Anticancer vaccine protects women from HPV-associated cervical cancer

GSK vaccine also protected against HPV types 45 and 31; HPV-16, -18, -45 and -31 lead to more than 80% of cervical cancer incidents.

Conservative estimates indicate that more than 50% of this country’s sexually active men and women will contract genital human papillomavirus infection. Thus, the FDA’s approval of Merck’s quadrivalent HPV (types 6, 11, 16, 18) L1 viruslike particle (VLP) vaccine Gardasil was this year’s top story by a wide margin.

However, the vaccine’s approval, although bolstered by impressive clinical results, has raised a significant number of questions, chiefly centering on who should be vaccinated and when this should occur. Earlier this year, the FDA’s Advisory Committee on Immunization Practices (ACIP) discussed possible vaccination strategies.

Cervarix data

A candidate vaccine from Glaxo-SmithKline (Cervarix, for HPV types 16 and 18) also demonstrated 100% efficacy against precancerous lesions associated with HPV types 16 and 18 that lasted up to 4.5 years. These results were reported in The Lancet.

Diane M. Harper, MD, MPH, gynecologic oncologist at Dartmouth Medical School, and colleagues conducted an extended follow-up analysis of women who participated in the primary efficacy study of the vaccine.

“The results of this long-term follow-up analysis are an exciting milestone for those of us who are working to prevent cervical cancer,” Harper said in a press release. “These data illustrate that this AS04-adjuvanted candidate vaccine has so far demonstrated sustained protection against HPV-16 and -18 infections and associated cervical lesions with no evidence of waning protection for these two HPV types. The vaccine is safe – long-term, 4.5 years safe, not just injection-site safe. Women do not develop any other diseases because of it.”

The study was a double-blind, controlled trial of 1,113 women aged 15 to 25. Researchers randomized participants to receive either three doses of the candidate vaccine or placebo at months zero, one and six.

“Initial studies have provided evidence that L1 viruslike particle vaccines against HPV-16 and HPV-18 (as monovalent, bivalent or quadrivalent vaccines) prevent at least 90% of incident and persistent infections and their associated precursors of cervical cancer,” according to the study.

The trial was conducted in the United States, Canada and Brazil, and researchers evaluated the efficacy, safety and immunogenicity of the vaccine for prevention of HPV-16 and/or -18 infections, as well as associated Pap smear abnormalities and cervical lesions.

The extended follow-up examined study endpoints for 776 women from the original cohort of 1,113 for a period of up to 53 months. A total of 393 had received vaccine and 383 received placebo. Researchers conducted this study between November 2003 and July 2004.

Researchers evaluated the women for HPV DNA using cervical samples every six months during the study and performed annual cervical cytology evaluations. They referred women for colposcopy following protocol guidelines. They also assessed women for long-term immunogenicity and safety.

Overall, researchers detected HPV-16 and -18 antibodies in more than 98% of women for up to 4½ years, indicating sustained vaccine response. The vaccine demonstrated 100% efficacy against histological and cytological intraepithelial neoplasia abnormalities, they reported.

Response to vaccination

Between the peak responses noted at one month after the third dose of vaccine and the end of follow-up, there was a less than 1 log₁₀ decline in geometric mean titer values. Researchers noted a 133-fold difference between the vaccine and placebo groups’ GMT.

“The high antibody titers may indicate that the vaccine may not need to be boosted,” Harper said, compared with the tetanus vaccine, which requires a booster shot every seven to 10 years. Aluminum is the adjuvant in the tetanus vaccine.”

More women in the placebo group reported adverse events associated with the shot than the vaccine group.

In addition, the vaccine demonstrated protection against HPV types 45 and 31. HPV-16, -18, -45 and -31 are collectively responsible for 80% of cervical cancers globally.

“Immunization with the HPV-16/-18 L1 viruslike particle vaccine adjuvanted with AS04 sustained high levels of antibodies that provide protection against HPV-16 and HPV-18 associated endpoints for up to [4½] years,” the researchers wrote. “These findings set the stage for the wide-scale adoption of HPV vaccination for prevention of cervical cancer.”

Will sexual behavior change?

Nicole Liddon, PhD, a sociologist with the Centers for Disease Control and Prevention, presented data to the FDA’s ACIP committee earlier this year. She discussed the possible sexual behavioral issues likely to be associated with an HPV vaccine.

“This idea that medical technology or intervention can lead to change in behaviors is conceptualized in social sciences and public health fields as behavioral disinhibition,” Liddon said. “We define it here as an increase in unsafe behaviors in response to perceptions to safety caused by introduction of a preventive or therapeutic intervention.”

According to 2003 data from the Youth Risk Behavior Surveillance System, 7.4% of adolescents initiate sexual activity before age 13, 32.8% initiate sex by ninth grade and 61.6% initiate sex by their senior year of high school.

More than 10% of ninth-graders and 20.3% of 12th-graders report four or more sexual partners. “Other sources of data are consistent with those findings,” Liddon said.

In 2002, the National Survey of Family Growth showed that the most common reason that 15- to 19-year-old male and female adolescents did not have sex was due to religious or moral reasons. A low percentage of adolescents cited a fear of sexually transmitted diseases as a reason for abstinence.

“From what we know about adolescent research, it is unlikely that disinhibition will follow the HPV vaccine,” Liddon said.

The data also indicate that early adolescence is a good time for vaccination, she added.

“These data point to a need for vaccination in early adolescence prior to sexual initiation and subsequent rapid partner acquisition,” Liddon said.

For more information:

• 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 randomised trial. Lancet. 2006;367:252-261.