HPV vaccination to prevent cervical cancer and other HPV-associated disease: from basic science to effective interventions

Abstract

Identification of HPV infection as the etiologic agent of virtually all cases of cervical cancer, as well as a proportion of other epithelial cancers, has led to development of three FDA-approved multivalent prophylactic HPV vaccines composed of virus-like particles (VLPs). This essay describes the research and development that led to the VLP vaccines; discusses their safety, efficacy, and short-term effect on HPV-associated disease; and speculates that even a single dose of these vaccines, when given to adolescents, might be able to confer long-term protection. The HPV field exemplifies how long-term funding for basic research has lead to clinical interventions with the long-term potential to eradicate most cancers attributable to HPV infection. Although this essay is the result of my receiving the 2015 Harrington Prize for Innovation in Medicine from the Harrington Discovery Institute and the American Society for Clinical Investigation, this clinical advance has depended on the research of many investigators, development of commercial vaccines by the pharmaceutical companies, and participation of many patient volunteers in the clinical trials.

Figure 3. Relationship between the number of HPV vaccine doses received and the HPV16 VLP antibody geometric mean titers during a 48-month trial of the bivalent vaccine in women in Costa Rica.

Women who received only one dose had stable antibody titers between months 12 and 48. In post-hoc analyses, vaccine efficacy was similar regardless of the number of doses given (6). Three doses of the bivalent vaccine were given at months zero, one, and six; two doses were given at months zero and six; and one dose was given at month zero. Asterisks indicate the months the vaccine was given. Reproduced with permission from The Lancet Oncology (50). For more information, see ref. and above.

Figure 2. HPV VLP types in the various HPV vaccines.

HPV VLP types (HPV6, HPV11, etc.) in the bivalent (Cervarix), quadrivalent (Gardasil), and 9-valent (Gardasil 9) vaccines are shown, with the approximate percentage of genital warts or cervical cancer attributable to the grouped HPV types. Reproduced with permission from The Lancet Oncology (50).

Figure 1. Assembly of L1 VLP vs. assembly of authentic virus.

Inside cells, five L1 monomers (5×) self-assemble to form a capsomere, and 72 capsomeres (72×) then self-assemble to form a VLP. In authentic virus, the capsid is composed of both L1 and L2, and it surrounds the 8-kb double-stranded (ds) viral DNA genome. L1, the PV major capsid protein; L2, the PV minor capsid protein. Reproduced with permission from The Lancet Oncology (50).