Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein

Abstract

Sero-surveillance can monitor and project disease burden and risk. However, SARS-CoV-2 antibody test results can produce false positive results, limiting their efficacy as a sero-surveillance tool. False positive SARS-CoV-2 antibody results are associated with malaria exposure, and understanding this association is essential to interpret sero-surveillance results from malaria-endemic countries. Here, pre-pandemic samples from eight malaria endemic and non-endemic countries and four continents were tested by ELISA to measure SARS-CoV-2 Spike S1 subunit reactivity. Individuals with acute malaria infection generated substantial SARS-CoV-2 reactivity. Cross-reactivity was not associated with reactivity to other human coronaviruses or other SARS-CoV-2 proteins, as measured by peptide and protein arrays. ELISAs with deglycosylated and desialated Spike S1 subunits revealed that cross-reactive antibodies target sialic acid on N-linked glycans of the Spike protein. The functional activity of cross-reactive antibodies measured by neutralization assays showed that cross-reactive antibodies did not neutralize SARS-CoV-2 in vitro. Since routine use of glycosylated or sialated assays could result in false positive SARS-CoV-2 antibody results in malaria endemic regions, which could overestimate exposure and population-level immunity, we explored methods to increase specificity by reducing cross-reactivity. Overestimating population-level exposure to SARS-CoV-2 could lead to underestimates of risk of continued COVID-19 transmission in sub-Saharan Africa.

Prepandemic cross-reactive humoral immunity to SARS-CoV-2 in Africa: Systematic review and meta-analysis

“…Lapidus et al . suggest that this immune response is more common and more intense in acute and recent malaria [10] , may reflect antibodies targeting sialic acid moieties on the S1 fragment, and cross-reactivity is effectively reduced when sialic acid is cleaved from the assay target [10] . The large between-dataset heterogeneity among studies with high malaria burden may reflect both antibody assay variability and diversity in the magnitude of the malaria burden: some datasets included exclusively acute malaria, others were heavily enriched in malaria cases, and others simply came from areas with substantial malaria burden.…”

“…Interestingly, reported dengue cases and deaths declined in 2020-2022 after a peak in 2019 [19] , but this may also reflect the impact of containment measures on communicable diseases in general. In-silico analysis shows possible similarities between SARS-CoV-2 epitopes in the HR2 domain of spike and the dengue envelope protein [18] , but evidence is again stronger for malaria, where cross-reactive antibodies specifically recognized the sialic acid moiety on N-linked glycans of spike [10] .…”

Plasmodium vivax and SARS-CoV-2 co-infection in Venezuelan pregnant women: a case series

“…In the case of the dead pregnant woman with cerebral malaria, although no co-infection by P. falciparum was detected in the Giemsa-stained peripheral blood smears, such possibility cannot be ruled out, since blood samples not taken during the febrile peak may not reveal low level circulating parasites, as most of them remain adhered to vascular endothelia. Because a high level of false-positive results with the SARS-CoV-2 serological assay has been identified in highly malaria-endemic areas [ 34 , 35 ], routine use of serological assay may overestimate the level of exposure and immunity of the population to SARS-CoV-2 in malaria-endemic countries [ 36 ].…”

Widespread exposure to SARS-CoV-2 in wildlife communities

“…Furthermore, our use of neutralization tests to detect evidence of prior SARS-CoV-2 exposure may have resulted in reduced sensitivity over approaches like ELISA that identify only binding antibodies. However, binding-antibody-based approaches also suffer from false-positivity to other coronaviruses 45 , other infectious diseases 46 , and even auto-immune diseases 47 . Thus, PRNT increases the confidence that animals tested here were truly exposed to SARS-CoV-2 and not to another related viruses.…”