What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Rigorous Simian Immunodeficiency Virus Vaccine Trials Can Be Instructive

Abstract

Simian immunodeficiency virus (SIV) challenge of rhesus macaques provides an invaluable tool to evaluate the clinical prospects of HIV-1 vaccine concepts. However, as with any animal model of human disease, it is crucial to understand the advantages and limitations of this system to maximize the translational value of SIV vaccine studies. Here, we discuss the importance of assessing the efficacy of vaccine prototypes using stringent SIV challenge regimens that mimic HIV-1 transmission and pathogenesis. We also review some of the cautionary tales of HIV-1 vaccine research because they provide general lessons for the preclinical assessment of vaccine candidates.

Figure 1.

Log-transformed viral loads over the courses of untreated HIV-1 and SIVmac239 infections. (A) Longitudinal viral loads (VLs) are plotted against the number of days since the first blood draw tested positive for HIV-1 RNA in 50 HIV-1-infected subjects (based on data in Robb et al. 2016). (B) Longitudinal VLs from 24 rhesus macaques that were rectally infected with SIVmac239 as part of previous and ongoing studies conducted by our laboratory (Martins et al. 2014; M Martins, unpubl.). Peak VL was defined as the highest plasma viral (v)RNA measurement within the initial 42 days since the first positive HIV-1 VL (A) or since the monkeys were infected with SIVmac239 (B). Nadir VL was defined as the lowest plasma vRNA measurement after peak viremia through day 42 in both A and B. The HIV-1 setpoint was calculated as the average VL of all samples collected after day 42 and until antiretroviral therapy was initiated up to 1 year after the first positive VL. The simian immunodeficiency virus (SIV) setpoint was calculated as the average VL of all measurements performed within days 42 and 112 postinfection. Log-transformed medians of peak (dashed vertical line), nadir (dotted vertical line), and setpoint VLs are shown in each graph. The time to peak VL is shown in parenthesis after the median peak VL in each panel and corresponds to the median number of days since HIV-1 vRNA was first detected in plasma (A) or since the establishment of productive SIV infection (B). The solid black line in each panel denotes the median of VLs measured at each time point.