Cervical Cancer Vaccines Show Sustained Protection

LOS ANGELES—Vaccines designed to protect against human papillomavirus (HPV)—and thus protect against cervical cancer—are showing sustained protection at 5 years, according to long-term data for Merck's FDA-approved vaccine, Gardasil, and the GlaxoSmithKline AS04 candidate vaccine presented at the 2007American Association of Cancer Research Annual Meeting (abstracts LB-187 and 4900).

Gardasil, a quadrivalent vaccine designed to protect against HPV types 16, 18, 6, and 11, was shown to provide nearly 100% protection against cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ caused by HPV types 16 and 18 at a follow-up time of 3 or more years after inoculation, reported Darron Brown, MD, professor of medicine, microbiology and immunology, Indiana University School of Medicine, Indianapolis.

Gardasil targets the HPV types responsible for the majority of clinical HPV disease, Dr. Brown said. Types 16/18 are responsible for 70% of cases of cervical cancer, anal/genital cancer, and vulvar and vaginal neoplasia, and 25% of CIN 1. Types 6/11 are responsible for 90% of cases of genital warts and recurrent respiratory papillomatosis, and 10% to 15% of CIN 1. Males are carriers for all four HPV types.

Dr. Brown's report encompassed 3 to 5 years of follow-up of the Gardasil trials. In the combined database of more than 20,000 patients, there has been only one case of CIN 2/3 related to HPV types 16/18 or 6/11. "The one patient who developed CIN 3 had HPV type 52, a cousin of HPV 16, upon enrollment, and she had an abnormal Pap smear at 28 months," he said. "Her biopsy was positive for both HPV 52 and 16, but in a second specimen obtained during the LEEP procedure, only HPV 52 was demonstrated. Whether this was a laboratory error or she was contaminated with HPV 16 is hard to say. She was counted as a positive case."

In an analysis of the general study population of randomized subjects who received at least one dose—which included subjects with pre-existing infection with one of the four HPV types, protocol violators, and subjects with fewer than three doses—efficacy was 44%, which is "still a considerable degree of efficacy," he said. Almost all cases in the vaccine arm occurred in women with prior infection with HPV 16/18. Efficacy against all high-grade disease (due to vaccine and also nonvaccine types) was 18%. "This shows that HPV is already a prevalent infection in this age group," Dr. Brown commented. "We need to vaccinate before there is a chance of infection."

The cross-protective effect of Gardasil against other HPV types is currently being studied. Preliminary studies show that antibodies triggered by the vaccine neutralized HPV types 31 and 45 as well, which are genetically related. "This is important since 30% of cervical cancer is caused by types other than HPV 16/18," Dr. Brown noted.

GSK Candidate Vaccine

Investigators reported the same high degree of sustained efficacy with the GSK candidate vaccine AS04. The vaccine also provided significant cross-protection for HPV types 45 and 31, reported Stanley Gall, MD, professor of obstetrics, gynecology, and women's health, and of public health and information sciences, University of Louisville, Kentucky.

The study was a phase II double-blind placebo-controlled study of 1,113 females aged 15 to 25 in North America and Brazil who were seronegative for HPV 16/18, and DNA-negative for 14 high-risk HPV types at entry to the study. Patients received three doses of the vaccine or the control, and were followed for up to 27 months in the primary efficacy analysis. In this extended analysis, 776 of the original cohort were followed for 5.5 years.

"The vaccine demonstrated 100% efficacy in preventing precancerous lesions for up to 5.5 years," Dr. Gall reported. "This is the longest duration of protection seen in any cancer vaccine trial to date."

During the extended follow-up phase, at least 98% HPV 16/18 seropositivity was maintained, and substantial efficacy was observed against the HPV 16/18 endpoints: incident infection (98%), 6-month persistent infection (100%), 12-month persistent infection (100%), and atypical cells of undetermined significance (ASCUS) or worse cytology (100%). The vaccine efficacy was 100% against HPV 16/18-associated CIN 1+ (0 vs 11 cases) and 100% against CIN2+ (0 vs 7 cases).

Beyond types 16/18, the vaccine showed 68% efficacy against CIN 2+ lesions independent of HPV status (5 vs 15 cases). Cross-protection against incident infection with nonvaccine oncogenic types HPV 45/31 was also sustained. "This protection goes beyond what might be expected from a vaccine designed to target HPV 16/18 alone," Dr. Gall noted.

The vaccine induced a very strong immune response (by antibody titer) in virtually 100% of subjects, he added. "At 24 to 30 months, we see the antibody level plateau and stay flat, without tailing off. If the response stays that strong, immunity may be lifelong, and we would not need a booster," he said.

At a press conference, Dr. Gall was asked how clinicians should choose between the two vaccines (once AS04 is approved). "I don't think it's fair to compare these two because head-to-head trials were not done," he responded. "They are both wonderful products, and it will be up to the physician and family to decide which to administer."

In further discussion, the speakers noted that 25% of potential vaccine recipients would already be infected with some type of HPV, which would not be impacted by vaccination. They also noted that the current upper age limit of 26 might eventually be lifted, since, as Dr. Gall put it, "any woman with a cervix and sexual partner could become infected at any point in time."