Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans

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Abstract

The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge–rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector–based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4+ T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.

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Figure 1: The goal of a successful CTL-based vaccine is to reduce HIV-1 replication to a level that reduces or eliminates transmission.
Figure 2: DNA–Ad5 Gag vaccination only shows protective effect in Mamu-A*01–positive rhesus macaques; Ad5 Gag vaccination has no effect.
Figure 3: Durable suppression of SIVmac239 replication in Mamu-A*01–positive macaques vaccinated with DNA-Ad5 encoding Gag, Tat, Ref and Nef.

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Acknowledgements

We thank J. Loffredo, A. Espinosa, N. Wilson Schlei, T. Friedrich and L. Valentine for help in preparing this article. We are also grateful to the members of the Watkins Laboratory for advice on its contents and to S. Noble of IAVI for assistance with editing. The preparation of this article and of the research it describes was supported by US National Institutes of Health grants R01 AI049120, R01 AI052056, R24 RR015371 and R24 RR016038 to D.I.W., grants R37 AI36082 and R01 AI45463 to J.P.M., grant U01 AI69420 to E.G.K. and grants R37 AI33292 and R01 AI055332 to D.R.B. We also wish to acknowledge Merck and IAVI for their support of the Watkins Laboratory and Fundação de Amparo à Pesquisa do Estado de São Paulo for support of the Kallas Laboratories.

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D.I.W. has enjoyed a long-standing collaboration with scientists at Merck. They have supplied his group with DNA and Ad5 constructs for vaccine studies. E.G.K. is a Federal University of SSãoo Paulo site principal investigator for the STEP trial and has been receiving funds from Merck to run clinical trials; he also provides consultant services for Merck and Bristol-Meyers Squibb.

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