Identification of RTS,S/AS01 vaccine-induced humoral biomarkers predictive of protection against controlled human malaria infection

BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection fr...

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Published in:	JCI insight Vol. 9; no. 19
Main Authors:	Spreng, Rachel L, Seaton, Kelly E, Lin, Lin, Hilliard, Sir'Tauria, Horn, Gillian Q, Abraha, Milite, Deal, Aaron W, Li, Kan, Carnacchi, Alexander J, Feeney, Elizabeth, Shabbir, Siam, Zhang, Lu, Bekker, Valerie, Mudrak, Sarah V, Dutta, Sheetij, Mercer, Laina D, Gregory, Scott, King, C Richter, Wille-Reece, Ulrike, Jongert, Erik, Kisalu, Neville K, Tomaras, Georgia D, Dennison, S Moses
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 08-10-2024
Subjects:	Antibodies, Protozoan - blood Antibodies, Protozoan - immunology Biomarkers - blood Child, Preschool Clinical Medicine Female Humans Immunoglobulin G - blood Immunoglobulin G - immunology Infant Malaria Vaccines - immunology Malaria, Falciparum - immunology Malaria, Falciparum - prevention & control Male Plasmodium falciparum - immunology Protozoan Proteins - immunology Vaccines, Synthetic Malaria Immunology Vaccines
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Summary:	BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.METHODSVaccine-induced total serum antibody (immunoglobulins, Igs) and subclass antibody (IgG1 and IgG3) responses were measured by biolayer interferometry and the binding antibody multiplex assay, respectively. Immune responses were compared between protected and nonprotected vaccinees using univariate and multivariate logistic regression.RESULTSBlinded prediction analysis showed that 5 antibody binding measures, including magnitude-avidity composite of serum Ig specific for PfCSP, major NANP repeats and N-terminal junction, and PfCSP- and NANP-specific IgG1 subclass magnitude, had good prediction accuracy (area under the receiver operating characteristic curves [ROC AUC] > 0.7) in at least 1 trial. Furthermore, univariate analysis showed a significant association between these antibody measures and protection (odds ratios 2.6-3.1). Multivariate modeling of combined data from 3 RTS,S CHMI trials identified the combination of IgG1 NANP binding magnitude plus serum NANP and N-junction Ig binding magnitude-avidity composite as the best predictor of protection (95% confidence interval for ROC AUC 0.693-0.834).CONCLUSIONThese results reinforce our previous findings and provide a tool for predicting protection in future trials.TRIAL REGISTRATIONClinicalTrials.gov NCT03162614, NCT03824236, NCT01366534, and NCT01857869.FUNDINGThis study was supported by Bill & Melinda Gates Foundation's Global Health-Discovery Collaboratory grants (INV-008612 and INV-043419) to GDT.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 Authorship note: RLS and KES are co–first authors. SMD and GDT are co–senior authors and contributed equally to this work.
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.178801