Research shows a relationship between increased SARS-CoV-2 seroreactivity and antimalarial humoral immunity

In a recent study published in the United States Centers for Disease Control and Prevention (CDC) Emerging Infectious Diseases journal, researchers investigate the cross-reactivity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with pre-pandemic malaria-exposed sera samples collected from Cambodia.

Study: SARS-CoV-2 Cross-Reactivity in Prepandemic Serum from Rural Malaria-Infected Persons, Cambodia. Image Credit: Lubo Ivanko / Shutterstock.com

Study: SARS-CoV-2 Cross-Reactivity in Prepandemic Serum from Rural Malaria-Infected Persons, Cambodia. Image Credit: Lubo Ivanko / Shutterstock.com

Background

Apart from the SARS-CoV-2 screening of healthcare workers in two urban hospital-based settings, no other SARS-CoV-2 serosurveys from the Greater Mekong Subregion (GMS) of Cambodia are available. Serosurveys of SARS-CoV-2 provide valuable insights about high-risk populations or disease management measures against the coronavirus disease 2019 (COVID-19).

However, the results of these serological assays showed variations that may be due to differences in assay methodologies and hypothesized cross-reactivity of previous common cold-type respiratory coronaviruses, uncharacterized beta coronaviruses, or Plasmodium infections in rural GMS populations with SARS-CoV-2.

Since the inhabitants of GMS are exposed to a diverse number of pathogens, the estimation of SARS-CoV-2 seroprevalence in this population is significant.

About the study

In this retrospective study, the researchers analyzed 528 malaria-infected serum samples for IgG reactivity towards the SARS-CoV-2 spike and receptor-binding domain (RBD) proteins using enzyme-linked immunosorbent assay (ELISA). The anonymized serum or plasma samples from the residents of Cambodia, who were infected with malaria between 2005-2011, stored in a biobank after malaria research studies were used for the study.

Since six other coronaviruses including 229E, HKU1, OC43, NL63, SARS-CoV-1, and the Middle East respiratory syndrome coronavirus (MERS-CoV), are able to infect humans, highly-specific ELISA was used to analyze SARS-CoV-2 in the current study.

A positive ELISA test with 100% sensitivity and specificity was expected once the seroreactivity towards the SARS-CoV-2 spike and RBD proteins were above the cutoff values.

Mean antibody intensity in arbitrary ELISA units to spike and RBD in serum samples from pre-pandemic, malaria-positive rural persons in Cambodia, 2005–2011. A) Provinces indicated by color: Preah Vihear (pink), Pursat (green), Ratanakiri (black). B) Years indicated by color: 2005 (purple), 2009 (turquoise), 2010 (orange), and 2011 (pink). RBD, receptor-binding domain.

Mean antibody intensity in arbitrary ELISA units to spike and RBD in serum samples from pre-pandemic, malaria-positive rural persons in Cambodia, 2005–2011. A) Provinces indicated by color: Preah Vihear (pink), Pursat (green), Ratanakiri (black). B) Years indicated by color: 2005 (purple), 2009 (turquoise), 2010 (orange), and 2011 (pink). RBD, receptor-binding domain.

A subset of the study population was analyzed to confirm the higher-than-expected seropositivity of samples towards SARS-CoV-2 using a commercially validated SARS-CoV-2 Spike S1-RBD IgG ELISA Detection Kit. The seroreactivity of a subset of samples towards coronaviruses OC43 and HKU1 was also determined.

The serum antibodies’ relationship between Plasmodium falciparum (P. falciparum) apical membrane antigen 1 (AMA-1) and P. falciparum Pfs25 protein (Pfs25) with SARS-CoV-2 spike, RBD, and nucleocapsid proteins were assessed in 289 samples.

The neutralizing capacities of the detected SARS-CoV-2 antibodies were determined using neutralization and surrogate virus neutralization assays.

Study findings

The results of the ELISA experiments showed that as compared to the six other coronaviruses, SARS-CoV-2 had varying levels of spike protein sequence homology. The highest and lowest levels were observed in SARS-CoV-1 and the common cold coronavirus HKU1, respectively.

The pre-pandemic malaria-positive samples had seropositivity ranging from 4.4% to 13.8% to both SARS-CoV-2 spike and RBD antigens.

Out of the 24 SARS-CoV-2-seronegative and 11 seropositive individuals by the in-house ELISA, 18 and nine tested seronegative and seropositive, respectively, using the commercial ELISA kit. The in-house and commercial ELISAs had an overall concordance of 77.1% and a higher-than-expected positivity rate.

Mean antibody levels in prepandemic serum samples from malaria-positive rural persons in Cambodia, 2005–2011, to A) common cold OC43 and HKU1 viruses, B) Plasmodium falciparum AMA-1 and C) P. falciparum Pfs25 protein by SARS-CoV-2 serosurvey statuses. D–E) Correlation of mean IgG levels of AMA-1 and Pfs25 against Spike (blue triangles), RBD (red circles) and NC (open circles) IgG levels in pre pandemic serum samples from malaria-positive rural persons in Cambodia. F) OD levels of RBD protein after preincubation of serum samples with 10mg/mL of AMA-1 or BSA. AMA-1, apical membrane antigen 1; BSA, bovine serum albumin; NC, nucleocapsid; OD, optical density; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Mean antibody levels in prepandemic serum samples from malaria-positive rural persons in Cambodia, 2005–2011, to A) common cold OC43 and HKU1 viruses, B) Plasmodium falciparum AMA-1 and C) P. falciparum Pfs25 protein by SARS-CoV-2 serosurvey statuses. D–E) Correlation of mean IgG levels of AMA-1 and Pfs25 against Spike (blue triangles), RBD (red circles) and NC (open circles) IgG levels in pre pandemic serum samples from malaria-positive rural persons in Cambodia. F) OD levels of RBD protein after preincubation of serum samples with 10mg/mL of AMA-1 or BSA. AMA-1, apical membrane antigen 1; BSA, bovine serum albumin; NC, nucleocapsid; OD, optical density; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

The cohort subgroups had comparable IgG levels against coronaviruses HKU1 and OC43, regardless of the SARS-CoV-2 serostatus.

Interestingly, SARS-CoV-2 seropositive individuals had a higher level of AMA-1 antibodies than the seronegative subjects. However, Pfs25 antibodies did not vary in association with the SARS-CoV-2 seropositivity. Although feeble, a statistically significant positive correlation was observed between the SARS-CoV-2 spike and RBD with AMA-1 IgG.

The IgG levels of AMA-1 and the SARS-CoV-2 nucleocapsid protein positively correlated in the samples. In contrast, the IgG levels of Pfs25 and SARS-CoV-2 nucleocapsid protein had a weak correlation.

Preincubated serum samples with 10 mg/mL of AMA-1 or bovine serum albumin (BSA) did not show any significant change in reactivity towards SARS-CoV-2 spike S1-RBD.

The neutralization assay of the 21 samples with high reactivity to SARS-CoV-2 total IgG indicated no neutralizing activity, despite high levels of antibodies against the spike and RBD proteins. An identical result was seen with the surrogate virus neutralization test targeting RBD-angiotensin converting enzyme 2 (ACE2) interaction.

Conclusions

The current study summarized that approximately 4-14% of pre-pandemic serum samples from malaria-infected individuals had non-neutralizing antibodies against the SARS-CoV-2 spike and RBD antigens. The current findings were in line with a recent study from Africa addressing the correlation between antimalarial humoral immunity and higher SARS-CoV-2 seroreactivity.

The higher SARS-CoV-2 cross-reactivity might be associated with exposure to uncharacterized beta coronaviruses or regular spillover events and cannot be neglected in the case of Cambodia, since 50-80% of GMS residents are from rural areas. Therefore, careful calibrations of serologic testing are required in the national and subnational SARS-CoV-2 serosurveys.

Moreover, economically feasible competitive ELISAs such as surrogate virus neutralization assays are recommended in large-scale serosurveys as compared to costly neutralization assays with live viruses.

Journal reference:
  • Manning, J., Zaidi, I., Lon, C., et al. (2022). SARS-CoV-2 Cross-Reactivity in Prepandemic Serum from Rural Malaria-Infected Persons, Cambodia. CDC Emerging Diseases. doi:10.3201/eid2802.211725.
Shanet Susan Alex

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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