Small Steps Forward
by Marilyn Grady
November 2007
Despite some significant setbacks, the search for an AIDS vaccine continues in earnest.
The ongoing search for an AIDS vaccine was dealt a blow in September when Merck discontinued its Phase II HIV vaccine (V520) trials due to ineffectiveness. The trial, called STEP, was an international phase II proof-of-concept trial in uninfected volunteers at high risk for acquiring HIV infection. The double-blind trial enrolled 3,000 HIV-negative volunteers from diverse backgrounds between 18 and 45 years of age.
A Data Safety Monitoring Board (DSMB) study of the trial evaluated two primary efficacy endpoints: whether the vaccine prevented HIV infection and whether the vaccine reduced the amount of virus in those who developed infection. As planned, an interim efficacy analysis was conducted in the approximately 1,500 volunteers expected to have the best response to the vaccine because they had low levels of pre-existing immunity to adenovirus 5.
The vaccine did not prevent infection: in volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were observed in the 741 volunteers who received vaccine, and 21 cases of HIV infection were observed in the 762 participants in the placebo group. In the subgroup who received at least two vaccinations and who were HIV negative for at least the first 12 weeks of the trial, 19 cases of HIV infection were observed in the 672 volunteers who received vaccine, and 11 cases were observed in the 691 volunteers who received placebo. In addition, the vaccine did not reduce the amount of virus in the bloodstream of those who became infected. Approximately 8 to 12 weeks after diagnosis of infection, HIV RNA levels were similar in the vaccine and the placebo volunteers.
Due to these results, DSMB recommended that vaccination be discontinued because the STEP trial would not meet its efficacy endpoints. A separate study of the same vaccine candidate—the Phambili trial—also was terminated in October.
“We share in the disappointment of the research and HIV communities today. Sadly, developing an effective AIDS vaccine remains one of the most challenging tasks facing modern medicine,” said Peter S. Kim, Ph.D., president, Merck Research Laboratories, in a September 2007 press release. “We are committed to studying the data closely and sharing it with the scientific community to inform the ongoing search for an effective HIV vaccine.”
Searching and Hoping
Despite these setbacks, biotech firms, nonprofits and international agencies continue to focus their efforts on developing a vaccination. The typical approach to vaccine development—a live, attenuated virus—has had mixed results for HIV. In animal testing, the vaccine protected monkeys challenged with homologous pathogenic simian immunodeficiency virus (SIV) for more than two years after immunization. However, the SIV vaccine establishes a persistent state in the vaccinated host, can revert to virulence in some animals and was pathogenic to neonatal monkeys when given at high doses.
Due to these problems, as well as fears of regulatory controls, live attenuation is not considered a viable design option. However, researchers are conducting ongoing investigations into this approach.
Meanwhile, the inactivated-virus approach is not in use for the development of an AIDS vaccine because it also has proven ineffective. Vaxgen’s monomeric gp120 is the only vaccine used in this approach that has progressed fully through to efficacy trials, but the vaccine did not protect from HIV infection and had no effect on viral load in patients who did become infected.
In addition to live, attenuated vaccines and inactivated virus approaches, a handful of prime-boost combinations are candidates in clinical trials. One candidate now in efficacy trials is a combination that includes Sanofi Pasteur’s canarypox vector as a prime, with Vaxgen’s gp120 as a boost. The candidate is being tested in Thailand with more than 16,000 study participants.
On the funding front, some challenges to vaccine research lie with small biotechnology companies. These companies generate a large proportion of innovations in health product development. However, because the highest need is in resource-poor countries, they do not have sufficient incentives to invest in AIDS vaccines.
Despite these setbacks, there have been advances in worldwide attention to the search for an AIDS vaccine, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, and PEPFAR, the U.S. President’s Emergency Plan for AIDS Relief. However, these efforts primarily focus on prevention, treatment and social migration, and are not directly involved in vaccine research.
In addition to these funds, major AIDS vaccine research agencies have come together as the Global HIV Vaccine Enterprise. The enterprise has launched collective initiatives such as the International AIDS Vaccine Initiative’s Neutralizing Antibody and Live Attenuated Consortia, the National Institutes of Health’s Vaccine Research Center and Center for HIV/AIDS Vaccine Immunology, the Gates Foundation’s Collaboration in AIDS Vaccine Discovery, EuroVac and the South Africa AIDS Vaccine Initiative.
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