Human Papillomavirus (HPV) Vaccines: An Interview with Douglas R. Lowy, M.D.

November 20, 2014, by NCI Staff

Douglas R. Lowy, M.D., heads the Laboratory of Cellular Oncology in NCI’s Center for Cancer Research. He and John Schiller, Ph.D., also of the Laboratory of Cellular Oncology, are recipients of the 2014 National Medal of Technology and Innovation—the nation’s highest honor for technological achievement—for discoveries that enabled the development of vaccines against infection by human papillomaviruses.

What are human papillomaviruses?

Human papillomaviruses (HPVs) are a group of more than 150 related viruses. They are called papillomaviruses because certain types cause warts, or papillomas, which are benign (noncancerous) growths. Some types of HPV are associated with certain types of cancer. These are called “high-risk,” oncogenic, or carcinogenic HPVs.

More than 40 types of HPV, including all 12-15 oncogenic types, can be passed from one person to another through sexual contact. Transmission can occur in the genital, anal, and oral regions. About 14 million new genital HPV infections occur each year in the United States. In fact, most sexually active men and women will be infected with at least one type of HPV at some point in their lives. Most HPV infections occur without any symptoms and go away without any treatment over the course of months to a few years. However, infections with oncogenic HPV types that persist for many years can cause cell abnormal ities that may lead to cancer.

Which kinds of cancer are related to infection by human papillomaviruses (HPV)?

Infection by oncogenic HPV types, especially HPV16 and HPV18, is responsible for virtually all cases of cervical cancer, as well as a substantial proportion of cancers of the anus, vulva, vagina, penis, and oropharynx (throat). In the United States, there are about 25,000 HPV-associated cancers each year.   

Are there vaccines to prevent HPV infection?

There are two FDA-approved HPV vaccines. The quadrivalent vaccine (Gardasil) was approved for females in 2006 and for males in 2009. The bivalent vaccine (Cervarix) was approved for females in 2009. Both vaccines are non-infectious subunit virus-like particle (VLP) vaccines composed of the main protein that forms the outer shell of the virus.

Which types of HPV are targeted by the vaccines?

Both vaccines target HPV16 and HPV18, which are responsible for about 70 percent of cervical cancers and an even higher percentage of the HPV-associated non-cervical cancers. In addition, the quadrivalent vaccine targets HPV6 and HPV11, two sexually transmitted HPV types that do not cause cervical cancer but that are responsible for about 90 percent of genital warts.

What is known about the protection offered by HPV vaccines?

The clinical efficacy trials that led to initial FDA approvals were conducted in females 16-23 years old. Among this group, systemic immunization with the vaccines conferred close to 100 percent protection against new infection and disease caused by the HPV types targeted by the vaccines during the 4 years of the trials. The high vaccine efficacy is probably due to several factors, including the strong immunogenicity of the VLPs, the induction of neutralizing antibodies by the vaccine, the exudation of neutralizing antibodies from the tissue to the potential sites of infection, and the high sensitivity of the virus to neutralizing antibodies.

There was also some cross-protection in the trials against infection and disease caused by non-vaccine types. The bivalent vaccine induced more cross-protection against the non-vaccine types than the quadrivalent vaccine, perhaps because the bivalent vaccine is more immunogenic. 

Who is the main target group for HPV vaccination?

Although the vaccines induce strong protection against new infection and disease, they are not effective at treating established HPV infection or disease. Because individuals are at high risk of developing HPV infections soon after initiating sexual activity, the main target group for the HPV vaccine is young adolescents. Recommendations from the US Centers for Disease Control and Prevention (CDC) are that all boys and girls ages 11 or 12 years old get vaccinated. Catch-up vaccination is recommended for males through age 21 and for females through age 26, if they did not get vaccinated when they were younger.

How widely are the HPV vaccines used in the United States?

A variety of issues have led to a lower uptake of the HPV vaccines in the United States than in some other developed nations. This has prompted the CDC to identify barriers to increased uptake and to promote increased uptake. The President’s Cancer Panel has made several recommendations to accomplish this goal. Despite the low uptake in the United States, there has been a reduction in the prevalence of HPV vaccine types.

How long does the protection from HPV vaccines last?

Long-term studies of vaccine efficacy are still in progress. To date, no waning of protection against the targeted HPV types has been seen for either vaccine; thus far, strong protection has been shown to last at least 8 years with the quadrivalent vaccine and at least 9 years with the bivalent vaccine.

Can the vaccines protect against other types of disease caused by HPV infection?

In post-approval studies, the bivalent vaccine has been found to reduce the incidence of cervical dysplasia as well as the prevalence of the HPV types targeted by the vaccine and those non-vaccine types for which some cross-protection was seen in the clinical efficacy trials. In addition, the quadrivalent vaccine reduced the incidence of cervical dysplasia and genital warts and the prevalence of the targeted HPV types. In Australia, where there has been high uptake of the vaccine, the incidence of genital warts was also decreased among young males who were not vaccinated, a reflection of herd immunity induced by the vaccine.

What is known about the safety of HPV vaccines?

Post-licensure safety monitoring of the two vaccines has shown their safety profiles to be similar to those of other licensed vaccines. The vaccines have been used in millions of people in the United States and many other countries. The most common problems have been brief soreness and other local symptoms at the injection site. There are also rare allergic reactions. These problems are similar to those commonly experienced with other vaccines. The vaccines have not been sufficiently tested during pregnancy and, therefore, should not be used by pregnant women.

Are additional HPV vaccines in development?

There has been clinical progress in the development of a second-generation vaccine. Merck has reported at meetings the results of an efficacy trial of an experimental “9-valent” (nonavalent) vaccine, which targets HPV16 and HPV18 (the HPV types responsible for most cases of cervical and other HPV-caused cancers), plus five additional oncogenic HPV types, plus HPV6 and HPV11. Together, the seven oncogenic HPV types targeted by the vaccine are found in almost 90 percent of cervical cancers. In this trial, the quadrivalent vaccine was used as the control. Compared with the quadrivalent vaccine, the 9-valent vaccine was highly (close to 97 percent) effective at preventing disease and persistent infections caused by the five oncogenic types not included in the quadrivalent vaccine. The 9-valent vaccine was also not inferior to the quadrivalent vaccine in terms of protection against the four HPV types in the quadrivalent vaccine. The FDA is currently considering whether to license this experimental vaccine.

For the approved vaccines, how many doses are given?

In the clinical efficacy trials that led to approval, individuals were given three vaccine doses over a 6-month period, so the regulatory approval was for three doses. However, the immune response in young adolescents (9-14 years old) was sufficiently stronger than that of the women in the efficacy trials that two doses, separated by 6 months, in young adolescents produced an immune response that was comparable to that of three doses in 16-25-year-olds. Post-hoc analysis of the data from one efficacy trial of the bivalent vaccine also indicated that even one or two doses were as effective as three doses at conferring protection throughout the 4-year trial period. These data recently led the European Medicines Agency (the “European FDA”) to approve the vaccines for two doses in young adolescents and the adoption of this standard by the World Health Organization. However, the current recommendations in the U.S. remain at 3 doses, even for young adolescents.

What is known about the effects of a single dose of the vaccines?

The ability of even a single dose of the bivalent vaccine to confer 4 years of strong protection has been correlated with stable HPV antibody levels during years 1-4. Such stable antibody levels are without precedent in a subunit protein vaccine, such as the HPV vaccine. The findings, which are probably related to the structure of the VLPs, raise the possibility that even a single dose of the current vaccine might be able to confer long-term protection. It would probably be necessary to undertake a clinical efficacy trial of one dose before it might be adopted as standard of care for young adolescents. Reducing the number of vaccine doses would simplify the logistics and costs of vaccination, which could have a major impact on uptake of the HPV vaccine in the developing world, where 85 percent of cervical cancers occur as well as 88 percent of deaths from the disease.

Thank you, Dr. Lowy, and congratulations on your award!