A Broad Safety Assessment of the 9-Valent Human Papillomavirus Vaccine

W. Katherine Yih; Martin Kulldorff; Inna Dashevsky; Judith C. Maro


Am J Epidemiol. 2021;190(7):1253-1259. 

In This Article

Abstract and Introduction


Parents indicate that safety is their top concern about human papillomavirus (HPV) vaccination. A data-mining method not requiring prespecification of health outcome(s) or postexposure period(s) of potentially increased risk can be used to identify possible associations between an exposure and any of thousands of medically attended health outcomes; this method was applied to data on the 9-valent HPV vaccine (HPV9) to detect potential safety problems. Data on 9- to 26-year-olds who had received HPV9 vaccine between November 4, 2016, and August 5, 2018, inclusive, were extracted from the MarketScan database and analyzed for statistically significant clustering of incident diagnoses within the hierarchy of diagnoses coded using the International Classification of Diseases and temporally within the 1 year after vaccination, using the self-controlled tree-temporal scan statistic and TreeScan software. Only 56 days of postvaccination enrollment was required; subsequent follow-up was censored at disenrollment. Multiple testing was adjusted for. The analysis included 493,089 doses of HPV9. Almost all signals resulted from temporal confounding, not unexpected with a 1-year follow-up period. The only plausible signals were for nonspecific adverse events (e.g., injection-site reactions, headache) on days 1–2 after vaccination, with attributable risks as low as 1 per 100,000 vaccinees. Considering the broad scope of the evaluation and the high statistical power, the findings of no specific serious adverse events should provide reassurance about this vaccine's safety.


The uptake of human papillomavirus (HPV) vaccine has lagged far behind that of other vaccines recommended for adolescents and young adults, despite the availability of HPV vaccines since 2006. Only 51.1% of US adolescents aged 13–17 years were current with the HPV vaccine series in 2018, compared with 86.6% and 88.9% who had received the recommended ≥1 dose of quadrivalent meningococcal vaccine and ≥1 dose of tetanus-diphtheria–acellular pertussis vaccine, respectively.[1] In recent surveys of parents regarding HPV vaccination, safety has been cited as the top concern.[2–4] A number of well-designed studies have investigated possible associations between HPV vaccination and certain health outcomes and not found any associations.[5–10] However, such studies might be too focused on specific outcomes to significantly allay concerns about HPV vaccine safety.

A recently developed data-mining method known as the self-controlled tree-temporal scan statistic can evaluate whether any of thousands of health outcomes is associated with receipt of a specific vaccine or drug.[11] This method, which builds on earlier work with tree-based scan statistics,[12–14] differs from traditional safety study methods in that it does not require prespecifying a specific health outcome of interest or a specific postexposure period of potentially increased risk. Instead, for an exposed population, data on all diagnoses recorded within a defined postexposure follow-up period are scanned to detect any statistically unusual clustering of cases within a large hierarchy, or "tree," of diagnoses as well as within the follow-up period. The method adjusts for the multiple testing entailed in evaluating the thousands of "branches" (e.g., nontraumatic joint disorders) and time intervals (e.g., days 19–27 after exposure) considered. Further, the method is self-controlled, eliminating confounding by fixed patient characteristics such as chronic disease status.

The method identified known vaccine-associated adverse events and produced few false signals when applied to 2 vaccines recommended for adolescents and young adults: a quadrivalent meningococcal conjugate vaccine (Menactra; Sanofi Pasteur Inc., Lyon, France)[15] and the quadrivalent HPV vaccine (HPV4) (Gardasil; Merck & Co., Inc., Whitehouse Station, New Jersey).[16] In this study, we applied it to the currently recommended 9-valent HPV vaccine (HPV9) (Gardasil 9; Merck & Co., Inc., Whitehouse Station, New Jersey). HPV9 was approved by the Food and Drug Administration for use in female persons aged 9–26 years and male persons aged 9–15 years on December 10, 2014. The Food and Drug Administration extended the indication to include male persons aged 16–26 years on December 14, 2015. The approved age range was further extended to include both female and male persons 27–45 years of age on October 5, 2018.