SARS-CoV-2 Cross-Reactivity in Prepandemic Serum from Rural Malaria-Infected Persons, Cambodia.

To the Editor: We read with interest the observations by Manning et al. () that serum collected from malaria-infected persons in Cambodia before the coronavirus disease (COVID-19) pandemic harbored seroreactivity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens but lacked neutralizing activity. These results suggest that malaria exposure may increase background reactivity in SARS-CoV-2 serosurveys and more specific measures of exposure, such as surrogate virus neutralization tests (sVNTs), may be necessary to capture functional SARS-CoV-2 seroreactivity in malaria-endemic areas. Additional studies in settings with distinct malaria transmission intensities would generalize and strengthen these findings.

One hypothesis for the unexpectedly moderate burden of SARS-CoV-2 in malaria-endemic countries in Africa is that exposure to Plasmodium falciparum confers functional protection against COVID-19 through cross-reactivity or general immune activation. To test this hypothesis, we analyzed 237 dried blood spot samples taken in January 2020 (prepandemic) from P. falciparum–exposed persons in a high-transmission setting in western Kenya for the presence of SARS-CoV-2 neutralizing antibodies (nAbs) using the GenScript SARS-CoV2 sVNT assay (https://www.genscript.com). Monthly P. falciparum real-time PCR results were collected in a previous study () for 138/237 persons in the 12 months prior to January 2020. Of these, 131 (95%) were infected with P. falciparum at least 1 time in 2019, suggesting that most persons included in this screening had been recently exposed to malaria parasites.

Consistent with findings in Manning et al. (), none of the 237 people harbored SARS-CoV-2 nAbs, despite high prior levels of exposure to P. falciparum. Although nAbs are subject to decay after infection (), this lack of nAb activity suggests that sVNTs offer a more specific measure of SARS-CoV-2 exposure than standard ELISAs (). We further suggest that, given that protection from SARS-CoV-2 infection may be associated with the presence of nAbs (), their absence in samples from both the Manning et al. study () and our study does not support the notion that P. falciparum infections elicit functional humoral responses against COVID-19.