Rosado, Jason, White, Michael T., Longley, Rhea J., Lacerda, Marcus, Monteiro, Wuelton, Brewster, Jessica, Sattabongkot, Jetsumon, Guzman-Guzman, Mitchel, Llanos-Cuentas, Alejandro, Vinetz, Joseph M., Gamboa, Dionicia, Mueller, Ivo, Malaria : parasites et hôtes - Malaria : parasites and hosts, Institut Pasteur [Paris], Santé publique : épidémiologie & sciences de l'information biomédicale (ED 393), Sorbonne Université (SU), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Instituto Leônidas e Maria Deane - Fiocruz Amazônia [Manaus, Brésil] (ILMD), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Mahidol University [Bangkok], Universidad Peruana Cayetano Heredia (UPCH), Yale University School of Medicine, This work was supported by National Health and Medical Research Council Australia grants 1092789, 1134989 and 1043345 to IM (https://www.nhmrc.gov.au/), the Global Health Innovative Technology Fund grant T2015-142 to IM (https://www.ghitfund.org/), National Institutes of Health-National Institute of Allergy and Infectious Diseases (NIH-NIAID) U19AI089681 to JMV (https://www.niaid.nih.gov). This work has been supported by FIND with funding from the Australian and British governments. The Brazilian team was partly funded by Fundação de Amparo à Pesquisa do Estado do Amazonas-FAPEAM (PAPAC 005/2019 and Pró-Estado). JR is supported by the Pasteur - Paris University (PPU) International PhD Program. RJL received the Page Betheras Award from WEHI to provide funding for technical support for this project during parental leave. RJL is supported by a NHMRC Early Career Investigator Fellowship (1173210). ML and WM are fellows of the Brazilian National Council for Scientific and Technological Development. MGG is supported by Training Grant 5D43TW007120 (https://www.fic.nih.gov)., Institut Pasteur [Paris] (IP), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), and Yale School of Medicine [New Haven, Connecticut] (YSM)
Background Antibody responses as serological markers of Plasmodium vivax infection have been shown to correlate with exposure, but little is known about the other factors that affect antibody responses in naturally infected people from endemic settings. To address this question, we studied IgG responses to novel serological exposure markers (SEMs) of P. vivax in three settings with different transmission intensity. Methodology We validated a panel of 34 SEMs in a Peruvian cohort with up to three years’ longitudinal follow-up using a multiplex platform and compared results to data from cohorts in Thailand and Brazil. Linear regression models were used to characterize the association between antibody responses and age, the number of detected blood-stage infections during follow-up, and time since previous infection. Receiver Operating Characteristic (ROC) analysis was used to test the performance of SEMs to identify P. vivax infections in the previous 9 months. Principal findings Antibody titers were associated with age, the number of blood-stage infections, and time since previous P. vivax infection in all three study sites. The association between antibody titers and time since previous P. vivax infection was stronger in the low transmission settings of Thailand and Brazil compared to the higher transmission setting in Peru. Of the SEMs tested, antibody responses to RBP2b had the highest performance for classifying recent exposure in all sites, with area under the ROC curve (AUC) = 0.83 in Thailand, AUC = 0.79 in Brazil, and AUC = 0.68 in Peru. Conclusions In low transmission settings, P. vivax SEMs can accurately identify individuals with recent blood-stage infections. In higher transmission settings, the accuracy of this approach diminishes substantially. We recommend using P. vivax SEMs in low transmission settings pursuing malaria elimination, but they are likely to be less effective in high transmission settings focused on malaria control., Author summary Plasmodium vivax still poses a threat in many countries due to its ability to cause recurrent infections. Key to achieving the goal of malaria elimination is the ability to quickly detect and treat carriers of relapsing parasites. Failing to identify this transmission reservoir will hinder progress towards malaria elimination. Recently, novel serological markers of recent exposure to P. vivax (SEM) have been developed and validated in low transmission settings. It is still poorly understood what factors affect the antibody response to these markers when evaluated in contrasting endemic contexts. To determine the factors that influence the antibody response to SEM, we compared the antibody levels in three sites with different transmission intensity: Thailand (low), Brazil (moderate) and Peru (high). In this study, we found that transmission intensity plays a key role in the acquisition of the antibody repertoire to P. vivax. In highly endemic sites, it is likely that immunological memory resulting from a constant and sustained exposure will impact the performance of SEMs to detect individuals with recent exposure to P. vivax. In summary, SEMs that perform well in low transmission sites do not perform as well in high transmission regions.