An article in the October
2005 issue of “PAP/NGC Programs Review” presented the background and state of the art for human papillomavirus prophylactic vaccines in development (“HPV Vaccines—Trying to Fill the Pap Gap”).
Since the publication of that review, substantial new information has
become available and new issues have been raised. Hence, a general
update on the subject follows:
On June 8, 2006, the Merck quadrivalent vaccine, Gardasil, was approved by the Food and Drug Administration for use in girls and young women, ages 9 to 26 years. In clinical trials, this vaccine has shown virtually 100 percent effectiveness in preventing lesions of cervical intraepithelial neoplasia (CIN), due to HPV types 16 and 18, and anogenital warts due to HPV types 6 and 11, in women not previously infected by one of the four covered HPV types. Studies showed that in cases of infection present at the time of vaccination, the course of that infection in process may not be affected. Gardasil requires three doses and is administered via an intramuscular route to the upper arm or thigh. The recommended sequencing of doses is at time zero, followed by doses at two- and then six-month time intervals. The Merck catalog price is $120/dose, for a total vaccination cost of $360.00.1
Subsequent to the FDA’s approval, more than 30 countries have approved Gardasil for use in their populations. These include the countries of the European Union, Canada, Mexico, Australia, New Zealand, Taiwan, and Brazil. On June 29, 2006, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices unanimously voted to recommend vaccination in 11- to 26-year-old females, with the 9–10 year age group added at the individual physician’s discretion. The advisory committee recommendation noted that prior Pap or HPV testing was not necessary before vaccination, and that individuals could receive the vaccine regardless of a prior positive HPV or abnormal Pap test. In addition, on Nov. 1, 2006, Gardasil was added to the CDC’s
Vaccines for Children Contract, meaning that the vaccine would be made
available to girls and women, ages 9 to 18, who are Medicaid-eligible,
un- or underinsured, or Native American. An additional Merck initiative
will make the vaccine available to women 19 years of age or older who
are uninsured or unable to pay themselves. Private insurers have also
been quick to provide coverage: Reportedly 94 percent of eligible privately
insured lives are now covered for the vaccine.1-4 (However,
anecdotes to date suggest that private insurers’ reimbursement levels
may not always be at the level required to cover completely the cost
of vaccine and administration.)
On the horizon is another HPV vaccine, that being Cervarix from GlaxoSmithKline. Phase III trials for this divalent (HPV types 16 and 18) vaccine have shown highly efficacious results similar to Gardasil. FDA and European Union regulatory decisions on this vaccine are anticipated in the near future.5
Though cervical cancer prevalence and mortality are relatively low in developed countries—a direct result of screening programs—screening for and treatment of precursor lesions remain a huge expense that could be reduced substantially by widespread vaccine use. However, in underdeveloped countries, cervical cancer is still a major cause of death. The World Health Organization estimates that nearly 300,000 women worldwide die from cervical cancer each year. Use of the vaccine in these populations gives significant hope for a reduction in that number. There are, however, important issues that need to be addressed regarding implementation in both settings.
In developed countries, where cost and availability are less of a concern, the most likely issues will be cultural and attitudinal. Will parents object to a vaccine against a sexually transmitted disease? What types of educational approaches will work best to overcome negative impacts? Data suggest that education aimed at highlighting the risks of HPV infection and the benefits of vaccination will be most successful.6 The role of the legislative process may also be important to adoption. This is illustrated by the Sept. 21, 2006 decision of the Michigan State Senate, which passed a bill indicating that immunization should occur for all girls entering the 6th grade.7
In underdeveloped countries, the issues are significantly different. In this setting, cost and access become major drivers of acceptance. At the current list price, widespread implementation would not be possible. In addition, prioritization of needs in conjunction with other health issues such as malaria, tuberculosis, and AIDS may not favor allocating scarce resources to HPV vaccination. To study these issues and promote a smooth introduction of the vaccine, the Bill and Melinda Gates Foundation awarded a $27.7 million grant to the Programme for Appropriate Technologies in Health organization on June 5, 2006. PATH is planning study projects in India, Peru, Uganda, and Vietnam.7
Unanswered questions about the vaccines remain:
- How long will the immunity last and will
booster shots be necessary to retain efficacy? Data from both vaccines
show immunity out to about five years with antibody titers remaining
elevated. This finding suggests that immunity will last longer—but
how long is as yet undetermined.5
- Should males be vaccinated too? Modeling
data suggest that through “herd immunity,” vaccination of both sexes
will increase the overall efficacy of vaccination programs. Only 60
percent to 75 percent of the full effect possible will be achieved
by vaccinating females alone. However, as of yet, data on efficacy
and safety in males have not been presented.8
- Is there cross-reactivity of the vaccine
with other cancer-related HPV types? Data from the GlaxoSmithKline
vaccine show some cross-reactivity, or potential protection, against
HPV types 45 (closely related to type 18) and 31 (closely related to
- How will the vaccine work in the HIV-infected
or immunocompromised populations? This question is as of yet not completely
answered and has significant ramifications for use of the vaccine in
underdeveloped countries with a high prevalence of HIV infection.9
Despite these concerns, the vaccine’s approval
and seemingly rapid acceptance should have a significant impact on
precancerous conditions and cancer in the future. In the meantime,
recommendations for screening in the populations not eligible for the
vaccine remain the same. Screening recommendations for vaccinated women
have not yet been made, though it is imperative that screening continue
in this population. The vaccines do not prevent infections from other
high-risk viral types and failures due to improper administration of
the vaccine, and as yet undetermined clinical factors will cause continued
incident disease, albeit at a much lower level, in the vaccinated population.
Recommendations in vaccinated women may come in the form of HPV testing
(type-specific testing to determine vaccine efficacy will become more
important) and cervical cytology, but the makeup of the combinations
and the frequency of testing (increased intervals) are likely to change
in the vaccine era.9
Additional products are in the pipeline, including vaccines covering additional high-risk HPV types for broader coverage and therapeutic vaccines designed to treat women who already have precancerous lesions or cancer. Further updates will be forthcoming in this venue as progress continues.
- Merck Press Release, June 8, 2006, www.merck.com/newsroom/press_releases/product/2006_0608.html.
Press Release, June 29, 2006, www.merck.com/newsroom/press_releases/product/2006_0629.html.
- Merck Press Release, Sept. 22, 2006, www.merck.com/newsroom/press_releases/product/2006_0922a.html.
Press Release, Nov. 1, 2006, www. merck.com/newsroom/press_releases/product/2006_1101.html.
- Harper DM, Franco EL, Wheeler CM, et
al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like
particle vaccine against human papillomavirus types 16 and 18: follow-up
from a randomized control trial. Lancet. 2006; 367: 1247–1255.
- Gonik B. Strategies for fostering HPV vaccine
acceptance. Infect Dis Obstet Gynecol. 2006; 2006:1–4.
- Editorial. Rolling out HPV vaccines worldwide. Lancet. 2006;367:2034.
- Editorial. Should HPV vaccines be mandatory
for all adolescents? Lancet. 2006;368:1212.
- Bosch X, Harper
D. Prevention strategies of cervical cancer in the HPV vaccine era.
Gynecol Oncol. 2006;103:21–24.
Dr. Wilbur, chair of the CAP Cytopathology Committee, is director of cytopathology, Massachusetts General Hospital, Boston.