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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

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 vacci...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239149/
https://www.ncbi.nlm.nih.gov/pubmed/34212134
http://dx.doi.org/10.3389/fdata.2021.672460
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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
author_facet 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
author_sort Young, William Chad
collection PubMed
description 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.
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spelling pubmed-82391492021-06-30 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 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 Front Big Data Big Data 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. Frontiers Media S.A. 2021-06-15 /pmc/articles/PMC8239149/ /pubmed/34212134 http://dx.doi.org/10.3389/fdata.2021.672460 Text en 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. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Big Data
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
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Big Data
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239149/
https://www.ncbi.nlm.nih.gov/pubmed/34212134
http://dx.doi.org/10.3389/fdata.2021.672460
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