HPV vaccine shows good prevention against cervical pre-cancers

November 2005

SAN FRANCISCO — Merck’s quadrivalent human papillomavirus (HPV) recombinant vaccine, Gardasil, prevented 100% of high-grade cervical pre-cancers and noninvasive cervical cancers associated with HPV-16 and -18, according to data from a phase-3 study reported at the 43rd Annual Meeting of the Infectious Diseases Society of America, held here.

Laura Koutsky, PhD, of the Merck phase-3 HPV Vaccine Steering Committee, said the analysis, dubbed Future II, compared the HPV vaccine with placebo in women who were not infected with HPV-16 and -18 at enrollment and who remained free of infection through the completion of the vaccination regimen. The researchers followed women for an average of two years after enrollment.

The trial is part of ongoing phase-3 trials of the HPV vaccine that involve more than 25,000 people in 33 countries. The vaccine protects against serotypes 6, 11, 16 and 18.

Koutsky said the Future II study is a prospective, randomized, double-blind, placebo-controlled study with two vaccination groups.

Researchers randomized 12,167 women aged 16 to 26 to receive a three-dose regimen of either the HPV vaccine or placebo at day 1, month 2 and month 6. A group of 6,082 women received the study vaccine and a group of 6,075 women received placebo.

Researchers evaluated the incidence of HPV-16 and -18–related cervical intraepithelial neoplasia (CIN) grades 2/3 and the development of adenocarcinoma in situ of the cervix. CIN 2 is a moderate-grade lesion of the cervix. CIN 3 represents high-grade lesions and carcinoma in situ, the immediate precursor to invasive squamous cell cervical cancer.

A pre-cancer vaccine?

Koutsky said that in the group of women who received three doses of the HPV vaccine, 100% of the women had no major protocol violations and remained free of HPV-16 and/or HPV-18 infection through the seventh month (P<.001). Researchers observed no cases of CIN 2/3 or adenocarcinoma in situ in the vaccine group (n=5,301) compared with 21 cases in the placebo group (n=5,258).

“These are the first pivotal data to show that vaccination with Gardasil reduced HPV-16 and -18–related cervical pre-cancer and noninvasive cervical cancer,” Koutsky said. “Further analyses are under way to evaluate vaccine efficacy of the vaccine against genital warts and reducing the overall burden of HPV-related clinical diseases among young women.”

A secondary analysis evaluated the incidence of CIN 2/3 and adenocarcinoma in situ in a broader group of women. This analysis started 30 days after administration of the first dose of the study vaccine or placebo. It included all of the women in the primary analysis group, as well as women who may have become infected with HPV-16 or -18 during the vaccination period and women who may have violated the protocol in significant ways.

On average, researchers followed these women for approximately two years. In this group, the vaccine reduced the risk of developing CIN 2/3 or adenocarcinoma in situ associated with HPV-16 and -18 by 97% (n=5,736); they observed one case in the vaccine group compared with 36 in the placebo group (n=5,766).

Researchers reported no discontinuations due to serious vaccine-related adverse events. Koutsky noted 17 adverse events, mostly gastroenteritis and pain in joint movement, among the vaccine group compared with 16 in the placebo group. Most of the reported adverse events in the placebo group included hypersensitivity and headache. The most common vaccine-related adverse event reported was local discomfort at the injection site.

Merck officials said they are on track to submit a Biologics License Application for Gardasil to the FDA in the fourth quarter of 2005.

Merck researchers designed the vaccine to target HPV-16 and -18, which account for 70% of cervical cancers, and HPV-6 and -11, which account for 90% of cases of genital warts. These four types also cause benign cervical changes that result in abnormal Pap tests.

For more information:

• Skjeldestad FE, for the Future II Steering Committee. Prophylactic quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine (Gardasil) reduces cervical intraepithelial neoplasia (CIN) 2/3 risk. Abstract LB-8a. Presented at the 43rd Annual Meeting of the Infectious Diseases Society of America. Oct. 6-9, 2005. San Francisco.