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

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.

Figure 1

The goal of a successful CTL-based vaccine is to reduce HIV-1 replication to a level that reduces or eliminates transmission. In practice, this is about a 1.5 log reduction, from a set point of 30,000 RNA copies/ml of plasma to less than about 1,500. A similar numerical reduction in SIVmac239 infection of rhesus macaques would be from about 10⁶ RNA copies/ml to <30,000, although whether this would be sufficient to reduce any hypothetical transmission of SIV from macaque to macaque is unknown.

Figure 2

DNA/Ad5 Gag vaccination only shows protective effect in Mamu-A*01 positive rhesus macaques; Ad5 Gag vaccination has no effect. A) Mamu-A*01 positive macaques were vaccinated with Gag, and then challenged with a high dose of SIVmac239 i.r. The animals were either primed three times with DNA, then boosted with Ad5 (DNA/Ad5), or were primed three times with Ad5 and boosted with Ad5 (Ad5). In animals primed with DNA Gag, the peak of viremia was 6 times lower than in control animals and the early chronic set point was 15 times lower. There were no differences in either peak viremia or the early chronic set point in animals primed with Ad5 Gag, compared to control animals. B) Mamu-A*01 negative macaques were primed with three doses of DNA Gag, and then boosted with Ad5 Gag. The vaccinated animals had a peak of viremia that was 3.2-fold lower than in control animals, but no difference was observed in viral loads at any subsequent time points, indicating that Mamu-A*01 has only a moderate protective effect in Gag-vaccinated animals .

Figure 3

Durable suppression of SIVmac239 replication in Mamu-A*01 positive macaques vaccinated with DNA/Ad5 encoding Gag, Tat, Ref and Nef. Mamu-A*01 positive rhesus macaques were primed with DNA encoding Gag, Tat, Rev and Nef three times, then boosted with an Ad5 vector encoding the same four proteins before a repeated low dose i.r. challenge. Both the peak and the set point viral loads were significantly lower in the vaccinees than in control animals .