PROJECT SUMMARY/ABSTRACT Safe and globally efficacious vaccines are needed to massively reduce the economic and human health costs of HIV-1/AIDS, dengue, and malaria. This goal has been hindered to varying extents by the genetic diversity of HIV-1, dengue virus, and Plasmodium falciparum, with the best available vaccines having only low-to-moderate or variable efficacy against these pathogens. Randomized, controlled clinical trials that rigorously assess the efficacy of candidate vaccines to prevent infection and/or disease caused by such pathogens are a core research platform for developing improved vaccines. In addition, randomized clinical efficacy trials of broadly neutralizing monoclonal antibody (bnAb) regimens aid vaccine development. This project develops statistical methods for the design and analysis of vaccine and bnAb prevention efficacy trials, with purpose to rigorously characterize multiple types of distinct and complementary “immune correlates,” which are critical tools for driving the iterative research process for improving vaccines. Aim 1 develops methods for assessing immunological markers measured over time as correlates of instantaneous risk of acquisition of HIV-1 (of any strain or with a strain with a particular feature such as an amino acid (AA) sequence or serotype) in (a) HIV-1 vaccine and (b) HIV-1 bnAb efficacy trials; such correlates are especially helpful for generating hypotheses and insights about mechanisms of protection. Aim 2 develops methods for assessing immune response markers measured by a given fixed time point post-vaccination in HIV-1, dengue, and malaria vaccine efficacy (VE) trials as two types of correlates of protection: (a) an estimated optimal surrogate, which is an optimal summary marker combining information from all markers that best predicts overall and feature-specific infection or disease occurrence over a specified cumulative period of time; and (b) a correlate of VE, which is a summary marker that is a modifier/predictor of the level of VE. Aim 3 develops dynamic recurrent event models for assessing (a) malaria VE against overall and circumsporozoite protein (CSP) AA-specific malaria infection and disease, and (b) how CSP AA-specific malaria risk depends on prior immune responses and malaria infections, improving models of vaccine- and natural-immunity. Aim 4, in recognizing the importance of pre-exposure prophylaxis (PrEP) as an effective modality for reducing HIV-1 acquisition, develops causal methods for assessing vaccine and bnAb efficacy to prevent (a) overall and (b) feature-specific HIV-1 infection in study populations defined by certain patterns of PrEP use, including zero use. The methods will be developed with application to 8 recently completed or ongoing VE trials (4 for HIV-1, 2 for dengue, 2 for malaria) and 2 bnAb efficacy trials for HIV-1. The two ongoing bnAb trials and the ongoing malaria VE trial are particularly groundbreaking; the former is the first evaluation of a bnA...