Pre-pandemic cross-reactive humoral immunity to SARS-CoV-2 in Africa: systematic review and meta-analysis

Abstract

Background: Low numbers of recorded COVID-19 deaths in Africa may be due to undercounting and/or protection due to demographic and/or other factors, including pre-existing immunity. Several studies have assessed pre-pandemic samples for anti-SARS-CoV-2 antibodies with heterogeneous results. Methods: We performed a systematic review and meta-analysis of studies evaluating pre-pandemic African samples for anti-SARS-CoV-2 antibody activity using pre-set assay-specific thresholds for seropositivity. Data where assay thresholds were calibrated on African populations were excluded. Searches used PubMed (September 13, 2022), reference lists of retrieved papers and citing articles (Google Scholar). Data were extracted independently by two authors on study and assay characteristics, and number of positive and tested samples. Datasets were classified according to malaria, dengue, and HIV burden. Proportions of seropositivity were combined with random effects meta-analysis. Results: 22 articles with 117 datasets were eligible, including 2,971 positives among 21,988 measurements (13.5%) with large between-dataset heterogeneity. Positivity was higher for anti-S1 (25%) and lower for anti-RBD antibodies (8%). Positivity was non-significantly higher for IgM than for IgG antibodies. Positivity was seen prominently in countries where malaria transmission occurs throughout and in datasets enriched in malaria cases (17%, 95% CI, 15-19%) versus 1%, 95% CI 0-2% in other datasets). There were modest differences according to dengue burden (15% versus 11%). Substantial SARS-CoV-2 reactivity was seen in high malaria burden with or without high dengue burden (seropositivity 19% and 12%, respectively), and not without high malaria burden (seropositivity 2% and 0% with and without high dengue burden, respectively). There were modestly lower proportions of positivity in datasets with >10% of HIV-infected participants (8% versus 15% in others), but no association according to HIV serostatus in individual samples (summary odds ratio 0.97, 95% CI, 0.55-1.70). Interpretation: Pre-pandemic samples from Africa show high levels of anti-SARS-CoV-2 seropositivity that tracks especially with malaria.

Malaria and other infections induce polyreactive antibodies that impact SARS‐CoV‐2 seropositivity estimations in endemic settings

“…33 Finally, a recent review of 26 publications confirmed a prominent SARS-CoV-2 seroreactivity in countries where malaria transmission occurs throughout and in datasets enriched in malaria cases, and reported associations of higher SARS-CoV-2 seroreactivity with Plasmodium parasitemia. 34 We have found that polyreactivity is higher in prepandemic African than European subjects, and positively correlates with anti-P.…”

“…A study with prepandemic samples from eight malaria endemic countries showed that malaria induces cross‐reactive antibodies against sialic acid on N‐linked glycans of the S protein 33 . Finally, a recent review of 26 publications confirmed a prominent SARS‐CoV‐2 seroreactivity in countries where malaria transmission occurs throughout and in datasets enriched in malaria cases, and reported associations of higher SARS‐CoV‐2 seroreactivity with Plasmodium parasitemia 34 …”

“…A study with 40 sera from patients with Chagas disease and presence of anti‐ Trypanosoma cruzi antibodies showed 6 sera reacting to SARS‐CoV‐2 N protein (15% false positives) 38 . Schistosoma , dengue virus and T. cruzi are also known to trigger polyclonal B‐cell activation leading to abnormalities in immunoglobulin secretion that can contribute to the production of antibodies, which could cause false‐positive reactions in antigen‐antibody tests 34,35,39,40 . The oxidized hemoglobin derived from the hemolysis that occurs in some infections, like malaria, dengue, and Chagas disease, modifies the antigen‐binding characteristics of IgG, also triggering IgG polyreactivity and autoreactivity 16 …”

Ethno‐demographic disparities in humoral responses to the COVID‐19 vaccine among healthcare workers

“…29 Several other studies have also reported the presence of cross-reactive antibodies in naïve or pre-COVID samples. [30][31][32][33] While several studies have assessed antibody variations in HCWs, few have investigated the association of sociodemographic factors. In a 10-month study of HCWs, IgG response was detected up to 10 months postvaccination.…”

“…A recent study identified a total of 15 such SARS‐CoV‐2 spike protein epitopes that cross‐react with antibodies generated against various acute and chronic viral antigens 29 . Several other studies have also reported the presence of cross‐reactive antibodies in naïve or pre‐COVID samples 30–33 …”