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Review 2: "Two Mosquito Salivary Antigens Demonstrate Promise as Biomarkers of Recent Exposure to P. Falciparum Infected Mosquito Bites"

Reviewers found the article to be compelling, highlighting the importance of finding new biomarkers for malaria surveillance, particularly in low-transmission settings.

Published onJun 18, 2024
Review 2: "Two Mosquito Salivary Antigens Demonstrate Promise as Biomarkers of Recent Exposure to P. Falciparum Infected Mosquito Bites"
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Two mosquito salivary antigens demonstrate promise as biomarkers of recent exposure to P. falciparum infected mosquito bites
Two mosquito salivary antigens demonstrate promise as biomarkers of recent exposure to P. falciparum infected mosquito bites
Description

Abstract Background Measuring malaria transmission intensity using the traditional entomological inoculation rate is difficult. Antibody responses to mosquito salivary proteins such as SG6 have previously been used as biomarkers of exposure to Anopheles mosquito bites. Here, we investigate four mosquito salivary proteins as potential biomarkers of human exposure to mosquitoes infected with P. falciparum: mosGILT, SAMSP1, AgSAP, and AgTRIO.Methods We tested population-level human immune responses in longitudinal and cross-sectional plasma samples from individuals with known P. falciparum infection from low and moderate transmission areas in Senegal using a multiplexed magnetic bead-based assay.Results AgSAP and AgTRIO were the best indicators of recent exposure to infected mosquitoes. Antibody responses to AgSAP, in a moderate endemic area, and to AgTRIO in both low and moderate endemic areas, were significantly higher than responses in a healthy non-endemic control cohort (p-values = 0.0245, 0.0064, and <0.0001 respectively). No antibody responses significantly differed between the low and moderate transmission area, or between equivalent groups during and outside the malaria transmission seasons. For AgSAP and AgTRIO, reactivity peaked 2-4 weeks after clinical P. falciparum infection and declined 3 months after infection.Discussion Reactivity to both AgSAP and AgTRIO peaked after infection and did not differ seasonally nor between areas of low and moderate transmission, suggesting reactivity is likely reflective of exposure to infectious mosquitos or recent biting rather than general mosquito exposure. Kinetics suggest reactivity is relatively short-lived. AgSAP and AgTRIO are promising candidates to incorporate into multiplexed assays for serosurveillance of population-level changes in P. falciparum-infected mosquito exposure.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: The study addresses an important aspect of malaria epidemiology by exploring potential reliable biomarkers for exposure to Plasmodium falciparum. This study's findings could contribute significantly to the deployment and application of these easy to use novel tools for understanding malaria transmission, especially now that traditional methods such as EIR are challenged by ethical concerns and lack of sufficient sensitivity to detect exposure to infectious mosquito bites in low transmission settings. 

This study has proven that human immune reactivity to AgSAP and AgTRIO peaks after infection with Plasmodium falciparum. This finding validates the potential of these biomarkers for detecting presence of exposure to malaria parasites and may be very useful for seroepidemiological studies for instance in places where submicroscopic infections are common such as where parasitaemias are too low to be regularly detected by mRDTs. These markers may also be useful to detect exposure where asymptomatic cases are common such as areas where most people are immune and may go undetected clinically.   

Although there was no statistical plausibility for the markers to distinguish transmission heterogeneity spatially and temporally, biological plausibility may be considered when applying these markers to distinguish heterogeneity of transmission intensities.

Nevertheless, the lack in statistical plausibility for these biomarkers in distinguishing seasonal and spatial transmission intensity may be caused by high measurement sensitivity to certainly distinguish exposure across seasons and transmission intensities. This study's findings also indicated that some uninfected individuals showed immune response to AgSAP and AgTRIO which also shows that this tool has high sensitivity or maybe subjected to cross reactivity. 

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