Application of 23 Novel Serological Markers for Identifying Recent Exposure to Plasmodium vivax Parasites in an Endemic Population of Western Thailand.

Patiwat Sa-Angchai,Matthias Harbers,Eizo Takashima,Wai-Hong Tham,Jenni Hietanen,Jessica Brewster,Narimane Nekkab,Jetsumon Sattabongkot,Kirakorn Kiattibutr,Julie Healer,Chetan E Chitnis,Kael Schoffer,Wang Nguitragool,Chalermpon Kumpitak,Sadudee Chotirat,Michael T White,Ivo Mueller,Takafumi Tsuboi,Rhea J Longley

doi:10.3389/fmicb.2021.643501

Abstract

Thailand is aiming for malaria elimination by the year 2030. However, the high proportion of asymptomatic infections and the presence of the hidden hypnozoite stage of Plasmodium vivax are impeding these efforts. We hypothesized that a validated surveillance tool utilizing serological markers of recent exposure to P. vivax infection could help to identify areas of ongoing transmission. The objective of this exploratory study was to assess the ability of P. vivax serological exposure markers to detect residual transmission “hot-spots” in Western Thailand. Total IgG levels were measured against a panel of 23 candidate P. vivax serological exposure markers using a multiplexed bead-based assay. A total of 4,255 plasma samples from a cross-sectional survey conducted in 2012 of endemic areas in the Kanchanaburi and Ratchaburi provinces were assayed. We compared IgG levels with multiple epidemiological factors that are associated with an increased risk of P. vivax infection in Thailand, including age, gender, and spatial location, as well as Plasmodium infection status itself. IgG levels to all proteins were significantly higher in the presence of a P. vivax infection (n = 144) (T-test, p < 0.0001). Overall seropositivity rates varied from 2.5% (PVX_097625, merozoite surface protein 8) to 16.8% (PVX_082670, merozoite surface protein 7), with 43% of individuals seropositive to at least 1 protein. Higher IgG levels were associated with older age (>18 years, p < 0.05) and males (17/23 proteins, p < 0.05), supporting the paradigm that men have a higher risk of infection than females in this setting. We used a Random Forests algorithm to predict which individuals had exposure to P. vivax parasites in the last 9-months, based on their IgG antibody levels to a panel of eight previously validated P. vivax proteins. Spatial clustering was observed at the village and regional level, with a moderate correlation between PCR prevalence and sero-prevalence as predicted by the algorithm. Our data provides proof-of-concept for application of such surrogate markers as evidence of recent exposure in low transmission areas. These data can be used to better identify geographical areas with asymptomatic infection burdens that can be targeted in elimination campaigns.

Highlights

Thailand is a region of low malaria transmission, with 5,432 reported confirmed clinical cases in 2019
Serological exposure markers for identifying regions of residual or ongoing transmission of P. vivax could play a unique role in control and elimination efforts of malaria-endemic countries in the Asia-Pacific
We measured total IgG antibody responses against a panel of 23 P. vivax proteins that we have previously shown to be accurate markers of recent exposure to P. vivax parasites

Summary

Introduction

Thailand is a region of low malaria transmission, with 5,432 reported confirmed clinical cases in 2019 (data obtained from the Bureau of Vector Borne Diseases Control, Ministry of Public Health, Thailand). As malaria transmission in Thailand has declined, a change in infection dynamics has occurred with a higher proportion of infections due to Plasmodium vivax Another notable feature is that a very high proportion of infections are asymptomatic (Nguitragool et al, 2019), suggesting the number of cases reported by the World Health Organization is likely an underestimate. National malaria control programs need to switch their primary focus from case management to interruption of transmission This requires monitoring and surveillance activities to detect infections, rather than just morbidity and mortality. Relapsing infections can be responsible for over 80% of all bloodstage infections (Robinson et al, 2015; Taylor et al, 2019), a major gap in our diagnostic/surveillance toolkit for malaria is the inability to identify individuals that harbor hypnozoites in the absence of concurrent blood-stage infections

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