Antibodies Generated Due to Malaria Cross-react with SARS-CoV-2

A study has revealed that acute malaria infection generates high levels of antibodies that cross-react with the viral spike protein of the novel SARS-CoV-2 virus. The routine use of spike-based assays for surveillance of COVID-19 disease risk and burden may overestimate exposure to SARS-CoV-2 and herd immunity in malaria-endemic countries. The study is published on a pre-print server. Using an enzyme-linked immunosorbent assay (ELISA), the team tested a total of 741 samples from 617 individuals for SARS-CoV-2 spike protein seropositivity. Samples were collected across eight countries before the first case of COVID-19 had been reported.

The researchers identified a high degree of cross-reactivity to subunit 1 (S1) of the spike protein among individuals with acute malaria infection. Rapid exoproteome antigen profiling of the samples showed that malaria-induced antibodies did not bind to the spike RBD. To test the specificity of the cross-reactivity to either structural epitopes such as the NTD or glycosylation, the researchers treated S1 to alter its structure and composition of glycans and carbohydrates. ELISAs showed that the cross-reactivity of immunoglobulin G antibodies was maximally reversed following treatment with the enzyme neuraminidase, which cleaves terminal sialic acids from glycosylated sites. In vitro neutralization assays of 11 samples with cross-reactive antibodies found that none demonstrated significant neutralizing activity against SARS-CoV-2 at any dilution tested. Although serological surveys are critical tools to understand disease burden,  the cross-reactivity in malaria-endemic regions could lead to false-positive antibody tests and overestimate population-level exposure.

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