AUTHOR=Young William Chad , Carpp Lindsay N. , Chaudhury Sidhartha , Regules Jason A. , Bergmann-Leitner Elke S. , Ockenhouse Christian , Wille-Reece Ulrike , deCamp Allan C. , Hughes Ellis , Mahoney Celia , Pallikkuth Suresh , Pahwa Savita , Dennison S. Moses , Mudrak Sarah V. , Alam S. Munir , Seaton Kelly E. , Spreng Rachel L. , Fallon Jon , Michell Ashlin , Ulloa-Montoya Fernando , Coccia Margherita , Jongert Erik , Alter Galit , Tomaras Georgia D. , Gottardo Raphael 

TITLE=Comprehensive Data Integration Approach to Assess Immune Responses and Correlates of RTS,S/AS01-Mediated Protection From Malaria Infection in Controlled Human Malaria Infection Trials

JOURNAL=Frontiers in Big Data

VOLUME=Volume 4 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/big-data/articles/10.3389/fdata.2021.672460

DOI=10.3389/fdata.2021.672460

ISSN=2624-909X

ABSTRACT=RTS,S/AS01 (GSK) is the world’s first malaria vaccine. However, despite initial efficacy of almost 70% over the first 6 months of follow-up, efficacy waned over time. A deeper understanding of the immune features that contribute to RTS,S/AS01-mediated protection could be beneficial for further vaccine development. In two recent controlled human malaria infection (CHMI) trials of the RTS,S/AS01 vaccine in malaria-naïve adults, MAL068 and MAL071, vaccine efficacy against patent parasitemia ranged from 44% to 87% across studies and arms (each study included a standard RTS,S/AS01 arm with three vaccine doses delivered in four-week-intervals, as well as an alternative arm with a modified version of this regimen). In each trial, RTS,S/AS01 immunogenicity was interrogated using a broad range of immunological assays, assessing  cellular and humoral immune parameters as well as gene expression. Here, we used a predictive modeling framework to identify immune biomarkers measured at day-of-challenge that could predict sterile protection against malaria infection.  Using cross-validation on MAL068 data (either the standard RTS,S/AS01 arm alone, or across both the standard RTS,S/AS01 arm and the alternative arm), top-performing univariate models identified variables related to Fc effector functions and titer of antibodies that bind to the central repeat region (NANP6) of CSP as the most predictive variables; all NANP6-related variables consistently associated with protection. In cross-study prediction analyses of MAL071 outcomes (the standard RTS,S/AS01 arm), top-performing univariate models again identified variables related to Fc effector functions of NANP6-targeting antibodies as highly predictive. We found little benefit – with this dataset – in terms of improved prediction accuracy in bivariate models versus univariate models.  These findings await validation in children living in malaria-endemic regions, and in vaccinees administered a fourth RTS,S/AS01 dose. Our findings support a “quality as well as quantity” hypothesis for RTS,S/AS01-elicited antibodies against NANP6, implying that malaria vaccine clinical trials should assess both titer and Fc effector functions of anti-NANP6 antibodies.