<i>Anopheles</i> salivary antigens as serological biomarkers of vector exposure and malaria transmission: A systematic review with multilevel modelling.

Abstract

Entomological surveillance for malaria is inherently resource-intensive and produces crude population-level measures of vector exposure which are insensitive in low-transmission settings. Antibodies against <i>Anopheles</i> salivary proteins measured at the individual level may serve as proxy biomarkers for vector exposure and malaria transmission, but their relationship is yet to be quantified. A systematic review of studies measuring antibodies against <i>Anopheles</i> salivary antigens (PROSPERO: CRD42020185449). Multilevel modelling (to account for multiple study-specific observations [level 1], nested within study [level 2], and study nested within country [level 3]) estimated associations between seroprevalence with <i>Anopheles</i> human biting rate (HBR) and malaria transmission measures. From 3981 studies identified in literature searches, 42 studies across 16 countries were included contributing 393 study-specific observations of anti-<i>Anopheles</i> salivary antibodies determined in 42,764 samples. A positive association between HBR (log transformed) and seroprevalence was found; overall a twofold (100% relative) increase in HBR was associated with a 23% increase in odds of seropositivity (OR: 1.23, 95% CI: 1.10-1.37; p<0.001). The association between HBR and <i>Anopheles</i> salivary antibodies was strongest with concordant, rather than discordant, <i>Anopheles</i> species. Seroprevalence was also significantly positively associated with established epidemiological measures of malaria transmission: entomological inoculation rate, <i>Plasmodium</i> spp. prevalence, and malarial endemicity class. <i>Anopheles</i> salivary antibody biomarkers can serve as a proxy measure for HBR and malaria transmission, and could monitor malaria receptivity of a population to sustain malaria transmission. Validation of <i>Anopheles</i> species-specific biomarkers is important given the global heterogeneity in the distribution of <i>Anopheles</i> species. Salivary biomarkers have the potential to transform surveillance by replacing impractical, inaccurate entomological investigations, especially in areas progressing towards malaria elimination. Australian National Health and Medical Research Council, Wellcome Trust.