella vaccine virus in an immunocompetent child. The Pediatric infectious disease journal 2011;30:266-8.
39. Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. Nature reviews Disease primers 2015;1:15016.
40. Baram TZ, Gonzalez-Gomez I, Xie ZD, et al. Subacute sclerosing panencephalitis in an infant: diagnostic role of viral genome analysis. Ann Neurol 1994;36:103-8.
41. 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.