The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

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The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

Several lines of evidence implicate immunological/inflammatory factors in development of schizophrenia. Complement is a key driver of inflammation, and complement dysregulation causes pathology in many diseases. Here we explored whether complement dysregulation occurred in first episode psychosis (FEP) and whether this provides a source of biomarkers. Eleven complement analytes (C1q, C3, C4, C5, factor B [FB], terminal complement complex [TCC], factor H [FH], FH-related proteins [FHR125], Properdin, C1 inhibitor [C1inh], soluble complement receptor 1 [CR1]) plus C-reactive protein (CRP) were measured in serum from 136 first episode psychosis (FEP) cases and 42 mentally healthy controls using established in-house or commercial ELISA. The relationship between caseness and variables (analytes measured, sex, age, ethnicity, tobacco/cannabis smoking) was tested by multivariate logistic regression. When measured individually, only TCC was significantly different between FEP and controls (p=0.01). Stepwise selection demonstrated interdependence between some variables and revealed other variables that significantly and independently contributed to distinguishing cases and controls. The final model included demographics (sex, ethnicity, age, tobacco smoking) and a subset of analytes (C3, C4, C5, TCC, C1inh, FHR125, CR1). A receiver operating curve analysis combining these variables yielded an area under the curve of 0.79 for differentiating FEP from controls. This model was confirmed by multiple replications using randomly selected sample subsets. The data suggest that complement dysregulation occurs in FEP, supporting an underlying immune/inflammatory component to the disorder. Classification of FEP cases according to biological variables rather than symptoms would help stratify cases to identify those that might most benefit from therapeutic modification of the inflammatory response.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-α . We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.

Purpose: To explore whether complement dysregulation occurs in a routinely recruited clinical cohort of epilepsy patients, and whether complement biomarkers have potential to be used as markers of disease severity and seizure control. analysis were used to test whether combinations of complement analytes were predictive of epilepsy diagnoses and seizure occurrence. Correlation between number and type of antiepileptic drugs (AED) and complement analytes was also performed. Methods Results:We found: 1) significant differences between all epilepsy patients and controls for TCC (p˂ 0.01) and FH (p˂ 0.01) after performing univariate analysis.2) multivariate analysis combining six analytes (C3, C4, Properdin, FH, C1Inh, Clu) to give a predictive value (area under the curve) of 0.80 for differentiating epilepsy from controls.3) significant differences in complement levels between patients with controlled seizures (n=65) in comparison with uncontrolled seizures (n=87). Levels of iC3b, Properdin and Clu were decreased and levels of C4 were increased in patients with uncontrolled seizures. 4) no correlation was found between the level of complement biomarkers and the number of AEDs taken, but an association between some analyte levels and drug therapy was seen in patients taking sodium valproate, clobazam, and perampanel. Complement biomarkers in EpilepsyPage 3 Conclusion: This study adds to evidence implicating complement in pathogenesis of epilepsy and may allow the development of better therapeutics and prognostic markers in the future.Replication in a larger sample set is needed to validate the findings of the study. Highlights:• Plasma complement biomarkers distinguish epilepsy patients from controls (area under the curve: 0.8).• Plasma complement biomarkers differ between controlled and uncontrolled epilepsy patients.• The data implicate complement dysregulation and inflammation in the pathogenesis of epilepsy.

Accurate assessment of SARS‐CoV‐2 immunity is critical in evaluating vaccine efficacy and devising public health policies. Whilst the exact nature of effective immunity remains incompletely defined, SARS‐CoV‐2‐specific T‐cell responses are a critical feature that will likely form a key correlate of protection against COVID‐19. Here, we developed and optimized a high‐throughput whole blood‐based assay to determine the T‐cell response associated with prior SARS‐CoV‐2 infection and/or vaccination amongst 231 healthy donors and 68 cancer patients. Following overnight in vitro stimulation with SARS‐CoV‐2‐specific peptides, blood plasma samples were analysed for T H 1‐type cytokines. Highly significant differential IFN‐γ + /IL‐2 + SARS‐CoV‐2‐specific T‐cell responses were seen amongst previously infected COVID‐19‐positive healthy donors in comparison with unknown / naïve individuals ( p < 0·0001). IFN‐γ production was more effective at identifying asymptomatic donors, demonstrating higher sensitivity (96·0% vs. 83·3%) but lower specificity (84·4% vs. 92·5%) than measurement of IL‐2. A single COVID‐19 vaccine dose induced IFN‐γ and/or IL‐2 SARS‐CoV‐2‐specific T‐cell responses in 116 of 128 (90·6%) healthy donors, reducing significantly to 27 of 56 (48·2%) when measured in cancer patients ( p < 0·0001). A second dose was sufficient to boost T‐cell responses in the majority (90·6%) of cancer patients, albeit IFN‐γ + responses were still significantly lower overall than those induced in healthy donors ( p = 0·034). Three‐month post‐vaccination T‐cell responses also declined at a faster rate in cancer patients. Overall, this cost‐effective standardizable test ensures accurate and comparable assessments of SARS‐CoV‐2‐specific T‐cell responses amenable to widespread population immunity testing, and identifies individuals at greater need of booster vaccinations.