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Are T-Cell-Based HIV Vaccines "Hanging by a Thread"?
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3rd International Workshop on HIV Transmission:
Principles of Intervention
July 31-August 2, 2008, Mexico City
Mark Mascolini
Failure of the Merck HIV vaccine in the STEP trial [1] fanned the flames of an already broiling debate over the value of vaccines that stimulate only T-cell-mediated immunity without recruiting antibodies to prevent infection. David Watkins, a University of Wisconsin expert in primate models of HIV infection, objected strenuously to a remark at a recent STEP postmortem that T-cell-stimulating HIV vaccines are "hanging by a thread" [2]. Vaccine scientists must find ways to prompt stronger and broader cellular immune responses, Watkins argued, not dump the concept entirely.
Julie McElrath, one of the STEP investigators from the University of Washington, Seattle, laid the groundwork for the debate by defining current thinking on vaccines that stimulate antibody- versus cell-based immunity [3]. HIV-specific antibodies should neutralize the virus before it enters target cells and thus stop HIV before it gets a cellular foothold. Cytotoxic T cells (CTLs) kill target cells after HIV has entered those cells and begun replicating. In theory an effective CTL response could contain HIV infection in its early stages or at least stifle the pace of HIV replication in an infected person. CD4 cells assist both antibody- and cell-mediated immunity.
Creating an antibody-driven vaccine proved difficult because HIV can mutate deftly to avoid antibody attack and because no one could figure out how to perk up the right antibodies in the right way. Some heard a death knell for the antibody approach when the AIDSVAX antibody-stimulating vaccine fell flat in a large efficacy trial [4]. But more than one HIV heavyweight predicted that the embrace of a cell-based vaccine would prove just as empty without an antibody component. In the keynote talk of the 2007 Transmission Workshop, Robert Gallo maintained that a vaccine aimed at stimulating only cell-mediated immunity will not prevent infection and insisted that sterilizing immunity via antibodies must remain the ultimate goal.
Merck's cellular immunity vaccine, MRKAd5, fell with an even louder thud than AIDSVAX because so many experts liked its prospects, while almost everyone predicted AIDSVAX would flop. MRKAd5 tried to stimulate CTLs by expressing three HIV-1 subtype B-derived proteins--Gag, Pol, and Nef. But people vaccinated with MRKAd5 ended up getting infected more than people who got dummy shots, and the vaccine did not constrain viral replication in people who did get infected [1]. In the wake of that collapse, the National Institutes of Health scuttled an already vastly downsized trial of a similar cell-stimulating vaccine [5].
These stinging results encouraged the "hanging-by-a-thread" judgment challenged by David Watkins. The problem with MRKAd5, he argued, was not that it tried to ignite a cellular response, but that it did so feebly. Julie McElrath confirmed that assessment in her presentation, noting low overall CD4 and CD8 response rates in vaccinated people [3]. And CD4 or CD8 cells inconsistently secreted the cytokines (cell-to-cell messengers) interferon-gamma, interleukin-2, and tumor-necrosis factor-alpha in vaccinated participants. Only one third of vaccinated people had measurable levels of all three cytokines.
In a published essay, the University of Oxford's Tomas Hanke propounded the same apologia Watkins advanced, writing that MRKAd5 "did not reach the limits of vaccine T-cell induction and its design can be improved both from the point of the HIV-1-derived immunogens and their delivery" [1]. So this vaccine's demise, Hanke concluded, "cannot be a reason for dismissal of the whole T-cell vaccine concept."
At the Transmission Workshop, Watkins went even further, hypothesizing that a robust and broad CD8 response may even prevent infection by demolishing HIV-infected cells so quickly that the virus never gets its hooks into enough cells to commandeer the immune system. But if acute infection reaches the point where a million HIV copies populate a milliliter of blood, he allowed, no cytotoxic response is likely to wipe out the virus.
Watkins failed to persuade another workshop participant, Giuseppe Pantaleo from the University of Lausanne. Pantaleo argued that even a diverse panoply of CD8s would probably not home to enough infected cells in mucosal tissues fast enough to fight HIV to an early stalemate.
Although Watkins presented preliminary data on a massive T-cell response he kicked off in macaques with a vaccine incorporating all simian immunodeficiency virus proteins except Env, none of the vaccine experts at this meeting proposed a next step in human HIV vaccine development.
References
1. Hanke T. STEP trial and HIV-1 vaccines inducing T-cell responses.
Expert Rev Vaccines. 2008;7:303-309.
2. Watkins D. Biology of transmission: focus on monkey models and in vitro methodologies. 3rd International Workshop on HIV Transmission: Principles of Intervention. July 31-August 2, 2008, Mexico City. Invited lecture.
3. McElrath J. Progress in HIV vaccine development: the post-STEP era. 3rd International Workshop on HIV Transmission: Principles of Intervention. July 31-August 2, 2008, Mexico City. Invited lecture.
4. Pitisuttithum P, Gilbert P, Gurwith M, et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis. 2006;194:1661-1671
5. National Institutes of Allergy and Infectious Diseases. NIAID Online Update. Statement: NIAID will not move forward with the PAVE 100 HIV vaccine trial. July 17, 2008. http://www.aegis.org/news/niaid/2008/NI080703.html
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