On September 21, 2007, Merck announced the disappointing news that the Phase IIb testing of it’s V520 as an HIV vaccine candidate would be cut short per recommendations of the study’s Data Safety and Monitoring Board. The National Institute of Health and the National Institutes of Allergy and Infectious Diseases worked with Merck in a clinical trial that began in 2004 named the Step Study involving 3,000 HIV-negative, but “high-risk” individuals in North America, South America and Australia. During a preliminary review of data, the DSMB found 24 of the 751 volunteers who received one dose of V520, and 19 of the 672 who received two doses became infected with HIV. They found nearly identical rates of infection in those who had received placebo. Moreover, those who became infected after being vaccinated with V520 did not show significantly reduced viral loads, indicating that the vaccine did not have the desired therapeutic effects.
Also put on hold was a study of the same vaccine candidate in South Africa. The so called Phambili study (from the Xhosa word for ‘moving forward’) began in February 2007 and involved around 800 candidates. V520 had been developed against the B subtype of HIV that is more common in the Americas, but smaller trials had shown that the vaccine had the potential to produce cross-clade immunogenicity to the C subtype that is prevalent in South Africa. The Phambili study also differed from the Step study in that in was aimed primarily at heterosexuals at high risk for infection, while the Step study centered on homosexuals. No more volunteers in either group will receive vaccinations, but those who have already been vaccinated will continue to be monitored.
Most previous vaccine attempts focused on the stimulation of production of antibodies capable of neutralizing the virus before infection is able to occur. This tactic makes successful vaccination difficult because of the high level of diversity that exists in HIV envelope proteins. The highly conserved portion of gp120 that binds with CD4 is not easily accessible to antibodies and so far current vaccination methods have not been able to produce a high enough titer of antibodies to provide immunity. In the V520 vaccine, Merck followed a different approach, aiming not for the production of neutralizing antibodies, but for a strong cytotoxic response capable of killing HIV-infected cells.
V520 is a modified adenovirus, the class of virus often responsible for the common cold. It was altered to display three synthetic HIV genes, gag, pol, and nef. The virus was changed in such a way that it was unable to replicate, and did not contain other HIV genetic information, so there was no chance of accidental infection. Gag, pol, and nef, code for HIV viral core proteins, enzymes necessary for replication and integration, and transcription regulatory proteins. By infecting human cells with a virus coding for these internal proteins of HIV, Merck sought to prime a cytotoxic T cell response directed against cells displaying these more conserved antigens, rather than trying to stimulate antibodies to HIV surface proteins. The vaccine was designed to stimulate the replication of enough cytotoxic T cells specific to gag, pol, and nef antigens that should HIV enter the body, infected cells would be killed before the virus spread to other cells. It was thought that if infection was still viable after vaccination, then the primed cytotoxic response might at least slow the rate of viral replication. Unfortunately, neither of these outcomes occurred.
While the failure of the vaccine was a disappointing setback in the quest for a cure, the study may still provide a useful example for future vaccine candidate trials. In most cases, the efficacy of a vaccine is not put to the test until phase III studies. These studies generally require around 10,000 volunteers and can cost more than $100 million to conduct. The Step study was what is often referred to as phase IIb, or a ‘test of concept’ study. While not in itself sufficient to license a vaccine, test of concept studies provide a less costly intermediate between phase II and phase III studies that allow researchers a relatively quick way of determining if it is worth it to proceed to phase III testing.
Despite this setback, other HIV vaccine research is still proceeding as planned. Sanofi-Aventis currently has a potential vaccine in a phase III trial in Thailand. The vaccine is also aimed at generating a cytotoxic response, but uses a modified canarypox virus as the vector and contains additional gene insertions. Sanofi-Aventis is expected to release data from the study in 2009.
I'm Andrew Johnson. Thanks for listening.