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Volume 28, Number 5—May 2022

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

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To the Editor: We read with interest the observations by Manning et al. (1) 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 ( Monthly P. falciparum real-time PCR results were collected in a previous study (2) 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. (1), 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 (3), this lack of nAb activity suggests that sVNTs offer a more specific measure of SARS-CoV-2 exposure than standard ELISAs (4). We further suggest that, given that protection from SARS-CoV-2 infection may be associated with the presence of nAbs (5), their absence in samples from both the Manning et al. study (1) and our study does not support the notion that P. falciparum infections elicit functional humoral responses against COVID-19.



This work was supported by the National Institute of Allergy and Infectious Diseases (R21AI167242 to W.P.O. and S.M.T. and F32AI149950 to C.F.M.)


Jillian T. Grassia, Christine F. MarkwalterComments to Author , Wendy P. O’Meara, Steve M. Taylor, and Andrew A. Obala



  1. Manning  J, Zaidi  I, Lon  C, Rosas  LA, Park  J-K, Ponce  A, et al. SARS-CoV-2 cross-reactivity in prepandemic serum from rural malaria-infected persons, Cambodia. Emerg Infect Dis. 2022;28:4404. DOIPubMedGoogle Scholar
  2. Sumner  KM, Mangeni  JN, Obala  AA, Freedman  E, Abel  L, Meshnick  SR, et al. Impact of asymptomatic Plasmodium falciparum infection on the risk of subsequent symptomatic malaria in a longitudinal cohort in Kenya. eLife. 2021;10:e68812. DOIPubMedGoogle Scholar
  3. Chia  WN, Zhu  F, Ong  SWX, Young  BE, Fong  S-W, Le Bert  N, et al. Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study. Lancet Microbe. 2021;2:e2409. DOIPubMedGoogle Scholar
  4. Tan  CW, Chia  WN, Qin  X, Liu  P, Chen  MIC, Tiu  C, et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol. 2020;38:10738. DOIPubMedGoogle Scholar
  5. Addetia  A, Crawford  KHD, Dingens  A, Zhu  H, Roychoudhury  P, Huang  M-L, et al. Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with a high attack rate. J Clin Microbiol. 2020;58:e0210720. DOIPubMedGoogle Scholar


Cite This Article

DOI: 10.3201/eid2805.220404

Original Publication Date: April 11, 2022

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Please use the form below to submit correspondence to the authors or contact them at the following address:

Christine Markwalter, Duke Global Health Institute, 310 Trent Dr, Durham, NC, 27707, USA

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Page created: March 10, 2022
Page updated: April 19, 2022
Page reviewed: April 19, 2022
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