At least 15 human papillomavirus (HPV) types are human carcinogens that play a central role in the pathogenesis of cervical cancer and other less common cancers, including vaginal, vulvar, anal, penile, and upper aerodigestive tract cancers.(1,2) Worldwide, cervical cancer is the second most common cancer in women, with the majority of cases (~80%) occurring in developing countries.(3) In the US and other developed countries, cervical cancer is no longer a leading cause of cancer-related mortality(4) because women undergo routine Pap screening and are treated if cervical intraepithelial neoplasia (CIN) is diagnosed. CIN, however, continues to cause significant psychological and physical morbidity.
Of the estimated 60 million Pap tests performed annually in the US, 3.1 million (5%) are read as abnormal.(5) In addition to the anxiety, distress, and negative self image an abnormal Pap test may cause,(6,7) it is also a trigger for more procedures including additional Pap and HPV DNA testing, colposcopy, biopsy, and treatment. In Australia, where the national screening policy consists of Pap testing every two years, the lifetime risk of colposcopy for a 15-year-old female is estimated to be 77%.(8) The majority of women in the US continue to receive annual Pap tests;(5) the lifetime risk of colposcopy appears to be at least as high as the Australian rate. Thus, a prophylactic vaccine to prevent HPV-related CIN and cancers would save lives, reduce the need for costly medical procedures, and ultimately provide substantial benefits to individual women and communities throughout the world.
A major breakthrough in the development of HPV vaccines came in 1991 when Zhou and colleagues(9) reported that they had synthesized three-dimensional virus-like particles (VLPs) by expressing only two HPV16 genes (L1 and L2) in eukaryotic cells (e.g., animal or yeast cells). Subsequently, other scientists refined the assembly of VLPs(10) and demonstrated that only L1 protein was needed to produce HPV VLPs that would stimulate high titers of neutralizing antibodies(11-13) when injected into human volunteers (Figure 1).
Since HPV16 is a cause of about 50% of cervical cancers,(1) a prophylactic HPV16 L1 VLP vaccine trial was undertaken to determine whether immunization would prevent persistent HPV16 infection. Female subjects (18 to 23 years of age) were randomized to receive placebo or 3 doses of 40 µg HPV16 L1 VLP vaccine in a 0-, 2-, or 6-month regimen.(14) After an average of 17.4 months following the immunization date, the incidence of persistent HPV16 infection (repeated detection of HPV16 DNA in genital samples obtained ≥ 4 months apart) was 3.8/100 subject-years at risk in the placebo group (41 cases in 765 women) and 0.0/100 subject-years at risk in the vaccine group (0 cases in 768 women) (100% efficacy, 95% CI, 90%--100%). All 9 cases of HPV16-related CIN occurred among placebo recipients. An additional 6 women in the vaccine group and 26 women in the placebo group were positive for HPV16 DNA on a single follow-up visit, suggesting that the vaccine was 91.2% (95% CI, 80%--97%) effective in preventing all HPV16 infections. After the third dose, the geometric mean titer of HPV16 antibodies was 1,510 mMU/mL in the vaccine group and < 6 mMU/mL in the placebo group. The seroconversion rate (99.7%) among the immunized women was quite high. Overall, the vaccine was generally well tolerated and there were no serious vaccine-related events in either the vaccine or placebo groups.
Currently, there are underway international, multicenter phase III trials of a tetravalent HPV 6/11/16/18 L1 VLP vaccine that includes VLPs from HPV16 and HPV18 (which cause about 70% of cervical cancers worldwide)(1) and VLPs from HPV6 and HPV11 (which cause about 90% of genital warts).(15) An interim analysis will likely occur in a few years. If the results show high efficacy for preventing HPV16- or 18-related high grade CIN and HPV6- or 11-related genital warts, the vaccine might be commercially available shortly thereafter. Another international, multicenter phase III trial is examining a bivalent HPV16 and 18 VLP vaccine; encouraging results from an earlier phase II trial of this vaccine have been reported.
As the phase III prophylactic HPV vaccine trials proceed, there is a growing sense of optimism that within a decade, HPV immunization will reduce the number of women who require colopscopy, biopsy, and treatment for CIN and cancer. By fostering collaborations between industry, governments, and charitable organizations, HPV vaccines will ultimately reach women who need them most--those who by virtue of geography or finances do not have access to Pap tests, diagnostic procedures, or effective treatments. Important issues to be addressed in the coming years include vaccine efficacy in men, long-term durability of protection after immunization, integration of HPV vaccines into on-going Pap screening programs, and public education.
References
- Muñoz N, Bosch FX, de Sanjose S, et al. International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-527.
- Gillison ML, Shah KV. Role of mucosal human papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr. 2003;9:57-65.
- Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94:153-156.
- Ries LAG, Eisner MP, Kosary CL, et al. (eds). SEER Cancer Statistics Review, 1973-1999, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1973_1999/, 2002.
- Sirovich BE, Welch HG. The frequency of Pap smear screening in the United States. J Gen Intern Med. 2004;19, 243-250.
- Bell S, Porter M, Kitchener H, et al. Psychological response to cervical screening. Prev Med. 1995;24: 610-616.
- Peters T, Somerset M, Baxter K, et al Anxiety among women with mild dyskaryosis: a randomized trial of an educational intervention. Br J Gen Pract. 1999;49:348-352.
- Kavanagh AM, Santow G, Mitchell H. Consequences of current patterns of Pap smear and colposcopy use. J Med Screen. 1996;3:29-34.
- Zhou J, Sun XY, Stenzel DJ, et al. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology. 1991;185:251-257.
- Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A. 1992;89:12180-12184.
- Evans TG, Bonnez W, Rose RC, et al. A Phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. J Infect Dis. 2001;183:1485-1493.
- Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst. 2001;93:284-292.
- Brown DR, Bryan JT, Schroeder JM, et al. Neutralization of human papillomavirus type 11 (HPV-11) by serum from women vaccinated with yeast-derived HPV-11 L1 virus-like particles: correlation with competitive radioimmunoassay titer. J Infect Dis. 2001;184:1183-1186.
- Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.
- Greer CE, Wheeler CM, Ladner MB, et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin Microbiol. 1995;33:2058-2063.
