Explore the vast range of titles available.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) pandemic is a serious global threat until we identify the effective preventive and therapeutic strategies. SARS-CoV-2 infection is characterized by various immunopathological consequences including lymphocyte activation and dysfunction, lymphopenia, cytokine storm, increased level of neutrophils, and depletion and exhaustion of lymphocytes. Considering the low level of antibody-mediated protection during coronavirus infection, understanding the role of T cell for long-term protection is decisive. Both CD4 + and CD8 + T cell response is imperative for cell-mediated immune response during COVID-19. However, the level of CD8 + T cell response reduced to almost half as compared to CD4 + after 6 months of infection. The long-term protection is mediated via generation of immunological memory response during COVID-19. The presence of memory CD4 + T cells in all the severely infected and recovered individuals shows that the memory response is predominated by CD4 + T cells. Prominently, the antigen-specific CD4 + and CD8 + T cells are specifically observed during day 0 to day 28 in COVID-19-vaccinated individuals. However, level of antigen-specific T memory cells in COVID-19-vaccinated individuals defines the long-term protection against forthcoming outbreaks of SARS-CoV-2.

Clinical trials and real-world evidence on COVID-19 vaccines have shown their effectiveness against severe disease and death but the durability of protection remains unknown. We analysed the humoral and T-cell immune responses in 110 healthcare workers (HCWs) vaccinated according to the manufacturer’s recommended schedule of dose 2 three weeks after dose 1 from a prospective on-going cohort in early 2021, 3 and 6 months after full vaccination with the BNT162b2 mRNA vaccine. Anti-RBD IgG titres were lower in HCWs over 60 years old 3 months after the second dose (p=0.03) and declined in all the subjects between 3 and 6 months with a median percentage change of -58.5%, irrespective of age and baseline comorbidities. Specific T-cell response measured by IGRA declined over time by at least 42% (median) in 91 HCWs and increased by 33% (median) in 17 others. Six HCWs had a negative T-cell response at 6 months. Ongoing follow-up should provide correlates of long-term protection according to the different immune response profiles observed. COVIDIM study was registered under the number NCT04896788 on clinicaltrials.gov.

Preexisting immunity against adeno-associated virus (AAV) is a major challenge facing AAV gene therapy, resulting in the exclusion of patients from clinical trials. Accordingly, proper assessment of anti-AAV immunity is necessary for understanding clinical data and for product development. Previous studies on anti-AAV prevalence lack method standardization, rendering the assessment of prevalence difficult. Addressing this need, we used clinical assays that were validated according to guidelines for a comprehensive characterization of anti-AAV1, -AAV2, -AAV5, and -AAV8 immunity in large international cohorts of healthy donors and patients with hemophilia B. Here, we report a higher than expected average prevalence for anti-AAV8 (∼40%) and anti-AAV5 (∼30%) neutralizing antibodies (NAbs), which is supported by strongly correlating anti-AAV IgG antibody titers. A similar anti-AAV8 NAb prevalence was observed in hemophilia B patients. In addition, a high co-prevalence of NAbs against other serotypes makes switching to gene therapy using another serotype difficult. As anti-AAV T cell responses are believed to influence transduction, we characterized anti-AAV T cell responses using interleukin-2 (IL-2) and interferon-γ (IFN-γ) ELISpot assays, revealing a similar prevalence of IFN-γ responses (∼20%) against different serotypes that did not correlate with NAbs. These data, along with the long-term stability of NAbs, emphasize the need to develop strategies to circumvent anti-AAV immunity.

For the development of new adenovirus (AdV)-based vectors, it is important to understand differences in immunogenicity. In a side-by-side in vitro analysis, we evaluated the effect of 40 AdV types covering human AdV (HAdV) species A through G on the expression of 11 activation markers and the secretion of 12 cytokines by AdV-transduced dendritic cells, and the effect on CD8 + T cell proliferation capacity. We found that the expression of activation markers and cytokines differed widely between the different HAdV types, and many types were able to significantly impair the proliferation capacity of CD8 + T cells. Univariate and multivariate regression analyses suggested an important role of type I interferons in mediating this suppression of CD8 + T cells, which we confirmed experimentally in a proliferation assay using a type I interferon receptor blocking antibody. Using Bayesian statistics, we calculated a prediction model that suggests HAdV types HAdV-C1, -D8, -B7, -F41, -D33, -C2, -A31, -B3 and -D65 as the most favorable candidates for vaccine vector development.

COVID-19 vaccines have significantly decreased the number of severe cases of the disease, but the virus circulation remains important, and questions about the need of new vaccination campaigns remain unanswered. The individual’s protection against SARS-CoV-2 infection is most commonly measured by the level and the neutralizing capacity of antibodies produced against SARS-CoV-2. T cell response is a major contributor in viral infection, and several studies have shown that cellular T cell response is crucial in fighting off SARS-CoV-2 infection. Actually, no threshold of protective immune response against SARS-CoV2 infection has been identified. To better understand SARS-CoV-2-mediated immunity, we assessed both B cell (measuring anti-Spike IgG titer and neutralization capacity) and T cell (measuring IFNγ release assay after specific SARS-CoV2 stimulation) responses to SARS-CoV-2 vaccination with or without virus encounter in a cohort of 367 working volunteers. Vaccinated individuals who had previously been infected had a stronger and more lasting immunity in comparison to vaccinated individuals naive to infection whose immunity started to decline 3 months after vaccination. IFNγ release ≥ 0.285 IU/mL and anti-Spike IgG antibodies ≥ 244 BAU/mL were associated with a sufficient immune response following vaccination preventing future infections. Individuals with comorbidities had a lower chance of reaching the protective thresholds of T cell and B cell responses as identified in multivariate analysis. A combined B cell and T cell analysis of immune responses to determine protective thresholds after SARS-CoV-2 vaccination will allow us to identify individuals in need of a booster vaccine dose, particularly in comorbid subjects.

Using nanoparticles (NPs) as a platform for multivalent antigen display is an effective strategy to increase the immunogenicity of subunit vaccines, which can induce high levels of humoral and cellular immunity. In addition, antigens that target antigen-presenting cells (APCs) can further increase their immunogenicity. To date, there are no commercially available ASFV vaccines available worldwide. The present study developed a dendritic cell (DC)-targeting ASFV biomimetic nanovaccine. First, a high-affinity and specific nanobody (Nb) targeting DCs was screened and expressed in tandem with B and T-cell epitopes of highly immunogenic p30, p54, p72, pB602L, and CD2V proteins of ASFV (Nb-rAg). The Nb-rAg complexes were then loaded onto azabisphosphonate-terminated phosphorus dendrimers (PPHs) to construct PPH-Nb-rAg NPs, which were subsequently coated with ASFV-infected activated porcine alveolar macrophage (PAM) membranes to prepare the PPH-Nb-rAg@PM biomimetic nanovaccine. Finally, the immune efficacy of the nanovaccine was evaluated in mice. Notably, compared with the PBS, rAg, Nb-rAg, and PPH-Nb-rAg immunization groups, the PPH-Nb-rAg@PM immunization group exhibited stronger ASFV antigen-specific humoral and cellular immune responses. Single-cell RNA sequencing (scRNA-seq) revealed that immunization with PPH-Nb-rAg@PM increased the proportions of B cells, T cells, NK cells, plasma cells, and macrophages in the mouse spleen. Further analysis revealed that PPH-Nb-rAg@PM immunization increased the numbers of memory B cells and plasma cells in the mouse spleen, and the numbers of CD4 + T cells, CD8 + T cells and NK cells also increased compared with those in the control group. These results suggest that PPH-Nb-rAg@PM is a promising and effective candidate vaccine against ASFV. Graphical abstract

Tumor‐specific CD8+ T cells play a pivotal role in anti‐tumor immunity. Here, we review the heterogeneity of CD8+ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8+ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8+ T cells, whereas the identification of TCF1+ stem‐like CD8+ T cells has highlighted their importance in anti‐tumor immunity. During tumor progression, TCF1+ stem‐like CD8+ T cells differentiate into cytotoxic Tim‐3+ terminally differentiated CD8+ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8+ T cell responses and showed that blocking CD69 function, either through the administration of anti‐CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim‐3+ terminally differentiated CD8+ T cells in both tumor‐draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti‐tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti‐tumor CD8+ T cell response. This review summarizes the current understanding of cytotoxic CD8+ T cell subset differentiation under tumor progression and highlights the crucial role of chronic CD8+ T cell responses in anti‐tumor immunity. CD69 is an important regulator of chronic CD8+ T cell response that contributes to the induction of the Tox gene via calcineurin/NFAT signaling.

To address the COVID-19 pandemic, diverse vaccination strategies, including homologous and heterologous schedules, were employed to enhance immune protection. This study evaluates the long-term humoral and cellular immune responses in individuals vaccinated with homologous (ChAdOx1-S/ChAdOx1-S [ChAd/ChAd]) and heterologous (ChAdOx1-S/BNT162b2 [ChAd/BNT]) schedules, followed by a third-dose mRNA booster (BNT162b2 [BNT] or mRNA-1273). Anti-Spike IgG titers were measured at 9-, 12-, and 21-months post-primary vaccination (corresponding to 3-, 6-, and 15-months post-booster), while SARS-CoV-2-specific B- and T-cell responses were assessed at 21-months post-booster. Antibody titers declined by 12-months post-primary vaccination, regardless of the third dose administered, and increased significantly by 21-months, potentially due to a fourth dose (BNT or mRNA-1273) or natural SARS-CoV-2 infection. The heterologous ChAd/BNT schedule elicited a stronger and more durable immune response than the homologous ChAd/ChAd, as evidenced by higher anti-Spike IgG titers, increased IgM-/IgG+ memory B-cell activation, and enhanced cytotoxic CD8+ T-cell cytokine expression in infected individuals. SARS-CoV-2 infection further boosted humoral and cellular responses, with infected individuals showing higher anti-Spike IgG titers and greater CD8+ T-cell activation compared to uninfected individuals. These findings highlight the benefits of heterologous vaccination schedules and the role of infection-driven immune activation, providing valuable insights for optimizing vaccination strategies to improve long-term immunity against SARS-CoV-2.

A number of immunotherapies, in particular immune checkpoint targeting antibodies and adoptive T-cell therapies, are starting to transform the treatment of advanced cancers. The likelihood to respond to these immunotherapies differs strongly across tumor types, with response rates for checkpoint targeting being the highest in advanced melanoma, renal cell cancer and non-small cell lung cancer. However, also non-responsiveness is observed, indicating the presence of intrinsic resistance or naturally acquired resistance. In addition, a subgroup of patients that do initially respond to immunotherapy will later recur, thereby also pointing towards a role of therapy-induced acquired resistance. Here, we review our current understanding of both intrinsic and acquired resistance mechanisms in cancer immunotherapy, and discuss potential strategies to overcome them. •Intrinsic and acquired immune resistance determine the efficiency of cancer immunotherapy.•An effective immune response requires T-cell activation, homing and effector function.•The development of immune resistance can be evaluated on the basis on these three requirements.•A personalized approach to assess immune resistance is likely to increase the efficacy of immunotherapy.