On Tuesday, September 18, HIV vaccine research suffered a major setback when it was announced that the vaccine expected to be our best hope for success has failed in its first large-scale human clinical trial. The trial, which consisted of 3000 HIV negative men and women from North and South America, the Caribbean, and Australia, was conducted by a tripartite team composed of pharmaceutical giant Merck , the National Institute of Allergy and Infectious Disease (NIAID) , and an academic consortium of HIV vaccine researchers known as the HIV Vaccine Trails Network (HVTN)
This is a particularly devastating set back for the field because the Merck vaccine utilizes a novel approach to the classic strategy of vaccine development. Classic vaccines work through stimulation of B-cells, the humoral arm of the immune system, to produce neutralizing antibodies directed against the invading virus. Once stimulated, immunologic â€œmemoryâ€ prevents subsequent infection by the natural virus providing immunity to the host. However, the biology of the HIV virus has proved problematic for such classic strategies. Similar to the avian flu viruses, HIV continually mutates and recombines. This means that a vaccine would need to protect the person against many strains of the virus. Further compounding the problem is the high degree of glycosylation, or sugar shroud, on surface proteins which limits the number of available epitopes for recognition by B-cells and effectively hides the virus from the immune system. As if that werenâ€™t enough, HIV can be transmitted as both free virus (susceptible to antibody mediated immunity) and in infected cells. This may mean that more than one form of immune response must be activated to protect the individual.
The promise of the Merck vaccine was that it relied on stimulation of the cellular arm of the immune response. Specifically, the vaccine stimulates â€œkiller T cellsâ€ that work against a wide array of variants by selectively targeting and eliminating cells that have been infected by the virus. Although this strategy would not prevent an individual from becoming infected with HIV the hope was that this vaccine would prevent the virus from causing a productive infection before it could take hold and/or keep viral loads below the threshold required to bring about the onset of AIDS.
The first clinical trial of this vaccine was begun in 2004 and halted last month after an interim analysis of 1500 participants, most of whom were men who have sex with men and also most likely to respond to the vaccine revealed that no protection was conferred. Of the 741 participants who received at least one dose of the vaccine 24 (3.2%) have become infected compared to 21 (2.7%) of the 762 participants who received a dummy shot. Even more discouraging, there was no difference in viral loads between the two groups.
HIV vaccine researchers were shocked.
According to John Moore, of the Weill Cornell Medical College in New York City, â€œThis was the first AIDS vaccine clinical trial in history where most people thought theyâ€™d at least see something positiveâ€.
Norman Letvin, an HIV vaccine researcher at Harvard Medical School in Boston Massachusettes â€œwas hopeful weâ€™d see some dampening of viral replicationâ€ similar to the results seen in trials with monkeys.
These findings call into question the efficacy of T-cell vaccines, though it should be noted that while this is clearly a failure of a particular product it does not necessarily mean that the broader concept of a â€œT-cell vaccineâ€ is unfounded. Despite this notion, a large scale trial of another T-cell based vaccine developed at the NIAID and set to begin this fall has been delayed pending a full review of the results obtained with the Merck vaccine.
Additional concerns about the future of HIV vaccine research were voiced by Anthony Fauci, director of the NIAID, who fears that this failure could result in a culling of funding by the pharmaceutical industry which is already wary of large scale investment in HIV vaccine research. According to Fauci, â€œThereâ€™s certainly a danger of industry scratching its head and saying before we put substantial resources in we need more sound scientific dataâ€.
Mark Feinberg, vice president of medial affairs for Merck, says â€œThe best thing we can contribute to the field overall is a thorough analysis of the dataâ€. Chiefly among the many questions that remain are what happened in the other 1500 participants, what was the immune response in breakthrough infection cases, and are there differences in heterosexual transmission? â€œItâ€™s not like weâ€™re not interested in the questions anymore, but its unclear where the next breakthrough will come fromâ€¦and thatâ€™s not just a question for Merck. Itâ€™s a question for the entire fieldâ€.
According to Lawrence Corey an AIDS researcher at the University of Washington, Seattle and the head of the HVTN, â€œIts very dispiriting for the fieldâ€¦It will take time to unravel where this leaves us and how we move forwardâ€.
Though, in biomedical research both time and money are needed to answer these fundamental questions of biology, and without the support of the pharmaceutical industry the road to development of an effective vaccine against HIV could be a very long and winding one.
Portions of this article were taken from: Jon Cohen, â€œPromising AIDS Vaccine's Failure Leaves Field Reelingâ€, Science, Vol. 318. no. 5847, pp. 28 â€“ 29
Photo: Electron micrograph of an HIV virion budding from an infected cell (lft); Schematic diagram of HIV invading a â€œhelperâ€ CD4 T-cell
Copyright © 2010 Jen
New HIV Vaccine Fails Clincal Trial. Scientists Devastated.
Copyright © 2010 Jen
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