Determinants of long-term SARS-CoV-2 immune responses in asymptomatic-to-moderate COVID-19 patients in sub-Saharan Africa

BACKGROUND: Immune responses after SARS-CoV-2 infection remain poorly characterized in African populations, despite widespread viral transmission and proportionally lower COVID-19 severity and mortality than in other regions. We aimed to define the determinants and durability of humoral and cellular immunity in sub-Saharan Africa and to identify immune correlates of protection against reinfection. METHODS: We conducted a 12-month longitudinal immunological study involving 513 adults with asymptomatic or mild-to-moderate COVID-19 enrolled across four sub-Saharan African countries (Ghana, Democratic Republic of Congo, Ethiopia, and Mozambique) during four pandemic waves (2020-2022). We profiled levels of IgA, IgG, and IgM against eight SARS-CoV-2 antigens and neutralizing antibody activity against ancestral and variant strains by Luminex, and antigen-specific T- and B-cell responses by flow cytometry. Immune kinetics, decay, immune escape, and reinfection risk were evaluated alongside the impact of clinical and demographic variables, including prior exposure, epidemic wave, geographic site, treatment allocation, and host factors. Statistical analyses included non-parametric tests (Kruskal-Wallis with Benjamini-Hochberg adjustment), Spearman correlations, logistic regression for reinfection, and mixed-effects models for longitudinal determinants. RESULTS: Humoral and cellular immune responses were robust and sustained across participants. Estimated antibody half-lives during the early decay phase exceeded 50 days for IgA and IgG. Higher IgA, IgG, and neutralizing levels were significantly associated with lower odds of reinfection during follow-up. Repurposed COVID-19 treatments showed no measurable impact on immune responses. Prior infection and vaccination were the main determinants of antibody magnitude and persistence, greatly surpassing the effects of age, sex, symptoms, and comorbidities. Antibody levels also varied significantly by epidemic wave and site, higher in later waves and, across sites, generally higher in Ethiopia and lower in DRC. Comorbidities were primarily associated with increased SARS-CoV-2-specific T-cell activation. Strong correlations were observed between binding and neutralizing antibodies, and variant-specific immune escape was confirmed for Beta, Gamma, and Omicron. CONCLUSIONS: This multi-country study provides a comprehensive characterization of SARS-CoV-2 humoral and cellular immune responses in African cohorts and identifies prior exposure and local epidemiological context as the main determinants of immune magnitude, durability, and protection, outweighing other host factors.