ABSTRACT
The highly contagious SARS-CoV-2 Omicron subvariants severely attenuated the effectiveness of currently licensed SARS-CoV-2 vaccines based on ancestral strains administered via intramuscular injection. In this study, we generated a recombinant, replication-incompetent human adenovirus type 5, Ad5-S-Omicron, that expresses Omicron BA.1 spike. Intranasal, but not intramuscular vaccination, elicited spike-specific respiratory mucosal IgA and residential T cell immune responses, in addition to systemic neutralizing antibodies and T cell immune responses against most Omicron subvariants. We tested intranasal Ad5-S-Omicron as a heterologous booster in mice that previously received intramuscular injection of inactivated ancestral vaccine. In addition to inducing serum broadly neutralizing antibodies, there was a significant induction of respiratory mucosal IgA and neutralizing activities against Omicron subvariants BA.1, BA.2, BA.5, BA.2.75, BF.7 as well as pre-Omicron strains Wildtype, Beta, and Delta. Serum and mucosal neutralizing activities against recently emerged XBB, BQ.1, and BQ.1.1 could also be detected but were much lower. Nasal lavage fluids from intranasal vaccination contained multimeric IgA that can bind to at least 10 spike proteins, including Omicron subvariants and pre-Omicron strains, and possessed broadly neutralizing activities. Intranasal vaccination using Ad5-S-Omicron or instillation of intranasal vaccinee's nasal lavage fluids in mouse nostrils protected mice against Omicron challenge. Taken together, intranasal Ad5-S-Omicron booster on the basis of ancestral vaccines can establish effective mucosal and systemic immunity against Omicron subvariants and multiple SARS-CoV-2 variants. This candidate vaccine warrants further development as a safe, effective, and user-friendly infection and transmission-blocking vaccine.
Subject(s)
COVID-19 , Vaccines , Animals , Humans , Mice , SARS-CoV-2 , COVID-19 Vaccines/genetics , COVID-19/prevention & control , Immunoglobulin AABSTRACT
Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.
ABSTRACT
The devastating COVID-19 pandemic caused by SARS-CoV-2 and multiple variants or subvariants remains an ongoing global challenge. SARS-CoV-2-specific T cell responses play a critical role in early virus clearance, disease severity control, limiting the viral transmission and underpinning COVID-19 vaccine efficacy. Studies estimated broad and robust T cell responses in each individual recognized at least 30 to 40 SARS-CoV-2 antigen epitopes and associated with COVID-19 clinical outcome. Several key immunodominant viral proteome epitopes, including S protein- and non-S protein-derived epitopes, may primarily induce potent and long-lasting antiviral protective effects. In this review, we summarized the immune response features of immunodominant epitope-specific T cells targeting different SRAS-CoV-2 proteome structures after infection and vaccination, including abundance, magnitude, frequency, phenotypic features and response kinetics. Further, we analyzed the epitopes immunodominance hierarchy in combination with multiple epitope-specific T cell attributes and TCR repertoires characteristics, and discussed the significant implications of cross-reactive T cells toward HCoVs, SRAS-CoV-2 and variants of concern, especially Omicron. This review may be essential for mapping the landscape of T cell responses toward SARS-CoV-2 and optimizing the current vaccine strategy.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Epitopes , COVID-19 Vaccines , Pandemics , Proteome , T-Lymphocytes , Immunodominant Epitopes , Immunity , Receptors, Antigen, T-CellABSTRACT
BACKGROUND: Timely medical intervention in severe cases of coronavirus disease 2019 (COVID-19) and better understanding of the disease's pathogenesis are essential for reducing mortality, but early classification of severe cases and its progression is challenging. OBJECTIVE: We investigated the levels of circulating phospholipid metabolites and their relationship with COVID-19 severity, as well as the potential role of phospholipids in disease progression. METHODS: We performed nontargeted lipidomic analysis of plasma samples (n = 150) collected from COVID-19 patients (n = 46) with 3 levels of disease severity, healthy individuals, and subjects with metabolic disease. RESULTS: Phospholipid metabolism was significantly altered in COVID-19 patients. Results of a panel of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) and of phosphatidylethanolamine and lysophosphatidylethanolamine (LPE) ratios were significantly correlated with COVID-19 severity, in which 16 phospholipid ratios were shown to distinguish between patients with severe disease, mild disease, and healthy controls, 9 of which were at variance with those in subjects with metabolic disease. In particular, relatively lower ratios of circulating (PC16:1/22:6)/LPC 16:1 and (PE18:1/22:6)/LPE 18:1 were the most indicative of severe COVID-19. The elevation of levels of LPC 16:1 and LPE 18:1 contributed to the changes of related lipid ratios. An exploratory functional study of LPC 16:1 and LPE 18:1 demonstrated their ability in causing membrane perturbation, increased intracellular calcium, cytokines, and apoptosis in cellular models. CONCLUSION: Significant Lands cycle remodeling is present in patients with severe COVID-19, suggesting a potential utility of selective phospholipids with functional consequences in evaluating COVID-19's severity and pathogenesis.
Subject(s)
COVID-19 , Phospholipids , Humans , Phospholipids/metabolism , Lysophosphatidylcholines/metabolismABSTRACT
BACKGROUND: China has been using inactivated COVID-19 vaccines as primary series and booster doses to protect the population from severe to fatal COVID-19. We evaluated primary and booster vaccine effectiveness (VE) against Omicron BA.2 infection outcomes. METHODS: This was a 13-province retrospective cohort study of quarantined close contacts of BA.2-infected individuals. Outcomes were BA.2 infection, COVID-19 pneumonia or worse, and severe/critical COVID-19. Absolute VE was estimated by comparison with an unvaccinated group. RESULTS: There were 289,427 close-contacts ≥3 years old exposed to Omicron BA.2 cases; 31,831 turned nucleic-acid amplification test (NAAT)-positive during quarantine, 97.2% with mild or asymptomatic infection, 2.6% had COVID-19 pneumonia, and 0.15% had severe/critical COVID-19. None died. Adjusted VE against any infection was 17% for primary series and 22% when boosted. Primary series aVE in adults >18 years was 66% against pneumonia or worse infection and 91% against severe/critical COVID-19. Booster dose aVE was 74% against pneumonia or worse, and 93% against severe/critical COVID-19. CONCLUSIONS: Inactivated COVID-19 vaccines provided modest protection from infection, very good protection against pneumonia, and excellent protection against severe/critical COVID-19. Booster doses are necessary to provide strongest protection.
ABSTRACT
In December 2019, the COVID-19 pandemic quickly spread throughout China and beyond, posing enormous global challenges. With prompt, vigorous, and coordinated control measures, mainland China contained the spread of the epidemic within two months and halted the epidemic in three months. Aggressive containment strategy, hierarchical management, rational reallocation of resources, efficient contact tracing, and voluntary cooperation of Chinese citizens contributed to the rapid and efficient control of the epidemic, thus promoting the rapid recovery of the Chinese economy. This review summarizes China's prevention and control strategies and other public health measures, which may provide a reference for the epidemic control in other countries.
ABSTRACT
Graphical Background Timely medical interventions in severe cases of COVID-19 and better understanding of the pathogenesis are essential for reducing the mortality, but early classification of severe cases and its progression is challenging. Objective To investigate the levels of circulating phospholipid metabolites and their relationship with the severity of COVID-19 and the potential role of phospholipids in the progression of the disease. Methods In this study, we performed non-targeted lipidomic analysis of plasma samples (n=150) collected from COVID-19 patients (N=46) with three levels of severity, healthy individuals and subjects with metabolic diseases. Results Results showed that phospholipid metabolism was significantly altered in COVID-19 patients. A panel of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) and of phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (LPE) ratios were significantly correlated with the severity of COVID-19, in which 16 phospholipid ratios were shown to distinguish severe patients from mild cases and healthy controls, and 9 of which were at variance with those in subjects with metabolic diseases. In particular, relatively lower ratios of circulating (PC16:1/22:6)/LPC16:1 and (PE18:1/22:6)/LPE18:1 were the most indicative of severe COVID-19. The elevation of levels of LPC16:1 and LPE18:1 contributed to the changes of related lipid ratios. An exploratory functional study of LPC16:1 and LPE18:1 demonstrated their ability in causing membrane perturbation, increased intracellular calcium, cytokines, and apoptosis in cellular models. Conclusion These results demonstrate significant Lands cycle remodeling in patients with severe COVID-19, and suggest the potential utility of selective phospholipids with functional consequences in evaluating COVID-19 severity and its pathogenesis. Phospholipid ratio correlated with the severity of COVID-19, and the biological functions of phospholipid derivatives may be associated with exacerbation of the disease
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The effects of different SARS-CoV-2 vaccinations and variant infection histories on imprinting population immunity and their influence on emerging escape mutants remain unclear. We found that Omicron (BA.1) breakthrough infection, regardless of vaccination with two-dose mRNA vaccines (M-M-o) or two-dose inactivated vaccines (I-I-o), led to higher neutralizing antibody levels against different variants and stronger T-cell responses than Delta breakthrough infection after two-dose inactivated vaccine vaccination (I-I-δ). Furthermore, different vaccination-infection patterns imprinted virus-specific T-cell differentiation; M-M-ο showed higher S/M/N/E-specific CD4+ T cells and less portion of virus-specific CD45RA+CD27-CD8+ T cells by ex vivo assay. Breakthrough infection groups showed higher proliferation and multi-function capacity by in vitro assay than three-dose inactivated vaccine inoculated group (I-I-I). Thus, under wide vaccination coverage, the higher immunogenicity with the Omicron variant may have helped to eliminate the population of Delta variant. Overall, our data contribute to our understanding of immune imprinting in different sub-populations and may guide future vaccination programs.
ABSTRACT
Introduction: SARS-CoV-2 has ravaged the world and undergone multiple mutations during the course of the COVID-19 pandemic. On 7 April 2022, an epidemic caused by SARS-CoV-2 Omicron (BA.2) variant broke out in Guangzhou, China, one of the largest transportation and logistical hubs of the country. Methods: To fast curtained the Omicron epidemic, based on the routine surveillance on the risk population of SARS-CoV-2 infection, we identify key places of the epidemic and implement enhanced control measures against Omicron. Results: Transmission characteristics of the Omicron variant were analyzed for 273 confirmed cases, and key places involved in this epidemic were fully presented. The median incubation time and the generation time were 3 days, and the reproduction number Rt was sharply increased with a peak of 4.20 within 2 days. We tried an all-out effort to tackle the epidemic in key places, and the proportion of confirmed cases increased from 61.17% at Stage 2 to 88.89% at Stage 4. Through delimited risk area management, 99 cases were found, and the cases were isolated in advance for 2.61 ± 2.76 days in a lockdown zone, 0.44 ± 1.08 days in a controlled zone, and 0.27 ± 0.62 days in a precautionary zone. People assigned with yellow code accounted for 30.32% (84/277) of confirmed COVID-19 cases, and 83.33% of them were detected positive over 3 days since code assignment. For the districts outside the epicenter, the implementation duration of NPIs was much shorter compared with the Delta epidemic last year. Conclusion: By blocking out transmission risks and adjusting measures to local epidemic conditions through the all-out effort to tackle the epidemic in key places, by delimiting risk area management, and by conducting health code management of the at-risk population, the Omicron epidemic could be contained quickly.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Communicable Disease Control , Pandemics , SARS-CoV-2ABSTRACT
SARS-CoV-2 Omicron variant infection generally gives rise to asymptomatic to moderate COVID-19 in vaccinated people. The immune cells can be reprogrammed or "imprinted" by vaccination and infections to generate protective immunity against subsequent challenges. Considering the immune imprint in Omicron infection is unclear, here we delineate the innate immune landscape of human Omicron infection via single-cell RNA sequencing, surface proteome profiling, and plasma cytokine quantification. We found that monocyte responses predominated in immune imprints of Omicron convalescents, with IL-1ß-associated and interferon (IFN)-responsive signatures with mild and moderate symptoms, respectively. Low-density neutrophils increased and exhibited IL-1ß-associated and IFN-responsive signatures similarly. Mild convalescents had increased blood IL-1ß, CCL4, IL-9 levels and PI3+ neutrophils, indicating a bias to IL-1ß responsiveness, while moderate convalescents had increased blood CXCL10 and IFN-responsive monocytes, suggesting durative IFN responses. Therefore, IL-1ß- or IFN-responsiveness of myeloid cells may indicate the disease severity of Omicron infection and mediate post-COVID conditions.
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Cytokines , Immunity, Innate/geneticsABSTRACT
The rapid widespread Omicron subvariant BA.5 of SARS-CoV-2 has become a potential imminent pandemic threat, but available vaccines lack high efficacy against this subvariant. Thus, it is urgent to find highly protective vaccination strategies within available SARS-CoV-2 vaccines. Here, by using a SARS-CoV-2 pseudovirus neutralization assay, we demonstrated that the aerosol inhalation of adenoviral vector COVID-19 vaccine after two dose of inactivated vaccine (I-I-Ad5) led to higher levels of neutralizing antibodies against D614G strain (2041.00[95% CI, 1243.00-3351.00] vs 249.00[149.10-415.70]), Omicron BA.2 (467.10[231.00-944.40] vs 72.21[39.31-132.70]), BA.2.12.1(348.5[180.3-673.4] vs 53.17[31.29-90.37]), BA.2.13 (410.40[190.70-883.3] vs 48.48[27.87-84.32]), and BA.5 (442.40 vs 56.08[35.14-89.51]) than three inactivated vaccine doses (I-I-I). Additionally, the level of neutralizing antibodies against BA.5 induced by I-I-Ad5 was 2.41-fold higher than those boosted by a third dose of RBD subunit vaccine (I-I-S) (p = 0.1308). The conventional virus neutralizing assay confirmed that I-I-Ad5 induced higher titre of neutralizing antibodies than I-I-I (116.80[84.51-161.5] vs 4.40[4.00-4.83]). In addition, I-I-Ad5 induced higher, but later, anti-RBD IgG and IgA in plasma than I-I-I. Our study verified that mucosal immunization with aerosol inhalation of adenoviral vector COVID-19 vaccine may be an effective strategy to control the probable wave of BA.5 pandemic in addition to two inactivated vaccines.
Subject(s)
COVID-19 , Viral Vaccines , Humans , COVID-19 Vaccines , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Vaccines, Inactivated , Adenoviridae/geneticsABSTRACT
SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl- is a crucial regulator of host defense, whereas the role of Cl- signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl- concentration ([Cl-]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl-]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl-]i. Our findings suggested that Cl- acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl- signaling pathway might be a novel therapeutic strategy for COVID-19.
Subject(s)
COVID-19 , Chlorine/metabolism , MicroRNAs , Animals , COVID-19/genetics , Humans , Inflammation/pathology , Mice , MicroRNAs/metabolism , Nucleocapsid Proteins , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , SARS-CoV-2Subject(s)
COVID-19 , SARS-CoV-2 , Enzyme-Linked Immunosorbent Assay , Humans , Spike Glycoprotein, CoronavirusABSTRACT
Background: The long-term prognosis of COVID-19 survivors remains poorly understood. It is evidenced that the lung is the main damaged organ in COVID-19 survivors, most notably in impairment of pulmonary diffusion function. Hence, we conducted a meta-analysis of the potential risk factors for impaired diffusing capacity for carbon monoxide (DLCO) in convalescent COVID-19 patients. Methods: We performed a systematic search of PubMed, Web of Science, Embase, and Ovid databases for relevant studies from inception until January 7, 2022, limited to papers involving human subjects. Studies were reviewed for methodological quality. Fix-effects and random-effects models were used to pool results. Heterogeneity was assessed using I2. The publication bias was assessed using the Egger's test. PROSPERO registration: CRD42021265377. Findings: A total of eighteen qualified articles were identified and included in the systematic review, and twelve studies were included in the meta-analysis. Our results showed that female (OR: 4.011; 95% CI: 2.928-5.495), altered chest computerized tomography (CT) (OR: 3.002; 95% CI: 1.319-6.835), age (OR: 1.018; 95% CI: 1.007-1.030), higher D-dimer levels (OR: 1.012; 95% CI: 1.001-1.023) and urea nitrogen (OR: 1.004;95% CI: 1.002-1.007) were identified as risk factors for impaired DLCO. Interpretation: Pulmonary diffusion capacity was the most common impaired lung function in recovered patients with COVID-19. Several risk factors, such as female, altered chest CT, older age, higher D-dimer levels and urea nitrogen are associated with impairment of DLCO. Raising awareness and implementing interventions for possible modifiable risk factors may be valuable for pulmonary rehabilitation. Funding: This work was financially supported by Emergency Key Program of Guangzhou Laboratory (EKPG21-29, EKPG21-31), Incubation Program of National Science Foundation for Distinguished Young Scholars by Guangzhou Medical University (GMU2020-207).
ABSTRACT
The SARS-CoV-2 B.1.617.2 (Delta) variant flared up in late May in Guangzhou, China. Transmission characteristics of Delta variant were analysed for 153 confirmed cases and two complete transmission chains with seven generations were fully presented. A rapid transmission occurred in five generations within 10 days. The basic reproduction number (R0) was 3.60 (95% confidence interval: 2.50-5.30). After redefining the concept of close contact, the proportion of confirmed cases discovered from close contacts increased from 43% to 100%. With the usage of a yellow health code, the potential exposed individuals were self-motivated to take a nucleic acid test and regained public access with a negative testing result. Facing the massive requirement of screening, novel facilities like makeshift inflatable laboratories were promptly set up as a vital supplement and 17 cases were found, with 1 pre-symptomatic. The dynamic adjustment of these three interventions resulted in the decline of Rt from 5.00 to 1.00 within 9 days. By breaking the transmission chain and eliminating the transmission source through extending the scope of the close-contact tracing, health-code usage and mass testing, the Guangzhou Delta epidemic was effectively contained.
ABSTRACT
Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.
Subject(s)
COVID-19 , Pulmonary Disease, Chronic Obstructive , Angiotensin-Converting Enzyme 2 , Epithelial Cells , Humans , Lung , Peptidyl-Dipeptidase A , SARS-CoV-2ABSTRACT
Background: The current COVID-19 pandemic is posing a major challenge to public health on a global scale. While it is generally believed that severe COVID-19 results from over-expression of inflammatory mediators (i.e., a "cytokine storm"), it is still unclear whether and how co-infecting pathogens contribute to disease pathogenesis. To address this, we followed the entire course of the disease in cases with severe or critical COVID-19 to determine the presence and abundance of all potential pathogens present-the total "infectome"-and how they interact with the host immune system in the context of severe COVID-19. Methods: We examined one severe and three critical cases of COVID-19, as well as a set of healthy controls, with longitudinal samples (throat swab, whole blood, and serum) collected from each case. Total RNA sequencing (meta-transcriptomics) was performed to simultaneously investigate pathogen diversity and abundance, as well as host immune responses, in each sample. A Bio-Plex method was used to measure serum cytokine and chemokine levels. Results: Eight pathogens, SARS-CoV-2, Aspergillus fumigatus (A. fumigatus), Mycoplasma orale (M. orale), Myroides odoratus (M. odoratus), Acinetobacter baumannii (A. baumannii), Candida tropicalis, herpes simplex virus (HSV) and human cytomegalovirus (CMV), identified in patients with COVID-19 appeared at different stages of the disease. The dynamics of inflammatory mediators in serum and the respiratory tract were more strongly associated with the dynamics of the infectome compared with SARS-CoV-2 alone. Correlation analysis revealed that pulmonary injury was directly associated with cytokine levels, which in turn were associated with the proliferation of SARS-CoV-2 and co-infecting pathogens. Conclusions: For each patient, the cytokine storm that resulted in acute lung injury and death involved a dynamic and highly complex infectome, of which SARS-CoV-2 was a component. These results indicate the need for a precision medicine approach to investigate both the infection and host response as a standard means of infectious disease characterization.