Immune responses to HPV vaccines: Understanding antigenic relationships between genotypes to inform control strategies

Cervical screening (the ‘smear test’) helps prevent cervical cancer by finding early signs of abnormalities that can be dealt with before they progress to cancer. Another way to prevent disease is to block infection by the human papillomavirus (HPV) types that can lead, usually after many years, to the development of cervical cancer. Vaccines are available that protect women from two of the most common types of HPV which should lead to a reduction of about 70% of cervical cancers. However, as there are other HPV types that also cause cervical cancer it will be necessary to maintain the cervical cancer screening programme, a significant recurrent investment by the NHS, to protect the UK population from this devastating disease. In this study, we will examine the antibodies produced by animals and humans in response to HPV immunisation and work out how effective the vaccines are against other types of HPV. This information will be used to map the relationships between HPV types and help predict what will happen to each HPV type when the population is vaccinated. We will also use this model to describe potential gaps in protection that can be filled by the next generation of vaccines. This information may also help to target limited NHS resources to those individuals who may not be sufficiently protected by vaccination.

The recent development of vaccines against the Human Papillomavirus (HPV) represents one of the most significant advances in human vaccination for many years. Two vaccines targeted against the principal causes of cervical cancer (HPV genotypes 16 and 18) have now been licensed and are being introduced in several countries following highly successful clinical trials. The UK Department of Health announced recently its agreement, in principle, with Joint Committee on Vaccination and Immunisation advice to introduce an HPV vaccination programme involving routine vaccination of girls around 12-13 years of age subject to favourable peer reviewed cost-effectiveness analyses. These vaccines promise to reduce dramatically the considerable global burden of cervical cancer. However, as humoral immunity to HPV is predominantly type-specific and the vaccine-incorporated oncogenic genotypes account for only ~70% of cervical cancers, the burden of disease due to other HPV types is likely to remain significant. While the diversity between HPV types is well recognised at the genetic level it is still unclear how, and to what extent, these differences impact on functionally-relevant antigenic relatedness. While monitoring incident type-specific HPV infection at a population level once routine HPV vaccination becomes implemented will improve predictions of cross-protection, true vaccine-induced cross-reactivity can only be determined empirically. Our goal is to build a comprehensive relational antigenic map of the HPV major capsid protein, using data generated from functional (neutralisation) assays, by making use of large panels of mono- and poly-specific sera. Serum samples will be obtained from human vaccines (N~400) and from animals (mice, N~100 and rabbits, N~20). Once the degree of antigenic relatedness of distinct HPV genotypes has been mapped, we will estimate the expected cross-protection of vaccines at a population level. We will also develop, as an integral part of the project, standards and reference materials, and assay protocols to be made available internationally to support HPV vaccine research. This work will contribute to priority setting for subsequent generations of HPV vaccines and to assessing the potential impact of future vaccination and cervical screening strategies.