{"doi":"10.3389/fdata.2021.672460","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","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 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.","journal":"Frontiers in Big Data","year":2021,"id":177405,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9254,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":539332,"name":"Lindsay N. Carpp","orcid":"0000-0003-0333-5925","position":1,"is_corresponding":false},{"id":454636,"name":"Sidhartha Chaudhury","orcid":"0000-0001-9513-6688","position":2,"is_corresponding":false},{"id":721697,"name":"Jason A. Regules","orcid":"0000-0001-9928-221X","position":3,"is_corresponding":false},{"id":305202,"name":"Elke S. Bergmann‐Leitner","orcid":"0000-0002-8571-8956","position":4,"is_corresponding":false},{"id":722426,"name":"Christian F. Ockenhouse","orcid":null,"position":5,"is_corresponding":false},{"id":722427,"name":"Ulrike Wille-Reece","orcid":null,"position":6,"is_corresponding":false},{"id":420012,"name":"Allan C. deCamp","orcid":"0000-0003-1404-4322","position":7,"is_corresponding":false},{"id":449547,"name":"Ellis Hughes","orcid":"0000-0003-0637-4436","position":8,"is_corresponding":false},{"id":722428,"name":"Celia R. Mahoney","orcid":null,"position":9,"is_corresponding":false},{"id":380957,"name":"Suresh Pallikkuth","orcid":"0000-0003-4451-8859","position":10,"is_corresponding":false},{"id":295814,"name":"Savita Pahwa","orcid":"0000-0002-4470-4216","position":11,"is_corresponding":false},{"id":303074,"name":"S. Moses Dennison","orcid":null,"position":12,"is_corresponding":false},{"id":722429,"name":"Sarah V. Mudrak","orcid":null,"position":13,"is_corresponding":false},{"id":258350,"name":"S. Munir Alam","orcid":"0000-0003-0941-0703","position":14,"is_corresponding":false},{"id":300922,"name":"Kelly E. Seaton","orcid":"0000-0002-2009-3270","position":15,"is_corresponding":false},{"id":300919,"name":"Rachel L. Spreng","orcid":"0000-0003-1254-0760","position":16,"is_corresponding":false},{"id":108370,"name":"Jon Fallon","orcid":null,"position":17,"is_corresponding":false},{"id":108382,"name":"Ashlin R. Michell","orcid":"0000-0002-7563-4345","position":18,"is_corresponding":false},{"id":722430,"name":"Fernando Ulloa‐Montoya","orcid":null,"position":19,"is_corresponding":false},{"id":721698,"name":"Margherita Coccia","orcid":"0000-0003-1947-4735","position":20,"is_corresponding":false},{"id":722431,"name":"Erik Jongert","orcid":null,"position":21,"is_corresponding":false},{"id":106757,"name":"Galit Alter","orcid":"0000-0002-7680-9215","position":22,"is_corresponding":false},{"id":258351,"name":"Georgia D. Tomaras","orcid":"0000-0001-8076-1931","position":23,"is_corresponding":false},{"id":18054,"name":"Raphaël Gottardo","orcid":"0000-0002-3867-0232","position":24,"is_corresponding":false},{"id":721696,"name":"William C. Young","orcid":"0000-0002-3368-052X","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T23:47:32.096934Z","pmid":"34212134","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}