Conclusion
Vaccines currently routinely recommended to the general population in the U.S.* have not been shown to cause optic neuritis or neuromyelitis optica (NMO).
Epidemiological Evidence
The 2012 report by the Institute of Medicine (IOM) 1, now called the National Academy of Medicine (NAM), described two studies assessing optic neuritis and MMR, influenza, hepatitis B, diphtheria and tetanus vaccines 2,3, 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 optic neuritis and pertussis vaccine or NMO and MMR, influenza, hepatitis B or HPV vaccines 1.
Studies published since the 2012 IOM report have not found evidence of an association between vaccination and optic neuritis. A 2012 prospective cohort study of 189,629 females receiving quadrivalent HPV vaccine (Gardasil®) in California did not find a statistically significant association with optic neuritis 4. A 2015 cohort study of 3,983,824 females 10-44 years of age in Denmark and Sweden found no association between quadrivalent HPV vaccine and demyelinating diseases including optic neuritis and NMO 5. A 2017 claims-based retrospective matched cohort analysis of females 9-26 years of age did not find an association between HPV vaccine and optic neuritis 6. A 2017 South Korean nationwide cohort study found no associations between HPV vaccination and 33 predefined serious adverse events (including optic neuritis) 7. A 2020 systematic review and meta-analysis found no association between HPV vaccines and many autoimmune or other rare diseases (including optic neuritis) 8. A 2013 Vaccine Safety Datalink study found no cases of optic neuritis in over 200,000 pregnant individuals within 42 days after receiving trivalent inactivated influenza vaccine 9. A 2016 case-centered analysis in a large integrated Californian health plan population did not find an association between vaccines and optic neuritis 10. A 2017 literature review found no increase in risk of optic neuritis after vaccination 11.
Proposed Biological Mechanism
Anti-phosphatidylcholine antibodies have been suggested as a potential cause of optic neuritis 12. A highly specific immunoglobulin G autoantibody that targets aquaporin-4 is present in up to 80% of patients with NMO 13,14. One possible mechanism for this is molecular mimicry, which refers to the possibility that similar epitopes shared between self-peptides and foreign peptides (introduced via infection or immunization) inadvertently cause the activation of autoreactive T or B cells, leading to autoimmunity. Another possible mechanism is activation of the complement system, in which a cascade of proteolysis and successive release of cytokines functions to amplify the immune response but can damage host cells if not properly regulated. Other mechanisms that could contribute to optic neuritis or NMO include formation of immune complexes, as well as direct or persistent viral infection. Natural infection with wild-type measles, mumps or rubella viruses has been associated with optic neuritis, albeit very rarely 1.
The 2012 IOM report described two cases of optic neuritis after MMR 15,16, two cases of optic neuritis after influenza vaccine showing a reoccurrence of symptoms after vaccine rechallenge 17,18, and one case of NMO after rubella vaccine 19; however, even when considering knowledge about the aforementioned natural infections, the IOM concluded that this mechanistic evidence was weak. The IOM also concluded that there was no mechanistic evidence for an association between optic neuritis and hepatitis B, diphtheria, tetanus or pertussis vaccines, or between NMO and influenza, hepatitis B, HPV, measles or mumps vaccines 1.
* 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.
References
1. 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.
2. DeStefano F, Verstraeten T, Jackson LA, Okoro CA, Benson P, Black SB, Shinefield HR, Mullooly JP, Likosky W, Chen RT. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003; 60(4): 504-9.
3. Payne DC, Rose CE, Jr., Kerrison J, Aranas A, Duderstadt S, McNeil MM. Anthrax vaccination and risk of optic neuritis in the United States military, 1998-2003. Arch Neurol 2006; 63(6): 871-5.
4. Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H, Ackerson B, Cheetham TC, Hansen J, Deosaransingh K, Emery M, Liaw KL, Jacobsen SJ. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 2012; 271(2): 193-203.
5. Scheller NM, Svanstrom H, Pasternak B, Arnheim-Dahlstrom L, Sundstrom K, Fink K, Hviid A. Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. Jama 2015; 313(1): 54-61.
6. Sridhar G, Tian F, Forshee R, Kulldorff M, Selvam N, Sutherland A, Bryan W, Barone S, Xu L, Izurieta HS. Evaluation of optic neuritis following human papillomavirus vaccination. Human vaccines & immunotherapeutics 2017; 13(7): 1705-13.
7. Yoon D, Lee JH, Lee H, Shin JY. Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study. BMJ (Clinical research ed) 2021; 372: m4931.
8. Willame C, Gadroen K, Bramer W, Weibel D, Sturkenboom M. Systematic Review and Meta-analysis of Postlicensure Observational Studies on Human Papillomavirus Vaccination and Autoimmune and Other Rare Adverse Events. The Pediatric infectious disease journal 2020; 39(4): 287-93.
9. Nordin JD, Kharbanda EO, Benitez GV, Nichol K, Lipkind H, Naleway A, Lee GM, Hambidge S, Shi W, Olsen A. Maternal safety of trivalent inactivated influenza vaccine in pregnant women. Obstet Gynecol 2013; 121(3): 519-25.
10. Baxter R, Lewis E, Fireman B, DeStefano F, Gee J, Klein NP. Case-centered Analysis of Optic Neuritis After Vaccines. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016; 63(1): 79-81.
11. Frederiksen JL, Topsoe Mailand M. Vaccines and multiple sclerosis. Acta neurologica Scandinavica 2017; 136 Suppl 201: 49-51.
12. Korematsu S, Miyahara H, Kakita A, Izumi T. Elevated serum anti-phosphatidylcholine IgG antibodies in patients with influenza vaccination-associated optic neuritis. Vaccine 2014; 32(48): 6345-8.
13. Jarius S, Wildemann B, Paul F. Neuromyelitis optica: clinical features, immunopathogenesis and treatment. Clin Exp Immunol 2014; 176(2): 149-64.
14. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica (Devic’s syndrome). Handbook of clinical neurology 2014; 122: 581-99.
15. Riikonen RS. Retinal vasculitis caused by rubella. Neuropediatrics 1995; 26(3): 174-6.
16. Stevenson VL, Acheson JF, Ball J, Plant GT. Optic neuritis following measles/rubella vaccination in two 13-year-old children. Br J Ophthalmol 1996; 80(12): 1110-1.
17. Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P. Safety of trivalent inactivated influenza vaccines in adults: background for pandemic influenza vaccine safety monitoring. Vaccine 2009; 27(15): 2114-20.
18. Hull TP, Bates JH. Optic neuritis after influenza vaccination. Am J Ophthalmol 1997; 124(5): 703-4.
19. Kline LB, Margulies SL, Oh SJ. Optic neuritis and myelitis following rubella vaccination. Arch Neurol 1982; 39(7): 443-4.
