Uncertainties Surrounding HPV Vaccination May Hamper the Full Potential of a Proven Cancer Prevention Strategy

It would be difficult to overstate the magnitude of the evidence supporting the clinical utility of HPV vaccination as a strategy to prevent malignant disease associated with persistent infection with this viral agent.

The benefits of vaccination can, and should be, characterized as a major public health success for several reasons. Chief among them is the initial landmark observation related to the presence of HPV in cervix cancer, leading to the awarding of the Nobel Prize,¹ followed by the striking evidence of the percentage of young individuals (both male and female) who experience at least short-term infection with the virus following sexual debut.² Moreover, there is the documented trial-and population-based substantial effect of several vaccine products on the risk of persistent infection and subsequent pre-malignant and malignant events.³

While the role of screening for cervix cancer has long been recognized as a highly effective approach to detection of pre-cancerous abnormalities and early-stage invasive disease, it is critical to note there are currently approximately 14,000 new cases of cervical cancer diagnosed in the United States each year, resulting in more than 4,000 deaths.⁴ Worldwide, the total yearly number of cancer deaths caused by this now highly preventable disease is estimated to be in the range of 350,000 women.⁴ To these numbers one must add the morbidity associated with curative treatment strategies and the frequently immense pain and suffering that accompany progressive, recurrent, and metastatic cervix cancer. 

Critical research continues to be undertaken in this arena, including exploration of optimal delivery strategies such as single vaccine dosing,⁵ as well as more detailed examination of the natural history of HPV vaccination of adolescent males. This specific issue becomes ever more relevant when one considers the role of persistent HPV infections in oropharyngeal cancers, a malignant condition more common in the United States than cervix cancer (approximately 60,000/year) with 60% to 70% of these malignancies currently diagnosed resulting from prior HPV infection.⁶ Again, these cancers are highly treatable when they present at an early stage, but the considerable morbidity of therapy must be acknowledged as well as mortality resulting from more advanced disease at diagnosis or with progression following unsuccessful attempts at disease control.

In addition to the enormous personal effect of HPV-related cancers on affected individuals as well as their families, the financial cost of therapy, including ever most expensive (and effective) anti-neoplastic chemotherapeutics must be acknowledged.⁷ 

Importantly, with increasing time since the introduction of HPV vaccination as a routine component of adolescent medical care it has become possible to begin to examine the specific influence of the strategy on the development of invasive cervix cancer itself at the population level, rather than solely the effect on pre-cancerous abnormalities.⁸

And critically, longer-term follow-up has continued to fully confirm the remarkable safety of HPV vaccination, as recently demonstrated in a peer-reviewed Cochrane Library publication involving 225 studies (132 million people) of “community rates of HPV-related disease.”⁹ The included efforts in this report employed a variety of designs (cohort, case-control, cross-sectional, pre-post vaccine introduction studies, randomized controlled extension trials and self-controlled case series). In this analysis the investigators found no evidence the HPV vaccine resulted in an increased risk of “postural orthostatic tachycardia syndrome, chronic fatigue syndrome/myalgic encephalomyelitis, paralysis, complex regional pain syndrome, premature ovarian failure, infertility or sexual activity, or an increase in Guillain-Barre syndrome.”

 Recent studies have also included the impressive effect of HPV vaccination on the development of herd immunity, where population-based benefits of a reduction in the risk of malignant or pre-malignant conditions are observed in individuals who have never been vaccinated.^10,11

However, it is essential to acknowledge that despite the overwhelming data demonstrating both the effectiveness and safety of this cancer prevention strategy, much remains to be learned regarding its optimal use and method of delivery. For example, what is the potential role of HPV vaccination in a patient with a prior cervical abnormality who has not previously been vaccinated? Provocative data suggest there may be clinical utility associated with subsequent vaccination following resection of macroscopic disease.¹² Should this become a standard-of-care component of a multipronged approach in cervix cancer prevention?

In addition, despite the impressive early evidence of the noninferiority of a single dose HPV vaccination strategy compared with a standard two-dose regimen, the actual duration of the benefits of this simpler and less expensive approach remains to be critically defined and this will only happen after mandated longer follow-up of this population.

Finally, it must be appreciated that while extensive data exist regarding the utility of HPV vaccination within the female population at risk for cervix cancer, far less data are currently available related to the prevention of oropharyngeal cancer. This issue is particularly relevant in the male population at risk for this group of malignances. To emphasize this point, in the previously noted Cochrane review of benefits of HPV vaccination in the community setting, there were 177 studies that reported only on females, 37 included both sexes, and only 11 that focused solely on males.⁹

Clearly, there is much more to learn regarding the optimal delivery of this essential public health strategy for cancer prevention.

References

1. Bagcchi S. Harald zur Hausen. Lancet Infectious Diseases. 2023;23(9):P1001. doi:10.1016/S1473-3099(23)00511-X
2. Moscicki AB. Impact of HPV infection in adolescent populations. J Adolesc Health. 2005; 37(suppl 6):S3-S9. doi:10.1016/j.jadohealth.2005.09.011
3. Markowitz LE, Unger E. Human papillomavirus vaccination. N Engl J Med. 2023;388(19):1790-1798. doi:10.1056/NEJMcp2108502
4. Tewari KS. Cervical cancer. N Engl J Med. 2025;392(1):56-71. doi:10.1056/NEJMra2404457
5. Kreimer AR, Porras C, Liu D, et al. Noninferiority of one HPV vaccine dose to two doses. N Engl J Med. 2025;393(24):2421-2433. doi:10.1056/NEJMoa2506765
6. Dunn LA, Ho AL, Pfister DG. Head and neck cancer: a review. JAMA. 2026;335(6):531-541. doi:10.1001/jama.2025/21733
7. Miller LE, Rocco JW, Rathi VK. Pembrolizumab in head and neck cancer––promise and price. JAMA Otolaryngol Head Neck Surg. 2026;152(2):113-114. doi:1001/jamaoto.2025.4624
8. Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383(14):1340-1348. doi:10.1056/NEJMoa1917338
9. Henschke N, Bergman H, Buckley BS, et al. Effects of human papillomavirus (HPV) vaccination programmes on community rates of HPV-related disease and harms from vaccination. Cochrane Database Syst Rev. 2025;11(11):CD015363. doi:10.1002/14651858.CD015363.pub2
10. Meglic E, Ploner A, Clements M, et al. Herd effect of human papillomavirus vaccination on incidence of high-grade cervical lesions: a population-based cohort study in Sweden.Lancet Public Health. 2026;11(1):e35-e43. doi:10.1016/S2468-2667(25)00297-X
11. DeSieghardt A, Ding L, Ermel A, et al. Population-level effectiveness and herd protection 17 years after HPV vaccine introduction. JAMA Pediatr. 2025;179(12):1326-1334 doi:10.1001/jamapediatrics.2025.3568
12. Reuschenbach M, Doorbar J, Del Pinto M, et al. Prophylactic HPV vaccines in patients with HPV associated diseases and cancer. Vaccine. 2023;41(42):6194-6205. doi:10.1016/j.vaccine.2023.08.047