Type-specific human papillomavirus antibodies : detection, characterization and application in seroepidemiology

Sammanfattning: Background: Human Papillomavirus (HPV) is a sexually transmitted DNA virus that causes several human cancers, notably cervical and other anogenital cancers. The antibody response to this virus is of interest both because knowledge of the antigenic structures that induce protective immunity forms the basis for prophylactic vaccine development and because it forms the basis of seroepidemiology, the method of choice for studies of HPV infectivity, of HPV spread in populations and of cancer risks following HPV exposure. Detection: Sixty-five to 75% of women with concomitant presence of HPV 16, 18 and 33 DNA in cervical brush samples were also found to have type-specific serum IgG to the corresponding HPV capsid. Typespecific IgA to HPV was also detected in cervical mucus samples. The most commonly detected isotypes of serum antibodies were IgG1 and IgA. Seropositivity for IgG or IgG1 correlated strongly with the life-time number of sexual partner, whereas positivity for IgA correlated more with recent number of sexual partners. This is in line with the known stability of serum IgG to HPV on long-term follow-up and suggests that IgG is a marker of life-time HPV exposure, whereas IgA may mark more recent or active infection. Characterization: The serum IgG response to intact HPV capsids could, for more than 75% of reactive human serum samples, be completely blocked with a single monoclonal antibody, indicating that intact HPV particles expose a single irnmunodominant type-specific epitope. Applications in Seroepidemiology: The availability of a type-specific serological marker of lifetime cumulative HPV exposure enabled elucidation of fundamental aspects of the epidemiology of HPV infection. In a hospital-based case-control study, the invasive cervical cancer risk after exposure to HPV was found to be increased, both among subjects exposed to HPV type 16, 18 and 33. In a population-based case-control study, the risk for the cervical cancer precursor, Cervical Intraepithelial Neoplasia grade 3 (CIN 3), was increased among HPV 16-exposed subjects. The risk for cervical cancer was found to be increased among HPV 16 IgG or IgG1 seropositive persons for >10 years before diagnosis of cancer in a prospective study. The cumulative exposure to HPV among pregnant women in Stockholm, Sweden, was found to have increased 1.5-fold from 1969 to 1983, but has remained stable during the 1980s. Antagonism between the benign HPV type 6 infection and the oncogenic HPV type 16 infection in cervical carcinogenesis was detected: HPV 16 exposure did not confer any excess risk for cervical cancer among HPV 6 seropositive women. Conclusion: The identification of a major irnmunodominant, neutralizing type-specific epitope on the HPV particle is of interest for design and evaluation of prophylactic HPV vaccines and has furthermore provided the necessary tool for the study of the epidemiology of HPV infection. Increased cancer risks associated with exposure to 3 major HPV types were found. An increasing trend over time in the spread of the infection and the existence of antagonism between benign and oncogenic HPV types were also described.