Reduced COVID-19 severity in Africa: a systematic review of host genetic and immunological responses to SARS-CoV-2 infection

Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had immense global consequences, leading to widespread illness, deaths, and devastated economies. Despite this, Africa has experienced a high prevalence of asymptomatic coronavirus disease 2019 (COVID-19) and mild cases. While reported cases and deaths have been lower, limited testing and undiagnosed infections make it difficult to determine the true burden of the disease. Understanding the unique immune response and the variations in genetics affect COVID-19 outcomes in African populations is important for shaping future public health responses. This review examines key immune factors and genetic variations in key host proteins that may help explain why COVID-19 was less severe in Africa. Methodology: A systematic review was conducted following PRISMA guidelines to identify studies published between 2019 and January 2026 that investigated immunological responses and genetic variations associated with COVID-19 in African populations. Literature searches were performed in PubMed, Scopus, and African Journals Online (AJOL). Inclusion criteria focused on studies reporting responses from cytokines, T-cells, antibodies or host genetic factors. After screening 4,170 records and removing duplicates, 420 studies were assessed for abstracts, and 240 full texts were reviewed. A total of 40 studies were included, and data synthesized narratively due to heterogeneity in study designs and outcomes. Results: Of the 40 studies analyzed from 19 African populations, 26 focused on immunological responses and 9 on host genetic factors. Immune studies revealed widespread pre-existing immunity, including cross-reactive antibodies (especially to the N proteins) and polyfunctional T-cell responses, likely shaped by exposure to malaria, helminths, and other coronaviruses. Severe COVID-19 cases showed elevated IL-6, TNF-α, and IFN-γ, while asymptomatic individuals had broader, milder cytokine profiles. Antibody responses were robust across disease severities, with long-lasting IgG activity. Genetic studies identified HLA-B41, B42, C16, and C17 as risk alleles, while HLA-DQB106, DQB103, and B*15 conferred protection. ACE2 polymorphisms including rs2285666, rs73635825 were reportedly prevalent in Africans and were linked to varied ACE2 expression, viral load, and disease severity. Conclusion: The findings suggest that immune and genetic adaptations in African populations may have modulated susceptibility and severity of SARS-CoV-2 infection outcomes in Africans. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view, identifier CRD420251121731.