Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness. Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID stable patients), patients with COVID-19 requiring ICU admission (COVID ICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP ICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID ICU patients could be clearly differentiated from COVID stable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP ICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission ( P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution ( P < 0.0001). Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

Background. Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope–thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy.Methods. We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP.Results. One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%–79%, compared with 79%–84% for ChAd63-MVA ME-TRAP.Conclusions. ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development.Clinical Trials Registration. NCT01623557.

Summary Endothelial cell (EC) activation plays a key role in the pathogenesis of pulmonary microvascular occlusion, which is a hallmark of severe coronavirus disease 2019 (COVID‐19). Consistent with EC activation, increased plasma von Willebrand factor antigen (VWF:Ag) levels have been reported in COVID‐19. Importantly however, studies in other microangiopathies have shown that plasma VWF propeptide (VWFpp) is a more sensitive and specific measure of acute EC activation. In the present study, we further investigated the nature of EC activation in severe COVID‐19. Markedly increased plasma VWF:Ag [median (interquatile range, IQR) 608·8 (531–830)iu/dl] and pro‐coagulant factor VIII (FVIII) levels [median (IQR) 261·9 (170–315) iu/dl] were seen in patients with severe severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. Sequential testing showed that these elevated VWF–FVIII complex levels remained high for up to 3 weeks. Similarly, plasma VWFpp levels were also markedly elevated [median (IQR) 324·6 (267–524) iu/dl]. Interestingly however, the VWFpp/VWF:Ag ratio was reduced, demonstrating that decreased VWF clearance contributes to the elevated plasma VWF:Ag levels in severe COVID‐19. Importantly, plasma VWFpp levels also correlated with clinical severity indices including the Sequential Organ Failure Assessment (SOFA) score, Sepsis‐Induced Coagulopathy (SIC) score and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio). Collectively, these findings support the hypothesis that sustained fulminant EC activation is occurring in severe COVID‐19, and further suggest that VWFpp may have a role as a biomarker in this setting.

Background We aimed to describe the clinical presentation of individuals presenting with prolonged recovery from coronavirus disease 2019 (COVID-19), known as long COVID. Methods This was an analysis within a multicenter, prospective cohort study of individuals with a confirmed diagnosis of COVID-19 and persistent symptoms &gt;4 weeks from onset of acute symptoms. We performed a multiple correspondence analysis (MCA) on the most common self-reported symptoms and hierarchical clustering on the results of the MCA to identify symptom clusters. Results Two hundred thirty-three individuals were included in the analysis; the median age of the cohort was 43 (interquartile range [IQR], 36–54) years, 74% were women, and 77.3% reported a mild initial illness. MCA and hierarchical clustering revealed 3 clusters. Cluster 1 had predominantly pain symptoms with a higher proportion of joint pain, myalgia, and headache; cluster 2 had a preponderance of cardiovascular symptoms with prominent chest pain, shortness of breath, and palpitations; and cluster 3 had significantly fewer symptoms than the other clusters (2 [IQR, 2–3] symptoms per individual in cluster 3 vs 6 [IQR, 5–7] and 4 [IQR, 3–5] in clusters 1 and 2, respectively; P &lt; .001). Clusters 1 and 2 had greater functional impairment, demonstrated by significantly longer work absence, higher dyspnea scores, and lower scores in SF-36 domains of general health, physical functioning, and role limitation due to physical functioning and social functioning. Conclusions Clusters of symptoms are evident in long COVID patients that are associated with functional impairments and may point to distinct underlying pathophysiologic mechanisms of disease.