Losing Less in Translation: Relating the Preclinical Evidence Base for Active and Passive Immunity to Prevention of HIV‐1 Infection in Humans

The nonhuman primate (NHP) model has been a cornerstone in the development of effective therapeutic and prophylactic interventions for HIV‐1 infection. Yet, despite promising results in this key preclinical setting, major efficacy trials of HIV vaccines have failed to exhibit sufficient protection to meet their endpoint efficacy criteria. Similarly, the recent Antibody‐Mediated Prevention (AMP) trials (HVTN 703, 704), which tested the ability of passive immunization with the broadly neutralizing antibody VRC01, also failed to meet predetermined overall efficacy criteria. Cumulatively, both active and passive vaccination regimens that have demonstrated the ability to provide protection in NHPs have not provided sufficient benefits in clinical field trials, raising questions about how to optimally model the challenging clinical reality facing HIV‐1 vaccine developers. Here, with a goal of highlighting means whereby gaps might be addressed, we discuss some factors that may influence consistency between NHP experiments and translation between clinical and preclinical settings in both active and passive vaccine regimens. We conclude that results from the AMP trials provide a key benchmark that has high value in gauging the clinical prospects of humoral immune responses induced by vaccines or provided by passive antibody prophylaxis. The promise of new knowledge gained through carefully designed testing of new interventions and therapeutics motivates continued exploration of means to model humoral immunity to HIV‐1 in preclinical models.