HPV Vaccine Offers Cross-Protection for HPV Types Not Covered By Vaccine

Roxanne Nelson

March 12, 2009

March 12, 2009 — The quadrivalent human papillomavirus (HPV) vaccine, marketed under the name Gardasil (Merck), is a recombinant vaccine that is effective against HPV types 6, 11, 16, and 18. The vaccine received approval for the prevention of cervical, vulvar, and vaginal intraepithelial lesions and genital warts associated with the vaccine HPV types, but 2 new studies indicate that the vaccine might offer protection from other types of HPV.

"There are many reasons to recommend vaccination with [the quadrivalent vaccine]," said study author Darron Brown, MD, professor of medicine, microbiology and immunology at Indiana University School of Medicine, in Indianapolis. "The most important reason is that the vaccine is safe and highly effective in reducing disease caused by the 4 HPV types, [which account for] approximately 80% of all HPV-related diseases of the genital tract. Cross-protection, although modest, indeed provides an extra benefit for young women who choose to be vaccinated."

Both studies, which appear in the April issue of the Journal of Infectious Diseases, demonstrate that vaccination provides cross-protection against nonvaccine HPV types, which are responsible for about 20% of all cervical cancers.

"The cross-protection reported in this issue of the Journal is definitely good news," writes Rolando Herrero, MD, from the Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, in San José, Costa Rica, in an accompanying editorial. The "30% maximum protection against precursor lesions could reduce the burden of cervical cancer an additional 6%, compared with that afforded by the HPV16/18 vaccine."

The cross-protection reported in this issue of the Journal is definitely good news.

"This could represent ~30,000 cases worldwide, but would still not afford protection against at least 25% of cancers, making the development of safe, effective, and low-cost polyvalent vaccines a major priority for both academia and industry, to ensure success in the fight against cervical cancer," he notes.

Reduces Infection Rate of Nonvaccine Types

In the first study, Dr. Brown and colleagues evaluated whether the quadrivalent vaccine would protect against infection and disease caused by 10 HPV types not included in the vaccine. The majority of known HPV types that infect the genital tract are members of the Alphapapillomavirus (or A) genus; of this group, 18 have been classified as oncogenic on the basis of epidemiologic and/or genetic evidence. HPV16 is the prototype of the A9 species, the researchers note, which includes 6 cancer-causing types (16, 31, 33, 35, 52, and 58), whereas HPV18 is the prototype of the A7 species, which includes 5 cancer-causing types (18, 39, 45, 59, and 66).

To analyze disease end points, the researchers used the database from the phase 3 FUTURE I and II clinical trials, which examined the efficacy of the quadrivalent HPV vaccine in 17,622 women aged 16 to 26 years (although there were two 15-year-old girls). The study participants were followed for a mean of 3.6 years after the first vaccine dose.

All of the women underwent cervicovaginal sampling and Pap smears at regular intervals for up to 4 years, and the analyses were conducted only on individuals who were negative for 14 HPV types on day 1. HPV genotyping was performed for biopsy samples, and histologic diagnoses were determined with a pathology panel.

The researchers found that the quadrivalent vaccine reduced the incidence of infection with HPV types 31 and 45 by 40.3% (95% confidence interval [CI], 13.9% to 59%), and related cervical intraepithelial neoplasia (CIN) 1–3/adenocarcinoma in situ (AIS]) by 43.6% (95% CI, 12.9% to 64.1%). It also decreased CIN1–3/AIS by 29.2% (95% CI, 8.3% to 45.5%), relative to HPV types 31, 33, 45, 52, and 58.

Overall, vaccine efficacy for CIN1–3/AIS associated with the 10 tested nonvaccine HPV types was 23.4%, and was 32.4% for high-grade lesions (CIN2–3/AIS), and was driven primarily by reductions in HPV types 31,33, 52, and 58.

Demonstrates Efficacy in Women With Pre-Existing HPV Infection

A related intention-to-treat analysis, led by Cosette Wheeler, PhD, professor of molecular genetics and microbiology at the University of New Mexico School of Medicine, in Albuquerque, examined the cross-protective vaccine impact for the same 10 nonvaccine HPV types. They also used the FUTURE I and II database, but in this study, the cohort included both HPV-naïve women and women with pre-existing HPV infection and/or HPV-related disease at enrollment.

They found that vaccination reduced the infection rate of HPV types 31, 33, 45, 52, and 58 by 17.7% (95% CI, 5.1% to 28.7%) and of CIN1–3 or AIS by 18.8% (95% CI, 7.4% to 28.9%). The quadrivalent vaccine also reduced the rate of HPV types 31, 58, and 59–related CIN1–3/AIS by 26.0%, 28.1%, and 37.6%, respectively.

Although a small decrease in HPV types 31, 33, 45, 52, and 58–related CIN2 or worse was observed, the estimated reduction was not found to be statistically significant.

The authors point out that nearly one third (32.8%) of the FUTURE I and II trial participants were infected, at the time of study enrollment, with 1 or more of the genital HPV types under evaluation for vaccine cross-protection. "Despite prevalent oncogenic HPV infections with vaccine and nonvaccine HPV types, cross-protective vaccine efficacy against infection was observed for both composite end points, as well as the individual HPV types 31 and 59," they write.

Vaccine Duration Not Yet Determined

"We don't know how long the high degree of protection will last, since there are very few cases of disease in vaccinated women," Dr. Brown told Medscape Oncology. "It is possible that a booster may eventually be desirable, but it is also possible that the high degree of protection elicited by [the quadrivalent vaccine] is life-long."

We have shown evidence of immune memory in young women vaccinated with [the quadrivalent vaccine].

"However, we have shown evidence of immune memory in young women vaccinated with [the quadrivalent vaccine]," he added. "This is important because immune memory is critical for long-lasting protection, as we expect to see in women vaccinated with [the quadrivalent vaccine]."

Long-term data are not yet available. "The phase 3 trials began in late 2002, and therefore some participants have been followed for more than 6 years," said Dr. Brown, adding that the next trials will probably be conducted in boys and men, and in sexually active women older than 26 years of age.

Both studies were designed and sponsored by Merck Research Laboratories. A number of authors from both studies have relationships with Merck, GlaxoSmithKline, and Sanofi Pasteur. These include receiving consulting fees, advisory board fees, grant support, and lecture fees. Several authors are also employees of Merck. See papers for details.

J Infect Dis.2009;199:919-922, 926-935, 936-944. Abstract, Abstract, Abstract

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