Leveraging novel pediatric SHIVs to identify biomarkers of prophylactic efficacy of bnAb against breast milk HIV transmission

Abstract Pediatric HIV continues to be an important public health concern in resource-limited areas. While antiretroviral therapy (ART) to pregnant and breastfeeding women has significantly reduced the rate of vertical transmission, in 2022, 130,000 new pediatric HIV infections occurred. Strategies that can complement ART, such as immune-based interventions, are critically needed to achieve the goal of a generation free of HIV. Animal studies and recent clinical trials have demonstrated the potential for passive immunization with broadly neutralizing antibodies (bnAbs) in HIV prevention. This strategy is especially suitable when transmission risk is well-defined in time such as during breast milk transmission, which accounts for almost 50% of pediatric infections. To advance the clinical development of this promising strategy, it is critical to define biomarkers of efficacy that can be used as a surrogate of protection in clinical trials to predict its efficacy. The predicted serum neutralization 80% inhibitory dilution titer (PT80) is a recently developed biomarker that integrates the IC80 and the serum concentration of the administered bnAb. In the adult AMP clinical trials, which evaluated the efficacy of the bnAb VRC01 for the prevention of sexual transmission of HIV in heterosexual women and in men who have sex with men, PT80 was strongly associated with the level of prevention efficacy. Moreover, PT80 has been associated with efficacy of single bnAb passive immunization in non-human primate models of sexual transmission. Yet, PT80 has not been validated in the setting of oral transmission or to date there is no biomarkers that predict the preventive efficacy of combination bnAbs. Using an infant non-human primate model of breast milk transmission, this project will test the hypothesis that PT80 or another biomarker can predict the efficacy of combination bnAb passive immunization for the prevention of breast milk HIV transmission. The specific aims are: 1) Engineer and characterize SHIVs expressing the Env of breast transmitted founder viruses; 2) Evaluate the ability of PT80 to predict the efficacy of passive immunization with a single bnAb in the setting of repeated oral breast milk TF SHIV exposure; and 3) Identify correlates of protection in the setting of combination bnAb and oral exposure to a virus swarm. By defining a biomarker that predicts the efficacy of bnAbs against breastmilk HIV acquisition, this study will provide novel insights for the design of clinical trials evaluating bnAb immunotherapy for the prevention of postnatal HIV acquisition; notably by 1) allowing for informed selection of bnAbs and combination bnAbs for clinical evaluation; 2) allowing for rationale design of an efficacy trial of a combination bnAb regimen to prevent breastmilk acquisition in infants, with the goal of licensure, and 3) ultimately, allowing cost saving 'surrogate endpoint' trials of bnAbs/combo bnAbs, as support for regulatory approval.