By the end of 2024, an estimated 40.8 million people were living with HIV worldwide, including 1.4 million children aged 0 - 14 years and 39.4 million adults aged ≥15 years [1]. Despite remarkable progress in HIV prevention and treatment, HIV remains a major global public health challenge. In 2024 alone, approximately 630,000 deaths were attributed to HIV-related causes, including 75,000 deaths among children aged 0 - 14 years and 550,000 deaths among adults aged ≥ 15 years. Although HIV-related mortality has declined by 54% since 2010 and by nearly 70% compared with the epidemic peak in 2004, the pandemic has claimed an estimated 44.1 million lives worldwide since its emergence [2].

Sub-Saharan Africa (SSA) continues to bear a disproportionate share of the epidemic, accounting for nearly two-thirds of the global HIV burden. Approximately 25.6 million individuals are living with HIV in the region, with the majority residing in Eastern and Southern Africa (20.8 million), while Western and Central Africa account for 4.8 million cases. In 2022, the region recorded an estimated 760,000 new HIV infections and 380,000 AIDS-related deaths, highlighting the persistent public health and socioeconomic impact of HIV despite decades of progress [3]. These figures underscore the urgent need for innovative, sustainable, and regionally relevant prevention and treatment strategies, including the development of next-generation HIV vaccines.

The advent of antiretroviral therapy (ART) has fundamentally transformed the natural history of HIV infection, converting a once-fatal disease into a manageable chronic condition and markedly reducing HIV-related morbidity and mortality [3] [4]. Nevertheless, several unresolved challenges continue to hinder efforts toward sustained viral remission and eradication. These include the persistence of latent viral reservoirs, chronic immune activation and systemic inflammation, incomplete immune reconstitution, and the emergence of drug-resistant viral variants [5]. Collectively, these biological constraints underscore the need for complementary immunotherapeutic strategies capable of achieving durable viral control and ultimately facilitating functional cure or sterilizing immunity [6]. Beyond these biological barriers, progress toward HIV control is further complicated by persistent structural, behavioral, and socioeconomic determinants [7]. In many settings, particularly in SSA, limited healthcare infrastructure, disparities in access to care, stigma and discrimination, poverty, gender inequities, and high-risk behavioral patterns continue to impede the uptake of preventive interventions, participation in vaccine trials, and equitable access to emerging therapeutic innovations [8][9].

HIV vaccines, encompassing both prophylactic and therapeutic approaches, represent a crucial addition to current HIV prevention and treatment paradigms [10]. Prophylactic vaccines aim to prevent viral acquisition by inducing protective immune responses prior to exposure, whereas therapeutic vaccines are designed to enhance immune-mediated control in individuals with established infection, with the long-term goals of reducing viral reservoirs, decreasing reliance on lifelong ART, and achieving sustained remission [11]. Recent advances in HIV vaccine research have been exemplified by the African-led Pre-Exposure Prophylaxis Vaccine (PrEPVacc) trial, which evaluated novel vaccine regimens alongside oral pre-exposure prophylaxis (PrEP) in Uganda, Tanzania, Mozambique, and South Africa [12]. Although the vaccine component of the trial was discontinued in late 2023 following interim analyses indicating a low probability of demonstrating efficacy against HIV acquisition [12][13], effective PrEP modalities, including long-acting injectable formulations such as lenacapavir and established oral PrEP regimens, have emerged as essential pillars of HIV prevention, demonstrating remarkable efficacy in reducing HIV transmission and contributing substantially to efforts aimed at alleviating the region’s disproportionate HIV burden [14].

Another recent development is the trial of the Gorilla Adenovirus Vectored HIV Networked Epitopes Vaccine candidate (GRAdHIVNE1), a novel CD8+ T-cell-inducing vector vaccine being evaluated in Phase 1 studies in Zimbabwe to assess safety and immunogenicity of networked HIV-epitope constructs [15]. The GRAdHIVNE1 vaccine faces challenges, including its early-phase focus on safety rather than efficacy, limited effectiveness of T-cell-based responses in preventing HIV infection, potential interference from pre-existing immunity, restricted population representativeness due to exclusion criteria, and lack of protection against early infection [16].

Studies of the unique immune landscape in SSA have identified key considerations for HIV vaccine development, including the induction of tissue-resident memory (TRM) cells, preservation of germinal center and T follicular helper (Tfh) cell function to promote broadly neutralizing antibody (bNAbs) responses, and enhancement of follicular cytotoxic (fCTLs) activity to limit viral reservoir formation [17][18]. Moreover, vaccine efficacy must be evaluated in the presence of endemic co-infections, such as tuberculosis, malaria, and helminthiasis, underscoring the need for integrated prevention strategies tailored to the epidemiological and immunological context of the region [19].

This systematic review critically evaluates the current landscape of HIV vaccine research in SSA, with particular emphasis on immunological correlates of protection, early host immune responses following HIV acquisition, strategies aimed at overcoming the limitations of ART, and the structural, socioeconomic and behavioural determinants that influence vaccine uptake and implementation. This review further examines emerging vaccine candidates and next-generation technologies, including epitope-network immunogens, germline-targeting approaches, and mRNA-based platforms, which collectively represent promising avenues for advancing HIV prevention, supporting remission-oriented interventions, and strengthening the continuum of HIV care in the region. Collectively, these developments underscore the transition toward increasingly precise and integrated approaches to HIV control in SSA.

This systematic review synthesized evidence from 125 studies investigating HIV vaccine development in SSA, with particular emphasis on immune correlates of protection, early immunological events following HIV acquisition, persistent ART gaps, and emerging prophylactic and therapeutic vaccine strategies. The findings highlight both the substantial scientific progress achieved in HIV vaccinology and the persistent biological, epidemiological, and implementation challenges that continue to impede the development of an effective vaccine. Despite more than four decades of research, HIV remains among the most challenging vaccine targets due to extensive viral diversity, rapid mutation rate, sophisticated immune escape mechanisms, and the early establishment of latent reservoirs. Consequently, successful vaccine development requires not only advances in immunogen design but also a comprehensive understanding of host immunity, epidemic heterogeneity, and health-system realities within SSA, which remains disproportionately affected by the global HIV epidemic [48].

A central finding emerging from this review is that protection against HIV is unlikely to be mediated by a single immune mechanism. Instead, effective immunity requires coordinated interactions between humoral, cellular, innate, and mucosal immune responses. Broadly neutralizing antibodies (bnAbs), Fc-mediated antibody functions, antibody-dependent cellular cytotoxicity, HIV-specific CD4⁺ and CD8⁺ T-cell responses, tissue-resident immunity, and durable immune memory have all been identified as important components associated with reduced susceptibility or improved viral control [49][50]. Unlike many vaccine-preventable infections where a single immune correlate can predict protection, HIV appears to require a multifaceted immune response capable of recognizing diverse viral variants, preventing early viral establishment at mucosal entry sites, and limiting systemic dissemination. This complexity highlights the need for vaccine approaches that generate coordinated immune networks rather than targeting isolated immune pathways.

The limitations of ART further emphasize the need for complementary vaccine-based strategies. Although ART, particularly dolutegravir-based regimens, has transformed HIV management by improving survival, reducing viral transmission, and increasing life expectancy across SSA, treatment alone has not achieved epidemic elimination [51]-[54]. Persistent challenges, including delayed diagnosis, treatment interruptions, loss to follow-up, incomplete viral suppression, and inequitable access to healthcare services, continue to compromise long-term epidemic control [55]. Progress toward the UNAIDS 95-95-95 targets remains highly variable across and within countries, reflecting persistent disparities in healthcare delivery and programme implementation [56]-[58]. These challenges disproportionately affect adolescents, young women, migrants, and key populations, who continue to experience elevated HIV acquisition risks due to overlapping biological, behavioural, and structural vulnerabilities. Furthermore, uptake of preventive interventions such as pre-exposure prophylaxis (PrEP) remains suboptimal among many African populations, demonstrating that biomedical availability alone is insufficient without addressing social barriers, stigma, gender inequality, poverty, and healthcare accessibility [59]-[61].

Beyond limitations in prevention and treatment delivery, ART does not eliminate HIV infection. Latent viral reservoirs established during the earliest stages of infection remain largely inaccessible to current therapies and represent the major barrier to achieving a cure [62][63]. In addition, persistent immune activation and chronic inflammation continue despite long-term viral suppression, contributing to increased risks of cardiovascular disease, neurocognitive impairment, malignancies, and accelerated ageing. These observations suggest that future HIV interventions must extend beyond viral suppression toward strategies capable of restoring immune function and achieving durable remission. Consequently, vaccines should not be viewed as alternatives to ART but as complementary components within an integrated prevention-to-remission (P2R) framework that combines prevention, optimized treatment, immune restoration, and reservoir-targeting strategies.

Understanding the earliest stages of HIV infection remains fundamental for designing effective vaccines. Following exposure, HIV rapidly disseminates, depletes CCR5-expressing CD4⁺ T cells, induces widespread immune activation, and establishes reservoirs within days, thereby narrowing the window for vaccine-mediated intervention. Early immune responses therefore represent both a challenge and an opportunity for vaccine development. Type I interferon responses illustrate this complexity, as early activation contributes to antiviral defence and viral containment, whereas prolonged activation promotes inflammation, immune exhaustion, and impaired adaptive immunity [64][65]. Future vaccines must therefore achieve a balance between inducing rapid and potent antiviral immunity while avoiding excessive immune activation that may enhance susceptibility or compromise immune regulation.

The immunological environment of SSA introduces additional considerations that may influence vaccine responsiveness. High exposure to endemic infections such as tuberculosis, malaria, helminth infections, and recurrent viral pathogens contributes to chronic immune stimulation and immune modulation, potentially altering vaccine-induced responses [66]. Furthermore, overlapping epidemics, including the COVID-19 pandemic, have demonstrated the vulnerability of HIV-affected populations to disruptions in healthcare delivery and competing health priorities [67]. Therefore, vaccine development strategies should incorporate region-specific factors, including co-infection burden, inflammatory profiles, microbiome composition, nutritional status, and environmental exposures, to better define determinants of vaccine responsiveness among African populations [68]. Immune correlates identified in one epidemiological setting may not necessarily translate directly to populations with different infectious exposures and immunological backgrounds.

Although several HIV vaccine efficacy trials have failed to demonstrate sufficient protection for widespread implementation, these studies have generated critical knowledge that continues to guide the field. Trials including RV144, HVTN 702 (Uhambo), HVTN 705 (Imbokodo), HVTN 706 (Mosaico), and PrEPVacc revealed important limitations of conventional vaccine approaches and demonstrated that immune responses must possess greater breadth, durability, and functional quality to overcome HIV diversity [69][70]. Rather than representing failures, these outcomes have refined understanding of protective immunity and accelerated the development of more rational vaccine strategies. For example, conserved-region approaches such as HIVconsvX have demonstrated the potential of targeted T-cell immunogens to generate broad cellular responses adapted to regional epidemiological characteristics [71].

Recent advances in vaccine science provide renewed optimism that these challenges may be overcome. HIV vaccine development has increasingly shifted from empirical approaches toward precision immune engineering informed by structural biology, computational modelling, artificial intelligence, and systems immunology. Germline-targeting strategies represent a major conceptual advance by attempting to guide naïve B-cell populations toward maturation pathways capable of producing bnAbs. Similarly, mRNA technologies provide new opportunities for delivering complex immunogens, enabling sequential immunization strategies, and accelerating vaccine development through flexible and scalable platforms [72]. Additional approaches, including mosaic vaccines, nanoparticle-based delivery systems, conserved-region immunogens, and structure-guided envelope designs, aim to overcome the limitations imposed by HIV genetic diversity [73][74]. Together, these innovations represent a transition toward vaccine strategies designed to deliberately shape protective immunity rather than relying on naturally occurring immune responses.

Parallel progress in therapeutic vaccines and remission-focused interventions has expanded the objectives of HIV vaccine research beyond prevention alone. Therapeutic vaccines aim to enhance immune-mediated control of HIV replication, reduce dependence on lifelong ART, and contribute to durable remission. Current strategies include dendritic cell vaccines, T-cell-directed immunotherapies, bnAb combinations, and latency-reversing approaches designed to expose reservoir cells for immune clearance. Evidence from bnAb studies in African populations suggests that antibody-based interventions may contribute to prolonged viral suppression and post-treatment control [75]. However, complete eradication remains unlikely through a single intervention. Future remission strategies will probably require combination approaches targeting viral reservoirs, residual replication, chronic inflammation, and immune dysfunction simultaneously [76].

However, scientific innovation alone will not guarantee public health impact. Lessons from previous vaccination programmes in SSA demonstrate that vaccine effectiveness depends not only on biological efficacy but also on health-system preparedness, community acceptance, and equitable access [77][78]. Successful introduction of future HIV vaccines will require investment in supply chains, healthcare workforce capacity, surveillance systems, sustainable financing, community engagement, and integration within existing HIV and primary healthcare programmes [79]-[81]. Implementation science should therefore be incorporated throughout vaccine development rather than considered only after regulatory approval.

Sustainable HIV vaccine deployment will also depend on addressing financial and structural challenges. Although international funding has driven major HIV control achievements over recent decades, dependence on external resources creates vulnerability to changing global priorities and funding reductions [82][83]. Strengthening domestic investment, regional vaccine manufacturing capacity, and sustainable healthcare infrastructure will be essential for maintaining long-term HIV control and ensuring equitable access to future innovations [84][85]. Furthermore, biomedical advances must be accompanied by interventions addressing social determinants of HIV vulnerability, including gender inequality, stigma, poverty, educational disparities, and social marginalization. Community trust and vaccine confidence will also be critical determinants of future vaccine uptake, requiring culturally appropriate communication strategies and meaningful community engagement [86]-[88].

This review provides a comprehensive multidisciplinary synthesis of HIV vaccine development in SSA by integrating evidence from immunology, vaccinology, epidemiology, implementation science, and HIV cure research. The inclusion of recent advances in germline-targeting immunogens, mRNA platforms, bnAbs, and therapeutic vaccine strategies provides an updated perspective on a rapidly evolving field. Nevertheless, substantial heterogeneity among included studies, differences in study populations and methodologies, limited availability of late-stage clinical data, and the dynamic nature of HIV vaccine research restrict definitive comparisons between approaches. These limitations highlight the need for continued longitudinal research and region-specific clinical evaluation.

Overall, HIV vaccine research in SSA is entering a transformative phase characterized by precision vaccine design, immune engineering, and remission-oriented strategies. Although previous efficacy trials have not produced a licensed vaccine, they have generated essential insights that now guide next-generation approaches. The evidence supports a shift away from a prevention-versus-treatment framework toward an integrated P2R continuum combining vaccination, long-acting prevention technologies, optimized ART delivery, immune restoration, reservoir-targeting interventions, and strengthened health systems. Achieving sustained HIV control and eventual functional cure will require not only scientific innovation but also equitable investment, political commitment, community partnership, and strengthened regional capacity to ensure that future breakthroughs benefit the populations most affected by the epidemic.

A limitation of this review relates to the substantial methodological heterogeneity among included studies, encompassing differences in study design, populations, vaccine platforms, immunological assays and outcome definitions. These variations limited the applicability of a single standardized risk-of-bias assessment tool across all studies and constrained direct comparisons of findings. Although a structured methodological quality appraisal was undertaken, the certainty and strength of the synthesized evidence could not be quantitatively graded using a uniform framework. Therefore, the findings should be interpreted within the context of the diversity and evolving nature of HIV vaccine research, particularly in SSA settings.

Despite major progress in ART scale-up across SSA, HIV remains incompletely controlled at both population and immunological levels. ART has substantially reduced HIV-associated morbidity, mortality, and transmission; however, it does not eliminate latent viral reservoirs, fully restore immune homeostasis, or resolve chronic immune activation. These persistent biological limitations, together with structural and health-system barriers, highlight the need for complementary prophylactic and therapeutic vaccine strategies.

To date, no HIV vaccine has achieved licensure, and previous efficacy trials have not demonstrated sufficient protection for population-level implementation. Although long-acting PrEP agents, including lenacapavir, have shown exceptional efficacy in preventing HIV acquisition, they provide pharmacological protection without generating durable immune memory, requiring continued access and administration. This underscores the need for vaccines capable of inducing sustained, broadly protective immune responses.

HIV vaccine development is now advancing through precision immunogen design, systems immunology, and immune engineering approaches. Emerging strategies include mRNA platforms, germline-targeting immunogens, stabilized SOSIP envelope constructs, viral vectors, and nanoparticle-based delivery systems designed to guide bnAb development, enhance cellular immunity, and overcome previous barriers to vaccine efficacy. However, most candidates remain in early clinical development, and their ability to generate durable protection across diverse populations remains to be determined.

Sub Saharan Africa presents unique challenges for HIV vaccine development, including HIV-1 subtype C diversity, complex mucosal transmission dynamics, and immune modulation driven by endemic co-infections such as tuberculosis, malaria, and helminths. These biological factors, combined with delayed diagnosis, ART access challenges, socioeconomic inequalities, and health-system constraints, influence immune responses and vaccine implementation outcomes.

This systematic review synthesizes evidence across four key domains: (i) immune correlates of HIV protection; (ii) early immune pathways following primary infection and their role in viral set point and reservoir establishment; (iii) persistent ART limitations, including reservoir persistence and incomplete immune restoration; and (iv) emerging prophylactic and therapeutic vaccine platforms relevant to SSA.

Collectively, the evidence supports a shift from a prevention-versus-treatment paradigm toward an integrated P2R framework. Within this model, prophylactic vaccines aim to prevent infection through rapid immune protection at viral entry sites, while therapeutic vaccines seek to enhance immune control and reduce reservoir persistence among individuals receiving ART. The convergence of vaccine innovation, systems immunology, and African-led research capacity offers a promising pathway toward durable HIV control and potential functional remission.

A limitation of this review is the considerable methodological heterogeneity among included studies, including differences in populations, vaccine platforms, immunological assays, and outcome measures. This variability limited application of a uniform risk-of-bias assessment framework and constrained direct comparisons across studies. Therefore, findings should be interpreted within the context of an evolving HIV vaccine research landscape.

The authors sincerely acknowledge the invaluable contributions of researchers, healthcare professionals, and scientific communities whose dedication to HIV research and vaccine development has advanced the field and made this review possible. We also extend our appreciation to our colleagues, mentors, and affiliated institutions for their guidance, support, and encouragement throughout the development of this manuscript.

Charline Mukasa Sangany developed the study concept and design, undertook the full literature review, and prepared the initial manuscript draft. She led all aspects of project management, ensuring coordination and integration of the research, analysis, and writing activities.

Kalala Elisée Kabuya contributed to the development of the study framework, conducted the data analysis, and participated in the review and revision of the manuscript.