Human Papillomavirus vaccination: Immunological and epidemiological studies

Sammanfattning: This thesis has evaluated the immunological- and epidemiological aspects of human papillomavirus transmission dynamics and its effect on circumcision. Effective prophylactic vaccines are based on type-specific neutralizing antibodies. A major neutralizing epitope is defined by the monoclonal antibody H16.V5. To investigate the importance of this epitope for overall immunogenicity of HPV16, we engineered HPV16 virus-like particles devoid of the H16.V5 epitope by site-directed mutagenesis of 10 non-conserved, surface exposed residues. Removal of the V5-defined epitope had only marginal effect on antigenic reactivity with antibodies in sera from infected subjects, but affected immunogenicity in experimental immunization of mice, with reduced induction of both antibody responses and CTL responses. A serological survey of HPV16 antibody prevalence by age and sex in Sweden was performed and used it as a basis for modeling the optimal vaccination strategies in this population. By the year 2055, vaccination of females starting at age 12 in 2008 was most efficient, estimated to prevent 5.8 million cumulative HPV16 infections. Catch-up programs had a strong additional preventive effect. Vaccination also targeting males increased protective effect by about 4 percent, but had lower preventive effect per vaccination given. Addition of an HPV serosurvey to existing models and data has enabled us to estimate effect of different vaccination strategies, optimised to the HPV epidemiology in our population. The age-dependent seroprevalence of HPV6, 11, 16, 18, and 52 infection was investigated and further used to asses the transmission dynamics in a representative Swedish population. Analyses of age-specific prevalence revealed different patterns for high- and low-risk HPV infections between females and males. Circumcision has been reported to protect against infection with human papillomavirus in men, but results have been inconsistent. We followed males in a birth cohort born in Dunedin, New Zealand from age 3 to 32 years. Circumcision was not found to be protective, with the adjusted odds ratio (95% confidence interval) for HPV6/11/16/18 seropositivity among the circumcised compared with the uncircumcised being 1.4 (0.89-2.2).