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An important challenge during the COVID-19 pandemic has been to understand asymptomatic disease and the extent to which this may be a source of transmission. As asymptomatic disease is by definition hard to screen for, there is a lack of clarity about this aspect of the COVID-19 spectrum. Studies have considered whether the prevalence of asymptomatic disease is determined by differences in age, demographics, viral load, duration of shedding, and magnitude or durability of immunity. It is clear that adaptive immunity is strongly activated during asymptomatic infection, but some features of the T cell and antibody response may differ from those in symptomatic disease. Areas that need greater clarity include the extent to which asymptomatic disease leads to persistent symptoms (long COVID), and the quality, quantity and durability of immune priming required to confer subsequent protection.Individuals with asymptomatic COVID-19 can transmit the virus and may be at risk of long-term disease. In this Progress article, Boyton and Altman present current insights into immune responses in asymptomatic SARS-CoV-2 infection and discuss the relevance of asymptomatic disease for public health strategies.

As SARS-CoV-2 vaccines are deployed worldwide, a comparative evaluation is important to underpin decision-making. We here report a systematic literature review and meta-analysis of Phase I/II/III human trials and non-human primates (NHP) studies, comparing reactogenicity, immunogenicity and efficacy across different vaccine platforms for comparative evaluation (updated to March 22, 2021). Twenty-three NHP and 32 human studies are included. Vaccines result in mostly mild, self-limiting adverse events. Highest spike neutralizing antibody (nAb) responses are identified for the mRNA-1273-SARS-CoV and adjuvanted NVX-CoV2373-SARS-CoV-2 vaccines. ChAdOx-SARS-CoV-2 produces the highest T cell ELISpot responses. Pre-existing nAb against vaccine viral vector are identified following AdH-5-SARS-CoV-2 vaccination, halving immunogenicity. The mRNA vaccines depend on boosting to achieve optimal immunogenicity especially in the elderly. BNT162b2, and mRNA-1273 achieve >94%, rAd26/5 > 91% and ChAdOx-SARS-CoV-2 > 66.7% efficacy. Across different vaccine platforms there are trade-offs between antibody binding, functional nAb titers, T cell frequency, reactogenicity and efficacy. Emergence of variants makes rapid mass rollout of high efficacy vaccines essential to reduce any selective advantage.

BackgroundModulation of adaptive immunity may underscore the efficacy of trans-arterial chemoembolization (TACE). We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment.MethodsWe profiled intratumoral (IT), peritumoral (PT) and non-tumoral (NT) background tissue to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD-1+ T-cells across T+ (n=58) and T− (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, indoleamine 2,3 dehydrogenase (IDO-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lag-3, Tim-3 and CD163.ResultsWe analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) hepatocellular carcinoma. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD-1+ and NT CD8+/PD-1+ (p<0.001) compared with T−. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed upregulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T−.ConclusionsTACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant upregulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumor microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314). Authors utilise a cohort of healthcare workers, infected during the first wave of the SARS-CoV-2 pandemic, to assess symptom persistence and humoral and cellular immunity.

Available evidences suggest that podoconiosis is triggered by long term exposure of bare feet to volcanic red clay soil particles. Previous genome-wide studies in Ethiopia showed association between the HLA class II region and disease susceptibility. However, functional relationships between the soil trigger, immunogenetic risk factors and the immunological basis of the disease are uncharted. Therefore, we aimed to characterise the immune profile and gene expression of podoconiosis patients relative to endemic healthy controls. Peripheral blood immunophenotyping of T cells indicated podoconiosis patients had significantly higher CD4 and CD8 T cell surface HLA-DR expression compared to healthy controls while CD62L expression was significantly lower. The levels of the activation markers CD40 and CD86 were significantly higher on monocytes and dendritic cell subsets in patients compared to the controls. RNA sequencing gene expression data indicated higher transcript levels for activation, scavenger receptors, and apoptosis markers while levels were lower for histones, T cell receptors, variable, and constant immunoglobulin chain in podoconiosis patients compared to healthy controls. Our finding provides evidence that podoconiosis is associated with high levels of immune activation and inflammation with over-expression of genes within the pro-inflammatory axis. This offers further support to a working hypothesis of podoconiosis as soil particle-driven, HLA-associated disease of immunopathogenic aetiology. Podoconiosis is triggered by long term barefoot exposure to volcanic red clay soil. Here, Negash et al characterise the immune profile of podoconiosis patients to show this disease is associated with high levels of immune activation and inflammation.

Sensitivity to immune checkpoint inhibitor (ICPI) therapy is governed by a complex interplay of tumor and host-related determinants. Epidemiological studies have highlighted that exposure to antibiotic therapy influences the probability of response to ICPI and predict for shorter patient survival across malignancies. Whilst a number of studies have reproducibly documented the detrimental effect of broad-spectrum antibiotics, the immune-biologic mechanisms underlying the association with outcome are poorly understood. Perturbation of the gut microbiota, an increasingly well-characterized factor capable of influencing ICPI-mediated immune reconstitution, has been indicated as a putative mechanism to explain the adverse effects attributed to antibiotic exposure in the context of ICPI therapy. Prospective studies are required to validate antibiotic-mediated gut perturbations as a mechanism of ICPI refractoriness and guide the development of strategies to overcome this barrier to an effective delivery of anti-cancer immunotherapy.

Since the 18th century a wealth of knowledge regarding infectious disease pathogenesis, prevention, and treatment has been accumulated from findings of infection challenges in human beings. Partly because of improvements to ethical and regulatory guidance, human challenge studies—involving the deliberate exposure of participants to infectious substances—have had a resurgence in popularity in the past few years, in particular for the assessment of vaccines. To provide an overview of the potential use of challenge models, we present historical reports and contemporary views from experts in this type of research. A range of challenge models and practical approaches to generate important data exist and are used to expedite vaccine and therapeutic development and to support public health modelling and interventions. Although human challenge studies provide a unique opportunity to address complex research questions, participant and investigator safety is paramount. To increase the collaborative effort and future success of this area of research, we recommend the development of consensus frameworks and sharing of best practices between investigators. Furthermore, standardisation of challenge procedures and regulatory guidance will help with the feasibility for using challenge models in clinical testing of new disease intervention strategies.

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.SARS-CoV-2 infection can lead to a diverse array of chronic symptoms, collectively termed ‘long COVID’. In this Review, Altmann and colleagues explore current thinking about the pathophysiology of long COVID and discuss potential immunological mechanisms.