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A Correction to this paper has been published: https://doi.org/10.1038/s41591-021-01248-2., Author(s): Joseph A. Fraietta [sup.1] [sup.2] [sup.3], Simon F. Lacey [sup.1] [sup.2] [sup.3], Elena J. Orlando [sup.4], Iulian Pruteanu-Malinici [sup.4], Mercy Gohil [sup.2], Stefan Lundh [sup.2], Alina C. Boesteanu [sup.2], [...]

This report describes the status of introduction of 8 WHO-recommended new and underutilized vaccines, comprising 10 individual vaccine antigens By 2021, 33 of 194 countries (17%) provided all 10 WHO-recommended antigens as part of their routine immunization schedules; only 1 low-income (LIC) had introduced all the recommended vaccines. Universal hepatitis B birth dose (HepB-BD); human papillomavirus (HPV) vaccine; rotavirus (RV) vaccine; and diphtheria, tetanus and pertussis-containing vaccine first booster dose have been introduced by 57%, 59%, 60% and 72% of all countries, respectively. Pneumococcal conjugate vaccine (PCV), rubella-containing vaccine (RCV), measles-containing vaccine second dose (MCV2) and Haemophilus influenzae type b (Hib) vaccine have been introduced by 78%, 89%, 94% and 99% of countries, respectively. The annual rate of new vaccine introductions decreased precipitously when the COVID-19 pandemic started, from 48 in 2019 to 15 in 2020, before rising to 26 in 2021. To achieve IA2030 targets, new and underutilized vaccine introductions are urgently needed for universal, equitable access to all recommended vaccines. Le present rapport fait le point sur l'introduction de 8 vaccins nouveaux et sous-utilises recommandes par l'OMS (contenant collectivement 10 antigenes), dont 5 sont administres apres la premiere annee de vie. En 2021, 33 pays sur 194 (17%) avaient inclus l'ensemble des 10 antigenes recommandes par l'OMS dans leur calendrier de vaccination systematique; seul 1 pays a faible revenu avait introduit tous les vaccins recommandes. La dose de naissance universelle du vaccin contre l'hepatite B (DN-HepB), le vaccin contre le papillomavirus humain (PVH), le vaccin antirotavirus et la premiere dose de rappel du vaccin contre la diphterie, le tetanos et la coqueluche (quatrieme dose de DTC [DTC4]) avaient ete introduits par 57%, 59%, 60% et 72% des pays, respectivement. Le vaccin antipneumococcique conjugue (VPC), le vaccin a valence rubeole (RCV), la deuxieme dose de vaccin a valence rougeole (MCV2) et le vaccin contre Haemophilus influenzae type b (Hib) avaient ete introduits respectivement par 78%, 89%, 94% et 99% des pays. Le nombre annuel d'introductions de nouveaux vaccins a brusquement chute au debut de la pandemie de COVID-19, passant de 48 en 2019 a 15 en 2020, avant de remonter a 26 en 2021. Pour atteindre les objectifs du Programme IA2030, il est urgent de poursuivre les introductions de vaccins nouveaux et sous-utilises afin de garantir un acces universel et equitable a tous les vaccins recommandes., Introduction The global Immunization Agenda 2021-2030 (IA2030) envisions a world in which, by increasing equitable access to and use of new and existing vaccines, everyone everywhere fully benefits. IA2030, endorsed [...]

Objective To evaluate the implementation of new operational workflows for simultaneous screening of coronavirus disease 2019 (COVID-19) and tuberculosis at four high-volume COVID-19 testing centres located in tertiary hospitals in Mumbai, India. Methods Each centre already offering antigen-detecting rapid diagnostic tests were equipped with a rapid molecular testing platform for COVID-19 and tuberculosis, sufficient laboratory staff, and reagents and consumables for screening. Using a verbal tuberculosis questionnaire, a patient follow-up agent screened individuals visiting the COVID-19 testing centres. Presumptive tuberculosis patients were asked to provide sputum samples for rapid molecular testing. Subsequently, we reversed our operational workflow to also screen patients visiting tuberculosis outpatient departments for COVID-19, using rapid diagnostic tests. Results From March to December 2021, we screened 14 588 presumptive COVID-19 patients for tuberculosis, of whom 475 (3.3%) were identified as having presumptive tuberculosis. Of these, 288 (60.6%) were tested and 32 individuals (11.1%) were identified as tuberculosis positive (219 cases per 100 000 individuals screened). Of the tuberculosis- positive individuals, three had rifampicin-resistant tuberculosis. Among the remaining 187 presumptive tuberculosis cases not tested, 174 reported no symptoms at follow-up and 13 individuals either refused testing or could not be traced. Of the 671 presumptive tuberculosis cases screened for COVID-19, 17 (2.5%) were positive by antigen rapid diagnostic tests, and five (0.7%) who tested negative, later tested positive on the molecular testing platform (2483 COVID-19 cases per 100 000 individuals screened). Conclusion Simultaneous screening for COVID-19 and tuberculosis in India is operationally feasible and can improve real-time on-site detection of COVID-19 and tuberculosis. [Phrase omitted] Depistage simultane de la COVID-19 et de la tuberculose en Inde Objectif Evaluer la mise en reuvre de nouveaux processus operationnels pour le depistage simultane de la maladie a coronavirus 2019 (COVID-19) et de la tuberculose au sein de quatre grands centres de depistage de la COVID-19 situes dans des hopitaux tertiaires a Mumbai, en Inde. Methodes Une plateforme de tests moleculaires rapides pour la COVID-19 et la tuberculose, des agents de laboratoire en suffisance ainsi que des reactifs et consommables destines au depistage ont ete mis a la disposition de chaque centre proposant deja des tests de diagnostic rapide bases sur la detection d'antigenes. Par le biais d'un questionnaire oral sur la tuberculose, un agent charge du suivi des patients a selectionne des individus se rendant dans les centres de depistage de la COVID-19. Les patients potentiellement atteints d'une tuberculose ont ete invites a fournir des echantillons d'expectorations en vue de realiser des tests moleculaires rapides. Ensuite, nous avons inverse notre processus operationnel et utilise des tests de diagnostic rapide afin de depister la COVID-19 chez les patients ayant effectue une visite dans des cliniques externes dediees a la tuberculose. Resultats Entre mars et decembre 2021, 14 588 cas presumes de COVID-19 ont ete retenus pour un depistage de la tuberculose; 475 (3,3%) d'entre eux presentaient une suspicion de tuberculose. Au sein de cette categorie, 288 (60,6%) individus ont ete testes, dont 32 (11,1%) se sont reveles positifs a la tuberculose (219 cas pour 100 000 individus selectionnes). Sur l'ensemble de ces individus positifs, trois souffraient d'une tuberculose resistant a la rifampicine. Parmi les 187 cas presumes de tuberculose restants qui n'ont pas ete testes, 174 n'ont declare aucun symptome lors du suivi et 13 ont refuse d'etre testes ou n'ont pas ete retrouves. D'autre part, sur les 671 cas presumes de tuberculose soumis a un depistage de la COVID-19, 17 (2,5%) ont obtenu un resultat positif lors des tests de diagnostic rapide bases sur la detection d'antigenes et cinq (0,7%) ont obtenu un resultat negatif, avant d'obtenir un resultat positif via la plateforme de tests moleculaires (2483 cas de COVID-19 pour 100 000 individus selectionnes). Conclusion Le depistage simultane de la COVID-19 et de la tuberculose en Inde est non seulement realisable sur le plan operationnel, mais peut aussi ameliorer la detection de la COVID-19 et de la tuberculose sur site et en temps reel. Examen de deteccion simultanea de COVID-19 y tuberculosis, India Objetivo Evaluar la implementacion de nuevos flujos de trabajo operativos para llevar a cabo examenes de deteccion simultanea de la enfermedad de coronavirus 2019 (COVID-19) y de tuberculosis en cuatro centros de pruebas de alta incidencia de COVID-19, ubicados en hospitales terciarios de Mumbai (India). Metodos Se equipo a cada uno de los centros que ya ofrecia pruebas de diagnostico rapido de deteccion de antigenos con una plataforma de pruebas rapidas moleculares para detectar COVID-19 y tuberculosis. Asimismo, se les doto de suficiente personal de laboratorio, de reactivos y de material para realizar los examenes de deteccion. Mediante un cuestionario oral sobre tuberculosis, la persona responsable del seguimiento de pacientes evaluo a las personas que visitaban los centros de pruebas de COVID-19. Se solicito a los pacientes que presuntamente padecian tuberculosis que proporcionaran muestras de esputo para realizar pruebas rapidas moleculares. Posteriormente, utilizando pruebas de diagnostico rapido, se cambio el flujo de trabajo operativo con el fin de realizar tambien examenes de deteccion de COVID-19 a pacientes que visitaban centros ambulatorios de tuberculosis. Resultados De marzo a diciembre de 2021, se realizaron examenes de deteccion de tuberculosis a 14 588 pacientes que presuntamente padecian COVID-19; entre estos pacientes, se identifico que 475 (3,3%) sufria una presunta tuberculosis. Entre estos pacientes, se realizaron pruebas a 288 (60,6%), llegandose a detectar tuberculosis positiva (219 casos por cada 100 000 individuos examinados) en 32 pacientes (11,1%). Entre los individuos con tuberculosis positiva, tres de ellos presentaban tuberculosis resistente a la rifampicina. De los 187 casos restantes no sometidos a pruebas y con presunta tuberculosis, 174 individuos informaron sobre la ausencia de sintomas en el seguimiento, y las 13 personas restantes o bien se negaron a hacerse las pruebas o no fue posible realizar su seguimiento. De los 671 casos con presunta tuberculosis en los que se llevo a cabo un examen de deteccion de COVID-19, 17 personas (2,5%) dieron positivo en pruebas de diagnostico rapido de antigenos, y cinco (0,7%) que dieron negativo en un principio arrojaron posteriormente un resultado positivo en la plataforma de pruebas moleculares (2483 casos de COVID-19 por cada 100 000 individuos examinados). Conclusion El examen de deteccion simultanea de COVID-19 y tuberculosis de la India es factible a nivel operativo y puede mejorar la deteccion de casos de COVID-19 y tuberculosis in situ en tiempo real., Introduction The overwhelming need for health care generated by the coronavirus disease 2019 (COVID-19) pandemic had a catastrophic effect on health-care programmes, particularly outpatient tuberculosis screening and detection. Before the [...]

BACKGROUND. HIV-1-infected [CD4.sup.+] T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing. METHODS. In this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous [CD8.sup.+] T cells. RESULTS. The proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous [CD8.sup.+] T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene. CONCLUSIONS. We provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence. FUNDING. Office of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research., Introduction Shortly after transmission, HIV-1 infection establishes a persistent reservoir of latently infected [CD4.sup.+] T cells (1-4). Although antiretroviral therapy halts viral replication and prevents disease progression, the long half-life [...]

* Context.--Coronavirus disease 2019 (COVID-19) rapid antigen tests generate intrinsically fast, inherently spatial, and immediately actionable results. They quickly confirm COVID-19, but weakly rule out infection. Test performance depends on prevalence and testing protocol. Both affect predictive values. Objectives.--To use original mathematics and visual logistics for interpreting COVID-19 rapid antigen test performance patterns, gauge the influence of prevalence, and evaluate repeated testing. Design.--Mathematica and open access software helped graph relationships, perform recursive computations, and compare performance patterns. PubMed retrieved articles addressing endemic COVID-19 were reviewed. Results.--Tiered sensitivity/specificity comprise the following: T1 (90%/95%), T2 (95%/97.5%), and T3 (100%/ >99%). Performance of self-tests and home antigen tests with US Food and Drug Administration Emergency Use Authorization peaks in low prevalence. Fall-off in performance appears with increasing prevalence because sub-optimal sensitivity creates false negatives. The rate of false omissions limits clinical use because of prevalence boundaries based on tolerance for risk. Mathematical analysis supports testing twice to improve predictive values and extend prevalence boundaries nearly to levels of herd immunity. Conclusions.--COVID-19 is quickly becoming endemic. Suboptimal sensitivity of rapid antigen tests limits performance in high prevalence. Risk of contagion in packed spaces (eg, airplanes) might be avoided with dual testing 36 hours apart, allowing time for viral load to increase. Awareness of community prevalence and proof of improved performance with repeated testing will help manage COVID-19 risk, while meeting rapid decision-making needs for highly contagious and new variants (eg, Delta). New COVID-19 variants call for high-quality, low cost, readily accessible, fast, user friendly, and ubiquitous point-of-care testing., GOALS The goals of this research are to apply mathematical relationships and visual logistics to reveal patterns of coronavirus disease 19 (COVID-19) rapid antigen test (RAgT) performance and to facilitate [...]

In 2015, the WHO Regional Office for the South-East Asia Region (SEARO) (1) estimated that 40 million people were living with chronic hepatitis B virus (HBV) infection and 285 000 [...]

Cellular therapy for hematologic malignancies is a rapidly evolving field, with new iterations of novel constructs being developed at a rapid pace. Since the initial reports of chimeric antigen receptor T cell (CAR T cell)success in CD19* B cell malignancies, multiple clinical trials of CAR T cell therapy directed to CD19 have led to the approval of this therapy by the FDA and the European Medicines Agency for specific indications. Despite strikingly similar efficacy, investigators at multiple centers participating in these studies have observed the nuances of each CAR T cell product, including variability in manufacturing, availability, and toxicity profiles. Here we review state-of-the-art clinical data on CD19-directed CAR T cell therapies in B cell hematologic malignancies, advances made in understanding and modeling associated toxicities, and several exciting advances and creative solutions for overcoming challenges with this therapeutic modality., Introduction The chimeric antigen receptor (CAR) constructs that would eventually become tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) were first reported in 2009. These second-generation, CD19-specific CAR T cell constructs were [...]

Highly pathogenic avian influenza (HPAI) A(H5N1) viruses of the goose/Guangdong (gs/GD) lineage emerged in domestic birds in China in 1996, causing high morbidity and mortality rates in poultry; subsequent zoonotic [...]

Agile malaria surveillance and response systems that can be sustained over time are needed for the optimal design of control programs (1,2). Rates of Plasmodium falciparum infection among pregnant women [...]

Induction of memory [CD8.sup.+] T cells is important for controlling infections such as malaria and HIV/AIDS and for cancer immunotherapy. Accurate assessment of antigen-specific (Ag-specific) [CD8.sup.+] T cells is critical for vaccine optimization and for defining correlates of protection. However, conditions for determining Ag-specific [CD8.sup.+] T cell responses ex vivo using intracellular cytokine staining (ICS) may be variable, especially in humans with complex antigens. Here, we used an attenuated whole parasite malaria vaccine model in humans and various experimental infections in mice to show that the duration of antigenic stimulation and timing of brefeldin A (BFA) addition influence the magnitude of Ag-specific and bystander T cell responses. Indeed, after immunization with an attenuated whole sporozoite malaria vaccine in humans, significantly higher numbers of IFN-[gamma]-producing memory [CD8.sup.+] T cells comprising Ag-specific and bystander responses were detected when the duration of Ag stimulation prior to addition of BFA was increased. Mechanistic analyses of virus-specific [CD8.sup.+] T cells in mice revealed that the increase in IFN-[gamma]-producing [CD8.sup.+] T cells was due to bystander activation of Ag-experienced memory [CD8.sup.+] T cells, and correlated with the proportion of Ag-experienced [CD8.sup.+] T cells in the stimulated populations. Incubation with anti-cytokine antibodies (e.g., IL-12) improved accuracy in detecting bona fide memory [CD8.sup.+] T cell responses, suggesting this as the mechanism for the bystander activation. These data have important implications for accurate assessment of immune responses generated by vaccines intended to elicit protective memory [CD8.sup.+] T cells., Introduction [CD8.sup.+] T cells have a role in mediating protection in humans against diverse pathogens impacting public health, such as HIV, influenza, and Plasmodium, the causative agent of malaria, and [...]

Combining HLA-DQ-gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4.sup.+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4.sup.+ T cells specific for disease-driving antigens in multiple autoimmune conditions. Mass cytometry identifies a unique phenotype enriched in CD4.sup.+ T cells isolated from autoimmune disease patients., Author(s): Asbjørn Christophersen [sup.1] [sup.2] [sup.3] [sup.4] , Eivind G. Lund [sup.1] [sup.2] [sup.3] , Omri Snir [sup.1] [sup.2] [sup.3] , Elsa Solà [sup.4] [sup.5] , Chakravarthi Kanduri [sup.1] [sup.6] [...]

Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract.sup.1-4. The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (T.sub.reg) cells.sup.4-8, and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease.sup.9. However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain T.sub.reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T.sub.reg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1[beta]. Macrophages in the small intestine produce IL-1[beta], and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining T.sub.reg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn's disease, and this correlated with lower frequencies of T.sub.reg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1[beta]-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine. A microbiota- and IL-1[beta]-dependent axis of IL-2 production by group-3 innate lymphoid cells is shown in a mouse model to be necessary to maintain immunological homeostasis and regulatory T cells in the small intestine., Author(s): Lei Zhou [sup.1] [sup.2] [sup.3] , Coco Chu [sup.1] [sup.2] [sup.3] , Fei Teng [sup.1] [sup.2] [sup.3] , Nicholas J. Bessman [sup.1] [sup.2] [sup.3] , Jeremy Goc [sup.1] [sup.2] [...]

Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen-driven, immunemediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies., Introduction Adverse reactions to food involve both immune-mediated and non-immune-mediated responses. Among these responses, there has been increasing attention to gastrointestinal (GI) allergic diseases, a spectrum of disorders classified by [...]

The rapid expansion in the number of encephalitis disorders associated with autoantibodies against neuronal proteins has led to an incremental increase in use of the term 'autoimmune epilepsy,' yet has occurred with limited attention to the physiopathology of each disease and genuine propensity to develop epilepsy. Indeed, most autoimmune encephalitides present with seizures, but the probability of evolving to epilepsy is relatively small. The risk of epilepsy is higher for disorders in which the antigens are intracellular (often T cell- mediated) compared with disorders in which the antigens are on the cell surface (antibody-mediated). Most autoantibodies against neuronal surface antigens show robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity. Here, we trace the evolution of the concept of autoimmune epilepsy and examine common inflammatory pathways that might lead to epilepsy. Then, we focus on several antibody-mediated encephalitis disorders that associate with seizures and review the synaptic alterations caused by patients' antibodies, with emphasis on those that have been modeled in animals (e.g., antibodies against NMDA, AMPA receptors, LGI1 protein) or in cultured neurons (e.g., antibodies against the GABAb receptor)., Seizures, epilepsy, and the concept of autoimmune epilepsy Many disorders can provoke seizures, which are defined as paroxysmal events due to an excessive, hypersynchronous discharge in central nervous system (CNS) [...]

Despite advances in understanding systemic lupus erythematosus (SLE) pathogenesis, most clinical trials of new targeted therapies have been met with disappointment. The type I IFN pathway is believed to play an important role in SLE, and the proposed involvement of this pathway helps explain the frustration behind the failure at targeting either IFN-[alpha] or the type 1 IFN receptor itself. In this issue of the JCI, Furie et al. report on an intriguing phase 1b study that demonstrates an approach for inhibiting this pathway in the skin using an mAB (BIIB059) that targets the blood DC antigen 2 (BDCA-2) receptor on plasmacytoid DCs (pDCs). BIIB059 decreased IFN expression and improved cutaneous lupus disease activity, with a favorable safety profile. Whether or not this strategy will be effective in managing SLE in other organs remains unanswered. However, these results suggest that closing the door on targeting the type 1 IFN pathway in SLE may be premature and highlight the emerging question of whether an organ-specific approach toward lupus trials and treatment should be the wave of the future., SLE treatment--unmet need and limitations of previous clinical trials Disease remission remains an elusive goal for many patients with systemic lupus erythematosus (SLE) (1), even as mortality rates for SLE [...]

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies.sup.1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response.sup.3,4. Here we show that durable neoantigen-specific immunity is regulated by mRNA N.sup.6-methyadenosine (m.sup.6A) methylation through the m.sup.6A-binding protein YTHDF1.sup.5. In contrast to wild-type mice, Ythdf1-deficient mice show an elevated antigen-specific CD8.sup.+ T cell antitumour response. Loss of YTHDF1 in classical dendritic cells enhanced the cross-presentation of tumour antigens and the cross-priming of CD8.sup.+ T cells in vivo. Mechanistically, transcripts encoding lysosomal proteases are marked by m.sup.6A and recognized by YTHDF1. Binding of YTHDF1 to these transcripts increases the translation of lysosomal cathepsins in dendritic cells, and inhibition of cathepsins markedly enhances cross-presentation of wild-type dendritic cells. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1.sup.-/- mice, implicating YTHDF1 as a potential therapeutic target in anticancer immunotherapy.The m.sup.6A reader protein YTHDF1 suppresses the clearance of tumour cells by enhancing the translation of lysosomal proteases in dendritic cells and thereby suppressing tumour antigen presentation., Author(s): Dali Han [sup.1] [sup.2] [sup.3] , Jun Liu [sup.4] [sup.5] [sup.6] , Chuanyuan Chen [sup.1] [sup.2] [sup.3] , Lihui Dong [sup.7] , Yi Liu [sup.7] , Renbao Chang [sup.1] [...]

In principle, humans can produce an antibody response to any non-self-antigen molecule in the appropriate context. This flexibility is achieved by the presence of a large repertoire of naive antibodies, the diversity of which is expanded by somatic hypermutation following antigen exposure.sup.1. The diversity of the naive antibody repertoire in humans is estimated to be at least 10.sup.12 unique antibodies.sup.2. Because the number of peripheral blood B cells in a healthy adult human is on the order of 5 × 10.sup.9, the circulating B cell population samples only a small fraction of this diversity. Full-scale analyses of human antibody repertoires have been prohibitively difficult, primarily owing to their massive size. The amount of information encoded by all of the rearranged antibody and T cell receptor genes in one person--the 'genome' of the adaptive immune system--exceeds the size of the human genome by more than four orders of magnitude. Furthermore, because much of the B lymphocyte population is localized in organs or tissues that cannot be comprehensively sampled from living subjects, human repertoire studies have focused on circulating B cells.sup.3. Here we examine the circulating B cell populations of ten human subjects and present what is, to our knowledge, the largest single collection of adaptive immune receptor sequences described to date, comprising almost 3 billion antibody heavy-chain sequences. This dataset enables genetic study of the baseline human antibody repertoire at an unprecedented depth and granularity, which reveals largely unique repertoires for each individual studied, a subpopulation of universally shared antibody clonotypes, and an exceptional overall diversity of the antibody repertoire. A genetic study of the baseline human antibody repertoire, based on the circulating B cell populations of ten subjects, reveals universally shared antibody clonotypes within repertoires that are largely unique to the individual., Author(s): Bryan Briney [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] , Anne Inderbitzin [sup.1] [sup.6] , Collin Joyce [sup.1] [sup.2] [sup.3] [sup.4] , Dennis R. Burton [sup.1] [sup.2] [sup.4] [sup.5] [sup.7] Author [...]

Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8.sup.+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.Deletion of the A-to-I double-stranded RNA-editing enzyme ADAR1 sensitizes tumour cells to immunotherapy., Author(s): Jeffrey J. Ishizuka [sup.1] [sup.2] [sup.3] , Robert T. Manguso [sup.1] [sup.3] , Collins K. Cheruiyot [sup.1] [sup.3] , Kevin Bi [sup.1] [sup.3] , Arpit Panda [sup.1] [sup.3] [sup.4] [...]

Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties.sup.1. CD19-specific CARs that comprise CD28 and CD3[zeta] signaling motifs.sup.2 have induced remarkable responses in patients with refractory leukemia.sup.3-5 and lymphoma.sup.6 and were recently approved by the US Food and Drug Administration.sup.7. These CARs program highly performing effector functions that mediate potent tumor elimination.sup.4,8 despite the limited persistence they confer on T cells.sup.3-6,8. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion.sup.9,10, which may be accentuated by the redundancy of CD28 and CD3[zeta] signaling.sup.11,12 as well as the spatiotemporal constraints imparted by the structure of second-generation CARs.sup.2. Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles. A novel chimeric antigen receptor (CAR) T cell design improves therapeutic efficacy by balancing effector and memory profiles., Author(s): Judith Feucht [sup.1] , Jie Sun [sup.1] [sup.2] , Justin Eyquem [sup.1] , Yu-Jui Ho [sup.3] , Zeguo Zhao [sup.1] , Josef Leibold [sup.3] , Anton Dobrin [sup.1] , [...]

The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for the mother and child, our knowledge of the human placenta is limited owing to a lack of functional experimental models.sup.1. After implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, proliferative villous cytotrophoblast cells differentiate into two main sub-populations: syncytiotrophoblast, the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast cells, which anchor the placenta to the maternal decidua and transform the maternal spiral arteries.sup.2. Here we describe the generation of long-term, genetically stable organoid cultures of trophoblast that can differentiate into both syncytiotrophoblast and extravillous trophoblast. We used human leukocyte antigen (HLA) typing to confirm that the organoids were derived from the fetus, and verified their identities against four trophoblast-specific criteria.sup.3. The cultures organize into villous-like structures, and we detected the secretion of placental-specific peptides and hormones, including human chorionic gonadotropin (hCG), growth differentiation factor 15 (GDF15) and pregnancy-specific glycoprotein (PSG) by mass spectrometry. The organoids also differentiate into HLA-G.sup.+ extravillous trophoblast cells, which vigorously invade in three-dimensional cultures. Analysis of the methylome reveals that the organoids closely resemble normal first trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.An in vitro system that generates three-dimensional cultures of extraembryonic fetal trophoblast cells that differentiate into the two main types of trophoblast can be used to study human placental development., Author(s): Margherita Y. Turco [sup.1] [sup.2] [sup.3] , Lucy Gardner [sup.1] [sup.3] , Richard G. Kay [sup.4] , Russell S. Hamilton [sup.2] [sup.3] , Malwina Prater [sup.2] [sup.3] , Michael [...]

Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans.sup.1,2. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients.sup.3. Previous vaccine development programs have not been successful.sup.4. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc).sup.5,6. It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS.sup.7, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5-40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences.Strains of methicillin-resistant Staphylococcus aureus use a prophage-encoded glycosyltransferase to alter the glycosylation of their wall teichoic acid and thereby evade antibody-mediated immune responses., Author(s): David Gerlach [sup.1] [sup.2] , Yinglan Guo [sup.3] , Cristina De Castro [sup.4] , Sun-Hwa Kim [sup.5] , Katja Schlatterer [sup.1] [sup.2] , Fei-Fei Xu [sup.6] , Claney Pereira [...]

Objective To estimate population-wide hepatitis B and C seroprevalence using dried blood spot samples acquired for human immunodeficiency virus (HIV) surveillance as part of the 2010-2011 Demographic and Health Survey in Burkina Faso.Methods We used the database acquired during the multistage, clustered, population-based survey, in which 15 377 participants completed questionnaires and provided dried blood spot samples for HIV testing. We extracted sociodemographic and geographic data including age, sex, ethnicity, education, wealth, marital status and region for each participant. We performed hepatitis B and C assays on 14886 HIV-negative samples between March to October 2015, and calculated weighted percentages of hepatitis seroprevalence for each variable.Findings We estimated seroprevalence as 9.1% (95% confidence interval, CI: 8.5-9.7) for the hepatitis B surface antigen and 3.6% (95% CI: 3.3-3.8) for hepatitis C virus antibodies, classifying Burkina Faso as highly endemic for hepatitis Band low-intermediate for hepatitis C. The seroprevalence of hepatitis was higher in men than in women, and varied significantly for both with age, education, ethnicity and region. Extremely high HCV-Ab seroprevalence (13.2%; 95% CI: 10.6-15.7) was identified in the Sud-Ouest region, in particular within the youngest age group (15-20 years), indicating an ongoing epidemicConclusion Our population-representative hepatitis seroprevalence estimates in Burkina Faso advocate for the inclusion of hepatitis serological tests and risk factor questionnaire items in future surveys, the results of which are crucial for the development of appropriate health policies and infection control programmes.Objectif Estimer la seroprevalence du virus de l'hepatite B et de l'hepatite C dans la population au moyen de gouttes de sang seche prelevees pour la surveillance du virus de 1'immunodeficience humaine (VIH) dans le cadre de l'enquete demographique et sanitaire realisee en 2010-2011 au Burkina Faso.Methodes Nous avons utilise la base de donnees constituee durant l'enquete en grappes a plusieurs degres menee aupres de la population, au cours de laquelle 15 377 participants ont rempli des questionnaires et fourni des echantillons de gouttes de sang seche pour le deplstage du VIH. Pour chaque participant, nous en avons extrait des donnees sociodemographiques et geographiques, concernant notamment l'age, le sexe, l'origine ethnique, le niveau d'education, le niveau de richesse, la situation matrimoniale et la region. Nous avons effectue des tests de l'hepatite Bet de l'hepatite C sur 14886 echantillons seronegatifs pour le VIH entre mars et octobre 2015, et nous avons calcule des pourcentages ponderes de la seroprevalence de l'hepatite pour chaque variable.Resultats Nous avons estime la seroprevalence a 9,1% (intervalle de confiance de 95%, IC: 8,5-9,7) pour l'antigene de surface de l'hepatite B et a 3,6% (IC 95%: 3,3-3,8) pour les anticorps du virus de l'hepatite C, ce qui classait le Burkina Faso comme zone de forte endemie de l'hepatite B et d'endemie faible a intermediaire de l'hepatite C. La seroprevalence de l'hepatite etait plus elevee chez les hommes que chez les femmes et variait fortement, quel que soit le sexe, en fonction de l'age, du niveau d'education, de l'origine ethnique et de la region. Une seroprevalence extremement elevee d'anticorps anti-VHC (13,2%; IC 95%: 10,6-15,7) a ete relevee dans la region Sud-Ouest, en particulier dans la tranche d'age la plus basse (15-20 ans), ce qui indiquait une epidemie en cours.Conclusion D'apres nos estimations de la seroprevalence de l'hepatite representatives de la population du Burkina Faso, il seralt bon d'inclure des tests serologiques de l'hepatite et des questions sur les facteurs de risque dans les prochaines enquetes, dont les resultats seront cruciaux pour Elaboration de politiques de sante appropriees et de programmes de lutte contre les infections.Objetivo estimar la seroprevalencia de la hepatitis B y C en toda la poblacion con muestras de sangre seca obtenidas para el control del virus de la inmunodeficiencia humana (VIH) como parte de la Encuesta demografica y de salud entre 2010 y 2011 en Burkina Faso.Metodos Se utilizo la base de datos adquirida durante la encuesta multietapica, agrupada y basada en la poblacion, en la que 15 377 participantes completaron cuestionarios y proporcionaron muestras de sangre seca para la prueba delVIH.Se extrajeron datos sociodemograficos y geograficos que incluyen edad, sexo, origen etnico, educacion, nivel economico, estado civil y region de cada participante. Se realizaron pruebas de hepatitis B y C en 14 886 muestras VIH negativas entre marzo y octubre de 2015, y se calcularon porcentajes ponderados de seroprevalencia de hepatitis para cada variable.Resultados Se estimo la seroprevalencia como el 9,1 % (Intervalo de confianza 95 %, IC: 8,5-9,7) para el antigeno de superficie de la hepatitis B y el 3,6 % (IC 95 %: 3,3-3,8) para anticuerpos del virus de la hepatitis C, clasificando a Burkina Faso como una zona altamente endemica para la hepatitis B y bajo intermedio para la hepatitis C. La seroprevalencia de la hepatitis fue mayor en los hombres que en las mujeres y vario significativamente para ambos con la edad, la educacion, la etnla y la region. Se identifico una seroprevalencia de HCV-Ab extremadamente alta (13,2 %; IC del 95 %: 10,6-15,7) en la region suroeste, en particular dentro del grupo de edad mas joven (15-20 anos), lo que Indica una epidemia en curso.Conclusion Nuestras estimaciones de seroprevalencia de hepatitis en poblaclonales de Burkina Faso abogan por la Inclusion de pruebas serologicas de hepatitis y elementos sobre factores de riesgo en encuestas futuras, cuyos resultados son cruciales para el desarrollo de politicas de salud apropiadas y programas de control de infecciones., [phrase omitted]IntroductionViral hepatitis is a global health challenge worldwide, particularly in low- and middle-income countries. (1) Hepatitis B virus (HBV) is estimated to affect around 75 million people in Africa, [...]

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia., Author(s): Thomas B. Alexander [sup.1] [sup.2] , Zhaohui Gu [sup.3] , Ilaria Iacobucci [sup.3] , Kirsten Dickerson [sup.3] , John K. Choi [sup.3] , Beisi Xu [sup.4] , Debbie Payne-Turner [...]