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Heterogeneity in response to serological exposure markers of recentPlasmodium vivaxinfections in contrasting epidemiological contexts

Antibody responses as serological markers ofPlasmodium vivaxinfection 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) ofP. vivaxin three settings with different transmission intensity.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 identifyP. vivaxinfections in the previous 9 months.Antibody titers were associated with age, the number of blood-stage infections, and time since previousP. vivaxinfection in all three study sites. The association between antibody titers and time since previousP. vivaxinfection 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.In low transmission settings,P. vivaxSEMs can accurately identify individuals with recent blood-stage infections. In higher transmission settings, the accuracy of this approach diminishes substantially. We recommend usingP. vivaxSEMs in low transmission settings pursuing malaria elimination, but they are likely to be less effective in high transmission settings focused on malaria control.Plasmodium vivaxstill 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 toP. 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 toP.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 toP.vivax. In summary, SEMs that perform well in low transmission sites do not perform as well in high transmission regions.