COVID-19
Abstract
Replication of SARS-CoV-2 in human population is defined by distributions of mutants that are present at different frequencies within the infected host, and can be detected by ultra-deep sequencing techniques. In this study, we have examined the SARS-CoV-2 mutant spectra of amplicons from the spike (S)-coding region of five nasopharyngeal isolates derived from vaccine-breakthrough patients. Interestingly, all patients became infected with the Alpha variant but amino acid substitutions that correspond to the Delta Plus, Iota and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from vaccine-breakthrough patients revealed a rich reservoir of mutant types, and may also inform of tolerated substitutions that can be represented in epidemiological dominant variants.
Authors
Brenda Martínez-González, Lucía Vázquez-Sirvent, María E. Soria, Pablo Mínguez, Llanos Salar-Vidal, Carlos García-Crespo, Isabel Gallego, Ana Ávila, Carlos Llorens, Beatriz Soriano, Ricardo Ramos-Ruiz, Jaime Esteban, Ricardo Fernandez-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruiz-Hornillos, Concepción Pérez-Jorge, Esteban Domingo, Celia Perales
Abstract
Authors
Eddie C.Y. Wang, Ceri A. Fielding, Richard J. Stanton
Abstract
Authors
Wan-Chen Hsieh, Shih-Yu Chen
Abstract
Many SARS-CoV-2 neutralizing antibodies (nAbs) lose potency against variants of concern. In this study, we developed 2 strategies to produce mutation-resistant antibodies. First, a yeast library expressing mutant receptor binding domains (RBDs) of the spike protein was utilized to screen for potent nAbs that are least susceptible to viral escape. Among the candidate antibodies, P5-22 displayed ultrahigh potency for virus neutralization as well as an outstanding mutation resistance profile. Additionally, P14-44 and P15-16 were recognized as mutation-resistant antibodies with broad betacoronavirus neutralization properties. P15-16 has only 1 binding hotspot, which is K378 in the RBD of SARS-CoV-2. The crystal structure of the P5-22, P14-44, and RBD ternary complex clarified the unique mechanisms that underlie the excellent mutation resistance profiles of these antibodies. Secondly, polymeric IgG enhanced antibody avidity by eliminating P5-22’s only hotspot, residue F486 in the RBD, thereby potently blocking cell entry by mutant viruses. Structural and functional analyses of antibodies screened using both potency assays and the yeast RBD library revealed rare, ultrapotent, mutation-resistant nAbs against SARS-CoV-2.
Authors
Jia Zou, Li Li, Peiyi Zheng, Wenhua Liang, Siyi Hu, Shuaixiang Zhou, Yanqun Wang, Jincun Zhao, Daopeng Yuan, Lu Liu, Dongdong Wu, Mengqiu Xu, Fangfang Zhang, Mengzhu Zhu, Zhihai Wu, Xiaochao Cao, Meng Ni, Xiaomin Ling, Yue Wu, Zhihui Kuang, Moyan Hu, Jianfeng Li, Xue Li, Xiling Guo, Tianmin Xu, Haiping Jiang, Changshou Gao, Michael Yu, Junjian Liu, Nanshan Zhong, Jianfeng Zhou, Jian-an Huang, Tengchuan Jin, Jianxing He
Abstract
BACKGROUND. Immunization against SARS-CoV-2, the causative agent of coronavirus disease-19 (COVID-19) occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last. METHODS. We performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to one year post infection and following mRNA vaccination in naïve and COVID-19 recovered individuals. RESULTS. We found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly especially in naïve subjects. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naïve subjects, while it results ineffective in previously SARS-CoV-2 infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to one year following natural infection in a cohort of unvaccinated individuals. CONCLUSION. Short-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. A booster dose restores optimal anti-spike immunity in naïve subjects, while the need for vaccinated COVID-19 recovered subjects has yet to be defined. TRIAL REGISTRATION. na FUNDING. This study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018-2022), by the University of Florence, project RICTD2122, by the Italian Ministry of Health (COVID-2020-12371849) and by Tuscany Region (TagSARS CoV 2).
Authors
Alessio Mazzoni, Anna Vanni, Michele Spinicci, Giulia Lamacchia, Seble Tekle Kiros, Arianna Rocca, Manuela Capone, Nicoletta Lauria, Lorenzo Salvati, Alberto Carnasciali, Elisabetta Mantengoli, Parham Farahvachi, Lorenzo Zammarchi, Filippo Lagi, Maria Grazia Colao, Francesco Liotta, Lorenzo Cosmi, Laura Maggi, Alessandro Bartoloni, Gian Maria Rossolini, Francesco Annunziato
Abstract
Recent studies have shown that vaccinated individuals harbor T cells that can cross-recognize SARS-CoV-2 and endemic human common cold coronaviruses (HCoVs). However, it is still unknown whether CD4+ T cells from vaccinated individuals recognize peptides from bat coronaviruses that may have the potential of causing future pandemics. In this study, we identified a SARS-CoV-2 spike protein epitope (S815-827) that is conserved in coronaviruses from different genera and subgenera including SARS-CoV, MERS-CoV, multiple bat coronaviruses and a feline coronavirus. Our results showed that S815-827 is recognized by 42% of vaccinated participants in our study who received the Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) COVID-19 vaccines. Using T cell expansion and T cell receptor sequencing assays, we demonstrated that S815-827-reactive CD4+ T cells from the majority of responders cross-recognize homologous peptides from at least 6 other diverse coronaviruses. Our results support the hypothesis that the current mRNA vaccines elicit T cell responses that can cross-recognize bat coronaviruses, and thus might induce some protection against potential zoonotic outbreaks. Furthermore, our data provide important insights that inform the development of T cell-based pan-coronavirus vaccine strategies
Authors
Bezawit A. Woldemeskel, Arbor G. Dykema, Caroline Garliss, Saphira Cherfils, Kellie N. Smith, Joel N. Blankson
Abstract
Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality. Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 Spike protein engaged the CD42b receptor to activate platelet via two distinct signaling pathways, and promoted platelet-monocyte communication through the engagement of P-selectin/PGSL-1 and CD40L/CD40, which led to pro-inflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation and a cytokine storm are correlated in severely affected COVID-19 patients, and suggest a potential target for therapeutic intervention.
Authors
Tianyang Li, Yang Yang, Yongqi Li, Zhengmin Wang, Faxiang Ma, Runqi Luo, Xiaoming Xu, Guo Zhou, Jianhua Wang, Junqi Niu, Guoyue Lv, Ian N Crispe, Zhengkun Tu
Abstract
Authors
Anthony T. Tan, Nina Le Bert, Antonio Bertoletti
Abstract
BACKGROUND. Severe coronavirus disease 2019 (COVID-19) infection is associated with a dysregulated immune response, which can result in cytokine release syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19–associated ARDS have elevated free serum levels of the cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT; also known as TNFSF14). Such patients may benefit from LIGHT neutralization therapy. METHODS. This randomized, double-blind, multicenter, proof-of-concept trial enrolled adults hospitalized with COVID-19–associated pneumonia and mild to moderate ARDS. Patients received standard of care plus a single dose of CERC-002 or placebo. The primary endpoint was the proportion of patients receiving CERC-002 who remained alive and free of respiratory failure through day 28. Safety was assessed via adverse event monitoring. RESULTS. For most of the 83 enrolled patients, standard of care included systemic corticosteroids (88.0%) or remdesivir (57.8%). A higher proportion of patients remained alive and free of respiratory failure through day 28 after receiving CERC-002 (83.9%) versus placebo (64.5%; P = .044), including in patients ≥60 years (76.5% vs 47.1%, respectively; P = .042). Mortality rates were 7.7% (CERC-002) and 14.3% (placebo) at day 28 and 10.8% and 22.5%, respectively, at day 60. Treatment-emergent adverse events were less frequent with CERC-002 than placebo. CONCLUSION. For patients with COVID-19–associated ARDS, adding CERC-002 to standard of care treatment reduces LIGHT levels and might reduce the risk of respiratory failure and death. TRIAL REGISTRATION. ClinicalTrials.gov NCT04412057. FUNDING. Avalo Therapeutics (formerly Cerecor, Inc.)
Authors
David S. Perlin, Garry A. Neil, Colleen Anderson, Inbal Zafir-Lavie, Shane Raines, Carl F. Ware, H. Jeffrey Wilkins
Abstract
Dear Editor, We read with interest the article by Li and colleagues on the association between ACE inhibitors/angiotensin receptor blockers (ACE-I/ARB) use and in-hospital mortality among COVID-19 patients (1). The authors concluded that the use of ARB was associated with a significant reduction in in-hospital mortality among African American (AA) patients but not non-AA patients. However, we believe this conclusion is not per statistical principles and potentially misguiding readers. As noted by Altman and Bland (2), statistical analysis should be targeted to the clinical question: is the association between ARB use and in-hospital mortality different between AA and non-AA patients? To answer this question, one should directly compare the estimates (interaction test) (2), performed and reported by the authors. Here we argue that they did not accurately interpret this analysis. The authors showed an odds ratio (OR) of 0.196 (95% confidence interval [CI], 0.074 – 0.516) in the AA population and an OR of 0.687 (95% CI, 0.427 – 1.106) in the non-AA population. Accordingly, the interaction term was non-significant (95% CI, 0.185–1.292; P = 0.149).[1] As the authors stated that “Statistical significance was defined as a 2-sided P value less than 0.05”, the correct interpretation of this result would be: the association of ACEi/ARB use and in-hospital mortality was not significantly different between these two populations (2). In contrast to this interpretation, the authors concluded that the association was only present in the AA population, which is not compatible with their analysis. The potential association between ACEi/ARB use and COVID-19 in-hospital mortality is of great interest to the medical community. Further, the ability to provide reliable subgroup analyses is vital in clinical decision-making (3). Interaction analyses are essential to answer the clinically relevant question of whether a specific subgroup of patients can benefit more from an intervention. However, we believe the correct interpretation of these results does not support the author’s conclusion.
Authors
Arthur M. Albuquerque, Carolina B. Santolia, Ashish Verma
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