MAIT Cells in Health and Disease.

Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor-mediated signals-substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology.

Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.

Adenovirus vector vaccination reprograms pulmonary fibroblastic niches to support protective inflating memory CD8+ T cells.

Pathogens and vaccines that produce persisting antigens can generate expanded pools of effector memory CD8+ T cells, described as memory inflation. While properties of inflating memory CD8+ T cells have been characterized, the specific cell types and tissue factors responsible for their maintenance remain elusive. Here, we show that clinically applied adenovirus vectors preferentially target fibroblastic stromal cells in cultured human tissues. Moreover, we used cell-type-specific antigen targeting to define critical cells and molecules that sustain long-term antigen presentation and T cell activity after adenovirus vector immunization in mice. While antigen targeting to myeloid cells was insufficient to activate antigen-specific CD8+ T cells, genetic activation of antigen expression in Ccl19-cre-expressing fibroblastic stromal cells induced inflating CD8+ T cells. Local ablation of vector-targeted cells revealed that lung fibroblasts support the protective function and metabolic fitness of inflating memory CD8+ T cells in an interleukin (IL)-33-dependent manner. Collectively, these data define a critical fibroblastic niche that underpins robust protective immunity operating in a clinically important vaccine platform.

Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming.

Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep phenotyping of the cellular populations and cell-free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof-of-concept and used single-cell RNA-sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone-fide LN-resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood-derived populations. LN FNA supernatants represent a specific source of lymph- and lymph node-derived proteins, and can, aided by transcriptomics, identify likely receptor-ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell-free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience.

Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients.

BACKGROUND & AIMS: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. METHODS: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). RESULTS: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p <0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. CONCLUSION: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease. IMPACT AND IMPLICATIONS: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease.

Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity.

Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8+ T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.

Adenovirus vectors activate Vδ2+ γδT cells in a type I interferon-, TNF-, and IL-18-dependent manner.

Vδ2+ γδT cells are unconventional T cells that can be activated by cytokines without TCR signaling. Adenovirus vaccine vectors activated Vδ2+ γδT cells in an interleukin 18-, TNF-, and type I interferon-dependent manner. This stimulatory capacity was associated with adenovirus vectors of non-species C origin, including the ChAdOx1 vaccine platform.

Targeting MAIT cells as a cellular adjuvant for humoral immunity: a new player in a very old game.

In this article, I discuss recent work by Pankhurst et al. They found that MAIT cells can serve as a cellular adjuvant to boost immunity to a protein adjuvant. Intranasal co-administration of protein antigen with a strong MAIT cell ligand results in the the production of mucosal IgA and IgG antibody responses. This process is driven by MAIT cell-mediated maturation of migratory dendritic cells.

Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy.

The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine-elicited immune responses. C57BL/6 mice were immunized with differing vaccine systems (adenoviral, protein) in prime-boost regimens under treatment with RMD, IBET151, or RMD+IBET151. The combined administration of RMD+IBET151 during vaccination resulted in a significant increase in the frequency and number of Ag-specific CD8+ T cells. RMD+IBET151 treatment significantly increased the frequency of vaccine-elicited IFN-γ+ splenic CD8+ T cells and conferred superior therapeutic and prophylactic protection against B16-OVA melanoma. RNA sequencing analyses revealed strong transcriptional similarity between RMD+IBET151 and untreated Ag-specific CD8+ T cells except in apoptosis and IL-6 signaling-related genes that were differentially expressed. Serum IL-6 was significantly increased in vivo following RMD+IBET151 treatment, with recombinant IL-6 administration replicating the effect of RMD+IBET151 treatment on vaccine-elicited CD8+ T cell responses. IL-6 sufficiency for protection was not assessed. Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8+ T cell responses and enhanced therapeutic and prophylactic protection against B16-OVA melanoma. Increased IL-6 production and the differential expression of pro- and anti-apoptotic genes following RMD+IBET151 treatment are likely contributors to the enhanced cancer vaccine responses.

Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors.

Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development.IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.

Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells.

CD4(+) T cell help is critical for optimal CD8(+) T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8(+) T cell responses in the absence of CD4(+) T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4(+) T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8(+) T cell functionality and differentiation. Unhelped CD8(+) T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8(+) T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4(+) T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4(+) T cell help is required to promote both the expansion and acquisition of effector functions by CD8(+) T cells, which is accomplished by preventing immediate dysfunction.

Transient CD4+ T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited Antibody Responses.

UNLABELLED: We have recently demonstrated that CD4(+)T cell help is required at the time of adenovirus (Ad) vector immunization for the development of functional CD8(+)T cell responses, but the temporal requirement for CD4(+)T cell help for the induction of antibody responses remains unclear. Here we demonstrate that induction of antibody responses in C57BL/6 mice can occur at a time displaced from the time of Ad vector immunization by depletion of CD4(+)T cells. Transient depletion of CD4(+)T cells at the time of immunization delays the development of antigen-specific antibody responses but does not permanently impair their development or induce tolerance against the transgene. Upon CD4(+)T cell recovery, transgene-specific serum IgG antibody titers develop and reach a concentration equivalent to that in undepleted control animals. These delayed antibody responses exhibit no functional defects with regard to isotype, functional avidity, expansion after boosting immunization, or the capacity to neutralize a simian immunodeficiency virus (SIV) Env-expressing pseudovirus. The development of this delayed transgene-specific antibody response is temporally linked to the expansion of de novo antigen-specific CD4(+)T cell responses, which develop after transient depletion of CD4(+)T cells. These data demonstrate that functional vaccine-elicited antibody responses can be induced even if CD4(+)T cell help is provided at a time markedly separated from the time of vaccination. IMPORTANCE: CD4(+)T cells have a critical role in providing positive help signals to B cells, which promote robust antibody responses. The paradigm is that helper signals must be provided immediately upon antigen exposure, and their absence results in tolerance against the antigen. Here we demonstrate that, in contrast to the current model that the absence of CD4(+)T cell help at priming results in long-term antibody nonresponsiveness, antibody responses can be induced by adenovirus vector immunization or alum-adjuvanted protein immunization even if CD4(+)T cell help is not provided until >1 month after immunization. These data demonstrate that the time when CD4(+)T cell help signals must be provided is more dynamic and flexible than previously appreciated. These data suggest that augmentation of CD4(+)T cell helper function even after the time of vaccination can enhance vaccine-elicited antibody responses and thereby potentially enhance the immunogenicity of vaccines in immunocompromised individuals.

CD4 T Cell Depletion Substantially Augments the Rescue Potential of PD-L1 Blockade for Deeply Exhausted CD8 T Cells.

In various models of chronic infections and cancers, blockade of the inhibitory programmed cell death-1 (PD-1) pathway has been shown to be promising at restoring immune function. However, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (PD-L1) blockade. In particular, it is currently unclear whether the efficacy of PD-L1 blockade is dependent on the stage of disease. In a model of chronic lymphocytic choriomeningitis virus infection in mice, we show that exhausted CD8 T cells during the late stage of infection are refractory to rescue by PD-L1 blockade. Interestingly, PD-L1 blockade during the late stage of infection resulted in a biased expansion of PD-1(+) CTLA-4(+) regulatory T cells (Tregs) over antiviral CD8 T cells. Although previous studies have shown that Treg ablation can enhance the immune rescue by PD-L1 blockade, this regimen may induce lethal autoimmunity. In this report, we show that PD-L1 blockade together with CD4 T cell depletion effectively rescued deeply exhausted CD8 T cells and enhanced antiviral control during the late stage of chronic infection without any associated mortality. These data demonstrate the pleiotropic effects of anti-PD-L1 therapy on both virus-specific CD8 T cells and Tregs, and suggest a novel strategy for effectively rescuing deeply exhausted CD8 T cells.

Longitudinal requirement for CD4+ T cell help for adenovirus vector-elicited CD8+ T cell responses.

Despite the widespread use of replication-incompetent recombinant adenovirus (Ad) vectors as candidate vaccine platforms, the mechanism by which these vectors elicit CD8(+) T cell responses remains poorly understood. Our data demonstrate that induction and maintenance of CD8(+) T cell responses by Ad vector immunization is longitudinally dependent on CD4(+) T cell help for a prolonged period. Depletion of CD4(+) T cells in wild type mice within the first 8 d following Ad immunization resulted in dramatically reduced induction of Ag-specific CD8(+) T cells, decreased T-bet and eomesodermin expression, impaired KLRG1(+) effector differentiation, and atypical expression of the memory markers CD127, CD27, and CD62L. Moreover, these CD8(+) T cells failed to protect against a lethal recombinant Listeria monocytogenes challenge. Depletion of CD4(+) T cells between weeks 1 and 4 following immunization resulted in increased contraction of memory CD8(+) T cells. These data demonstrate a prolonged temporal requirement for CD4(+) T cell help for vaccine-elicited CD8(+) T cell responses in mice. These findings have important implications in the design of vaccines aimed at eliciting CD8(+) T cell responses and may provide insight into the impaired immunogenicity of vaccines in the context of AIDS and other CD4(+) T cell immune deficiencies.

Augmented replicative capacity of the boosting antigen improves the protective efficacy of heterologous prime-boost vaccine regimens.

UNLABELLED: Prime-boost immunization regimens have proven efficacious at generating robust immune responses. However, whether the level of replication of the boosting antigen impacts the magnitude and protective efficacy of vaccine-elicited immune responses remains unclear. To evaluate this, we primed mice with replication-defective adenovirus vectors expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), followed by boosting with either LCMV Armstrong, which is rapidly controlled, or LCMV CL-13, which leads to a more prolonged exposure to the boosting antigen. Although priming of naive mice with LCMV CL-13 normally results in T cell exhaustion and establishment of chronic infection, boosting with CL-13 resulted in potent recall CD8 T cell responses that were greater than those following boosting with LCMV Armstrong. Furthermore, following the CL-13 boost, a greater number of anamnestic CD8 T cells localized to the lymph nodes, exhibited granzyme B expression, and conferred improved protection against Listeria and vaccinia virus challenges compared with the Armstrong boost. Overall, our findings suggest that the replicative capacity of the boosting antigen influences the protective efficacy afforded by prime-boost vaccine regimens. These findings are relevant for optimizing vaccine candidates and suggest a benefit of robustly replicating vaccine vectors. IMPORTANCE: The development of optimal prime-boost vaccine regimens is a high priority for the vaccine development field. In this study, we compared two boosting antigens with different replicative capacities. Boosting with a more highly replicative vector resulted in augmented immune responses and improved protective efficacy.

An attenuated Listeria monocytogenes vector primes more potent simian immunodeficiency virus-specific mucosal immunity than DNA vaccines in mice.

A human immunodeficiency virus type 1 (HIV-1) vaccine that induces potent immune responses in the gastrointestinal mucosa would be highly desirable. Here we show that attenuated recombinant Listeria monocytogenes, administered orally utilizing its natural route of infection, induces potent mucosal as well as systemic immune responses in mice. Moreover, these responses can be boosted efficiently with replication-incompetent adenoviral vectors. L. monocytogenes elicited more potent simian immunodeficiency virus (SIV) Gag-specific CD8(+) T lymphocyte responses in mucosal compartments than DNA vaccines.

Alternative serotype adenovirus vaccine vectors elicit memory T cells with enhanced anamnestic capacity compared to Ad5 vectors.

The failure of the adenovirus serotype 5 (Ad5) vector-based human immunodeficiency virus type 1 (HIV-1) vaccine in the STEP study has led to the development of adenovirus vectors derived from alternative serotypes, such as Ad26, Ad35, and Ad48. We have recently demonstrated that vaccines using alternative-serotype Ad vectors confer partial protection against stringent simian immunodeficiency virus (SIV) challenges in rhesus monkeys. However, phenotypic differences between the T cell responses elicited by Ad5 and those of alternative-serotype Ad vectors remain unexplored. Here, we report the magnitude, phenotype, functionality, and recall capacity of memory T cell responses elicited in mice by Ad5, Ad26, Ad35, and Ad48 vectors expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP). Our data demonstrate that memory T cells elicited by Ad5 vectors were high in magnitude but exhibited functional exhaustion and decreased anamnestic potential following secondary antigen challenge compared to Ad26, Ad35, and Ad48 vectors. These data suggest that vaccination with alternative-serotype Ad vectors offers substantial immunological advantages over Ad5 vectors, in addition to circumventing high baseline Ad5-specific neutralizing antibody titers.

Role of mucosal-associated invariant T cells in coronavirus disease 2019 vaccine immunogenicity.

Mucosal-associated invariant T (MAIT) cells are an unconventional T cell population that are highly abundant in humans. They possess a semi-invariant T cell receptor (TCR) that recognises microbial metabolites formed during riboflavin biosynthesis, presented on a nonpolymorphic MHC-like molecule MR1. MAIT cells possess an array of effector functions, including type 1, type 17, and tissue repair activity. Deployment of these functions depends on the stimuli they receive through their TCR and/or cytokine receptors. Strong cytokine signalling, such as in response to vaccination, can bypass TCR triggering and provokes a strong proinflammatory response. Although data are still emerging, multiple aspects of MAIT cell biology are associated with modulation of immunity induced by the coronavirus disease 2019 mRNA and adenovirus vector vaccines. In this review, we will address how MAIT cells may play a role in immunogenicity of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and how these cells can be harnessed as cellular adjuvants.

The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity.

Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.