Bob Roehr

September 20, 2007

September 20, 2007 (Chicago) — The quadrivalent vaccine (Gardasil, Merck & Co, Inc) that protects nearly universally against the 2 most common oncogenic forms of human papillomavirus (HPV) also provides about 40% cross-protection against other common oncogenic strains of HPV.

The first evidence of this cross-protection comes from the original and ongoing Merck trials of the vaccine, which protects against HPV types 6, 11, 16, and 18. These new data were presented here at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

The dominant HPV 16/18 strains account for about 70% of all cervical cancers; the vaccine protects against approximately 99% of infections and almost 100% against the development of lesions by those strains. Ten other strains of HPV (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) account for approximately an additional 20% of cervical cancers worldwide.

Combining analysis of all 10 strains showed cross-protection that reduced incidence of precursor lesions by about 38%. The effect was most dramatic with strains 31 and 45, where protection reached about 45%.

Lead investigator Darron Brown, MD, PhD, professor of medicine, microbiology, and immunology at the Indiana University School of Medicine, Indianapolis, said this analysis had been built into the initial study design. The foundation for the work "came from in vitro cross-neutralization studies that showed some suggestion that antibodies to closely related types may be able to cross-neutralize other close types.

"But I think that we all are pleasantly surprised with the high degree of cross-protection that was shown to occur, both in terms of resisting infection and, more importantly, disease," he told Medscape Infectious Diseases.

Dr. Brown suspects that the different degrees of cross-protection the researchers observed are probably related to the level of antibody generated, and perhaps to memory B cells, both of which are likely have an individual genetic component to them.

All of the data to date have come from studies in women, and there is some reason to be cautious about automatically extrapolating its application to men. Dr. Brown pointed out that there are differences between the cervical and penile epithelium and in the lesions seen in each tissue.

"However, penile and vulvar epithelium are quite similar. In our studies, vulvar lesions were nearly 100% prevented, giving us hope that that the vaccine will offer similar cross-protection in analogous penile epithelium. But that data is still being analyzed," Dr. Brown cautioned.

Some have hypothesized that preventing infection from these dominant strains of HPV might open up an ecological niche for other strains to expand. Dr. Brown expressed skepticism: "When one looks at situations where there has been replacement or niche filling, these have been pathogens in which mutation is frequent and likely to occur, for example, streptococcus," he said. "In contrast, HPV has a very stable genome and replicates at about the same rate as the human genome.

"Secondly, we would expect that if fill-in would occur, we might see competition between HPV virus types. But we see just the opposite; we see cooperation. If you are infected with 16, you are more likely to be infected with additional oncogenic types."

Dr. Brown said it would be 5 to 10 years before we get a solid sense as to which of the opposing theories of niche filling could be documented with epidemiologic studies.

Scott Hammer, MD, cochair of ICAAC and a professor of medicine at Columbia University, New York City, called the findings "very important on a public health basis. We didn't know if the type-specific protection stopped at the water's edge or if there was cross-protection."

He said the finding, if confirmed, will affect both future vaccine design and decisions about which additional strains to add to a single vaccine to get the broadest possible cross-protection.

Dr. Brown and Dr. Hammer are academic investigators who have participated in clinical trials and education programs organized by the vaccine sponsor, Merck.

47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy: Abstract G-172b. Presented September 19, 2007.

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