Lowy started his presentation by discussing the epidemiology of HPV-associated cancers. He notes that cervical cancer mortality rates will continue to increase in less developed regions of the world, with 251,000 cervical deaths in 2015 expected to reach 363,000 in 2030. Indeed, less developed regions account for ~90% of the worldwide cervical cancer deaths. In these regions, cervical cancer accounts for 10% of all female cancer-related deaths and represents 90% of HPV-associated cancers. In the US, HPV infection induces several types of cancer and affects both sexes: the annual number of total HPV-positive cancer is 31,000, 65% occurring in women, 35% in men. Additional points relating to HPV infection among patients in the US:
- HPV16/18: accounts for 70% of cervical cancers, and 90% of non-cervical cancers
- Pap screening has reduced cervical cancer incidence by ~80%
- Incidence of HPV-positive oropharynx cancer between 1988-2004 has increased >3-fold
- 63% of penile cancers are HPV positive
According to Lowy, it is important to choose an appropriate molecular target for a preventative HPV vaccine. Induction of neutralizing antibodies is usually the main protective activity; HPVs contain viral oncogenes (E5, E6, and E7) and one needs a subunit vaccine lacking oncogenes. L1 and L2 are two HPV proteins that can induce neutralizing antibodies, where L1 contains the most immunogenic neutralization epitopes. Lowy and his research group’s hypothesis when developing vaccines was: L1 self-assembles makes empty particles with correct conformation and induces high levels of neutralizing antibodies. Three different HPV L1 vaccines have been FDA approved:
Each of these vaccines was initially approved for three doses in 9-26 year olds, however the new generation of Gardasil (Gardasil-9) was approved in 2016 for two doses for 9-14 year olds since younger adolescents make a stronger immune response. As Lowy notes, high efficacy of HPV L1 vaccines against new cervical precancer and genital warts by vaccine-targeted types has been reported in several randomized trials, with efficacy rates ranging from 96.3-100%.
The goals of HPV vaccination are twofold: directly reduce the risk of infection and disease with vaccines, and indirectly reduce risk by reducing the prevalence of “HPV vaccine types” in the general population (herd immunity). The herd immunity concept has been demonstrated by decreased incidence of genital warts in heterosexual Australian men following female HPV vaccine implementation in 2007. These results have not necessarily been recapitulated in US men, although decreased infection rates are encouraging among women. According to Dr. Lowy, in the US, the reason for poorer outcomes is secondary to under-utilization of HPV vaccination and mismatch between cervical cancer mortality rates and vaccine uptake: the highest cervical cancer mortality rates are located in the Southeast and southern Midwest, whereas the highest vaccination rates are located on the West coast and Northeast.
In addition to statements from the CDC, NCI-designated cancer centers are urging HPV vaccination for prevention of cancer. A statement from January 2016 notes “HPV vaccination represents a rare opportunity to prevent many cases of cancer that is tragically underused. As national leaders in cancer research and clinical care, we are compelled to jointly issue this call to action.” A similar statement was recently (May 23, 2018) issued by Dr. Tedros Adhanom Ghebreyesus, the Director-General of the World Health Organization: “We will eliminate cervical cancer, one of the greatest threats to women’s health. We have the tools and now we have the political commitment.” The goals of these global governing bodies are to avert 365,000 cases and 150,000 deaths worldwide through vaccination. However, as Lowy notes, the highest rates of non-vaccination occur in upper-middle and lower middle-income nations, where the risk of infection and mortality are the highest. Unfortunately, the predictions are that the cumulative cervical cancer cases over the next 65 years is 19 million cases and 10 million deaths worldwide.
One of Lowy’s postulation is: Might a single HPV vaccine dose confer years of protection? Indeed, in post-hoc analyses of randomized controlled trials, 1, 2, or 3 doses of bivalent vaccine confer at least 7 years of protection against incident HPV 16/18/31/33/45 infections. Even one dose of HPV vaccine induces levels of high avidity antibodies comparable to those receiving three doses. To evaluate this prospectively, a recently designed randomized controlled trial will test the efficacy of 1 vs 2 doses of vaccine. This will be a four-arm trial comparing 1 vs 2 doses of Cervarix, and 1 vs 2 doses of Gardasil-9, requiring 5,000 females 12-15 years of age per arm, expecting to take four years to complete. The potential impact of demonstrating one dose of vaccine conferring strong protection is massive: the US could save >$300 million each year in vaccine costs, and it would be more feasible to control the worldwide public health problem of cervical cancer and other HPV-associated cancers.
Lowy concluded this presentation with several take-home messages:
- Basic research led to the identification of HPV as the cause of several cancers and to the development of the HPV vaccine
- The high immunogenicity and efficacy of the HPV vaccine may make it possible to induce long-term protection by a single vaccine dose
- Control of HPV-associated cancer as a worldwide public health problem may soon be feasible
Presented by: Douglas Lowy, MD, Laboratory of Cellular Oncology, Center for Cancer Research, NCI, Bethesda, MD, USA
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA