Assessing vaccine effects in repeated low-dose challenge experiments

Abstract

Evaluation of HIV vaccine candidates in nonhuman primates (NHPs) is a critical step toward developing a successful vaccine to control the HIV pandemic. Historically, HIV vaccine regimens have been tested in NHPs by administering a single high dose of the challenge virus. More recently, evaluation of candidate HIV vaccines has entailed repeated low-dose challenges, which more closely mimic typical exposure in natural transmission settings. In this article, we consider evaluation of the type and magnitude of vaccine efficacy from such experiments. Based on the principal stratification framework, we also address evaluation of potential immunological surrogate endpoints for infection.

Figure 1

Left panel: Nonparametric (solid line) and parametric (dotted line) estimates of the survival functions based on data from Ellenberger et al. (2006) and fitted leaky vaccine model from Table 1. Right panel: Nonparametric estimates of the complementary log-log survival functions.

Figure 2

Difference in nonparametric estimates of the complementary log-log survival functions between the vaccine and control arms for the observed data (bold lines) and 25 simulated data sets (gray lines) for each of the four different mechanism of protection models.

Figure 3

Results from simulation study described in Section 3.2 with m = 20 NHPs per arm. Solid lines denote the true transmission probability curves p(z, s; β) for z = 0 (upper line) and z = 1 (lower line). Dotted lines depict the mean of the estimated curves p(z, s; β̂) over 500 simulated data sets.