The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention

While all HPV vaccines were originally licensed and recommended as a three-dose schedule, in 2014, the World Health Organisation (WHO) recommended a two-dose HPV vaccination schedule for girls starting the vaccination series at age 9 through 14 years [1]. This decision was based on immunogenicity data showing non-inferior immune response of two doses in this age group compared to three doses in women in the age group for whom data are available from efficacy trials [2]. Studies using post-licensure data from national immunisation programs have been undertaken to compare the effectiveness of one, two or three vaccine doses. The aim of this article is to summarise the results of post-licensure studies assessing HPV vaccine effectiveness by the number of doses and discuss some limitations of these studies.

We performed a literature search and identified 11 published studies examining the post-licensure effectiveness of HPV vaccination by number of doses [3-13]. These studies, conducted in 7 countries within the context of a three-dose schedule of either the bivalent or quadrivalent HPV vaccine, examined the effectiveness by number of doses for three HPV-related endpoints: HPV infections, anogenital warts (AGW), and cervical lesions or abnormal cytology (Table I). The great majority of studies showed that two or three doses significantly decreased the incidence/prevalence of HPV-related endpoints. Several studies also suggest limited effectiveness with one dose. Furthermore, most studies showed a dose-response relationship, although not always statistically significant, between HPV vaccination effectiveness and number of doses.

Greater decreases in HPV-related endpoints were generally observed with three doses, followed by two doses, and one dose. However, there are important caveats when using post-licensure effectiveness studies to understand dose-specific efficacy that could bias results; these should be taken into account when interpreting the findings.

There are important caveats when using post-licensure effectiveness studies to understand dose-specific efficacy that could bias results; these should be taken into account when interpreting the findings.

Girls vaccinated with one, two or three doses are different
Firstly, these post-licensure studies were all conducted in settings of a national threedose recommendation and girls who received one or two doses differed from those completing the recommended schedule. Most of the studies published to date included girls who were vaccinated beyond the routine target age group, in the early years of the vaccination programs. In several studies, the partially vaccinated girls were older at the time of vaccination, had lower socio-economic status, and/or had indicators of earlier sexual exposure (e.g., younger cervical screening, vaccination at a family planning clinic, screening for a sexually transmitted infection). Th erefore, these partially vaccinated girls were at higher risk of HPV infection and related diseases, which biases the studies’ results towards a greater eff ectiveness of three doses compared to one or two doses. Although several studies attempted to control for this bias by adjusting their analyses for some risk factors which diff ered between partially and fully-vaccinated girls, there is likelihood that residual confounding remains (it is often impossible to control for all factors associated with non-completion of a vaccination schedule).

Post-licensure studies examining HPV vaccine effectiveness by number of doses have several challenges that bias the results towards greater effectiveness of three doses compared to two or one dose(s)

Girls infected prior to vaccination are more likely to have incident AGW between the fi rst and third dose than after
Secondly, in population-level databases, it is impossible to identify individuals who were already infected with HPV at the time of vaccination. Since HPV vaccination is prophylactic, it has no curative eff ect on these prevalent infections; this is the reason that HPV vaccination is recommended to pre-adolescents prior to sexual debut and potential HPV infection. However, in reality, a non-negligible proportion of individuals are already infected at the time of vaccination, and this proportion increases with older age at vaccination. AGW is more likely to occur between the 1st and 3rd doses of the vaccine, considering that the median delay between HPV6/11 infection and anogenital warts appearance is 2.9 months [14].

Prevalent infections at the time of vaccination consequently biases towards lower vaccine effectiveness of one and two doses. Furthermore, as previously mentioned, girls vaccinated with one or two doses in the studies were often older when vaccinated and had indicators of earlier sexual exposure. Th ey were thus more likely to have prevalent HPV infections at the time of vaccination, further reducing the eff ectiveness of vaccination with one or two doses (vs three doses). To overcome this problem, researchers have introduced “buff er” periods in their analyses, which delay the case counting to exclude conditions caused by a prevalent infection. For example, in Herweijer et al., the eff ectiveness of 1 dose compared to no vaccination was 16% (p-value=0.06) without any buffer period [3]. However, with a buffer period of only one month (i.e., cases started to be counted 1 month after vaccination), the effectiveness of one dose compared to no vaccination increased to 28% (p-value <0.0001) and eff ectiveness increased to more than 50% with buff er periods greater than 4 months. While ideally buff er periods should be used for eff ectiveness studies, they reduce the number of person-years with one or two doses, which is generally small in post-licensure studies; this results in low statistical power (i.e., insuffi cient power to detect statistically signifi cant diff erences in eff ectiveness between one, two and three doses).

In conclusion, post-licensure studies examining HPV vaccine eff ectiveness by number of doses have several challenges. Th e caveats discussed in this article consistently bias the results towards greater eff ectiveness of three doses compared to two or one dose(s).

Since many countries have recently switched to a two-dose schedule, it will be important to continue to examine the realworld impact of reduced-dose schedules.

Table 1. Studies examining the post-licensure effectiveness of HPV vaccination by number of doses
*cervical lesion include cytology and/or histology outcomes

References
1. World Health Organization. Summary of the SAGE April 2014 meeting. Available at http://www.who.int/immunization/sage/ meetings/2014/april/report_summary_ april_2014/en/. Accessed November 2014.
2. Dobson SR et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA 2013; 309(17): 1793-802.
3. Herweijer E et al. Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma. JAMA 2014; 311(6): 597-603.
4. Dominiak-Felden G et al. Evaluating the early benefit of quadrivalent HPV vaccine on genital warts in Belgium: A cohort study. PLoS ONE 2015; 10(7).
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14. Winer RL et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005; 191(5): 731-8.