PART 5

HIGH-PRIORITY RESEARCH TO ADVANCE PREVENTION OF HPV-ASSOCIATED CANCERS

HPV vaccines and their public health benefits were enabled by decades of laboratory, clinical, and population-based research. Additional research in several areas could increase the impact of HPV vaccination. These include the potential for a two- or one-dose vaccine and better vaccines, as well as improved ways to communicate about HPV vaccines. Finally, it is not too early to anticipate the time when HPV vaccination is disseminated widely across populations, and to ask how cervical cancer screening guidelines will then need to be changed.

Investigate More Convenient Dosing Schedules for Current Vaccines

Develop Next-Generation Vaccines That Provide Broader Protection and/or Are Easier to Store and Administer

Explain the Natural History of Oropharyngeal HPV Infections

Develop More Effective Ways to Communicate About HPV-Associated Diseases and HPV Vaccines

Determine How Best to Integrate HPV Vaccination with Cervical Cancer Screening

Investigate More Convenient Dosing Schedules for Current Vaccines

Recommended dosing regimens for HPV vaccines—three doses over six months—are expensive and create logistical and other difficulties for organizations that purchase and administer them. Confirmation that extended dosing schedules and/or fewer vaccine doses adequately protect against HPV infections would have enormous implications for HPV vaccine programs in both high- and low-resource settings. Evidence that one or two doses are sufficient to protect against particular HPV infections could be an important factor in increasing HPV vaccine uptake in the U.S. and around the world.

EXTENDED DOSING SCHEDULE

In the U.S., many adolescents who initiate the HPV vaccine series do not complete it within the recommended six months or at all.[1,2] This is in part because most adolescents do not visit their providers this frequently. The six-month schedule can be even more challenging in low-resource settings with suboptimal healthcare delivery infrastructure. Spreading doses out over one to two years would ease the logistical challenges of HPV vaccine delivery in both high- and low-resource settings. In the U.S., a two-year schedule would mean that adolescents could receive one dose at each of three annual preventive visits. In low-income countries, an extended schedule may provide an opportunity to incorporate HPV vaccination into existing vaccine programs.[3] A study of adolescent girls in Vietnam found similar immune responses to Gardasil® whether the three doses were spread over 6, 9, 12, or 24 months.[3] However, additional research may be needed to determine whether this protection is long-lasting and/or whether similar results will be seen in other populations and with Cervarix®.

FEWER DOSES

Increasing evidence suggests that fewer than three HPV vaccine doses may be efficacious. In one clinical trial, women who received only one or two doses of Cervarix® were protected against persistent cervical infections with HPV16 and 18.[4] Antibodies against HPV16 and HPV18 remained stable for up to four years in women who received one dose, suggesting that even a single dose of the vaccine may induce long-term protection.[5] Studies in Canada[6] and Vietnam[3] suggest that Gardasil® also may induce lasting immunity to target HPV types in adolescent girls after only two doses. While these results are promising, additional research is needed to confirm that one- or two-dose protection is long-lasting and occurs in other populations (e.g., other age groups, men).

Insight into the effectiveness of fewer than three doses likely will be gained as adoption of HPV vaccines increases in a variety of settings around the world. Some regions, including parts of Canada,[7,8] have implemented two-dose regimens. In the U.S., NCI and CDC are monitoring results of ongoing clinical trials. It is critical that mechanisms are in place to help FDA reach decisions about dose and schedule as soon as valid data are available. The Panel recommends strongly that funding agencies place a very high priority on answering critical questions about HPV vaccine dose and scheduling.

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Develop Next-Generation Vaccines That Provide Broader Protection and/or Are Easier to Store and Administer

Efforts already are underway to improve the effectiveness of currently available HPV vaccines. A vaccine under development by Merck, V503, is designed to protect against the four HPV types covered by Gardasil® and five additional cancer-causing HPV strains (31, 33, 45, 52, and 58). In a Phase III clinical trial of V503, the vaccine prevented approximately 97 percent of cervical, vaginal, and vulvar precancers caused by these five strains in women who were not infected with these HPV types prior to vaccination. The vaccine also generated immune responses to HPV6, 11, 16, and 18 that were comparable to those generated by Gardasil®.[9] V503 has potential to prevent 90 percent of the world's cervical cancer cases, as well as provide broader protection against other anogenital and oropharyngeal cancers caused by HPV. Other research groups are experimenting with the inclusion of different viral proteins in an effort to achieve broader protection against more HPV types.[10]

Changes in vaccine formulation that would make HPV vaccines easier to administer or store also could increase vaccine coverage. For example, dissemination of the vaccine in low-resource settings would be more feasible if vaccines did not need to be refrigerated. A noninjected form of the vaccine also would ease delivery.

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Explain the Natural History of Oropharyngeal HPV Infections

Over the past several decades, research has yielded extensive knowledge about how HPV infections of the cervix progress to invasive cervical cancer.[11] There still is much to be learned about how HPV infections lead to cancer at other sites. Knowledge of the natural history of oropharyngeal HPV infection is particularly weak, in large part because the location of the oropharynx makes it difficult to collect tissue samples for study. Limited knowledge about oropharyngeal precancers creates challenges for testing the efficacy of HPV vaccines in preventing oropharyngeal cancers in clinical trials. There is an urgent need to develop biomarkers or other markers that would provide better ways to understand the natural history of oropharyngeal cancers.[12] Natural history studies of the oropharynx would benefit from technologies that permit noninvasive detection and characterization of lesions.

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Develop More Effective Ways to Communicate About HPV-Associated Diseases and HPV Vaccines

HPV vaccines are a safe and effective way to prevent multiple cancers, genital warts, and RPP. Surveys of physicians, parents, and other caregivers indicate a lack of understanding about HPV-associated diseases and the safety, efficacy, and need for HPV vaccines.[2,13-20] Communication and behavioral research are needed to determine the best ways to convey messages to important stakeholders involved in decisions about HPV vaccination. This includes research using mobile health interventions and behavioral economics approaches. Specific strategies and messages should be tested and optimized for different populations, with consideration of sociocultural factors, specific barriers experienced by particular populations, numeracy, and health literacy. Research should focus on both initiation and completion of the vaccine series. Research also should inform development of tools that can be used by providers to facilitate communication with parents and adolescents. The process by which parents and caregivers accept vaccines for their children and agree for them to be vaccinated is complex and involves health providers, parents or other caregivers, and adolescents themselves. Better understanding about how each step in the process is influenced could lead to more effective interventions.

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Determine How Best to Integrate HPV Vaccination with Cervical Cancer Screening

Though widespread adoption of HPV vaccines has potential to reduce cervical cancer incidence and mortality significantly, cervical cancer screening programs remain an essential part of cervical cancer control programs. However, with time, modification of screening practices likely will be warranted. As rates of infection with the most oncogenic forms of HPV decline, fewer abnormal screening tests will occur, and those that do occur likely will be due to low-grade lesions with low probability of progressing to invasive cancer. A higher proportion of abnormalities identified through screening could result in unnecessary clinical interventions associated with risks for patients as well as higher costs.[21,22]

Modification of screening guidelines may help reduce unnecessary risks and costs. Currently, women are advised to begin screening at age 21 and be screened every three to five years, depending on the testing used.[23-25] As vaccination diffuses across the population, it may be appropriate for women to begin screening at later ages, be screened less often, and/or move to primary HPV-based screening. Any modifications to screening guidelines must be based on solid evidence. As HPV vaccine use increases, research is needed to monitor population changes in risk of cervical cancer and precancers. Ideally, studies should determine how risks differ for unvaccinated women compared with women who were vaccinated prior to initiation of sexual activity. This type of research will benefit from highly integrated data systems that include linkages among immunization information systems, screening registries, and cancer registries.

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