Explore the vast range of titles available.

Although guidelines for COVID-19 additional vaccination strategies generally prioritise people with advanced HIV infection, recommendations vary globally, with some countries recommending an annual vaccination for all people with HIV (PWH), while others restrict this to PWH with a CD4.sup.+ T-cell count < 200 cells per [micro]L. We conducted a prospective cohort study in 448 adult PWH. The primary outcome was the SARS-CoV-2 spike (S1)-specific IgG antibody level at 1, 6, 12, 18, and 24 months after completing a primary COVID-19 vaccination series (two doses of BNT162b2, mRNA-1273, or ChAdOx1-S, or one dose of Ad26.COV2.S). We compared the antibody kinetics over two years between PWH with a baseline CD4.sup.+ T-cell count < 200 cells per [micro]L (n = 16) vs. [greater than or equal to] 200 cells per [micro]L (n = 432) with a mixed-effects model. Secondary outcomes included variables associated with the kinetics of S1-specific antibody levels and the incidence of breakthrough infections. The median most recent CD4.sup.+ T-cell count prior to primary vaccination was 140 (IQR 80-165) in the < 200 cells per [micro]L group, and 688 (IQR 520-899) in the [greater than or equal to] 200 cells per [micro]L group at the time of primary vaccination. S1-specific antibodies were lower in PWH with a CD4.sup.+ T-cell count < 200 vs. [greater than or equal to] 200 cells per [micro]L during the two-year follow-up, with predicted S1-specific antibody levels of 514 (95% CI 456-578) vs. 2758 (95% CI 1488-5110) BAU per mL at 12 months (p < 0.001) and 839 (95% CI 732-959) vs. 3505 (95% CI 1712-7175) BAU per mL at 24 months (p < 0.001). The overall incidence of SARS-CoV-2 infections was 55% and comparable between groups. A CD4.sup.+ T-cell count < 200 cells per [micro]L, higher age, and a vector-based primary vaccination series were negatively associated with S1-specific antibody levels over time. Long-term humoral responses were lower in PWH with a CD4.sup.+ T-cell count < 200 cells per [micro]L compared to those with a CD4.sup.+ T-cell count [greater than or equal to] 200 cells per [micro]L. National COVID-19 vaccine guidelines recommending booster vaccines for all PWH, should therefore specifically emphasise the need for booster vaccines in those with a CD4.sup.+ T-cell count < 200 cells per [micro]L.

A safe, highly immunogenic multivalent vaccine to protect against all nine serotypes of African horse sickness virus (AHSV), will revolutionise the AHS vaccine industry in endemic countries and beyond. Plant-produced AHS virus-like particles (VLPs) and soluble viral protein 2 (VP2) vaccine candidates were developed that have the potential to protect against all nine serotypes but can equally well be formulated as mono- and bi-valent formulations for localised outbreaks of specific serotypes. In the first interferon [alpha]/[beta] receptor knock-out (IFNAR.sup.-/-) mice trial conducted, a nine-serotype (nonavalent) vaccine administered as two pentavalent (5 [mu]g per serotype) vaccines (VLP/VP2 combination or exclusively VP2), were directly compared to the commercially available AHS live attenuated vaccine. In a follow up trial, mice were vaccinated with an adjuvanted nine-serotype multivalent VP2 vaccine in a prime boost strategy and resulted in the desired neutralising antibody titres of 1:320, previously demonstrated to confer protective immunity in IFNAR.sup.-/- mice. In addition, the plant-produced VP2 vaccine performed favourably when compared to the commercial vaccine. Here we provide compelling data for a nonavalent VP2-based vaccine candidate, with the VP2 from each serotype being antigenically distinguishable based on LC-MS/MS and ELISA data. This is the first preclinical trial demonstrating the ability of an adjuvanted nonavalent cocktail of soluble, plant-expressed AHS VP2 proteins administered in a prime-boost strategy eliciting high antibody titres against all 9 AHSV serotypes. Furthermore, elevated T helper cells 2 (T.sub.h 2) and T.sub.h 1, indicative of humoral and cell-mediated memory T cell immune responses, respectively, were detected in mouse serum collected 14 days after the multivalent prime-boost vaccination. Both T.sub.h 2 and T.sub.h 1 may play a role to confer protective immunity. These preclinical immunogenicity studies paved the way to test the safety and protective efficacy of the plant-produced nonavalent VP2 vaccine candidate in the target animals, horses.

T cell repertoire diversity and clonotype follow-up in vaccination, cancer, infectious and immune diseases represent a major challenge owing to the enormous complexity of the data generated. Here we describe a next generation methodology, which combines 5′RACE PCR, 454 sequencing and, for analysis, IMGT, the international ImMunoGeneTics information system (IMGT), IMGT/HighV-QUEST web portal and IMGT-ONTOLOGY concepts. The approach is validated in a human case study of T cell receptor beta (TRB) repertoire, by chronologically tracking the effects of influenza vaccination on conventional and regulatory T cell subpopulations. The IMGT/HighV-QUEST paradigm defines standards for genotype/haplotype analysis and characterization of IMGT clonotypes for clonal diversity and expression and achieves a degree of resolution for next generation sequencing verifiable by the user at the sequence level, while providing a normalized reference immunoprofile for human TRB. Dynamic changes in T cell repertoire underlie immune responses during infection, allergy, autoimmunity and cancer. Here, Li et al . present a workflow for high throughput sequencing and analysis of T cell receptor sequences, and use it to monitor the T cell response to influenza vaccination in a human patient.

ObjectiveHepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice.DesignWe harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings.ResultsTumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis.ConclusionThere is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.

Lymph nodes (LNs) are strategically positioned at dedicated sites throughout the body to facilitate rapid and efficient immunity. Central to the structural integrity and framework of LNs, and the recruitment and positioning of leukocytes therein, are mesenchymal and endothelial lymph node stromal cells (LNSCs). Advances in the last decade have expanded our understanding and appreciation of LNSC heterogeneity, and the role they play in coordinating immunity has grown rapidly. In this review, we will highlight the functional contributions of distinct stromal cell populations during LN development in maintaining immune homeostasis and tolerance and in the activation and control of immune responses. Turley and Krishnamurty review new insights into lymph node stromal cells, a heterogeneous cell population that serves distinct functions during development, in maintaining lymphocyte homeostasis, and in coordinating immune responses.

Kawasaki disease (KD) is a medium vessel vasculitis that affects young children. Despite extensive research over the last 50 years, the etiology of KD remains an enigma. Seasonal change in wind patterns was shown to have correlation with the epidemics of KD in Japan. Occurrence of disease in epidemiological clusters, seasonal variation, and a very low risk of recurrence suggest that KD is triggered by an infectious agent. The identification of oligoclonal IgA response in the affected tissues suggests an antigen-driven inflammation. The recent identification of a viral antigen in the cytoplasm of bronchial ciliated epithelium also favors infection as the main trigger for KD. Pointers that suggest a genetic basis of KD include a high disease prevalence in North-East Asian populations, a high risk among siblings, and familial occurrence of cases. Dysregulated innate and adaptive immune responses are evident in the acute stages of KD. In addition to the coronary wall inflammation, endothelial dysfunction and impaired vascular remodeling contribute to the development of coronary artery abnormalities (CAAs) and thrombosis. Genetic aberrations in certain intracellular signaling pathways involving immune effector functions are found to be associated with increased susceptibility to KD and development of coronary artery abnormalities (CAAs). Several susceptible genes have been identified through genome-wide association studies (GWAS) and linkage studies (GWLS). The genes that are studied in KD can be classified under 4 major groups—enhanced T cell activation (ITPKC, ORAI1, STIM1), dysregulated B cell signaling (CD40, BLK, FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta signaling (TGFB2, TGFBR2, MMP, SMAD). The review aims to highlight the role of several genetic risk factors that are linked with the increased susceptibility to KD.

Turner syndrome (TS) is a female phenotypic condition characterized by one or more typical clinical features and the partial or complete absence of a second X chromosome as determined by karyotype analysis. TS, among the most common chromosomal abnormalities, has an estimated prevalence of approximately 1 in 2,500 live-born females, with ethnic and racial differences. TS encompasses a wide array of medical challenges, including cardiovascular, endocrine, autoimmune, and mental health issues, as well as a heightened cancer risk. The somatic stigmata of TS are thought to arise from haploinsufficiency of the X chromosomes. This review explores the lifelong medical challenges and immunogenetics of individuals with TS and aimed to investigate strategies for preventing and managing TS while considering the implications of immunogenetics.

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org . An analysis of single-cell transcriptomics datasets from different tissues shows that ACE2 and TMPRSS2 are co-expressed in respiratory, corneal and intestinal epithelial cell populations, and that respiratory expression of ACE2 is associated with genes involved in innate immunity.

SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024]. The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.

Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score (TIGS), which combines tumor mutational burden (TMB) and an expression signature of the antigen processing and presenting machinery (APM). In both correlation with pan-cancer ICI objective response rates (ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor-inherent biomarker for ICI-response prediction. In the last decade a new kind of cancer therapy, called immunotherapy, has changed how doctors treat cancer patients. These therapies mean that previously incurable cancers, including some skin and lung cancers, can now sometimes be cured. Immunotherapy does this by activating the patient’s own immune system so that it will attack the cancer cells. But for this to work, the cancer cells, much like invading bacteria or viruses, need to be recognized as foreign. Cancer cells contain many DNA mutations that cause the cell to make mutated proteins it would not normally make. These proteins betray the cancer cells as foreign to the immune system. The extent to which cancer cells make mutated proteins – also called the ‘tumor mutational burden’ – can sometimes predict whether a patient will respond to immunotherapy. In general, patients with a high mutational burden respond well to immunotherapy, but overall fewer than one in five cancer patients are cured by this treatment. An important question is whether there are better ways of predicting if a cancer patient will respond to immunotherapy. Wang et al. have addressed this problem by adding a second variable to the prediction. Not only do cancer cells have to make mutated proteins, but these proteins also have to be ‘seen’ by immune cells. Cancer cells, like normal cells, have mechanisms to present protein fragments to immune cells. Wang et al. hypothesized that patients with a high mutational burden would not respond to immunotherapy if they were lacking the machinery required for presenting protein fragments. The experiments revealed that measuring both tumor mutational burden and the levels of the machinery that presents protein fragments resulted in better predictions of patients’ responses to immunotherapy than measuring tumor mutational burden alone. Additionally, this new way of predicting responses to immunotherapy was successful across many different cancer types. The combined measurement of these two variables could be applied in clinical practice as a way to predict cancer patients’ response to immunotherapy. This should allow doctors to determine which course of treatment will work best for a specific patient. The results also suggest that inducing tumor cells to produce more of the machinery that presents protein fragments to the immune system could increase their responsiveness to immunotherapy. In the future, predicting how well a patient will respond to immunotherapy could become even more accurate by incorporating additional variables.