IAVI Report - October / November 2002
Emily Bass

Merck presented two sets of encouraging data from Phase I and II studies of a vaccine against human papilloma virus (HPV) at the HPV Clinical Workshop and 20th International Papillomavirus Conference (4-9 October, 2002).* HPV is the virus that causes genital warts and is linked to anal and cervical cancer-the leading cause of cancer deaths among women in the developing world. Merck's candidates, among the most advanced in the HPV vaccine pipeline, use HPV's L1 capsid protein. The capsid assembles itself into non-infectious "virus-like particles" (VLPs) that elicit both antibodies and, in some cases, cell-mediated immunity against HPV. Pre-clinical models show that protection is "exclusively dependent on neutralizing antibody responses," says Kathrin Jansen, director of Merck's HPV vaccine program.

Other firms are also developing HPV vaccines, which are likely to have markets in the developed world-where 75 percent of adults have HPV, by some estimates-as well as in developing countries. GlaxoSmithKline (in collaboration with biotech firm MedImmune) is developing a vaccine based on VLP technology, that has completed Phase I proof-of-principle studies. Other strategies in early development stages are looking at vectors based on Salmonella bacteria and yeast, which can be given orally.

There are over 100 different types of HPV. Of these, a few are associated with the majority of cases of genital warts (HPV 6 and 11) or cancer (HPV 16 and 18). L1 proteins are well-conserved within types, but have considerable inter-type variation, meaning that separate vaccines are needed for each type. HPV is more difficult to diagnose in men than women. While anal pap smears can detect HPV infection in the rectum, this is not the site of exposure for all men. Consequently, nearly all HPV vaccine trials to date have involved exclusively women volunteers.

Designed to determine safety and immunogenicity, Phase I trials of the Merck vaccine have also provided early signs of promising efficacy. At the October meeting, Laura Koutsky (University of Washington), a principal investigator in the Merck HPV vaccine program, presented an analysis of combined data from Phase I trials of HPV-16 and HPV-11 vaccines (Abs. #P450). She looked for cases of HPV-16 in participants who received the HPV-16 vaccine, compared to those receiving the placebo or the HPV-11 vaccine. There were no cases of HPV-16 among the 66 women who received the HPV-16; in contrast, 14/129 of the women in the combined control group were infected with HPV-16 (including 10 who received the HPV-11 vaccine).

Koutsky also presented encouraging data from a Phase II proof-of-principle study of HPV-16 vaccine (Abs. #O98), in which 1,533 HPV-16 -negative women between 16 and 23 years of age completed the full course of immunization (given at 0, 2 and 6 months) with either vaccine or placebo, and were followed for average of a year and a half following the final immunization. Out of more than 750 women who received the HPV-16 vaccine, none developed persistent HPV-16 infection, compared with 41 women in the control group, which was roughly the same size.

Merck has also completed a multicenter Phase IIb dose-ranging study of an HPV vaccine that includes capsid proteins from four HPV types (6, 11, 16 and 18) (Abs. # O99). This "quadrivalent" vaccine would address the type specificity of vaccine-induced immunity and protection. GlaxoSmith-Kline has also completed early phase trials of a combined HPV-16/HPV-18 vaccine. A Phase III trial of Merck's quadrivalent vaccine is ongoing.

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