Globally, cervical cancer is the second most common cancer among women and is thought to be the largest single cause of years of life lost to cancer in low-income countries (3
). Approximately 490,000 women are diagnosed and 270,000 die from cervical cancer each year (24
). In the U.S., despite organized cervical cancer prevention programs involving regular Pap screening in reproductive-age women, approximately 11,000 women are still diagnosed with cervical cancer and 4,000 women die from the disease annually (http://seer.cancer.gov/cgi-bin/csr/1975_2005/search.pl#results
). Substantial racial, ethnic, and socioeconomic disparities exist for HPV infection, cervical cancer incidence, and cervical cancer mortality (45
). Direct costs associated with the prevention and treatment of HPV-related disease are at least 4 billion U.S. dollars (USD) per year, and indirect costs such as productivity losses add 1.3 USD per year (63
Clinical trials of the bivalent vaccine have been conducted in women 10-55 and men 10-18 years of age; trials of the quadrivalent vaccine have been conducted in women 9-45 and men 10-26 years of age (12
). The clinical endpoints in efficacy studies of both vaccines include cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in-situ (AIS), generally considered to be cervical cancer precursors, as well as other anogenital cancer precursors (e.g. anal intraepithelial neoplasia). Anogenital warts are also an endpoint for clinical trials of the quadrivalent vaccine.
Information about the immunogenicity and efficacy of the bivalent and quadrivalent HPV vaccines is available from several international, randomized clinical trials. Seroconversion rates are ≥ 97.5% for both vaccines (18
). Studies suggest that although immune responses tend to be durable for at least five years after vaccination, antibody levels do eventually decline, especially for HPV-18 (44
). However, lower antibody levels do not appear to lead to breakthrough disease, possibly due to immune memory (70
). Data from ongoing clinical trials will be needed to confirm the duration of immunity and to determine whether there will be a need for a booster dose. Both HPV vaccines appear to generate cross-neutralizing antibodies against related HPV types not targeted by the vaccines, and therefore may provide protection against disease caused by those types (7
Clinical trials of both the bivalent and quadrivalent vaccines have demonstrated 90%-100% efficacy in preventing precancerous cervical lesions attributable to HPV-16 and -18, among women who were uninfected with those HPV types before vaccination and who received all three vaccine doses (6
). The quadrivalent vaccine is also highly effective in preventing anogenital disease caused by HPV-6 and -11 (48
). Efficacy is substantially lower among women who may be HPV-infected at the time of vaccination (47
), because vaccination does not protect against HPV-16 or -18 infection or disease in women infected with those HPV types at the time of vaccination (47
). In addition, vaccination does not facilitate clearance of HPV-16 and -18 in infected women (59
). Thus, HPV vaccines will have the most significant impact on individual and population health if vaccination is targeted to early adolescents, prior to sexual initiation and thus before HPV acquisition.
Extensive clinical trials data and post-marketing safety monitoring data have demonstrated that both HPV vaccines are generally safe and well-tolerated. The Centers for Disease Control and Prevention (CDC) in the U.S. (http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm
) and the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety have concluded that data support the safety of both HPV vaccines (http://www.who.int/vaccine_safety/reports/June_2007/en/index.html
). Mild injection-site adverse events (e.g. pain, redness, itching, and swelling) are fairly common, while mild systemic adverse events such as low-grade fevers are uncommon. Serious adverse events were rare in the clinical trials, and did not occur more frequently in vaccine than placebo participants (47
). Post-licensing studies to evaluate quadrivalent vaccine safety, and especially to detect rare adverse events, have been conducted by the CDC, other public health organizations globally, and the vaccine manufacturers since 2006. Rare post-marketing reports of serious illness or death occurring at some point after receipt of the quadrivalent vaccine have been reported, but none of these events appear to be caused by the vaccine (http://www.fda.gov/cber/safety/gardasil071408.htm
Both the quadrivalent and bivalent vaccines have been licensed in many countries, and in those countries with national immunization programs that have established recommendations for HPV vaccination, there is general consensus that young adolescent girls should be targeted for vaccination (80
). In the U.S., it is recommended that HPV vaccination be targeted to 11- to 12-year-old girls, and catch-up immunization is also recommended for 13- to 26-year-old women (84
In summary, HPV vaccines are available and recommended for use in many countries. The data thus far suggest that they are safe, and are highly effective when administered to young women who are uninfected with HPV types included in the vaccine. However, the public health impact of vaccination can only be realized if vaccine uptake is high in young women who have not yet initiated sexual intercourse, and are therefore unlikely to be infected with HPV. Thus, integrating community and policy perspectives related to HPV vaccine access and uptake is critical to maximizing the potential health impact of these vaccines.