Understanding and learning from the success of prophylactic human papillomavirus vaccines

Abstract

An estimated 5% of human cancers are caused by human papillomavirus (HPV) infections, and most of these cancers are of the cervix. Two prophylactic HPV vaccines that target the two most oncogenic virus types, HPV16 and HPV18, are now commercially available. In controlled clinical trials, the vaccines proved to be effective at preventing incident anogenital infection and the associated neoplastic disease that is induced by these virus types. Here, we highlight the specific aspects of HPV biology and vaccine composition that are likely to contribute to the efficacy of these vaccines, and we discuss how these particular features might or might not be relevant for the development of effective vaccines against other sexually transmitted viruses such as HIV and herpes simplex virus (HSV).

Figure 1 |. Prevalence of human papillomavirus-associated cancers.

a | Worldwide annual number of reported cancer cases for each of the indicated body sites. b | Annual number of reported cancer cases in the United States for each of the indicated body sites.

Figure 2 |. Mouse cervicovaginal-challenge model to detect protection by passively transferred antibody.

Serum is withdrawn from a mouse that has been vaccinated with human papillomavirus (HPV) virus-like particles (VLPs); the serum is diluted (step 1) and transferred by intraperitoneal injection into a naive mouse (step 2). After 24 hours, serum from the recipient mouse is withdrawn, and the in vitro neutralization titre of this serum (determined by neutralization of pseudovirus infectivity) is measured (step 3). The recipient mouse is then challenged by intravaginal instillation of luciferase-expressing HPV pseudovirions (step 4). After 2 days, the extent of infection is assessed by intravaginal instillation of the luciferase substrate, luciferin (step 5). The luciferase catalyses an ATP-dependent reaction that results in the emission of light by luciferin. By measuring the amount of light emitted, the degree of infection with HPV pseudovirions can be estimated for the recipient ‘immune’ mouse. As a comparison, the same procedure is carried out using serum withdrawn from a mouse before vaccination with VLPs; the recipient mouse in this case is referred to here as ‘pre-immune’.

Figure 3 |. Mechanism of infection of cervicovaginal epithelium by human papillomavirus, and infection inhibition by virus-like particle-induced antibodies.

a | Human papillomavirus (HPV) virions cannot bind or infect intact squamous epithelium. They must first bind the basement membrane via heparan sulphate proteoglycans. Then, in a process that takes several hours, they must undergo a series of conformational changes, beginning with furin-mediated cleavage of the minor capsid protein, L2 (yellow), to expose their receptor-binding site on the major capsid protein, L1 (blue), followed by binding to the cell surface receptor and infection of basal epithelial keratinocytes. b | High levels of virus-like particle (VLP)-induced antibodies prevent attachment of the virus to the basement membrane, and this in turn prevents the conformational changes required for cell surface binding. Virus-antibody complexes associate with neutrophils in the cervicovaginal mucus. c | Low levels of VLP-induced antibodies permit basement membrane attachment and the conformational changes leading to furin-mediated L2 cleavage, but they prevent a stable association of the virion with the cell surface. N, amino.