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 bnAb for HIV-1 prevention and the latter is the first direct assessment of VE against malaria infection, enabled by frequent serial deep sequencing of malaria parasites in blood samples. Collectively, the aims are designed to advance development of immune correlates involving both immune response marker and pathogen features.

Public Health Relevance

Genetically diverse pathogens including HIV-1, dengue virus, and Plasmodium falciparum (the most common causative agent of malaria) incur large morbidity, mortality, social, and economic burdens that could be majorly ameliorated if improved preventive vaccines were available. Such improved vaccines can be developed iteratively through randomized, controlled vaccine efficacy trials that, in addition to determining the protective levels of candidate vaccines and how the protection depends on immune responses to vaccination, also determine how protection is influenced by genetic and immunological features of the relevant pathogen. This project develops innovative statistical methods that are critically needed for driving and accelerating the process of answering these questions for vaccine efficacy trials and also for prevention efficacy trials of broadly neutralizing monoclonal antibodies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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HIV Comorbidities and Clinical Studies Study Section (HCCS)
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Gezmu, Misrak
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Fred Hutchinson Cancer Research Center
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