Antibodies to malaria and other pathogens can cause false seropositive results when testing for past SARS-CoV-2 infection, shows an analysis of more than 600 pre-pandemic blood samples from Africa and Europe
The true prevalence of SARS-CoV-2 infections in Africa has likely been underestimated due to the limited availability of PCR or rapid diagnostic tests. Seroprevalence studies, which measure antibodies to SARS-CoV-2, are one solution to estimating viral exposure. However, previous studies have observed a high rate of false seropositivity with African samples when using COVID-19 tests developed using European/USA samples as negative controls. This could be due to cross-reactive antibodies elicited by other common infections in Africa, such as malaria.
“When conducting SARS-CoV-2 seroprevalence studies, we must first determine the baseline signal (or “background noise”) using pre-pandemic samples from the same study population. This is the only way to distinguish truly positive samples with low antibody levels from negative samples,” says Gemma Moncunill, ISGlobal researcher and co-leader of ENDVOC’s Work Package on COVID-19 immunity together with Carlota Dobaño.
In the study, the researchers analysed IgG, IgA and IgM antibodies to a broad panel of antigens from different pathogens in pre-pandemic plasma samples from 602 individuals from Africa and Europe. They found that pre-pandemic African samples had higher levels of antibodies reactive to SARS-CoV-2 than European samples. This cross-reactivity was due to antibodies against other common pathogens in Africa: coronaviruses, helminths, protozoa, and especially the malaria parasite P. falciparum. The researchers also found that African samples had higher levels of autoantibodies, which are indicators of polyreactivity—a condition where antibodies react to multiple antigens. This polyreactivity was mainly due to antibodies against P. falciparum.
“We do not know if the higher seroreactivity of African samples provides any protection against SARS-CoV-2 infection or disease, although it has been suggested as an explanation for the lower severity of COVID-19 in Africa,” says Dobaño.
To improve the accuracy of COVID-19 antibody tests, the researchers suggest using chaotropic agents, like urea, that can reduce unspecific antibody binding. This assay modification could lead to more accurate estimates of COVID-19 exposure in regions heavily affected by other infectious diseases.
The findings underscore the importance of adapting immunoassay techniques to account for regional differences in disease exposure, particularly in areas such as sub-Saharan Africa where the burden of infectious diseases is high.
In addition to ENDVOC funding, this study was also supported by the Daniel Bravo Andreu Private Foundation and the ANTICOV consortium.
Reference
Aguilar R, Jiménez A, Santano R et al. Malaria and other infections induce polyreactive antibodies that impact SARS-CoV-2 seropositivity estimations in endemic settings. J Med Virol. 2024 Jun;96(6):e29713. doi: 10.1002/jmv.29713.
