Conclusion
Vaccines in routine use in the United States* have not been shown to cause primary ovarian insufficiency (POI, formerly called primary ovarian failure), and the available evidence does not support a causal relationship.
Epidemiological Evidence
The 2012 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), did not assess POI as a potential outcome of vaccination 1. A VSD retrospective cohort study of nearly 200,000 young women in Oregon and Washington found no association between HPV, Tdap, or MenACWY vaccines and POI 2. A Danish nationwide retrospective cohort study found no association between HPV vaccination and POI 3. Publications of case series include a combined six total case reports of POI that may have had onset at varying times after HPV vaccination 4-6. Other publications are mostly limited to commentaries about the reports, and preliminary analyses from passive surveillance or ecological data.
Proposed Biological Mechanism
The cause of POI is not known for most affected patients and only a very small proportion of cases are due to autoimmunity 7. Mechanisms proposed by authors of case reports for HPV to be involved with the pathogenesis involve either toxic effects or autoimmune responses to the vaccine 8,9. However, questions have been raised regarding the validity of the arguments put forth in these publications in several letters to the editor 10,11 and a special editorial 12. Major problems with the proposed associations include the inconsistent time intervals between vaccination and onset, the plausibility of the proposed mechanism, the lack of population-level or passive surveillance changes in rates, and potential conflicts of interest of several of the authors. A systematic review and critical appraisal of the proposed mechanism found no evidence to suggest it is a viable explanation for autoimmunity 13.
* 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. Naleway AL, Mittendorf KF, Irving SA, Henninger ML, Crane B, Smith N, Daley MF, Gee J. Primary Ovarian Insufficiency and Adolescent Vaccination. Pediatrics 2018.
3. Hviid A, Myrup Thiesson E. Association Between Human Papillomavirus Vaccination and Primary Ovarian Insufficiency in a Nationwide Cohort. JAMA Netw Open 2021; 4(8): e2120391.
4. Colafrancesco S, Perricone C, Tomljenovic L, Shoenfeld Y. Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants. American journal of reproductive immunology (New York, NY : 1989) 2013; 70(4): 309-16.
5. Little DT, Ward HR. Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination: A Case Series Seen in General Practice. Journal of investigative medicine high impact case reports 2014; 2(4): 2324709614556129.
6. Little DT, Ward HR. Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination. BMJ Case Rep 2012; 2012.
7. Gordon CM, Kanaoka T, Nelson LM. Update on primary ovarian insufficiency in adolescents. Current opinion in pediatrics 2015; 27(4): 511-9.
8. Gruber N, Shoenfeld Y. A link between human papilloma virus vaccination and primary ovarian insufficiency: current analysis. Current opinion in obstetrics & gynecology 2015; 27(4): 265-70.
9. Shoenfeld Y, Agmon-Levin N. ‘ASIA’ – autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 2011; 36(1): 4-8.
10. Pellegrino P, Carnovale C, Perrone V, Salvati D, Gentili M, Brusadelli T, Pozzi M, Antoniazzi S, Clementi E, Radice S. On the association between human papillomavirus vaccine and primary ovarian failure. American journal of reproductive immunology (New York, NY : 1989) 2014; 71(4): 293-4.
11. Wiznitzer M. RE: Human papillomavirus vaccine and primary ovarian failure paper. American journal of reproductive immunology (New York, NY : 1989) 2014; 72(3): 259.
12. Hawkes D, Buttery JP. Human papillomavirus vaccination and primary ovarian insufficiency: an association based on ideology rather than evidence. Current opinion in obstetrics & gynecology 2016; 28(1): 70-2.
13. Hawkes D, Benhamu J, Sidwell T, Miles R, Dunlop RA. Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA). Journal of autoimmunity 2015; 59: 77-84.
