Long-Term Immune Consequences of Initial SARS-CoV-2 A.23.1 Exposure: A Longitudinal Study of Antibody Responses and Cross-Neutralisation in a Ugandan Cohort
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Background: This study assessed the long-term dynamics of neutralising antibodies in a Ugandan cohort primarily exposed to the A.23.1 SARS-CoV-2 variant, examining how this shaped immune breadth and potency against diverse strains following infection and prototype-based vaccination. Methods: We conducted a 427-day retrospective analysis of 41 participants across multiple SARS-CoV-2 waves, assessing binding and neutralising antibody responses using in-house ELISA and pseudotyped virus neutralisation assays. We quantified immune responses to key SARS-CoV-2 variants, A.23.1, D614G, Delta, and BA.4, capturing evolving immunity across the pandemic. Results: Neutralising antibody titres against A.23.1 remained significantly higher than those against D614G, Delta, and BA.4, highlighting the solid immune memory following A.23.1 infection. Consistently lower titres were observed for BA.4 across all time points, aligning with its strong immune-evasion capability. Correlations between neutralising titres and spike-directed IgG (S-IgG) concentrations were significantly stronger for A.23.1 than for D614G, with no correlation for BA.4. ChAdOx1-S vaccination substantially elevated the neutralising titres across all variants, most notably BA.4, highlighting the essential role of vaccination in boosting immunity, even in individuals with initially low titres. Conclusions: Initial exposure to the A.23.1 variant triggered potent immune responses, shaping neutralising antibody dynamics during subsequent exposures. These findings highlight the importance of accounting for early viral exposures in vaccine development and public health planning. The distinctly lower immune response to BA.4 highlights the need for continuous antigenic monitoring and timely vaccine updates for protection against emerging variants. Vaccination remains essential, reinforcing and sustaining im-munity against evolving variants.