Respiratory viruses such as influenza do not typically cause viremia; however, SARS-CoV-2 has been detected in the blood of COVID-19 patients with mild and severe symptoms. Detection of SARS-CoV-2 in blood raises questions about its role in pathogenesis as well as transfusion safety concerns. Blood donor reports of symptoms or a diagnosis of COVID-19 after donation (post-donation information, PDI) preceded or coincided with increased general population COVID-19 mortality. Plasma samples from 2,250 blood donors who reported possible COVID-19 related PDI were tested for the presence of SARS-CoV-2 RNA. Detection of RNAemia peaked at 9-15% of PDI donors in late 2020 to early 2021 and fell to ~4% after implementation of widespread vaccination in the population. RNAemic donors were 1.2 to 1.4-fold more likely to report cough or shortness of breath and 1.8-fold more likely to report change in taste or smell compared to infected donors without detectable RNAemia. No infectious virus was detected in plasma from RNAemic donors; inoculation onto permissive cell lines showed <0.7-7 plaque forming units (PFU)/mL and into susceptible mice <100 PFU/mL in RNA positive plasma based on limits of detection in these models. These findings suggest that blood transfusions are highly unlikely to transmit SARS-CoV-2 infection.
Paula Saá, Rebecca V. Fink, Sonia Bakkour, Jing Jin, Graham Simmons, Marcus O. Muench, Hina Dawar, Clara Di Germanio, Alvin J. Hui, David J. Wright, David E. Krysztof, Steven H. Kleinman, Angela Cheung, Theresa Nester, Debra A. Kessler, Rebecca L. Townsend, Bryan R. Spencer, Hany Kamel, Jacquelyn M. Vannoy, Honey Dave, Michael P. Busch, Susan L. Stramer, Mars Stone, Rachael P. Jackman, Philip J. Norris
BACKGROUND. Patients undergoing immune-modifying therapies demonstrate a reduced humoral response after COVID-19 vaccination, but we lack a proper evaluation of the impact of such therapies on vaccine-induced T cell responses. METHODS. We longitudinally characterized humoral and Spike-specific T cell responses in inflammatory bowel disease (IBD) patients who are on antimetabolite therapy (azathioprine or methotrexate), TNF inhibitors and/or other biologic treatment (anti-integrin or anti-p40) for up to 6 months after completing two-dose COVID-19 mRNA vaccination. RESULTS. We demonstrated that a Spike-specific T cell response is not only induced in treated IBD patients at levels similar to healthy individuals, but also sustained at higher magnitude for up to 6 months after vaccination, particularly in those treated with TNF inhibitor therapy. Furthermore, the Spike-specific T cell response in these patients is mainly preserved against mutations present in SARS-CoV-2 B.1.1.529 (Omicron) and characterized by a Th1/IL-10 cytokine profile. CONCLUSION. Despite the humoral response defects, patients under immune-modifying therapies demonstrated a favorable profile of vaccine-induced T cell responses that might still provide a layer of COVID-19 protection. FUNDING. This study was funded by the National Centre for Infectious Diseases NCID Catalyst Grant (FY2021ES) and the National Research Fund Competitive Research Programme (NRF-CRP25-2020-0003). The funders played no role in the design, conduct, or reporting of this study.
Martin Qui, Nina Le Bert, Webber Pak Wo Chan, Malcolm Tan, Shou Kit Hang, Smrithi Hariharaputran, Jean Xiang Ying Sim, Jenny Guek Hong Low, Weiling Ng, Wei Yee Wan, Tiing Leong Ang, Antonio Bertoletti, Ennaliza Salazar
BACKGROUND. Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy (CPT), remains to be fully elucidated. METHODS. Here, we conducted a proof-of-principle study of CPT based on a phase I trial in thirty hospitalized COVID-19 patients with a median interval between the onset of symptoms and the first transfusion of 9 days (IQR, 7-11.8 days). A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends. RESULTS. In the context of this trial CPT was safe as evidenced by the absence of transfusion related adverse events and a low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (p= 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio (HR)= 3.0 [95% confidence interval (CI) 1.1;8.1], p= 0.026). The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their pre-transfusion endogenous neutralization status recipients benefitted from plasma therapy with high neutralizing antibodies (HR= 3.5 [95% CI 1.1;11], p= 0.034). CONCLUSION. In summary, our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response and more broadly point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT04869072 FUNDING. This study was funded via an “Innovation-Pool” project by the University Hospital Zurich, the “Swiss Red Cross “Glückskette” Corona Funding”, Pandemiefonds of the UZH Foundation and the Clinical Research Priority Program ‘Comprehensive Genomic Pathogen Detection’ of the University of Zurich.
Maddalena Marconato, Irene A. Abela, Anthony Hauser, Magdalena Schwarzmüller, Rheliana Katzensteiner, Dominique L. Braun, Selina Epp, Annette Audigé, Jacqueline Weber, Peter Rusert, Emèry Schindler, Chloé Pasin, Emily West, Jürg Böni, Verena Kufner, Michael Huber, Maryam Zaheri, Stefan Schmutz, Beat M. Frey, Roger D. Kouyos, Huldrych F. Günthard, Markus G. Manz, Alexandra Trkola
BACKGROUND. The Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase 1/2 trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing Sarbecovirus conserved Th and CTL epitopes on the nucleocapsid (N), membrane (M) and spike (S2) proteins. METHODS. We conducted a phase-1 primary 2-dose (28-day apart) trial of 10-, 30-, or 100-μg UB-612 in sixty healthy young adults aged 20-55 years, and fifty of them were boosted with 100-μg of UB-612 ~7-9 months post-2nd dose. A separate placebo-controlled and randomized phase-2 study was conducted with two doses of 100-μg UB-612 (n = 3,875, aged 18-85 years). We evaluated interim safety and immunogenicity of the phase-1 until 14 days post-3rd (booster) dose and of the phase-2 until 28 days post-2nd dose. RESULTS. No vaccine-related serious adverse events (SAE) were recorded. The most common solicited AEs were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were: long-lasting viral-neutralizing antibodies and broad T-cell immunity against SARS-CoV2 Variants of Concern (VoCs) including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron variants. CONCLUSION. UB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B- and broad T-cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines. TRIAL REGISTRATION. Clinical Trials.gov: NCT04545749, NCT04773067 and NCT04967742. FUNDING. United Biomedical Inc., Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.
Chang Yi Wang, Kao-Pin Hwang, Hui-Kai Kuo, Wen-Jiun Peng, Yea-Huei Shen, Be-Sheng Kuo, Juin-Hua Huang, Hope Liu, Yu-Hsin Ho, Feng Lin, Shuang Ding, Zhi Liu, Huan-Ting Wu, Ching-Tai Huang, Yuarn-Jang Lee, Ming-Che Liu, Yi-Ching Yang, Po-Liang Lu, Hung-Chin Tsai, Chen-Hsiang Lee, Zhi-Yuan Shi, Chun-Eng Liu, Chun-Hsing Liao, Feng-Yee Chang, Hsiang-Cheng Cheng, Fu-Der Wang, Kuo-Liang Hou, Jennifer Cheng, Min-Sheng Wang, Ya-Ting Yang, Han-Chen Chiu, Ming-Han Jiang, Hao-Yu Shih, Hsuan-Yu Shen, Po-Yen Chang, Yu-Rou Lan, Chi-Tian Chen, Yi-Ling Lin, Jian-Jong Liang, Chun-Che Liao, Yu-Chi Chou, Mary Kate Morris, Carl V. Hanson, Farshad Guirakhoo, Michael Hellerstein, Hui Jing Yu, Chwan-Chuen King, Tracy Kemp, D. Gray Heppner, Thomas P. Monath
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.
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
Eddie C.Y. Wang, Ceri A. Fielding, Richard J. Stanton
Wan-Chen Hsieh, Shih-Yu Chen
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.
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
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).
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
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
Bezawit A. Woldemeskel, Arbor G. Dykema, Caroline Garliss, Saphira Cherfils, Kellie N. Smith, Joel N. Blankson
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