Rachel L Spreng, Kelly E Seaton, Lin Lin, Sir'Tauria Hilliard, Gillian Q Horn, Milite Abraha, Aaron W Deal, Kan Li, Alexander J Carnacchi, Elizabeth Feeney, Siam Shabbir, Lu Zhang, Valerie Bekker, Sarah V Mudrak, Sheetij Dutta, Laina D Mercer, Scott Gregory, C Richter King, Ulrike Wille-Reece, Erik Jongert, Neville K Kisalu, Georgia D Tomaras, S Moses Dennison
{"title":"鉴定 RTS,S/AS01 疫苗诱导的体液生物标志物，预测受控人类疟疾感染的保护作用。","authors":"Rachel L Spreng, Kelly E Seaton, Lin Lin, Sir'Tauria Hilliard, Gillian Q Horn, Milite Abraha, Aaron W Deal, Kan Li, Alexander J Carnacchi, Elizabeth Feeney, Siam Shabbir, Lu Zhang, Valerie Bekker, Sarah V Mudrak, Sheetij Dutta, Laina D Mercer, Scott Gregory, C Richter King, Ulrike Wille-Reece, Erik Jongert, Neville K Kisalu, Georgia D Tomaras, S Moses Dennison","doi":"10.1172/jci.insight.178801","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 19","pages":""},"PeriodicalIF":6.3000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466194/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identification of RTS,S/AS01 vaccine-induced humoral biomarkers predictive of protection against controlled human malaria infection.\",\"authors\":\"Rachel L Spreng, Kelly E Seaton, Lin Lin, Sir'Tauria Hilliard, Gillian Q Horn, Milite Abraha, Aaron W Deal, Kan Li, Alexander J Carnacchi, Elizabeth Feeney, Siam Shabbir, Lu Zhang, Valerie Bekker, Sarah V Mudrak, Sheetij Dutta, Laina D Mercer, Scott Gregory, C Richter King, Ulrike Wille-Reece, Erik Jongert, Neville K Kisalu, Georgia D Tomaras, S Moses Dennison\",\"doi\":\"10.1172/jci.insight.178801\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":14722,\"journal\":{\"name\":\"JCI insight\",\"volume\":\"9 19\",\"pages\":\"\"},\"PeriodicalIF\":6.3000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466194/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JCI insight\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1172/jci.insight.178801\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCI insight","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/jci.insight.178801","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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 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.
期刊介绍：
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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