Post-randomization Biomarker Effect Modification in an HIV Vaccine Clinical Trial

TL;DR

This paper develops new assumption-lean statistical methods to detect effect modification by immune response markers in HIV vaccine trials, revealing partial protection linked to specific immune responses.

Contribution

It introduces adapted PSEM methods based on SACE techniques for binary intermediate responses, enabling more robust analysis of vaccine effect modification.

Findings

Vaccine partially protected high CD8+ T cell responders

New methods allow assumption-lean analysis of effect modification

Supports immune response markers as correlates of protection

Abstract

While the HVTN 505 trial showed no overall efficacy of the tested vaccine to prevent HIV infection over placebo, previous studies, biological theories, and the finding that immune response markers strongly correlated with infection in vaccine recipients generated the hypothesis that a qualitative interaction occurred. This hypothesis can be assessed with statistical methods for studying treatment effect modification by an intermediate response variable (i.e., principal stratification effect modification (PSEM) methods). However, available PSEM methods make untestable structural risk assumptions, such that assumption-lean versions of PSEM methods are needed in order to surpass the high bar of evidence to demonstrate a qualitative interaction. Fortunately, the survivor average causal effect (SACE) literature is replete with assumption-lean methods that can be readily adapted to the PSEM application for the special case of a binary intermediate response variable. We map this adaptation, opening up a host of new PSEM methods for a binary intermediate variable measured via two-phase sampling, for a dichotomous or failure time final outcome and including or excluding the SACE monotonicity assumption. The new methods support that the vaccine partially protected vaccine recipients with a high polyfunctional CD8+ T cell response, an important new insight for the HIV vaccine field.