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Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses. Although it was initially thought that AAV vectors induce only marginal innate responses below the threshold of systemic symptoms recent trials have shown that complement activation can results in serious adverse events. Dorsal root ganglia toxicity has also been identified as a complication of high vector doses as has severe hepatotoxicity. Most of the critical complications occur in patients who are treated with very high vector doses indicating that the use of more efficient AAV vectors to allow for dose sparing or giving smaller doses repeatedly, the latter in conjunction with antibody or B cell depleting measures, should be explored.

CD4 + T cells migrate throughout the body and form immune synapses to carry out their functions. Both of these actions require dynamic actin structures, which are disrupted by HIV proteins. Our study suggests that a key HIV protein, Nef, might disrupt a vital internal cellular machinery that helps immune cells move and function properly. Our microscopic and proteomics studies suggest a new model in which Nef inhibits a large protein complex at the front of migrating T cells. Restoring this cytoskeletal dysfunction may be key to restoring CD4 + T-cell survival and function, which may improve adaptive immune responses during HIV infection.

The West African Ebola virus disease (EVD) outbreak was the largest EVD outbreak in history. However, data on lymphocyte dynamics and the antigen specificity of T cells in Ebola survivors are scarce, and our understanding of EVD pathophysiology is limited. A case of EVD survival in which the patient cleared Ebola virus (EBOV) infection without experimental drugs allowed for the detailed examination of lymphocyte dynamics. We demonstrate the persistence of T-cell activation well beyond viral clearance and detect EBOV-specific T cells. Our study provides significant insights into lymphocyte specificity during the recovery phase of EVD and may inform novel strategies to treat EVD.

We developed an ELISPOT assay for evaluating Middle East respiratory syndrome coronavirus (MERS-CoV)‒specific T-cell responses in dromedary camels. After single modified vaccinia virus Ankara-MERS-S vaccination, seropositive camels showed increased levels of MERS-CoV‒specific T cells and antibodies, indicating suitability of camel vaccinations in disease-endemic areas as a promising approach to control infection.

Objectives Immunisation remains the most cost‐effective mechanism to combat influenza infection and is widely employed against seasonal influenza viruses. Zoonotic transmission of avian influenza A viruses represents a significant threat to human health given the lack of population‐level immunity. Therefore, there is a need to better understand pre‐existing cross‐reactive human immunity against avian influenza strains, as highlighted by the recent global spread of avian H5Nx clade 2.3.4.4b variants. Methods Here, we quantified the frequencies and specificities of B and T cells recognising avian hemagglutinin (HA) within unexposed adults and characterised the ability of seasonal immunisation to boost cross‐reactive immune responses to H5Nx strains, including from clade 2.3.4.4b. Results Low but detectable serum antibody titres against H5 and H7 avian influenza HA were observed in donors. The frequency of memory B cells with cross‐reactive recognition of H5 and H7 HA was below 0.13% and two‐ to five‐fold lower than populations of seasonal HA‐specific B cells. Boosting of B‐cell responses against clade 2.3.4.4b H5Nx HA following seasonal immunisation was sporadic with only three of 19 individuals showing an increased population of probe‐positive cells. Cross‐reactive B cells generally expressed immunoglobulins drawn from variable heavy chain genes associated with HA stem recognition. CD4+ T‐cell responses towards H5 HA were weakly boosted with little increase in circulating T follicular helper cell populations. Conclusion These findings highlight the need for avian influenza‐specific vaccine products to bolster immunity in human populations. Such vaccines could aid pre‐pandemic preparedness by expanding baseline frequencies of avian influenza‐specific memory lymphocytes. In this study, we found low but detectable antibody responses against H5 and H7 avian influenza hemagglutinin in unexposed human cohorts. B‐ and T‐cell responses against these avian‐origin hemagglutinins were poorly boosted by seasonal influenza vaccination.

Clinical administration of Interferon α (IFNα) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8 T cell responses during IFNα therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFNα subtype 2. To date, the immunomodulatory roles of the remaining 10-13 IFNα subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8 T cell responses were influenced to various extents by individual IFNα subtypes. IFNα4, 6, and 9 had the strongest effects on CD8 T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFNα subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8 T cells or DCs. Thus, precise modulation of virus-specific CD8 T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFNα subtypes.

Accumulating evidence has shown the protective role of CD8+ T cells in vaccine-induced immunity against Mycobacterium tuberculosis (Mtb) despite controversy over their role in natural immunity. However, the current vaccine BCG is unable to induce sufficient CD8+ T cell responses, especially in the lung. Sendai virus, a respiratory RNA virus, is here engineered firstly as a novel recombinant anti-TB vaccine (SeV85AB) that encodes Mtb immuno-dominant antigens, Ag85A and Ag85B. A single mucosal vaccination elicited potent antigen-specific T cell responses and a degree of protection against Mtb challenge similar to the effect of BCG in mice. Depletion of CD8+ T cells abrogated the protective immunity afforded by SeV85AB vaccination. Interestingly, only SeV85AB vaccination induced high levels of lung-resident memory CD8+ T (TRM) cells, and this led to a rapid and strong recall of antigen-specific CD8+ T cell responses against Mtb challenge infection. Furthermore, when used in a BCG prime-SeV85AB boost strategy, SeV85AB vaccine significantly enhanced protection above that seen after BCG vaccination alone. Our findings suggest that CD8+ TRM cells that arise in lungs responding to this mucosal vaccination might help to protect against TB, and SeV85AB holds notable promise to improve BCG’s protective efficacy in a prime-boost immunization regimen. Hu et al. demonstrate that a Sendai virus-based anti-tuberculosis vaccine, SeV85AB, establishes strong CD8+ resident memory T (TRM) cell immunity in the lung parenchyma when delivered intranasally. This strategy compensates for the weakness of BCG in a prime-boost model and results in markedly enhanced protection against Mycobacterium tuberculosis challenge.

Antigen self-assembly nanovaccines advance the minimalist design of therapeutic cancer vaccines, but the issue of inefficient cross-presentation has not yet been fully addressed. Herein, we report a unique approach by combining the concepts of “antigen multi-copy display” and “calcium carbonate (CaCO 3 ) biomineralization” to increase cross-presentation. Based on this strategy, we successfully construct sub-100 nm biomineralized antigen nanosponges (BANSs) with high CaCO 3 loading (38.13 wt%) and antigen density (61.87%). BANSs can be effectively uptaken by immature antigen-presenting cells (APCs) in the lymph node upon subcutaneous injection. Achieving efficient spatiotemporal coordination of antigen cross-presentation and immune effects, BANSs induce the production of CD4 + T helper cells and cytotoxic T lymphocytes, resulting in effective tumor growth inhibition. BANSs combined with anti-PD-1 antibodies synergistically enhance anti-tumor immunity and reverse the tumor immunosuppressive microenvironment. Overall, this CaCO 3 powder-mediated biomineralization of antigen nanosponges offer a robust and safe strategy for cancer immunotherapy.

Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C‐type lectin Langerin/CD207 are cross‐presented to CD8 + T cells in vivo . We investigated the relative roles of Langerhans cells (LCs) and Langerin + dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti‐CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)‐coupled anti‐Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin + dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8 + T‐cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross‐presentation to CD8 + T cells. Langerin/OVA combined with imiquimod could not prime CD8 + T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin + dDCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8 + T‐cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs. Synopsis The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo . Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin. Both Langerin + dermal DCs and epidermal Langerhans cells (LC) can present exogenous antigen to CD8 + T cells. Langerin + dermal DCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8 + T‐cell priming. Specific adjuvants can be used to independently harness the different potential of distinct DC subsets simultaneously targeted by an antigen. Treatment of skin with imiquimod, an agonist of TLR7, does not result in potent immune responses when the antigen is targeted to Langerin, thereby relativizing the paradigm stating that mature DCs always promote immunity. Graphical Abstract The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo . Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.

Background Human adenoviruses (HAdVs) frequently cause common respiratory or gastrointestinal infections among children, adults, individuals with immune deficiencies, and other vulnerable populations with varying degree of symptoms, ranging from mild to server, and in some cases, even fatalities. Despite the significant clinical impact of HAdVs, there is currently no approved vaccine available. Methods This study explores the potential of the adenovirus type 5 fiber knob (Ad5-FK) to stimulate the production of Ad-specific neutralizing antibodies and T-cell responses in mice. Based on structure predictions, we first expressed Ad5-FK in E. coli and confirmed the assembly of FK into its trimeric form. After testing the binding capability of the trimeric FK to susceptible cells, the immunogenicity of the protein in combination with the c-di-AMP adjuvant was assessed in BALB/c mice. Results The purified Ad5-FK exhibited self-trimerization and maintained correct conformation akin to the authentic FK structure. This facilitated effective binding to susceptible HEK293 cells. Notably, the protein demonstrated significant inhibition of HEK293 cells infection by rAd5-GFP. Immunization of BALB/c mice with Ad5-FK, or Ad5-FK mixed with c-di-AMP yielded FK-specific antibodies with potent neutralization capacity. Significantly, Ad5-FK was found to elicit a vigorous CD4 + T-cell response in the immunized mice. Conclusion Our findings underscore the efficacy of FK-based vaccine in eliciting anti-Ad humoral immune response and CD4 T-cell immune reactions essential for protection against viral infections.