TY - JOUR
T1 - 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
AU - Young, William Chad
AU - Carpp, Lindsay N.
AU - Chaudhury, Sidhartha
AU - Regules, Jason A.
AU - Bergmann-Leitner, Elke S.
AU - Ockenhouse, Christian
AU - Wille-Reece, Ulrike
AU - deCamp, Allan C.
AU - Hughes, Ellis
AU - Mahoney, Celia
AU - Pallikkuth, Suresh
AU - Pahwa, Savita
AU - Dennison, S. Moses
AU - Mudrak, Sarah V.
AU - Alam, S. Munir
AU - Seaton, Kelly E.
AU - Spreng, Rachel L.
AU - Fallon, Jon
AU - Michell, Ashlin
AU - Ulloa-Montoya, Fernando
AU - Coccia, Margherita
AU - Jongert, Erik
AU - Alter, Galit
AU - Tomaras, Georgia D.
AU - Gottardo, Raphael
N1 - Funding Information:
the Bill and Melinda Gates Foundation (OPP1066832) for antibody production work. GA’s work was supported by the Malaria Vaccine Initiative, Ragon Institute, MGH SAMANA Cay Research Scholar, Bill and Melinda Gates Foundation, and NIH. The work done at the University of Miami was supported by PATH’s Malaria Vaccine Initiative. Generation of RNA-seq data reported in Du et al. was supported by research grants from PATH’s Malaria Vaccine Initiative and from the Bill and Melinda Gates Foundation (OPP1087783). Work done by Kazmin et al. was supported by a research grant from MVI-Path, the National Institutes of Health (U19AI090023 and U19AI057266), and the National Science Foundation Grants (NSF-1516074 and NSF-1361532). Work by Radin et al. was supported by CEVAC and GlaxoSmithKline Biologicals SA. The MAL068 trial was supported by the PATH Malaria Vaccine Initiative (Washington, DC) and the Military Infectious Diseases Research Program (Fort Detrick, MD). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army, the US Department of Defense, or The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc. The MAL071 trial was supported by GSK Biologicals, the Military Infectious Diseases Research Program (Fort Detrick, MD), the PATH Malaria Vaccine Initiative (to GSK Vaccines and the MIDRP), and the Bill and Melinda Gates Foundation (to the Malaria Vaccine Initiative and Atreca).
Funding Information:
We thank the participants in the MAL068 and MAL071 trials. We thank Milite Abraha, Matthew Reichartz, Michelle Key, Frederick Feely II, and Richard H.C. Huntwork for technical help, Sheetal Sawant, and Lu Zhang for statistical input, Marcella Sarzotti-Kelsoe, Judith Lucas, and Kaia Lyons for Good Clinical Laboratory Practice (GCLP) management at Duke University. We thank Eva Chung for project management support.
Funding Information:
All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was supported by the National Institute of Allergy and Infectious Diseases (award U19AI128914 Human Immunology Project Consortium to RG) and the Vaccine Statistical Support (Bill and Melinda Gates Foundation award INV-008576/OPP1154739 to RG). The clinical studies MAL068 and MAL071 were sponsored by GlaxoSmithKline Biologicals SA. This study was also supported by grants for the Antibody Dynamics platform of the Global Health–Vaccine Accelerator Platforms (GH-VAP) from the Bill and Melinda Gates Foundation (OPP1151372, OPP12109388) to GT. We acknowledge James Peacock in the Duke Human Vaccine Institute Protein Production Facility which received funding support from the Collaboration for AIDS Vaccine Research of
Publisher Copyright:
Copyright © 2021 Young, Carpp, Chaudhury, Regules, Bergmann-Leitner, Ockenhouse, Wille-Reece, deCamp, Hughes, Mahoney, Pallikkuth, Pahwa, Dennison, Mudrak, Alam, Seaton, Spreng, Fallon, Michell, Ulloa-Montoya, Coccia, Jongert, Alter, Tomaras and Gottardo.
PY - 2021/6/15
Y1 - 2021/6/15
N2 - 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 vs. 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.
AB - 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 vs. 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.
KW - correlates of protection
KW - immune response
KW - machine learning
KW - malaria
KW - vaccine
UR - http://www.scopus.com/inward/record.url?scp=85113828060&partnerID=8YFLogxK
U2 - 10.3389/fdata.2021.672460
DO - 10.3389/fdata.2021.672460
M3 - Article
AN - SCOPUS:85113828060
SN - 2624-909X
VL - 4
JO - Frontiers in Big Data
JF - Frontiers in Big Data
M1 - 672460
ER -