An ultimate goal of HIV/AIDS research is the development of a vaccine that prevents HIV infection, which will be needed for eliminating HIV/AIDS in the U.S. and globally. Randomized clinical trials that rigorously assess the efficacy of candidate HIV vaccines are a core research approach to meeting this goal. This project develops statistical methods for HIV vaccine efficacy trials and for parallel repeated low-dose challenge trials of SIV vaccines in nonhuman primates. For efficacy trials.
Aims 1 and 2 develop novel and interdigitating statistical methods for: (1) sieve analysis, i.e., the assessment of how vaccine efficacy against HIV infection varies with genetic features of transmitting HIVs; and (2) immune correlates of protection analysis, i.e., the assessment of how vaccine efficacy against HIV infection and against genotype-specific HIV infection varies with immune responses to vaccination. The overarching objective of these two aims is development of immune correlates of protection (CoPs), which are needed for guiding the optimal choice of HIV sequences to include in vaccines, for guiding the choice of immunogenicity endpoints for benchmarking refined vaccine regimens in Phase l/ll trials, and for immuno-bridging of efficacy trial results to predict vaccine efficacy in new settings. The methods will focus on (A) efficiently and flexibly accommodating time- variations in vaccine efficacy; (B) maximizing the immunological relevance ofthe HIV genetic features; (C) improving the sampling design for measuring immune responses; and (D) developing the best threshold or score immune CoPs that combine information from the large set of immune responses that are assessed. Many ofthe new methods will improve validity, efficiency, and robustness via the targeted maximum likelihood statistical framework. The methods will be developed with application to 13 vaccine efficacy trials (8 for HIV, 3 for dengue, 1 for herpes zoster, 1 for influenza).
Aim 3 parallels Aims 1 and 2 by developing novel statistical methods for assessing within nonhuman primate repeated low-dose challenge trials how vaccine efficacy to prevent SIV infection over time varies with genetic features of exposing SIVs and with immune responses to vaccination.
The Aim 3 research plan focuses on issues (A), (B), and (D)and will be developed with application to several trials from three research groups.

Public Health Relevance

A vaccine that prevents HIV infection is needed for eliminating HIV/AIDS in the U.S. and globally. Such avaccine may be developed through a series of vaccine efficacy trials that identify candidate vaccines conferring partial protection against HIV infection, and that identify how the protection varies with the genetics of HIV and with immune responses to vaccination. This project develops novel statistical methods for improving and accelerating this process; these methods also apply to the development of vaccines for other infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI054165-14
Application #
8997052
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gezmu, Misrak
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
14
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Huang, Ying (2017) Evaluating principal surrogate markers in vaccine trials in the presence of multiphase sampling. Biometrics :
Yang, Guangren; Sun, Yanqing; Qi, Li et al. (2017) Estimation of Stratified Mark-Specific Proportional Hazards Models under Two-Phase Sampling with Application to HIV Vaccine Efficacy Trials. Stat Biosci 9:259-283
Fu, Rong; Gilbert, Peter B (2017) Joint modeling of longitudinal and survival data with the Cox model and two-phase sampling. Lifetime Data Anal 23:136-159
Huang, Ying; Gilbert, Peter B; Fu, Rong et al. (2017) Statistical methods for down-selection of treatment regimens based on multiple endpoints, with application to HIV vaccine trials. Biostatistics 18:230-243
Fiore-Gartland, Andrew; Kullman, Nicholas; deCamp, Allan C et al. (2017) SieveSifter: a web-based tool for visualizing the sieve analyses of HIV-1 vaccine efficacy trials. Bioinformatics 33:2386-2388
Qi, Li; Sun, Yanqing; Gilbert, Peter B (2017) Generalized semiparametric varying-coefficient model for longitudinal data with applications to adaptive treatment randomizations. Biometrics 73:441-451
Spieker, Andrew J; Huang, Ying (2017) A method to address between-subject heterogeneity for identification of principal surrogate markers in repeated low-dose challenge HIV vaccine studies. Stat Med 36:4071-4080
Gilbert, Peter B; Juraska, Michal; deCamp, Allan C et al. (2017) Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials. Stat Commun Infect Dis 9:
Sun, Yanqing; Qian, Xiyuan; Shou, Qiong et al. (2017) Analysis of two-phase sampling data with semiparametric additive hazards models. Lifetime Data Anal 23:377-399
Gilbert, Peter B; Huang, Ying (2016) Predicting Overall Vaccine Efficacy in a New Setting by Re-Calibrating Baseline Covariate and Intermediate Response Endpoint Effect Modifiers of Type-Specific Vaccine Efficacy. Epidemiol Methods 5:93-112

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