to the editor: Dr. Ebell's review of the study by Joura and colleagues¹ asserts that the 9-valent human papillomavirus (HPV) vaccine offers only a small advantage over the quadrivalent vaccine. He bases this on his assessment of data presented for the modified intention-to-treat population that includes persons who were already infected before vaccination.

HPV vaccines are prophylactic (i.e., they prevent HPV infection in persons who have not been exposed to the virus). They have no impact on HPV infections acquired before vaccination. Thus, an intention-to-treat analysis, which includes persons infected with HPV before vaccination, is not a suitable evaluation of prophylactic efficacy.² Prophylactic efficacy is assessed in the per-protocol population, which approximates a susceptible population of HPV-naïve individuals.

The per-protocol analysis showed that vaccine effectiveness against disease caused by the additional HPV types in the 9-valent vaccine was 96.7% (95% confidence interval, 80.9 to 99.8).¹ Based on these results, the Advisory Committee on Immunization Practices (ACIP) has included the 9-valent HPV vaccine in its recommended routine HPV vaccinations for girls and boys 11 and 12 years of age, and catch-up vaccination of girls and women 13 to 26 years of age and boys and men 13 to 21 years of age who have not been vaccinated previously.³ The introduction of 9-valent HPV vaccination in both males and females was cost-saving compared with the quadrivalent HPV vaccine in cost-effectiveness analyses.³

From these results, we can conclude that the 9-valent HPV vaccine represents a meaningful advantage over existing HPV vaccines. This added protection against infection and disease caused by HPV types 31, 33, 45, 52, and 58 offers the potential to prevent an additional 30% to 35% more high-grade cervical lesions⁴ and to increase cervical cancer prevention from approximately 70% to 90%.^4,5 Early vaccination before HPV exposure is key to derive the optimal benefit. Health care professionals should vaccinate all eligible 11- to 12-year-old patients using every appropriate opportunity, because these preadolescents are much less likely to have been exposed to HPV than are older adolescents. In addition, clinicians should vaccinate older patients who have not been previously vaccinated according to the ACIP recommendations for these catch-up cohorts.

in reply: I do not dispute the results of the per-protocol analysis. I acknowledged in my review that among uninfected women, there is a statistically significant reduction in the likelihood of HPV infection, but that this is relatively small (number needed to treat = 160 for three years to prevent one high-grade lesion). The per-protocol analysis that is emphasized by Dr. Joura provides the most optimistic estimate of benefit and does not reflect what would happen in primary care practice, where physicians do not typically check for evidence of previous HPV exposure before beginning a series of immunizations. As I stated, the 9-valent HPV vaccine provides an overall benefit, but it is modest. Fortunately, the cost of these two immunizations is fairly similar. It is also important to note that the ACIP recommends a ceiling age of 21 years for men and 26 years for women for catch-up immunization.¹