Association of Varying Number of Doses of Quadrivalent Human Papillomavirus Vaccine With Incidence of Condyloma

JAMA   
February 12, 2014, Vol 311, No. 6
http://jama.jamanetwork.com/issue.aspx

Association of Varying Number of Doses of Quadrivalent Human Papillomavirus Vaccine With Incidence of Condyloma
Eva Herweijer, MSc1; Amy Leval, PhD2,3; Alexander Ploner, PhD1; Sandra Eloranta, PhD1; Julia Fridman Simard, ScD4; Joakim Dillner, MD1; Eva Netterlid, PhD5,6,7; Pär Sparén, PhD1; Lisen Arnheim-Dahlström, PhD1
Author Affiliations
JAMA. 2014;311(6):597-603. doi:10.1001/jama.2014.95.
http://jama.jamanetwork.com/article.aspx?articleid=1829685

ABSTRACT
Importance
Determining vaccine dose-level protection is essential to minimize program costs and increase mass vaccination program feasibility. Currently, a 3-dose vaccination schedule is recommended for both the quadrivalent and bivalent human papillomavirus (HPV) vaccines. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, condyloma related to HPV types 6 and 11 is also prevented with the quadrivalent vaccine and represents the earliest measurable preventable disease outcome for the HPV vaccine.

Objective
To examine the association between quadrivalent HPV vaccination and first occurrence of condyloma in relation to vaccine dose in a population-based setting.

Design, Setting, and Participants
An open cohort of all females aged 10 to 24 years living in Sweden (n = 1 045 165) was followed up between 2006 and 2010 for HPV vaccination and first occurrence of condyloma using the Swedish nationwide population-based health data registers.

Main Outcomes and Measures
Incidence rate ratios (IRRs) and incidence rate differences (IRDs) of condyloma were estimated using Poisson regression with vaccine dose as a time-dependent exposure, adjusting for attained age and parental education, and stratified on age at first vaccination. To account for prevalent infections, models included a buffer period of delayed case counting.

Results
A total of 20 383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an IRR of 0.18 (95% CI, 0.15-0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21-0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20-0.49), which corresponds to an IRD of 384 cases (95% CI, 305-464) per 100 000 person-years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346-454) and for 3 doses, 459 cases (95% CI, 437-482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2-117) per 100 000 person-years.

Conclusions and Relevance
Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation.

Human papillomavirus (HPV) types 16 and 18, two HPV types included in the prophylactic HPV vaccines, are implicated in multiple cancer outcomes, including cervical cancer.1,2 The quadrivalent HPV vaccine also protects against HPV types 6 and 11, which cause about 90% of condylomas, also referred to as genital warts.3 Condyloma is the first HPV-related disease end point that can be measured after quadrivalent HPV vaccination because of its short incubation time of between 1 and 6 months.4– 6

Between 2007 and 2011, Sweden had a partially subsidized, opportunistic HPV vaccination program for girls aged 13 to 17 years. Vaccine coverage within this target group was about 25% in 2010.7 Ninety-nine percent of girls vaccinated received the quadrivalent vaccine. In 2012, a school-based vaccination program was launched for girls aged 10 to 12 years, with a catch-up program for girls aged 13 to 18 years, all free of charge.

Both the bivalent and quadrivalent vaccines currently have a 3-dose schedule, which is associated with increased cost and other program feasibility issues.8,9 Dose efficacy has been widely discussed as a fundamental factor in decisions regarding vaccination strategies.8,10,11     The overall protective effects of HPV vaccination programs and requisite efforts appropriate for ensuring complete 3-dose vaccinations are unclear. Small clinical trials have reported measures of vaccine efficacy with less than 3 doses.8,12,13

In contrast to vaccine efficacy trials, population-based studies can examine reduction in disease end points and are more likely to reflect the vaccinated population.14,15 Population-based studies measuring HPV-related diseases provide essential complementary information to studies of vaccine dose efficacy, which primarily assess nondisease end points such as immune response or are designed so that efficacy comparisons cannot be made between multiple dose levels. Registry data in Sweden include unique information on vaccination dose dates for the entire population. The aim of this study was to assess the association between quadrivalent HPV vaccination and condyloma per vaccine dose among young females in a population-based setting.