PROJECT SUMMARY (See instructions): Safe and efficacious vaccines are needed to massively reduce the economic and human health costs of HIV-1/AIDS, dengue, malaria, and COVID-19. This goal has been hindered by the genetic diversity of the etiological pathogens. Randomized, controlled trials that rigorously assess the efficacy of candidate vaccines to prevent infection and/or disease caused by these pathogens are a core research platform for improving vaccines. Moreover, randomized efficacy trials of broadly neutralizing monoclonal antibody (bnAb) regimens aid vaccine development. This project develops statistical methods for vaccine and bnAb prevention efficacy trials, with purpose lo 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 immune markers measured over lime as correlates of instantaneous risk of acquisition of HIV-1 or SARS-CoV-2 (of any strain or with a strain with a particular feature such as an amino acid (AA) sequence or neutralization phenotype) in (a) HIV-1 and COVID-19 vaccine and (b) HIV-1 bnAb efficacy trials. Aim 2 develops methods for assessing immune markers measured by a fixed time point post-vaccination in HIV-1, dengue, malaria, and COVID-19 vaccine efficacy (VE) trials as multiple types of correlates of protection: (a) an estimated optimal surrogate a summary marker combining information from all markers that best predicts overall or feature-specific outcome; (b) a correlate of VE la marker that modifies VE, studied via the statistical frameworks principal stratification, controlled causal effects, and stochastic interventional causal effects. 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 malaria infections and vaccination. Aim 4 develops causal methods for assessing vaccine and bnAb efficacy to prevent (a) overall and (b) feature-specific HIV-1 acquisition in study populations defined by certain patterns of pre-exposure prophylaxis use. The methods are developed with application lo 14 recently completed or ongoing VE trials (4 for HIV-1, 2 for dengue, 2 for malaria, 6 for COVID-19) and 2 HIV-1 bnAb efficacy trials. Collectively, the aims advance development of immune correlates based on both immune marker data and pathogen genetic sequence/immunophenotype data.