How did discoveries made with bovine papillomavirus help scientists develop the human papillomavirus vaccine? Doug Lowy discusses his journey that began with basic research and led to the production of the HPV vaccine.

Julie's Biggest Takeaways

In the early 1950s, the U.S. was a high-incidence country for cervical cancer. Through application of screens using the Pap smear, doctors have been able to catch and excise suspicious tissue, leading to a significant drop in incidence. Cervical cancer remains high-incidence in low- and middle-income countries; in high-incidence countries, cervical cancer is the most common form of HPV-associated cancer. In the U.S., cervical cancer represents around 50% of the HPV-associated cancers, with others like penile, anal, and oropharyngeal cancers also represented. Henrietta Lacks, the woman from whom HeLa cells were derived, had a cervical adenocarcenoma caused by HPV-16. The viral DNA had integrated near the myc oncogene to generate high expression of this oncogene. The cell lines have been growing for decades but the epigenetic changes from HPV infection have led to a dependence of the cells on E6 and E7; if they are blocked or removed, the HeLa cells undergo apoptosis. Lowy's work on bovine papilloma virus (BPV) played a key role in development of the HPV vaccine. Other researchers attempting to generate a neutralizing response to the HPV capsid failed, but Lowy and his colleague Reinhard Kirnbauer had successfully achieved neutralization using BPV. By comparing HPV and BPV sequences, Lowy realized there was a single amino acid change in the HPV-16 strain that was being used as a lab standard strain; fixing this restored capsid self-assembly, led to immunogenicity and provided the basis for the HPV vaccine. HPV L1 capsid protein has a repeating structure that induces a very high level of immune protection. Protection is so high that it is sterilizing, meaning that exposed individuals prevent any infection, not just disease. This may serve as the basis for a new strategy, using repeating structures such as ferretin in vaccine development. The incubation between infection and development of cancer can take decades, and the vaccine has not been on the market long enough to assess a difference in cancer incidence. It has resulted in a decrease in cervical dysplasia, the endpoints used in cervical cancer screening via pap smear, but no cancer reduction has been observed yet.

Links for this Episode:

• Harold zur Hausen Nobel Prize for association between HPV and cancer
• Lowy D. HPV Vaccination to Prevent Cervical Cancer and Other HPV-Associated Disease: From Basic Science to Effective Interventions. Journal of Clinical Investigation. Jan 2016.
• Schiller J. and Lowy D. Explanations for the High Potency of HPV Prophylactic Vaccines. Vaccine. August 6 2018.
• VAERS Vaccine Adverse Event Reporting System
• ASM Article: A Brief History of Cancer Virology
• JHU Press: Vaccines Did Not Cause Rachel's Autism