HIV Vaccines in Sub-Saharan Africa: Linking Correlates of Protection, Early Immune Pathways, and ART Gaps to Advance Prophylactic and Therapeutic Strategies: A Systematic Review

Abstract

Background: Sub-Saharan Africa (SSA) remains the epicenter of the global HIV epidemic, accounting for nearly two-thirds of people living with HIV worldwide. While antiretroviral therapy (ART) has transformed HIV into a manageable chronic condition by substantially reducing morbidity, mortality, and transmission, major challenges persist, including latent viral reservoirs, chronic immune activation, incomplete immune restoration, treatment access gaps, and structural barriers. Consequently, effective prophylactic and therapeutic HIV vaccines remain essential components of long-term HIV prevention and remission strategies. Objective: This systematic review synthesizes the current landscape of HIV vaccine research in SSA, focusing on immune correlates of protection, early immunological events following primary HIV infection, persistent challenges associated with ART, and emerging prophylactic and therapeutic vaccine strategies. Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive search of electronic databases identified 300 records using predefined search terms related to HIV vaccines, immune correlates of protection, ART-associated immune dysfunction, and vaccine efficacy. After removal of duplicates (n = 35), 265 records underwent title and abstract screening, with 165 articles assessed for full-text eligibility. Following application of predefined inclusion and exclusion criteria, 125 studies were included in the final qualitative synthesis. Data were extracted and narratively synthesized across four thematic domains: (i) correlates of HIV protection, (ii) immune responses during primary HIV infection, (iii) ART-related immunological and virological limitations, and (iv) advances in prophylactic and therapeutic HIV vaccine development. A formal risk-of-bias assessment was not performed due to substantial heterogeneity in study designs, populations, methodologies, and outcome measures, which limited comparability across studies. Results: Evidence from SSA cohorts indicates that effective HIV control is associated with a multifaceted immune profile involving broadly neutralizing antibodies, Fc-mediated antibody functions, HIV-specific T-cell responses, favorable cytokine signatures, mucosal immunity, and host genetic factors. Following primary infection, rapid innate immune activation, type I interferon signaling, depletion of CCR5⁺ CD4 + T cells in gut-associated lymphoid tissue, microbial translocation, immune exhaustion, and early establishment of viral reservoirs contribute to persistent infection. Despite effective viral suppression with ART, challenges remain, including delayed diagnosis, treatment interruptions, residual inflammation, incomplete immune reconstitution, and persistence of viral reservoirs in anatomical and cellular compartments. Recent advances in HIV vaccine development include germline-targeting immunogens, broadly neutralizing antibody-based strategies, mRNA vaccine platforms, mosaic immunogens, conserved-region T-cell vaccines, dendritic cell-based approaches, and combination strategies integrating therapeutic vaccination with latency-targeting and immune-modulating interventions. Conclusions: HIV vaccine research in SSA is entering a new era characterized by precision immunogen design, systems immunology, and integrated prevention-to-remission (P2R) approaches. Although the absence of a formal methodological quality assessment and heterogeneity among included studies warrant cautious interpretation, decades of vaccine research have generated critical biological insights that are informing next-generation strategies. Future progress will require integration of advanced immune engineering approaches with context-specific implementation frameworks, strengthened health systems, and expanded African-led research, manufacturing, and clinical trial capacity. The convergence of prophylactic and therapeutic vaccine approaches provides a promising pathway toward durable immune-mediated viral control, reduced reliance on lifelong ART, and the possibility of functional HIV remission in SSA.