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Updated: Jul 4, 2026
Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells
Published on: February 15, 2019
Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans
David I Watkins1, Dennis R Burton, Esper G Kallas
1Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, Wisconsin 53715, USA. watkins@primate.wisc.edu
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.
Insights
Merck's adenovirus type 5 (Ad5) HIV vaccine failed in human trials. The simian immunodeficiency virus (SIV) model showed promise for T cell vaccines in reducing viral load, unlike previous macaque studies.
Area of Science:
- Immunology
- Vaccinology
- Virology
Background:
- Adenovirus type 5 (Ad5)-based vaccines for Human Immunodeficiency Virus type 1 (HIV-1) have faced challenges in clinical efficacy.
- Previous studies using analogous vaccines in simian immunodeficiency virus (SIV) challenge models in rhesus macaques also showed limited success.
Purpose of the Study:
- To evaluate the predictive value of animal models for HIV-1 vaccine efficacy in humans.
- To identify potential reasons for the failure of Ad5-based HIV vaccines in the STEP trial.
Main Methods:
- Comparison of results from the Merck STEP Phase 2b HIV-1 human efficacy trial with macaque studies using SIV and simian-human immunodeficiency virus (SHIV89.6P) challenge models.
- Analysis of vaccine-induced immune responses and their correlation with protection or viral load control.
Main Results:
- The Ad5-based vaccine failed to prevent HIV-1 infection or suppress viral load in the human STEP trial.
- Macaque studies with SHIV89.6P challenge did not accurately predict human trial outcomes, despite showing some viral load reduction and CD4+ T cell preservation.
- The SIV challenge model, though imperfectly validated, demonstrated potential for T cell vaccine strategies to reduce viral load.
Conclusions:
- The predictive validity of current animal models for HIV-1 vaccine development requires re-evaluation.
- Expanded use of the SIV challenge model may aid in prioritizing candidate HIV-1 vaccines.
- Future HIV vaccine development should focus on T cell strategies aimed at reducing viral load post-infection.
