Harnessing Coordinated CD4⁺ and CD8⁺ T-Cell Immunity for Virus-Specific Adoptive Immunotherapy in Africa

Caroline MANGARE^*1

*Corresponding Author: cmangare@mut.ac.ke

Submitted: 10th August 2026 | Accepted: 26th August 2026 | Published Online: 21st September 2026

Keywords: virus-specific T cells; adoptive immunotherapy; emerging viral infections; CD4⁺ T cells; CD8⁺ T cells; HLA; Africa

Introduction

Advancing Pathogen Control through Coordinated CD4⁺ and CD8⁺ T-Cell Immunity

Virus-specific T-cell (VST) therapy seeks to restore or augment antiviral cellular immunity through the isolation, enrichment or ex vivo expansion of virus-reactive T cells followed by adoptive transfer (Riddell & Greenberg, 1995; Barrett et al., 2018; Smith & Khanna, 2025). The approach developed largely in haematopoietic stem-cell transplantation (HSCT), where delayed immune reconstitution and prolonged immunosuppression increase susceptibility to viral reactivation and disease. Clinical studies have evaluated VSTs targeting cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human adenovirus (HAdV), while multivirus platforms have expanded coverage to BK polyomavirus (BKPyV) and human herpesvirus 6 (HHV-6) (Gerdemann et al., 2013; Leen et al., 2013; Tzannou et al., 2017). Contemporary clinical experience includes both transplant-donor-derived and partially HLA-matched third-party products, providing a basis for more readily available cellular therapy.

The biological rationale for VST therapy extends beyond the presence of virus-reactive cells. Effective antiviral immunity depends on coordinated CD4⁺ and CD8⁺ T-cell responses. CD4⁺ T cells support antigen presentation, cytokine production, CD8⁺ T-cell expansion and memory development, while CD8⁺ T cells recognise infected cells and mediate antiviral activity through cytotoxic mechanisms and cytokine secretion. Clinical VST products can contain both populations, and CD4⁺ T cells may support the persistence and expansion of transferred cytotoxic T cells. Functional quality is therefore important alongside cell frequency. Antigen specificity, proliferative capacity, cytotoxic activity, differentiation state, persistence and tissue trafficking may determine whether transferred cells achieve sustained viral control (Mangare et al., 2019).

Advances in manufacturing have enabled antigen-specific cells to be generated using peptide pools targeting several viral antigens within a single product, reducing reliance on infectious viral material and facilitating broader antiviral coverage (Papadopoulou et al., 2014). Third-party banking further addresses limitations associated with donor availability and manufacturing time by providing cryopreserved products for selection according to relevant HLA restriction. These advances provide a foundation for extending VST therapy beyond established transplant-associated infections.

However, emerging and re-emerging viruses differ in antigen expression, viral kinetics, tissue tropism, persistence, sequence diversity and mechanisms of immune evasion. Translation therefore requires pathogen-specific evidence rather than extrapolation from established VST platforms. This review examines how coordinated CD4⁺ and CD8⁺ T-cell immunity, functional competence and memory differentiation inform VST development, evaluates the evidence supporting VST approaches for emerging and re-emerging viral infections, and considers how HLA diversity, donor selection, manufacturing capacity and clinical infrastructure may shape their future development in African populations.

Biological Requirements for Effective Antiviral VSTs

Effective virus-specific T-cell (VST) therapy requires transferred cells to recognise relevant viral antigens, retain antiviral function, expand following antigen encounter and persist sufficiently to mediate viral control. Clinical studies of third-party VSTs demonstrate that partially HLA-matched cells can expand and remain functional after infusion, supporting antiviral activity in immunocompromised recipients (Leen et al., 2013; Tzannou et al., 2017). Therapeutic activity depends not only on the number of infused cells but also on antigen specificity, functional potency, CD4⁺/CD8⁺ composition, differentiation state, proliferative capacity and persistence (Mangare et al., 2019; Tzannou et al., 2017). These biological requirements and their relationship to clinical activity are summarised in Figure 1. Viral antigens must first be processed by antigen-presenting cells and presented through appropriate HLA molecules to activate virus-specific CD4⁺ and CD8⁺ T cells. CD4⁺ T cells provide helper signals that support antigen presentation, CD8⁺ T-cell priming, expansion and memory formation, whereas CD8⁺ T cells contribute directly to elimination of infected cells through cytotoxic mechanisms and antiviral cytokine production. This coordinated response provides the biological basis for selecting functional cells for adoptive therapy. Figure 1 illustrates that effective VST products require relevant HLA-restricted antigen specificity, appropriate differentiation, functional potency, persistence and trafficking to infected tissues. Complete donor–recipient HLA identity is not always required when the HLA molecule restricting the antiviral response is shared (Leen et al., 2013; Tzannou et al., 2017). Antigen selection is equally important because therapeutic targets must be expressed by infected cells, naturally processed and presented, and recognised by functional T cells. Multivirus platforms demonstrate that carefully selected antigen combinations can broaden antiviral coverage within a single cellular product (Gerdemann et al., 2013; Papadopoulou et al., 2014).

Figure 1 places VST characteristics within broader viral and clinical contexts. Post-infusion expansion, persistence and antiviral activity are influenced by antigen expression, viral variation, HLA diversity, donor immunity, recipient immune reconstitution and immunosuppression. Because emerging viruses differ from transplant-associated pathogens in viral kinetics, tissue tropism and immunopathology, VST development requires pathogen-specific targets, appropriate HLA restriction, reproducible manufacture and suitable therapeutic windows.

Figure 1. Biological and Clinical Determinants of Virus-specific T-cell Responses and their Translation to Adoptive VST Therapy. Antigen-presenting cells initiate virus-specific CD4⁺ and CD8⁺ T-cell responses. CD4⁺ T cells provide helper signals that support antigen presentation and the expansion and maintenance of CD8⁺ T cells, while CD8⁺ T cells eliminate infected cells through cytotoxic mechanisms and antiviral cytokine production. Effective VST products require relevant HLA-restricted specificity, functional activity, appropriate differentiation, persistence and trafficking to sites of infection. Post-infusion expansion and antiviral activity may also be influenced by viral antigen expression, latency, sequence variation, donor immune history, recipient immune reconstitution and immunosuppression.

CD4⁺ and CD8⁺ T-cell Cooperation

Virus-specific T-cell responses are initiated through recognition of viral peptides presented by antigen-presenting cells. Peptide–major histocompatibility complex (MHC) class II recognition activates CD4⁺ T cells, whereas peptide–MHC class I recognition promotes differentiation of CD8⁺ T cells into cytotoxic effectors. CD4⁺ T cells can enhance CD8⁺ T-cell priming through CD40–CD40L-mediated licensing of dendritic cells and provide cytokine signals that support CD8⁺ T-cell proliferation, differentiation and memory formation (Smith et al., 2004; Castellino & Germain, 2006; Bedoui et al., 2016).

CD4⁺ and CD8⁺ T-cell responses function cooperatively, although dependence on CD4⁺ help varies by infection. During some acute viral infections, strong innate activation and dendritic-cell co-stimulation can support substantial primary CD8⁺ T-cell expansion despite limited CD4⁺ help (Bevan, 2004; Bedoui et al., 2016). The effects of inadequate help may become more apparent during memory formation and recall, when CD4⁺ T cells contribute to the development and maintenance of functional CD8⁺ memory (Shedlock & Shen, 2003; Topchyan et al., 2023). CD4⁺ help assumes particular importance during prolonged antigen exposure. Persistent T-cell receptor stimulation and inflammatory signalling can reduce CD8⁺ T-cell proliferative and effector capacity and promote sustained inhibitory-receptor expression and transcriptional and epigenetic programmes associated with exhaustion (Wherry & Kurachi, 2015; McLane et al., 2019). CD4⁺ helper signals contribute to the maintenance of functional antiviral CD8⁺ populations under these conditions (Topchyan et al., 2023). Experimental studies further show that CD4⁺-derived interleukin-21 (IL-21) supports cytolytic CX3CR1⁺ CD8⁺ T-cell populations during persistent viral infection (Zander et al., 2019; Zander et al., 2022). These observations are important to VST product composition whereby, products dominated by cytotoxic CD8⁺ T cells may provide immediate effector activity, whereas inclusion of virus-specific CD4⁺ T cells may support expansion, differentiation and persistence after transfer. The required CD4⁺/CD8⁺ composition is unlikely to be uniform across viruses and should be considered in relation to antigen persistence, host immune status and the intended therapeutic indication.

Functional Competence Beyond Antigen-specific T-cell Frequency

The frequency of antigen-specific T cells provides an incomplete measure of antiviral competence. Proliferative capacity, cytokine production, cytotoxic activity and differentiation provide additional information about the ability of virus-specific populations to respond after antigen encounter (Seder et al., 2008; Riou et al., 2012). These properties are critical for adoptive therapy, as transferred cells must retain functional activity after manufacture and respond effectively following infusion, with polyfunctionality providing an important measure of antiviral T-cell quality. Virus-specific T cells capable of producing combinations of interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukin-2 (IL-2) provide broader functional activity than populations with restricted cytokine profiles. During primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, stronger early polyfunctional CD4⁺ and CD8⁺ T-cell responses were associated with lower upper-airway viral RNA independently of neutralising antibody titres (Ramirez et al., 2024). Cross-reactive functional memory populations were also more frequent in asymptomatic infection, whereas severe and fatal disease was associated with increased co-expression of PD-1, TIM-3, TIGIT and CTLA-4 (Coulon et al., 2024). These observations support assessment of cytokine production and inhibitory-receptor expression alongside enumeration of antigen-specific cells.

Proliferative capacity provides complementary information because antigen-specific cells may remain detectable despite functional impairment. Following direct-acting antiviral treatment of hepatitis C virus (HCV) infection, proliferation of HCV-specific CD4⁺ and CD8⁺ T cells improved without complete restoration of cytokine production, indicating that recovery of individual functions does not necessarily represent complete restoration of antiviral competence (Llorens-Revull et al., 2021). Cytotoxic activity can be assessed through perforin and granzyme expression, degranulation and direct target-cell killing. Inhibitory-receptor expression should similarly be interpreted together with proliferative, cytokine and cytotoxic measurements rather than used alone to define T-cell exhaustion. These considerations are therefore particularly relevant during ex vivo VST manufacture. Repeated antigenic stimulation and prolonged culture can alter differentiation and proliferative potential. Product characterisation should therefore extend beyond the number of antigen-reactive cells to include functional measurements capable of determining whether expanded populations retain the properties required for activity after transfer.

Memory Differentiation, Persistence and Tissue Localisation

Following resolution or control of primary infection, a proportion of activated T cells survives contraction and differentiates into memory populations capable of responding to subsequent antigen exposure (Kaech & Cui, 2012). These populations differ in proliferative capacity, trafficking and effector function. Central-memory T cells have strong proliferative capacity and preferential lymphoid homing, whereas effector-memory populations provide more immediate effector activity and preferentially circulate through peripheral tissues (Sallusto et al., 1999; Appay et al., 2008). Tissue-resident memory T (T_RM) cells remain within lymphoid and non-lymphoid tissues, where they provide local immune surveillance (Masopust & Soerens, 2019; Christo et al., 2024).

The relevance of differentiation state and T cell subsets to adoptive immunotherapy is illustrated by cytomegalovirus (CMV)-specific T cells. CMV-reactive populations are distributed across CD45RA/CD62L-defined central-memory, effector-memory and terminally differentiated subsets that differ in proliferative and functional characteristics. These differences can influence cell-selection strategies and the composition of products intended for adoptive transfer (Mangare et al., 2019). Thus, products containing similar frequencies of virus-specific cells may differ substantially in their capacity to proliferate, persist and mediate antiviral activity after infusion. Importantly, tissue localisation adds a further consideration because measurements in peripheral blood may not adequately represent antiviral immunity within infected tissues because T_RM and other tissue-associated populations are poorly represented in circulation (Masopust & Soerens, 2019; Christo et al., 2024). This may be particularly important for viruses that establish infection or persistence within anatomically restricted sites, where effective VSTs must not only recognise infected cells but also traffic to the relevant tissue. This shows that the phenotype that is required for therapeutic activity may consequently differ according to pathogen biology. Persistent or latent infections may benefit from populations with strong proliferative capacity and long-term persistence, whereas rapidly replicating acute infections may require earlier cytotoxic activity and rapid tissue access. Therefore, VST assessment should integrate antigen specificity, CD4⁺/CD8⁺ composition, proliferative capacity, cytokine production, cytotoxic activity, differentiation state, persistence and tissue trafficking rather than relying on antigen-specific cell frequency alone.

Coordinated T-Cell Immunity Across Human Viral Infections

Evidence across acute and persistent viral infections supports a role for coordinated CD4⁺ and CD8⁺ T-cell immunity in viral control, although the relative contribution and phenotype of these populations vary with the pathogen and duration of antigen exposure. In HIV infection, preservation of virus-specific CD4⁺ T-cell function has been associated with sustained CD8⁺ responses and improved viral control (Jain et al., 2024), while experimental HBV and hepacivirus models demonstrate roles for CD4-associated CD40L–CD40 signalling in CD8⁺ T-cell priming, differentiation and antiviral activity (Bailey et al., 2024; Lopez-Scarim et al., 2024). Persistent herpesvirus infection provides further evidence of heterogeneous antiviral memory populations, including functionally distinct CMV-specific CD4⁺ and CD8⁺ subsets relevant to adoptive T-cell selection (Mangare et al., 2019; Kar et al., 2024). Comparable associations are observed in acute and outbreak-prone infections. SARS-CoV-2 control has been associated with early polyfunctional CD4⁺ and CD8⁺ responses (Koutsakos et al., 2023; Ramirez et al., 2024), while Ebola virus disease survivors develop detectable EBOV-specific cellular responses, in contrast to the high viral loads, systemic inflammation and increased inhibitory-receptor expression reported in fatal disease (Ruibal et al., 2016). YF-17D vaccination generates CD8⁺ T-cell responses capable of forming durable memory (Akondy et al., 2009; Zarnitsyna et al., 2021), whereas DENV infection induces substantial effector-memory responses that may be influenced by previous serotype exposure (de Matos et al., 2015; Rivino & Lim, 2017). Acute CHIKV infection is similarly accompanied by activated cytotoxic CD8⁺ T cells expressing granzyme B and perforin, together with CD4⁺ responses (Wauquier et al., 2011; Dias et al., 2018). Collectively, these observations provide a biological rationale for investigating virus-specific T cells therapeutically, but evidence of protective cellular immunity alone is insufficient to establish suitability for adoptive VST therapy; candidate pathogens require further evaluation of antigen specificity, HLA restriction, functional activity and, ultimately, the capacity of transferred cells to mediate antiviral effects.

Established Clinical VST Therapy as the Translational Benchmark

Clinical development of virus-specific T-cell (VST) therapy has focused largely on viral complications in immunocompromised patients, particularly recipients of allogeneic haematopoietic stem-cell transplantation (HSCT). Cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human adenovirus (HAdV) have the longest clinical experience, with later multivirus platforms extending coverage to BK polyomavirus (BKPyV) and human herpesvirus 6 (HHV-6) (Gerdemann et al., 2013; Leen et al., 2013; Papadopoulou et al., 2014; Tzannou et al., 2017). These studies provide the main clinical foundation for considering VST therapy against other viral infections. Early studies concentrated on individual pathogens. In EBV-associated post-transplant lymphoproliferative disease, banked allogeneic EBV-specific cytotoxic T lymphocytes selected according to HLA compatibility and in vitro activity showed that third-party cells could be used without manufacturing a separate product for each recipient (Haque et al., 2007). Multivirus approaches subsequently broadened this strategy. Gerdemann et al. generated CMV-, EBV- and HAdV-specific T cells using overlapping peptide libraries and a shortened 2–3-week culture. Complete virological responses were reported in 80% of ten treated HSCT recipients, demonstrating that multivirus products could be generated without the prolonged culture and viral vectors used in earlier methods (Gerdemann et al., 2013).

Third-party banking further improved the practicality of VST therapy. Leen et al. established a bank of 32 VST lines and treated 50 HSCT recipients with severe or refractory CMV, EBV or HAdV infection using partially HLA-matched products. The cumulative complete or partial response at six weeks was 74%, with no immediate infusion-related adverse events and two cases of de novo graft-versus-host disease (Leen et al., 2013). Papadopoulou et al. subsequently generated VSTs recognising 12 antigens from CMV, EBV, HAdV, BKPyV and HHV-6. Among 11 HSCT recipients, including patients with concurrent infections, the overall virological and clinical response was 94% (Papadopoulou et al., 2014). In a phase II study of banked pentavalent VSTs, 38 HSCT recipients with 45 infections achieved a cumulative complete or partial response of 92%. Functional third-party cells remained detectable for up to 12 weeks after infusion (Tzannou et al., 2017). Targeted BKPyV therapy has also produced responses in patients with BK viraemia and haemorrhagic cystitis, including recipients of donor-derived and third-party cells (Nelson et al., 2020). These features are relevant to future VST development. Therapeutic activity requires recognition of appropriate viral epitopes through recipient HLA molecules; complete donor–recipient HLA identity is not necessarily required when the relevant restricting HLA molecule is shared (Leen et al., 2013; Tzannou et al., 2017). Antigen selection is equally important because therapeutic targets must be expressed in infected cells, naturally processed and presented, and recognised by functional T cells. Multivirus products illustrate how selected antigen combinations can broaden coverage without requiring separate manufacture for each pathogen (Gerdemann et al., 2013; Papadopoulou et al., 2014). Post-infusion proliferation and persistence also contribute to activity, making antigen specificity, CD4⁺/CD8⁺ composition, differentiation and functional capacity important alongside the administered cell dose (Tzannou et al., 2017).

The stated principles provide a foundation for emerging-virus VST development but do not establish efficacy in that setting. Acute emerging infections may differ substantially from transplant-associated infections in viral kinetics, tissue tropism, antigen expression and immunopathology. Translation therefore requires pathogen-specific evidence for protective T-cell targets, HLA restriction, reproducible manufacture and an appropriate therapeutic window. SARS-CoV-2 provides an important example of this transition from established VST practice to a newly emerging pathogen. Table 1 summarises these targets, viral persistence or latency, HLA and epitope considerations, clinical evidence and potential relevance to African settings. Despite substantial viral disease burden and extensive HLA diversity, clinical implementation of VST therapy in Africa remains limited.

SARS-CoV-2 as a model for Clinical Proof-of-Concept for VST Therapy Against an Emerging Virus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides the clearest example of extending VST beyond established transplant-associated viruses. Human studies show that early virus-specific cellular responses contribute to viral control. During breakthrough infection, rapid recall of spike-specific CD4⁺ T cells and expansion of activated SARS-CoV-2-specific CD8⁺ T cells were associated with lower peak nasal viral RNA and faster clearance (Koutsakos et al., 2023). During primary infection, early polyfunctional CD4⁺ and CD8⁺ responses were similarly associated with lower upper-airway viral RNA independently of neutralising antibody titres (Ramirez et al., 2024). Cross-reactive memory to common-cold coronaviruses may also contribute, whereas severe disease has been associated with fewer cross-reactive cells and greater expression of inhibitory receptors (Coulon et al., 2024).

This biological evidence was followed by clinical evaluation of SARS-CoV-2-reactive cellular products. In a randomised phase I/II trial involving 90 patients with severe COVID-19, partially HLA-matched convalescent donor-derived SARS-CoV-2-specific T cells expanded in vivo and were well tolerated. Recovery occurred in 65% of VST-treated participants compared with 38% receiving standard care alone, although larger studies were considered necessary to confirm efficacy (Papadopoulou et al., 2023).

The multicentre RELEASE trial subsequently evaluated off-the-shelf CD45RA⁻ memory T cells in patients with COVID-19 pneumonia and/or lymphopenia, reporting achievement of the prespecified recovery endpoint and faster lymphocyte recovery without treatment-related adverse events (Ferreras et al., 2024).

Third-party banking has also been explored in immunocompromised patients. Twelve high-risk patients received HLA-matched SARS-CoV-2-specific T cells, with donor cells subsequently detected in eight recipients and no treatment-attributable cytokine-release syndrome, graft-versus-host disease or acute respiratory distress syndrome reported (Seng et al., 2024). A further phase I study in six immunocompromised cancer patients with refractory infection reported viral-load improvement in four patients, while one developed cytokine-release syndrome and diffuse alveolar haemorrhage after infusion (Henden et al., 2025). SARS-CoV-2 therefore provides clinical proof-of-concept that HLA-informed donor selection, third-party banking and adoptive transfer can be applied to an emerging virus. However, efficacy, optimal timing and appropriate patient populations remain to be established before these findings can inform broader emerging-virus VST development.

Ebola Virus and the Evidence from Human Immunology and Preclinical Adoptive Transfer

Ebola virus (EBOV) has progressed beyond descriptive T-cell immunology, although clinical VST therapy has not been established. During the West African epidemic, fatal Ebola virus disease was associated with high viral load, systemic inflammation and increased PD-1 and CTLA-4 expression on CD4⁺ and CD8⁺ T cells, whereas survivors developed EBOV-specific responses during viral clearance (Ruibal et al., 2016). In Sierra Leone survivors, 26 of 30 individuals responded to at least one EBOV antigen, with nucleoprotein most frequently recognised; 34 CD8⁺ T-cell epitopes were identified across several viral proteins (Sakabe et al., 2018). Experimental evidence further supports the therapeutic potential of these responses. Transfer of activated EBOV-specific CD8⁺ T cells protected naïve mice against lethal EBOV challenge but not Marburg virus, demonstrating virus-specific protection (Bradfute et al., 2008). Thus, EBOV combines human antigen-specific responses and epitope evidence with preclinical adoptive-transfer protection, but no comparable human therapeutic VST trial was identified in the literature reviewed.

Dengue Virus and Extensive Human T-Cell Evidence Without Clinical VST Therapy

Dengue virus (DENV) has one of the most extensively characterised T-cell repertoires among arboviruses, although its suitability for adoptive T-cell therapy remains uncertain. Studies across the four DENV serotypes have identified broad HLA-restricted CD8⁺ T-cell responses and suggest that functional cellular immunity can contribute to protection. In a dengue-hyperendemic population, Weiskopf et al. examined responses to more than 400 epitopes and found that HLA alleles associated with lower susceptibility to severe disease were also associated with stronger, polyfunctional DENV-specific CD8⁺ T-cell responses (Weiskopf et al., 2013). Moreover, CD8⁺ T-cell targeting varies between DENV serotypes, indicating that infecting serotype, viral sequence and previous exposure may influence antigen recognition (Weiskopf et al., 2015). Experimental studies have further identified naturally presented MHC-I-restricted epitopes. Comber et al. described four DENV epitopes, including HLA-A24-restricted and HLA-A2/A24-binding targets capable of stimulating CD8⁺ T cells from DENV-seropositive individuals (Comber et al., 2014). These studies provide a basis for selecting candidate antigens and HLA-restricted targets but do not establish DENV-specific adoptive immunotherapy. No comparable human therapeutic DENV-VST trial was identified in the literature reviewed. Future development would need to account for serotype cross-reactivity, HLA and viral sequence diversity, previous DENV exposure and the potential for some T-cell responses to contribute to inflammatory pathology.

Chikungunya Virus and Preclinical Adoptive-Transfer Evidence

Human chikungunya virus (CHIKV) infection induces strong cellular responses. During acute disease, CD8⁺ T cells show increased granzyme B, perforin and CD107a expression, consistent with cytotoxic effector activity (Dias et al., 2018). Preclinical studies have also examined adoptive transfer. In mice, activated CHIKV-specific CD8⁺ effector T cells enhanced systemic viral clearance, but failed to eliminate persistent virus from joint-associated tissues (Davenport et al., 2020). This finding is relevant to VST development because antiviral cytotoxicity alone may be insufficient when transferred cells cannot effectively access or function within sites of viral persistence. CHIKV therefore has human functional T-cell evidence and preclinical adoptive-transfer support, but no established human CHIKV-specific VST trial was identified.

Lassa Virus and Human T-Cell Epitope Evidence for Adoptive Immunotherapy

Lassa virus (LASV) infection provides substantial evidence for the contribution of cellular immunity to viral control. Recovery from Lassa fever may occur before measurable neutralising antibodies develop, supporting investigation of T-cell-mediated responses. Early studies in seropositive West African individuals demonstrated proliferative responses to LASV nucleoprotein (NP), and NP-specific human CD4⁺ T-cell clones recognising defined viral peptides were generated from exposed individuals (ter Meulen et al., 2000). A conserved glycoprotein-2 epitope recognised by human LASV-specific CD4⁺ T-cell clones was subsequently characterised (Meulen et al., 2004). CD8⁺ T-cell targets have also been defined experimentally. Botten et al. identified three HLA-A02:01-restricted glycoprotein complex (GPC) epitopes, GPC₄₂₋₅₀, GPC₆₀₋₆₈ and GPC_441−449. These epitopes induced high-avidity CD8⁺ T-cell responses in transgenic mice and were naturally processed and presented by human HLA-A02:01-positive target cells. Immunisation with two of the epitopes also provided protection against recombinant vaccinia virus expressing LASV GPC (Botten et al., 2006).

Evidence from African survivors is particularly relevant to therapeutic target selection. Analysis of survivors from Nigeria and Sierra Leone identified three shared CD8⁺ T-cell epitopes and nine additional targets within conserved LASV regions despite circulation of distinct viral lineages (Sakabe et al., 2020). More recent work has further characterised the human LASV CD4⁺ T-cell repertoire and identified conserved regions showing cross-mammarenavirus recognition (Lee et al., 2026). Overall, these studies provide candidate antigens and epitopes for future LASV-specific VST development. However, no established human LASV-specific adoptive VST trial was identified in the literature reviewed, placing LASV at the human antigen and epitope characterisation stage rather than clinical cellular therapy.

Marburg Virus and Current Evidence Gaps

Marburg virus (MARV) remains at an earlier stage of VST development than Ebola virus (EBOV), despite both being filoviruses. Human studies of MARV survivors have demonstrated multivariate CD4⁺ T-cell responses but comparatively limited CD8⁺ T-cell responses, indicating that cellular immunity develops after natural infection but remains incompletely characterised (Stonier et al., 2017). Experimentally validated, naturally processed HLA-restricted MARV epitopes are also limited, while many proposed T-cell targets have been derived from computational prediction or preclinical vaccine studies (Baral et al., 2022). Preclinical vaccination studies have demonstrated induction of broad MARV-specific cytotoxic T-cell responses, supporting further investigation of cellular immunity (Shedlock et al., 2013). No human MARV-specific adoptive T-cell trial has been established. Priorities include defining HLA-restricted epitopes, characterising survivor T-cell responses, and evaluating protective efficacy of MARV-specific T cells in adoptive-transfer models.

Rift Valley Fever Virus and Human T-Cell Evidence

Rift Valley fever virus (RVFV) has experimentally defined human T-cell targets relevant to VST development in Africa. Two immunodominant HLA-A*02:01-restricted nucleocapsid epitopes, N_121−129 (VLSEWLPVT) and N_165−173 (ILDAHSLYL), elicited cytotoxic and polyfunctional CD8⁺ T-cell responses (Xu et al., 2013). Long-term cellular immunity has also been demonstrated in recipients of an inactivated RVFV vaccine, with responses to N, Gn and Gc detectable up to 24 years after vaccination (Harmon et al., 2020). These findings identify functional human T-cell targets and durable memory responses that could inform VST development, although no established human RVFV-specific adoptive T-cell trial was identified in the literature reviewed.

Mpox Virus and Human T-Cell Epitope Evidence

Human T-cell responses to mpox virus (MPXV) have been increasingly characterised since the 2022 outbreak. Grifoni et al. compiled 318 CD4⁺ and 659 CD8⁺ orthopoxvirus epitopes and developed MPXV peptide pools capable of detecting cross-reactive human T-cell responses following infection or vaccination (Grifoni et al., 2022). More recent work identified seven immunodominant HLA-A*02:01-restricted MPXV CD8⁺ epitopes and reported differences in cytotoxicity, migration and clonal expansion between infection- and MVA-BN vaccine-induced responses (Chen et al., 2025). Hence, these studies provide human antigen-specific and epitope-level evidence, but no established therapeutic MPXV-specific adoptive T-cell trial was identified in the literature reviewed.

Translational Pathway for Emerging-Virus VST Development in Africa

Development of virus-specific T-cell (VST) therapy for emerging and re-emerging infections requires progression from evidence of antiviral cellular immunity to a reproducible therapeutic product. Established VST programmes demonstrate that clinical activity depends on appropriate antigen specificity, HLA restriction, functional competence and persistence following infusion (Leen et al., 2013; Papadopoulou et al., 2014; Tzannou et al., 2017). Emerging viruses currently occupy different positions along this pathway. As discussed in previous sections, SARS-CoV-2 has progressed to clinical evaluation of manufactured and third-party products (Papadopoulou et al., 2023; Seng et al., 2024), whereas EBOV and CHIKV have reached preclinical adoptive-transfer studies (Bradfute et al., 2008; Davenport et al., 2020). LASV, DENV, RVFV and MPXV are supported mainly by human T-cell characterisation and epitope mapping (Weiskopf et al., 2013; Sakabe et al., 2020; Harmon et al., 2020; Chen et al., 2025), while MARV remains less extensively characterised. These differences provide a framework for defining the evidence and infrastructure required for VST development in African populations, with Table 2 summarising the current stage of evidence, key translational gaps and relevance to African VST development for each emerging and re-emerging virus reviewed.

Protective T-cell Immunity and Candidate Viral Targets

Evidence of virus-specific cellular immunity provides the biological basis for considering VST development. EBOV survivors develop virus-specific responses, whereas fatal Ebola virus disease has been associated with high viral loads, systemic inflammation and increased expression of inhibitory receptors on T cells (Ruibal et al., 2016). LASV survivors show responses against glycoprotein complex and nucleoprotein, including conserved targets recognised across distinct viral lineages (Sakabe et al., 2020). HLA-associated differences in DENV-specific CD8⁺ T-cell magnitude and polyfunctionality have been linked to disease severity (Weiskopf et al., 2013), while cytotoxic CD8⁺ responses have been demonstrated during acute CHIKV infection (Dias et al., 2018). Durable cellular memory has also been reported following RVFV vaccination (Harmon et al., 2020), and MPXV infection induces functional CD4⁺ and CD8⁺ memory responses (Chen et al., 2025). These findings establish biological relevance but do not, independently, demonstrate suitability for therapeutic transfer.

Antigen Selection, HLA Restriction and African Population Coverage

Therapeutic development requires identification of viral targets that are naturally processed, presented by relevant HLA molecules and recognised by functional T cells. Human studies have identified multiple EBOV CD8⁺ T-cell epitopes (Sakabe et al., 2018), conserved LASV targets across viral lineages (Sakabe et al., 2020), naturally processed HLA-A02:01-restricted LASV GPC epitopes (Botten et al., 2006), an extensive DENV HLA-restricted repertoire (Weiskopf et al., 2013), mapped RVFV N, Gn and Gc targets (Harmon et al., 2020), and immunodominant HLA-A02:01-restricted MPXV epitopes (Chen et al., 2025).

For African VST development, target selection must account for substantial HLA diversity. High-resolution studies demonstrate marked differences in HLA allele and haplotype distributions among African populations (Mentzer et al., 2024; Banjoko et al., 2025). Associations of HLA-B57:03 and HLA-B81:01 with HIV control further illustrate the functional relevance of population-specific HLA variation (Prentice et al., 2013). Viral diversity adds another consideration because sequence variation can alter antigen processing, HLA binding and T-cell recognition. Candidate VST targets should therefore be selected using high-resolution HLA data, viral genomic surveillance and experimental epitope validation, with emphasis on naturally presented and conserved targets that provide adequate population coverage rather than predominantly relying on frequently studied alleles such as HLA-A*02:01.

Generation and Manufacture of Functional VST Products

Candidate virus-reactive T cells must be isolated or expanded ex vivo without losing antigen specificity, proliferative capacity or antiviral function. Established CMV-, EBV-, HAdV-, BKPyV- and HHV-6-specific platforms demonstrate that defined antigens and overlapping peptide pools can generate clinically applicable products (Gerdemann et al., 2013; Papadopoulou et al., 2014; Tzannou et al., 2017). SARS-CoV-2 extended this principle to an emerging pathogen through manufacture of donor-derived and partially HLA-matched products. Comparable manufacturing evidence remains limited for other emerging viruses. Modular African platforms could standardise cell processing, expansion, cryopreservation and quality control while incorporating pathogen-specific antigens and optimised manufacturing protocols. Peptide-based stimulation may also reduce the need to handle infectious material during production of VSTs targeting high-consequence pathogens. Nevertheless, culture conditions, antigen composition and cellular phenotype require pathogen-specific optimisation. Product assessment should include identity, viability, sterility, antigen specificity, proliferation, cytokine production, cytotoxicity and alloreactivity. In addition, differentiation state should be considered because memory subsets differ in proliferative potential and persistence (Mangare et al., 2019).

Preclinical Adoptive-transfer Evidence

Preclinical adoptive-transfer studies provide an important bridge between endogenous immunity and therapeutic development. In experimental EBOV infection, transferred virus-specific CD8⁺ T cells expanded in recipient animals and protected against lethal EBOV challenge but not MARV infection, demonstrating virus-specific protection (Bradfute et al., 2008). CHIKV provides a contrasting example: transferred effector CD8⁺ T cells improved viral clearance from the spleen but had limited activity against persistent infection in joint-associated tissues (Davenport et al., 2020). These findings show that antigen recognition alone may not predict therapeutic activity and support assessment of in vivo expansion, persistence, trafficking and access to infected tissues during preclinical development.

Third-party Banking and Donor Selection

Third-party banking may be particularly valuable for emerging infections because cryopreserved products can be selected rapidly without patient-specific manufacture. Partially HLA-matched VST banks have been used successfully for transplant-associated viral infections (Leen et al., 2013; Tzannou et al., 2017), while SARS-CoV-2 demonstrated that banked products can also be developed from convalescent or vaccinated donors for an emerging pathogen (Seng et al., 2024). VST donor banks developed for African populations should incorporate regional HLA distributions and prospective population-coverage modelling (Mentzer et al., 2024; Banjoko et al., 2025). Suitable donors may include survivors or vaccinated individuals, depending on the pathogen, but previous exposure or seropositivity alone should not determine eligibility. Donor selection should confirm antigen-specific T-cell recognition and functional activity.

Clinical Translation, Therapeutic Window and Patient Selection

SARS-CoV-2 provides the strongest clinical precedent for extending VST therapy to an emerging pathogen. In a randomised phase I/II study, partially HLA-matched SARS-CoV-2-specific T cells expanded after infusion and were well tolerated, with a 30-day recovery rate of 65% among VST-treated participants compared with 38% receiving standard care alone (Papadopoulou et al., 2023). Other studies have evaluated off-the-shelf CD45RA⁻ memory T cells and banked HLA-matched SARS-CoV-2-specific products (Ferreras et al., 2024; Seng et al., 2024). The therapeutic window may be narrower for rapidly progressive infections such as EBOV, LASV, DENV and CHIKV than for CMV or EBV reactivation. Patient-specific manufacture initiated after diagnosis may therefore be impractical, strengthening the rationale for pre-existing third-party products where therapeutic benefit is biologically justified. Initial studies may be more appropriate in patients with severe or persistent infection, impaired cellular immunity or inadequate responses to available therapies. Therefore, clinical indications should be defined according to pathogen biology, disease kinetics and tissue distribution. VSTs should be evaluated as adjuncts to vaccination, antiviral treatment and supportive care rather than as replacements for established interventions.

Infrastructure, Regulatory Readiness and Implementation in Africa

Clinical implementation will require specialised cell-processing facilities, trained laboratory and clinical personnel, reliable reagent and cold-chain supply systems, quality assurance, regulatory oversight and sustainable financing. Broader assessments of cellular and gene therapy in Africa identify infrastructure and financial constraints as important barriers to implementation (Obiozor et al., 2025). These observations do not demonstrate existing VST manufacturing capacity across Africa but identify systems that would also be required for VST programmes. Thus, initial development could be concentrated in centres with existing transplantation, haematology, immunology or cellular-therapy capacity, while regional collaboration could support HLA datasets, donor registries, biobanking, immune monitoring and specialised manufacturing expertise. Expansion should follow demonstration of manufacturing feasibility, regulatory compliance, safety and a defined clinical benefit.

Research Priorities and Implementation Agenda for VST Development in Africa

Virus-specific T-cell (VST) therapy in Africa remains a research priority rather than an established clinical platform. Development should initially focus on identifying population-relevant viral targets and establishing whether these can be translated into reproducible cellular products. Studies involving survivors, exposed individuals and vaccinated cohorts should combine functional T-cell profiling, high-resolution HLA typing and viral genomic surveillance to identify naturally presented, conserved epitopes with sufficient population coverage. This is particularly important given the substantial HLA diversity within and between African populations (Mentzer et al., 2024; Banjoko et al., 2025). Existing studies of Lassa virus (LASV) and Ebola virus (EBOV) provide experimentally characterised antigens and epitopes that could support this approach (Sakabe et al., 2018; Sakabe et al., 2020).

Candidate products should then undergo pathogen-specific ex vivo optimisation and assessment of antigen specificity, proliferation, cytotoxicity, phenotype, alloreactivity and stability following cryopreservation. Preclinical studies should determine whether transferred cells persist, traffic to infected tissues and control viral replication without exacerbating immunopathology. EBOV-specific CD8⁺ T cells have demonstrated protective activity following adoptive transfer in experimental models, whereas CHIKV studies indicate that effective systemic antiviral activity may not ensure clearance from tissue reservoirs (Bradfute et al., 2008; Davenport et al., 2020). Thus, clinical development should proceed only where these studies establish a clear therapeutic indication. Experience with CMV-, EBV-, HAdV-, BKPyV- and HHV-6-specific products provides established manufacturing and third-party banking models (Leen et al., 2013; Tzannou et al., 2017), while SARS-CoV-2 demonstrates that similar technology can be adapted to an emerging pathogen (Papadopoulou et al., 2023; Seng et al., 2024). Cryopreserved third-party banks may be particularly relevant for rapidly progressing infections where patient-specific manufacture would be impractical.

Implementation will require GMP-compatible manufacturing, quality assurance, regulatory oversight, skilled personnel and sustainable financing (Obiozor et al., 2025). Locally manufactured anti-CD19 CAR-T therapy in South Africa provides evidence that advanced cellular therapies can be produced and delivered within specialised African centres. This experience could inform VST development through existing transplantation and cellular-therapy expertise, while regional collaboration could strengthen biobanking, immune monitoring, donor registries and shared manufacturing capacity (Obiozor et al., 2025).

Literature Identification

This narrative review was informed by searches of PubMed, Scopus and Web of Science for literature on coordinated CD4⁺ and CD8⁺ T-cell immunity, antiviral T-cell differentiation and memory, virus-specific T-cell therapy, HLA-restricted viral epitopes and African HLA diversity. Search terms included combinations of "CD4 T cells", "CD8 T cells", "antiviral immunity", "T-cell memory", "T-cell exhaustion", "virus-specific T cells", "adoptive T-cell therapy", "HLA", "viral epitopes", "Africa" and individual viral pathogens discussed in the review. Priority was given to primary human studies and clinical VST studies, supplemented by mechanistic animal studies and reviews where appropriate. Reference lists of relevant articles were also examined to identify additional studies.

Conclusion

Virus-specific T-cell therapy demonstrates how coordinated CD4⁺ and CD8⁺ T-cell immunity can be translated into cellular treatment. Clinical experience with transplant-associated viruses and SARS-CoV-2 shows that antiviral T cells can be manufactured, banked and administered therapeutically (Leen et al., 2013; Tzannou et al., 2017; Papadopoulou et al., 2023). However, evidence of endogenous virus-specific immunity alone does not establish suitability for adoptive therapy. For emerging and re-emerging viruses, development should be guided by antigen specificity, HLA restriction, functional competence, persistence, tissue trafficking and pathogen biology. EBOV and CHIKV provide preclinical adoptive-transfer evidence, whereas LASV, DENV, RVFV and MPXV remain supported predominantly by human immunological and epitope studies, with MARV requiring further characterisation. In Africa, substantial HLA and viral diversity strengthens the need for population-relevant antigen selection and donor-bank design (Mentzer et al., 2024; Banjoko et al., 2025). An adaptable African VST platform therefore remains a prospective research objective. Its development will depend on linking locally relevant antiviral T-cell biology with reproducible manufacturing, rigorous preclinical evaluation, appropriate clinical indications and sustainable cellular-therapy infrastructure.

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