The goal of the project is to develop statistical methods for the design and analysis of preventive HIV vaccine efficacy trials and repeated low-dose non-human primate (NHP) challenge trials. Specifically the methods are for (1) Sieve Analysis: Assessing the impact of HIV genotypic and phenotypic variation on HIV vaccine efficacy; (2) Post-infection Vaccine Efficacy: Assessing HIV vaccine effects on post-HIV infection disease progression; and (3) Correlates/Surrogates of Protective Immunity: Assessing correlations of immunological measurements with risk of HIV/SIV infection rate and of post-infection outcomes, and evaluating whether and to what extent the correlations are causative.
Aim 1 will develop a model for studying the relationship between vaccine efficacy and multivariate summary measures of distance of an exposing virus to the immunogen, accounting for subject characteristics including their immune responses to vaccination, and will develop high-dimensional data methods for relating HIV amino acid sequences in breakthrough infections with viral load and other post-infection endpoints.
Aim 2 will develop methods for studying durability of vaccine effects on viral load over time, tackling the problems of selection bias that may arise because the analyzed groups are selected after randomization, and """"""""missing"""""""" viral loads that may arise because infected subjects initiate antiretro viral therapy.
Aim 3 will develop methods for assessing correlates/surrogates of protection in efficacy trials and in NHP trials.
The aims are complementary and integrated, with HIV sequence, immunological, and viral load data used for each aim. The methods will be applied to analyze several HIV vaccine efficacy trial and NHP challenge trial datasets. Primary goals of HIV vaccine research include developing a vaccine that protects broadly against many HIV strains and that can durably suppress viremia, and developing a correlate of protective immunity, which would streamline vaccine development and provide the basis for bridging efficacy of a vaccine observed in a Phase 3 trial to a new setting. By improving the design and analysis of efficacy and NHP trials for addressing these areas, the project will benefit public health. ? ? ?
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