247 results on '"Yong Shi"'
Search Results
2. Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants
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Panke Qu, John P. Evans, Chaitanya Kurhade, Cong Zeng, Yi-Min Zheng, Kai Xu, Pei-Yong Shi, Xuping Xie, and Shan-Lu Liu
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Virology ,Microbiology - Abstract
Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and reduced disease severity; however, the underlying mechanism is not fully understood. In addition, whether the most recent Omicron subvariants, including BA.5 and BA.2.75, use the same pathway as their ancestor for entry is currently not known.
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- 2023
3. Correction for Zhou et al., 'Neutralization Titers in Vaccinated Patients with SARS-CoV-2 Delta Breakthrough Infections'
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Jing Zou, Xuping Xie, Mingru Liu, Pei-Yong Shi, and Ping Ren
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Virology ,Microbiology - Published
- 2022
4. Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages
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Hongjie Xia, Jason Yeung, Birte Kalveram, Cody J. Bills, John Yun-Chung Chen, Chaitanya Kurhade, Jing Zou, Steven G. Widen, Brian R. Mann, Rebecca Kondor, C. Todd Davis, Bin Zhou, David E. Wentworth, Xuping Xie, and Pei-Yong Shi
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Infectious Diseases ,Epidemiology ,Virology ,Drug Discovery ,Immunology ,Parasitology ,General Medicine ,Microbiology - Abstract
The rapid evolution of SARS-CoV-2 Omicron sublineages mandates a better understanding of viral replication and cross-neutralization among these sublineages. Here we used K18-hACE2 mice and primary human airway cultures to examine the viral fitness and antigenic relationship among Omicron sublineages. In both K18-hACE2 mice and human airway cultures, Omicron sublineages exhibited a replication order of BA.5 ≥ BA.2 ≥ BA.2.12.1 > BA.1; no difference in body weight loss was observed among different sublineage-infected mice. The BA.1-, BA.2-, BA.2.12.1-, and BA.5-infected mice developed distinguisable cross-neutralizations against Omicron sublineages, but exhibited little neutralizations against the index virus (i.e., USA-WA1/2020) or the Delta variant. Surprisingly, the BA.5-infected mice developed higher neutralization activity against heterologous BA.2 and BA.2.12.1 than that against homologous BA.5; serum neutralizing titers did not always correlate with viral replication levels in infected animals. Our results revealed a distinct antigenic cartography of Omicron sublineages and support the bivalent vaccine approach.
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- 2022
5. Neutralization Titers in Vaccinated Patients with SARS-CoV-2 Delta Breakthrough Infections
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Jing Zou, Xuping Xie, Mingru Liu, Pei-Yong Shi, and Ping Ren
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Viral Envelope Proteins ,Neutralization Tests ,SARS-CoV-2 ,Virology ,COVID-19 ,Humans ,Antibodies, Viral ,Microbiology ,Antibodies, Neutralizing - Abstract
Given that neutralizing antibodies play a key role in protection of SARS-CoV-2 infection, it is important to define the neutralization levels in vaccinated individuals when they contracted breakthrough infections. In this study, we analyzed the neutralization levels from 64 vaccinated patients on days 0 to 5 before they tested positive for Delta breakthrough infections.
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- 2022
6. The multiple roles of nsp6 in the molecular pathogenesis of SARS-CoV-2
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Cody Bills, Xuping Xie, and Pei-Yong Shi
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Pharmacology ,Virology - Published
- 2023
7. Corrigendum to 'Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics' 'Antiviral Research 209 (2023)/105484'
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Jimena Perez-Vargas, Tirosh Shapira, Andrea D. Olmstead, Ivan Villanueva, Connor A.H. Thompson, Siobhan Ennis, Guang Gao, Joshua De Guzman, David E. Williams, Meng Wang, Aaleigha Chin, Diana Bautista-Sanchez, Olga Agafitei, Paul Levett, Xuping Xie, Genoveffa Nuzzo, Vitor F. Freire, Jairo I. Quintana-Bulla, Darlon I. Bernardi, Juliana R. Gubiani, Virayu Suthiphasilp, Achara Raksat, Pornphimol Meesakul, Isaraporn Polbuppha, Sarot Cheenpracha, Wuttichai Jaidee, Kwanjai Kanokmedhakul, Chavi Yenjai, Boonyanoot Chaiyosang, Helder Lopes Teles, Emiliano Manzo, Angelo Fontana, Richard Leduc, Pierre-Luc Boudreault, Roberto G.S. Berlinck, Surat Laphookhieo, Somdej Kanokmedhakul, Ian Tietjen, Artem Cherkasov, Mel Krajden, Ivan Robert Nabi, Masahiro Niikura, Pei-Yong Shi, Raymond J. Andersen, and François Jean
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Pharmacology ,Virology - Published
- 2023
8. CMPK2 restricts Zika virus replication by inhibiting viral translation
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Joanna B. Pawlak, Jack Chun-Chieh Hsu, Hongjie Xia, Patrick Han, Hee-Won Suh, Tyler L. Grove, Juliet Morrison, Pei-Yong Shi, Peter Cresswell, and Maudry Laurent-Rolle
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Virology ,Immunology ,Genetics ,Parasitology ,Molecular Biology ,Microbiology - Abstract
Flaviviruses continue to emerge as global health threats. There are currently no Food and Drug Administration (FDA) approved antiviral treatments for flaviviral infections. Therefore, there is a pressing need to identify host and viral factors that can be targeted for effective therapeutic intervention. Type I interferon (IFN-I) production in response to microbial products is one of the host’s first line of defense against invading pathogens. Cytidine/uridine monophosphate kinase 2 (CMPK2) is a type I interferon-stimulated gene (ISG) that exerts antiviral effects. However, the molecular mechanism by which CMPK2 inhibits viral replication is unclear. Here, we report that CMPK2 expression restricts Zika virus (ZIKV) replication by specifically inhibiting viral translation and that IFN-I- induced CMPK2 contributes significantly to the overall antiviral response against ZIKV. We demonstrate that expression of CMPK2 results in a significant decrease in the replication of other pathogenic flaviviruses including dengue virus (DENV-2), Kunjin virus (KUNV) and yellow fever virus (YFV). Importantly, we determine that the N-terminal domain (NTD) of CMPK2, which lacks kinase activity, is sufficient to restrict viral translation. Thus, its kinase function is not required for CMPK2’s antiviral activity. Furthermore, we identify seven conserved cysteine residues within the NTD as critical for CMPK2 antiviral activity. Thus, these residues may form an unknown functional site in the NTD of CMPK2 contributing to its antiviral function. Finally, we show that mitochondrial localization of CMPK2 is required for its antiviral effects. Given its broad antiviral activity against flaviviruses, CMPK2 is a promising potential pan-flavivirus inhibitor.
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- 2023
9. AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5
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Mikael Feracci, Cécilia Eydoux, Véronique Fattorini, Lea Lo Bello, Pierre Gauffre, Barbara Selisko, Priscila Sutto-Ortiz, Ashleigh Shannon, Hongjie Xia, Pei-Yong Shi, Mathieu Noel, Françoise Debart, Jean-Jacques Vasseur, Steve Good, Kai Lin, Adel Moussa, Jean-Pierre Sommadossi, Aurélie Chazot, Karine Alvarez, Jean-Claude Guillemot, Etienne Decroly, François Ferron, Bruno Canard, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The University of Texas Medical Branch (UTMB), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), and European Virus Bioinformatics Center [Jena]
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STRUCTURAL BASIS ,Pharmacology ,RNAPOLYMERASE ,Virology ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,2'-OPROTEIN MOTIF ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry - Abstract
International audience; AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2 '-methyl-2 '-fluoro guanosine 5 '-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show that AT-9010 has several modes of action on DENV full-length NS5. AT-9010 does not inhibit the primer pppApG synthesis step significantly. However, AT-9010 targets two NS5-associated enzyme activities, the RNA 2 '-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. Crystal structure and RNA methyltransferase (MTase) activities of the DENV 2 MTase domain in complex with AT-9010 at 1.97 angstrom resolution shows the latter bound to the GTP/RNA-cap binding site, accounting for the observed inhibition of 2 '-O but not N7-methylation activity. AT-9010 is discriminated-10 to 14-fold against GTP at the NS5 active site of all four DENV1-4 NS5 RdRps, arguing for significant inhibi-tion through viral RNA synthesis termination. In Huh-7 cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC50 approximate to 0.50 mu M), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses.
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- 2023
10. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans
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John L. Perez, Isabel Vogler, Evelyna Derhovanessian, Gábor Boros, David A. Cooper, Camila R. Fontes-Garfias, Kristen E. Pascal, Armin Schultz, Alexander Muik, Martin Bexon, Pei Yong Shi, Peter Koch, Ann Kathrin Eller, Verena Lörks, Mark Cutler, Daniel Maurus, Ludwig Heesen, Philip R. Dormitzer, Ugur Sahin, Kathrin U. Jansen, Manuel Tonigold, Jan Grützner, Azita J. Mahiny, Corinna Rosenbaum, Stefanie Bolte, Mathias Vormehr, Marie Cristine Kühnle, Sybille Baumann, Asaf Poran, Alexander Ulges, Alexandra Kemmer-Brück, Christos A. Kyratsous, Dirk Becker, Özlem Türeci, Alina Baum, Sebastian Brachtendorf, Lena M. Kranz, Carsten Boesler, Rolf Hilker, Tania Palanche, Julian Sikorski, Nicole Bidmon, Ulrich Luxemburger, David J. Langer, Jesse Z. Dong, Gábor Szabó, Jasmin Quandt, Katalin Karikó, and Jonas Reinholz
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0301 basic medicine ,Interleukin 2 ,Multidisciplinary ,Biology ,Major histocompatibility complex ,Virology ,Immunoglobulin G ,Epitope ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,biology.protein ,medicine ,Interferon gamma ,030212 general & internal medicine ,Antibody ,CD8 ,medicine.drug - Abstract
BNT162b2, a lipid nanoparticle (LNP) formulated nucleoside-modified messenger RNA (mRNA) that encodes the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) stabilized in the prefusion conformation, has demonstrated 95% efficacy in preventing coronavirus disease-19 (COVID-19)1. Here we extend our previous phase 1/2 trial report2 and present BNT162b2 prime/boost induced immune response data from a second phase 1/2 trial in healthy adults (18-55 years of age). BNT162b2 elicited strong antibody responses, with SARS-CoV-2 serum 50% neutralizing geometric mean titers up to 3.3-fold above those observed in COVID-19 human convalescent samples (HCS) one week post-boost. BNT162b2-elicited sera neutralized 22 pseudoviruses bearing SARS-CoV-2 S variants. Most participants had a strong IFNγ- or IL-2-positive CD8+ and CD4+ T helper type 1 (TH1) T cell response, detectable throughout the full observation period of nine weeks following the boost. pMHC multimer technology identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week post-boost, epitope-specific CD8+ T cells of the early differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes conserved in a broad range of variants at well tolerated doses.
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- 2021
11. Erratum for Vanderheiden et al., 'CCR2 Signaling Restricts SARS-CoV-2 Infection'
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Abigail Vanderheiden, Jeronay Thomas, Allison L. Soung, Meredith E. Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A. Cowan, Kathryn Pellegrini, Adrian Creanga, Amarendra Pegu, Alexandrine Derrien-Colemyn, Pei-Yong Shi, Arash Grakoui, Robyn S. Klein, Steven E. Bosinger, Jacob E. Kohlmeier, Vineet D. Menachery, and Mehul S. Suthar
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Virology ,Microbiology - Published
- 2022
12. Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein
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Kamyab Javanmardi, Thomas H. Segall-Shapiro, Chia-Wei Chou, Daniel R. Boutz, Randall J. Olsen, Xuping Xie, Hongjie Xia, Pei-Yong Shi, Charlie D. Johnson, Ankur Annapareddy, Scott Weaver, James M. Musser, Andrew D. Ellington, Ilya J. Finkelstein, and Jimmy D. Gollihar
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Membrane Glycoproteins ,SARS-CoV-2 ,COVID-19 ,Antibodies, Viral ,Microbiology ,Antibodies, Neutralizing ,Epitopes ,Viral Envelope Proteins ,Virology ,Mutation ,Spike Glycoprotein, Coronavirus ,Humans ,Parasitology ,Angiotensin-Converting Enzyme 2 - Abstract
SummaryThe worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the repeated emergence of variants of concern. The Omicron variant has two dominant sub-lineages, BA.1 and BA.2, each with unprecedented numbers of nonsynonymous and indel spike protein mutations: 33 and 29, respectively. Some of these mutations individually increase transmissibility and enhance immune evasion, but their interactions within the Omicron mutational background is unknown. We characterize the molecular effects of all Omicron spike mutations on expression, human ACE2 receptor affinity, and neutralizing antibody recognition. We show that key mutations enable escape from neutralizing antibodies at a variety of epitopes. Stabilizing mutations in the N-terminal and S2 domains of the spike protein compensate for destabilizing mutations in the receptor binding domain, thereby enabling the record number of mutations in Omicron sub-lineages. Taken together, our results provide a comprehensive account of the mutational effects in the Omicron spike protein and illuminate previously unknown mechanisms of how the N-terminal domain can compensate for destabilizing mutations within the more evolutionarily constrained RBD.
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- 2022
13. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies
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Alfred H.J. Kim, Mahima Thapa, Jane A. O’Halloran, Emma S. Winkler, Aaron J. Schmitz, Xianwen Zhang, Herbert W. Virgin, Jackson S. Turner, Seth J. Zost, John M. Errico, Xuping Xie, Davide Corti, Lindsay Droit, Yang Liu, Naveenchandra Suryadevara, Daved H. Fremont, Stephen Tahan, Pei Yong Shi, Jianying Liu, Wooseob Kim, Michael S. Diamond, Parakkal Deepak, Adrianus C. M. Boon, James E. Crowe, Dora Pinto, James Brett Case, Laura A. VanBlargan, Ali H. Ellebedy, Pavlo Gilchuk, Rachel M. Presti, Rita E. Chen, and David Wang
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0301 basic medicine ,biology ,medicine.drug_class ,General Medicine ,Monoclonal antibody ,Virology ,General Biochemistry, Genetics and Molecular Biology ,Neutralization ,In vitro ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,law ,Polyclonal antibodies ,030220 oncology & carcinogenesis ,Monoclonal ,medicine ,Vero cell ,Recombinant DNA ,biology.protein ,Antibody - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.
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- 2021
14. Molecular epidemiological characteristics of echovirus 6 in mainland China: extensive circulation of genotype F from 2007 to 2018
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Qian Yang, Tianjiao Ji, Wenbo Xu, Lili Jiang, Shuaifeng Zhou, Dongmei Yan, Yong Zhang, Wenjun Cheng, Yang Song, Ru Cai, and Yong Shi
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Most recent common ancestor ,China ,Genotype ,Echovirus Infections ,Biology ,Evolution, Molecular ,03 medical and health sciences ,Phylogenetics ,Virology ,Echovirus 6, Human ,Prevalence ,Humans ,Phylogeny ,030304 developmental biology ,Genetics ,Molecular Epidemiology ,0303 health sciences ,Molecular epidemiology ,Phylogenetic tree ,030306 microbiology ,Population size ,Nucleic acid sequence ,General Medicine ,Phylogeography ,RNA, Viral ,Capsid Proteins ,Original Article ,Hand, Foot and Mouth Disease - Abstract
Echovirus 6 (E6) is associated with various clinical diseases and is frequently detected in environmental sewage. Despite its high prevalence in humans and the environment, little is known about its molecular phylogeography in mainland China. In this study, 114 of 21,539 (0.53%) clinical specimens from hand, foot, and mouth disease (HFMD) cases collected between 2007 and 2018 were positive for E6. The complete VP1 sequences of 87 representative E6 strains, including 24 strains from this study, were used to investigate the evolutionary genetic characteristics and geographical spread of E6 strains. Phylogenetic analysis based on VP1 nucleotide sequence divergence showed that, globally, E6 strains can be grouped into six genotypes, designated A to F. Chinese E6 strains collected between 1988 and 2018 were found to belong to genotypes C, E, and F, with genotype F being predominant from 2007 to 2018. There was no significant difference in the geographical distribution of each genotype. The evolutionary rate of E6 was estimated to be 3.631 × 10-3 substitutions site-1 year-1 (95% highest posterior density [HPD]: 3.2406 × 10-3-4.031 × 10-3 substitutions site-1 year-1) by Bayesian MCMC analysis. The most recent common ancestor of the E6 genotypes was traced back to 1863, whereas their common ancestor in China was traced back to around 1962. A small genetic shift was detected in the Chinese E6 population size in 2009 according to Bayesian skyline analysis, which indicated that there might have been an epidemic around that year.
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- 2021
15. BNT162b vaccines protect rhesus macaques from SARS-CoV-2
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Bernadette Jesionek, Charles Tan, Christoph Kröner, Jennifer Obregon, Stephanie Hein, Kathleen M. Brasky, Andreas Kuhn, Leyla Fischer, Guy Singh, Diana Schneider, Kathrin U. Jansen, Jane Fontenot, Seungil Han, Michal Gazi, Corinna Rosenbaum, Ingrid L. Scully, Pei Yong Shi, Parag Sahasrabudhe, Stefanie A. Krumm, Hanna Junginger, Camila R. Fontes-Garfias, Julia Schlereth, Bonny Gaby Lui, Mathias Vormehr, Andre P. Heinen, Alptekin Güler, Stephanie Fesser, Sarah C. Dany, Ellene H. Mashalidis, Danka Pavliakova, Shambhunath Choudhary, Mohan S. Maddur, Petra Adams-Quack, Yvonne Feuchter, Matthew C. Griffor, Ferdia Bates, Ramón de la Caridad Güimil Garcia, Tara Ciolino, Özlem Türeci, Stefan Schille, Kena A. Swanson, Kerstin C. Walzer, Alexander Muik, Jakob Loschko, Ayuko Ota-Setlik, Nicole L. Nedoma, Lena M. Kranz, Tompkins Kristin Rachael, Thorsten Klamp, Ugur Sahin, Ann Kathrin Wallisch, Warren Kalina, Olga Gonzalez, Fulvia Vascotto, Philip R. Dormitzer, Ye Che, Kendra J. Alfson, Ricardo Carrion, Thomas Ziegenhals, Shannan Hall-Ursone, Rani S. Sellers, Thomas Hiller, Isis Kanevsky, Matthew R. Gutman, Michael W. Pride, Stephanie Erbar, Bianca Sänger, Deepak Kaushal, Journey Cole, David Eisel, Andreas A.H. Su, Joshua A. Lees, Annette B. Vogel, and Arianne Plaschke
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Male ,Models, Molecular ,0301 basic medicine ,Aging ,Internationality ,T-Lymphocytes ,Respiratory System ,Antibodies, Viral ,Mice ,0302 clinical medicine ,Antigens, Viral ,chemistry.chemical_classification ,Clinical Trials as Topic ,Mice, Inbred BALB C ,Vaccines, Synthetic ,Multidisciplinary ,Vaccination ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,RNA, Viral ,Female ,Antibody ,COVID-19 Vaccines ,T cell ,Biology ,Cell Line ,03 medical and health sciences ,Antigen ,medicine ,Animals ,Humans ,BNT162 Vaccine ,COVID-19 Serotherapy ,SARS-CoV-2 ,Immunization, Passive ,COVID-19 ,RNA ,Antibodies, Neutralizing ,Macaca mulatta ,Virology ,Disease Models, Animal ,030104 developmental biology ,Solubility ,Immunization ,chemistry ,biology.protein ,Protein Multimerization ,Glycoprotein ,CD8 - Abstract
A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime–boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2–18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1–3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728). BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge.
- Published
- 2021
16. Reverse genetic systems of SARS-CoV-2 for antiviral research
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Chaitanya Kurhade, Xuping Xie, and Pei-Yong Shi
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Pharmacology ,Virology - Published
- 2023
17. Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics
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Jimena Pérez-Vargas, Tirosh Shapira, Andrea D. Olmstead, Ivan Villanueva, Connor A.H. Thompson, Siobhan Ennis, Guang Gao, Joshua De Guzman, David E. Williams, Meng Wang, Aaleigha Chin, Diana Bautista-Sánchez, Olga Agafitei, Paul Levett, Xuping Xie, Genoveffa Nuzzo, Vitor F. Freire, Jairo I. Quintana-Bulla, Darlon I. Bernardi, Juliana R. Gubiani, Virayu Suthiphasilp, Achara Raksat, Pornphimol Meesakul, Isaraporn Polbuppha, Sarot Cheenpracha, Wuttichai Jaidee, Kwanjai Kanokmedhakul, Chavi Yenjai, Boonyanoot Chaiyosang, Helder Lopes Teles, Emiliano Manzo, Angelo Fontana, Richard Leduc, Pierre-Luc Boudreault, Roberto G.S. Berlinck, Surat Laphookhieo, Somdej Kanokmedhakul, Ian Tietjen, Artem Cherkasov, Mel Krajden, Ivan Robert Nabi, Masahiro Niikura, Pei-Yong Shi, Raymond J. Andersen, and François Jean
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Pharmacology ,Virology ,PRODUTOS NATURAIS - Abstract
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC
- Published
- 2023
18. BNT162b2-Elicited Neutralization against New SARS-CoV-2 Spike Variants
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Jianying Liu, Yang Liu, Wei Chen, Kathrin U. Jansen, Alexander Muik, Philip R. Dormitzer, Xianwen Zhang, Scott C. Weaver, Hui Cai, Ritu Sarkar, Pei Yong Shi, Mark Cutler, Hongjie Xia, Xuping Xie, Camila R. Fontes-Garfias, Kena A. Swanson, Ugur Sahin, Jing Zou, and David A. Cooper
- Subjects
2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Antibodies, Viral ,Neutralization ,law.invention ,Immunogenicity, Vaccine ,law ,Correspondence ,Humans ,Medicine ,BNT162 Vaccine ,biology ,SARS-CoV-2 ,business.industry ,Immunogenicity ,COVID-19 ,General Medicine ,Serum samples ,Antibodies, Neutralizing ,Virology ,biology.protein ,Recombinant DNA ,Antibody ,business - Abstract
BNT162b2 Vaccine and Emerging SARS-CoV-2 Variants A total of 20 serum samples from 15 persons who received the BNT162b2 vaccine showed strong neutralization activity against recombinant viruses eng...
- Published
- 2021
19. Spike mutation D614G alters SARS-CoV-2 fitness
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Zhiqiang Ku, Scott C. Weaver, Xianwen Zhang, Hongjie Xia, Jessica A. Plante, Jing Zou, Yang Liu, Zhiqiang An, John P. Bilello, Kenneth S. Plante, Dionna Scharton, Alexander N. Freiberg, Antonio E. Muruato, Xuping Xie, Camila R. Fontes-Garfias, Pei Yong Shi, Divya Mirchandani, Jianying Liu, Birte Kalveram, Bryan A. Johnson, Vineet D. Menachery, and Kumari G. Lokugamage
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Male ,0301 basic medicine ,COVID-19 Vaccines ,viruses ,Virus Replication ,medicine.disease_cause ,Models, Biological ,Article ,Virus ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,Neutralization Tests ,Cricetinae ,medicine ,Animals ,Humans ,Lung ,Mutation ,Multidisciplinary ,Mesocricetus ,biology ,Protein Stability ,SARS-CoV-2 ,Virion ,COVID-19 ,Viral Load ,biology.organism_classification ,Vaccine efficacy ,Antibodies, Neutralizing ,Virology ,Trachea ,Disease Models, Animal ,Nasal Mucosa ,030104 developmental biology ,medicine.anatomical_structure ,Viral replication ,Spike Glycoprotein, Coronavirus ,biology.protein ,Genetic Fitness ,Antibody ,Viral load ,030217 neurology & neurosurgery ,Respiratory tract - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein substitution D614G became dominant during the coronavirus disease 2019 (COVID-19) pandemic1,2. However, the effect of this variant on viral spread and vaccine efficacy remains to be defined. Here we engineered the spike D614G substitution in the USA-WA1/2020 SARS-CoV-2 strain, and found that it enhances viral replication in human lung epithelial cells and primary human airway tissues by increasing the infectivity and stability of virions. Hamsters infected with SARS-CoV-2 expressing spike(D614G) (G614 virus) produced higher infectious titres in nasal washes and the trachea, but not in the lungs, supporting clinical evidence showing that the mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increase transmission. Sera from hamsters infected with D614 virus exhibit modestly higher neutralization titres against G614 virus than against D614 virus, suggesting that the mutation is unlikely to reduce the ability of vaccines in clinical trials to protect against COVID-19, and that therapeutic antibodies should be tested against the circulating G614 virus. Together with clinical findings, our work underscores the importance of this variant in viral spread and its implications for vaccine efficacy and antibody therapy.
- Published
- 2020
20. A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission
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Rubing Chen, Hongjie Xia, Scott C. Weaver, Sasha R. Azar, Maki Wakamiya, Sanjay K. Singh, Yang Liu, Rongjuan Pei, Chao Shan, Sherry L. Haller, Nikos Vasilakis, Jianying Liu, Pei Yong Shi, Camila R. Fontes-Garfias, Shannan L. Rossi, Antonio E. Muruato, and Xuping Xie
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Male ,0301 basic medicine ,Mutation rate ,030106 microbiology ,Virulence ,Viremia ,Aedes aegypti ,medicine.disease_cause ,law.invention ,Zika virus ,Mice ,03 medical and health sciences ,Viral Envelope Proteins ,Pregnancy ,law ,medicine ,Animals ,Humans ,Epidemics ,Phylogeny ,Mutation ,Multidisciplinary ,biology ,Zika Virus Infection ,virus diseases ,Zika Virus ,Viral Load ,Biological Sciences ,medicine.disease ,biology.organism_classification ,Virology ,Mice, Inbred C57BL ,Macaca fascicularis ,030104 developmental biology ,Transmission (mechanics) ,Female ,Viral load - Abstract
Arboviruses maintain high mutation rates due to lack of proofreading ability of their viral polymerases, in some cases facilitating adaptive evolution and emergence. Here we show that, just before its 2013 spread to the Americas, Zika virus (ZIKV) underwent an envelope protein V473M substitution (E-V473M) that increased neurovirulence, maternal-to-fetal transmission, and viremia to facilitate urban transmission. A preepidemic Asian ZIKV strain (FSS13025 isolated in Cambodia in 2010) engineered with the V473M substitution significantly increased neurovirulence in neonatal mice and produced higher viral loads in the placenta and fetal heads in pregnant mice. Conversely, an epidemic ZIKV strain (PRVABC59 isolated in Puerto Rico in 2015) engineered with the inverse M473V substitution reversed the pathogenic phenotypes. Although E-V473M did not affect oral infection of Aedes aegypti mosquitoes, competition experiments in cynomolgus macaques showed that this mutation increased its fitness for viremia generation, suggesting adaptive evolution for human viremia and hence transmission. Mechanistically, the V473M mutation, located at the second transmembrane helix of the E protein, enhances virion morphogenesis. Overall, our study revealed E-V473M as a critical determinant for enhanced ZIKV virulence, intrauterine transmission during pregnancy, and viremia to facilitate urban transmission.
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- 2020
21. A cocrystal structure of dengue capsid protein in complex of inhibitor
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William K. Russell, Hongjie Xia, Christian G. Noble, Mark A. White, Pei Yong Shi, Luis Marcelo F. Holthauzen, Kyung H. Choi, Jing Zou, and Xuping Xie
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Models, Molecular ,Protein Conformation ,medicine.drug_class ,viruses ,Dengue virus ,medicine.disease_cause ,Antiviral Agents ,Dengue fever ,Structure-Activity Relationship ,medicine ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Nucleocapsid ,chemistry.chemical_classification ,Mutation ,Binding Sites ,Multidisciplinary ,biology ,Rational design ,virus diseases ,Dengue Virus ,Biological Sciences ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,medicine.disease ,Virology ,Amino acid ,Flavivirus ,chemistry ,Capsid ,Capsid Proteins ,Antiviral drug ,Protein Binding - Abstract
Dengue virus (DENV) was designated as a top 10 public health threat by the World Health Organization in 2019. No clinically approved anti-DENV drug is currently available. Here we report the high-resolution cocrystal structure (1.5 Å) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes. The inhibitor induces a “kissing” interaction between two capsid dimers. The inhibitor-bound capsid tetramers are assembled inside virions, resulting in defective uncoating of nucleocapsid when infecting new cells. Resistant DENV-2 emerges through one mutation that abolishes hydrogen bonds in the capsid structure, leading to a loss of compound binding. Structure-based analysis has defined the amino acids responsible for the inhibitor’s inefficacy against other DENV serotypes. The results have uncovered an antiviral mechanism through inhibitor-induced tetramerization of the viral capsid and provided essential structural and functional knowledge for rational design of panserotype DENV capsid inhibitors.
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- 2020
22. Zika structural genes determine the virulence of African and Asian lineages
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Daniele Barbosa de Almeida Medeiros, Pedro Fernando da Costa Vasconcelos, Pei Yong Shi, Camila R. Fontes-Garfias, Jannyce G. C Nunes, Bruno Tardelli Diniz Nunes, Rommel Rodríguez Burbano, Antonio E. Muruato, and Chao Shan
- Subjects
0301 basic medicine ,lineages ,Asia ,Lineage (genetic) ,Genes, Viral ,Linhagem Celular ,Epidemiology ,030106 microbiology ,Immunology ,Clone (cell biology) ,Virulence ,Viremia ,Biology ,Microbiology ,Zika virus ,Mice ,03 medical and health sciences ,Zika ,Virology ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Animals ,Humans ,Vero Cells ,Gene ,Asian ,Zika Virus Infection ,Strain (biology) ,African ,Structural gene ,Genetic Variation ,Zika Virus ,Articles ,General Medicine ,biology.organism_classification ,medicine.disease ,Zika virus / patogenicidade ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,Africa ,Parasitology ,Americas ,Fatores de Virul?ncia ,Research Article - Abstract
This work was supported by Amon G. Carter Foundation; Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico: [Grant Number 303999/2016-0,440405/2016-5]; Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior: [Grant Number Zika fast track project]; John S. Dunn Foundation; Gilson Longenbaugh Foundation; NIH: [Grant Number AI127744,AI136126,AI142759];PAHO: [Grant Number SCON2016-01353]; Summerfield Robert Foundation; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation; Sealy & Smith Foundation. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Health Sciences Institute. Belem, PA, Brazil. Department of Biochemistry & Molecular Biology. Galveston, TX, USA. Department of Biochemistry & Molecular Biology. Galveston, TX, USA. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Department of Microbiology & Immunology. Galveston, TX, USA. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Health Sciences Institute. Belem, PA, Brazil. Health Sciences Institute. Belem, PA, Brazil / Federal University of Par?. Biological Sciences Institute. Belem, PA, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Par? State University. Department of Pathology. Bel?m, PA, Brazil. Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Institute for Human Infections & Immunity. Galveston, TX, USA / Institute for Translational Science. Galveston, TX, USA / Sealy Institute of Vaccine Sciences. Galveston, TX, USA / Texas Medical Branch. Sealy Center for Structural Biology & Molecular Biophysics. Galveston, TX, USA. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Department of Biochemistry & Molecular Biology. Galveston, TX, USA / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa de P?s-Gradua??o em Virologia. Ananindeua, PA, Brasil / Health Sciences Institute. Bel?m, PA, Brazil. The Asian lineage of Zika virus (ZIKV) is responsible for the recent epidemics in the Americas and severe disease, whereas the African lineage of ZIKV has not been reported to cause epidemics or severe disease. We constructed a cDNA infectious clone (IC) of an African ZIKV strain, which, together with our previously developed Asian ZIKV strain IC, allowed us to engineer chimeric viruses by swapping the structural and non-structural genes between the two lineages. Recombinant parental and chimeric viruses were analyzed in A129 and newborn CD1 mouse models. In the A129 mice, the African strain developed higher viremia, organ viral loading, and mortality rate. In CD1 mice, the African strain exhibited a higher neurovirulence than the Asian strain. A chimeric virus containing the structural genes from the African strain is more virulent than the Asian strain, whereas a chimeric virus containing the non-structural genes from the African strain exhibited a virulence comparable to the Asian strain. These results suggest that (i) African strain is more virulent than Asian strain and (ii) viral structural genes primarily determine the virulence difference between the two lineages in mouse models. Other factors may contribute to the discrepancy between the mouse and epidemic results.
- Published
- 2020
23. Omicron: a drug developer's perspective
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Fang 'Flora' Fang and Pei-Yong Shi
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COVID-19 Vaccines ,COVID19vaccines ,Epidemiology ,Coronaviruses ,COVID19 ,viruses ,Immunology ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,Antiviral Agents ,Omicron variants ,Virology ,Drug Discovery ,Humans ,Immune Evasion ,COVID19drugs ,Binding Sites ,SARS-CoV-2 ,COVID-19 ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,QR1-502 ,COVID-19 Drug Treatment ,Infectious Diseases ,Drug Design ,Mutation ,Spike Glycoprotein, Coronavirus ,Receptors, Virus ,Parasitology ,Angiotensin-Converting Enzyme 2 ,Protein Binding ,Article Commentary - Abstract
We performed an annotation of 35 mutations in the spike protein of the SARS-CoV-2 Omicron variant. Our analysis of the mutations indicates that Omicron has gained prominent immune evasion and potential for enhanced transmissibility. Previous modeling study has revealed that continued evolution in both immune evasion and enhanced transmissibility by SARS-CoV-2 would compromise vaccines as tools for the pandemic control. To combat the future variants of SARS-CoV-2, the world needs novel antiviral drugs that are effective at curb viral spreading without introducing additional selective pressure towards resistant variants.
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- 2021
24. Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis
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Bryan A. Johnson, Yiyang Zhou, Kumari G. Lokugamage, Michelle N. Vu, Nathen Bopp, Patricia A. Crocquet-Valdes, Birte Kalveram, Craig Schindewolf, Yang Liu, Dionna Scharton, Jessica A. Plante, Xuping Xie, Patricia Aguilar, Scott C. Weaver, Pei-Yong Shi, David H. Walker, Andrew L. Routh, Kenneth S. Plante, and Vineet D. Menachery
- Subjects
viruses ,Immunology ,Mutant ,Biology ,medicine.disease_cause ,Microbiology ,Article ,Pathogenesis ,Glycogen Synthase Kinase 3 ,Variant of concern ,Virology ,Genetic variation ,Genetics ,medicine ,Humans ,skin and connective tissue diseases ,Nucleocapsid ,Molecular Biology ,Gene ,Alanine ,Mutation ,SARS-CoV-2 ,COVID-19 ,Phenotype ,Coronavirus ,SR Region ,Spike Glycoprotein, Coronavirus ,2019-nCoV ,Phosphorylation ,Parasitology - Abstract
While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203–205 in SARS-CoV-2 nucleocapsid protein. Recreating the alpha variant mutation in an early pandemic (WA-1) background, we found that the R203K/G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. Importantly, the R203K/G204R mutation increases nucleocapsid phosphorylation, providing a molecular basis for these phenotypes. Notably, an analogous alanine substitution mutant also increases SARS-CoV-2 fitness and phosphorylation, suggesting that infection is enhanced through ablation of the ancestral ‘RG’ motif. Overall, these results demonstrate that variant mutations outside spike are also key components in SARS-CoV-2’s continued adaptation to human infection., One-Sentence Summary: A mutation in the nucleocapsid gene of the SARS-CoV-2 alpha variant is found to enhance replication, fitness, and pathogenesis.
- Published
- 2021
25. A mutation-mediated evolutionary adaptation of Zika virus in mosquito and mammalian host
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Yibin Zhu, Chao Shan, Enhao Ma, Pei Yong Shi, Gong Cheng, Penghua Wang, Xi Yu, and Jinglin Wang
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Infectivity ,Mutation ,Multidisciplinary ,Transmission (medicine) ,Mutant ,Outbreak ,Genome, Viral ,Mosquito Vectors ,Zika Virus ,Biological Sciences ,Biology ,medicine.disease_cause ,biology.organism_classification ,Virology ,Zika virus ,Evolution, Molecular ,Mice ,Capsid ,medicine ,Animals ,Humans ,Vector (molecular biology) ,Phylogeny - Abstract
Zika virus (ZIKV) caused millions of infections during its rapid and expansive spread from Asia to the Americas from 2015 to 2017. Here, we compared the infectivity of ZIKV mutants with individual stable substitutions which emerged throughout the Asian ZIKV lineage and were responsible for the explosive outbreaks in the Americas. A threonine (T) to alanine (A) mutation at the 106th residue of the ZIKV capsid (C) protein facilitated the transmission by its mosquito vector, as well as infection in both human cells and immunodeficient mice. A mechanistic study showed that the T106A substitution rendered the C a preferred substrate for the NS2B-NS3 protease, thereby facilitating the maturation of structural proteins and the formation of infectious viral particles. Over a complete “mosquito-mouse-mosquito” cycle, the ZIKV C-T106A mutant showed a higher prevalence of mosquito infection than did the preepidemic strain, thus promoting ZIKV dissemination. Our results support the contribution of this evolutionary adaptation to the occasional widespread reemergence of ZIKV in nature.
- Published
- 2021
26. Flavivirus NS4B protein: Structure, function, and antiviral discovery
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Yan Wang, Xuping Xie, and Pei-Yong Shi
- Subjects
Pharmacology ,Zika Virus Infection ,Flavivirus ,Virology ,Animals ,Humans ,Zika Virus ,Dengue Virus ,Antiviral Agents ,Article ,Flavivirus Infections - Abstract
Infections with mosquito-borne flaviviruses, such as Dengue virus, ZIKV virus, and West Nile virus, pose significant threats to public health. Flaviviruses cause up to 400 million infections each year, leading to many forms of diseases, including fatal hemorrhagic, encephalitis, congenital abnormalities, and deaths. Currently, there are no clinically approved antiviral drugs for the treatment of flavivirus infections. The non-structural protein NS4B is an emerging target for drug discovery due to its multiple roles in the flaviviral life cycle. In this review, we summarize the latest knowledge on the structure and function of flavivirus NS4B, as well as the progress on antiviral compounds that target NS4B.
- Published
- 2022
27. BNT162b2-Elicited Neutralization of Delta Plus, Lambda, and Other Variants
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Hongjie Xia, Ugur Sahin, Pei Yong Shi, Kathrin U. Jansen, Yang Liu, Kena A. Swanson, Xuping Xie, Mark Cutler, Scott C. Weaver, Hui Cai, Jianying Liu, Alexander Muik, Philip R. Dormitzer, Jing Zou, and David A. Cooper
- Subjects
Delta ,Titer ,Lineage (genetic) ,Antigen ,biology.protein ,Alpha (ethology) ,Biology ,Antibody ,Virology ,Virus ,Neutralization - Abstract
BNT162b2-elicited human sera are known to neutralize the currently dominant Delta SARS-CoV-2 variant. Here, we report the ability of 20 human sera, drawn 2 or 4 weeks after two doses of BNT162b2, to neutralize USA-WA1/2020 SARS-CoV-2 bearing variant spikes from Delta plus (Delta-AY.1, Delta-AY.2), Delta-Δ144 (Delta with the Y144 deletion of the Alpha variant), Lambda, and B. 1.1.519 lineage viruses. Geometric mean plaque reduction neutralization titers against Delta-AY.1, Delta-AY.2, and Delta-Δ144 viruses are slightly lower than against USA-WA1/2020, but all sera neutralize the variant viruses to titers of ≥80.Neutralization titers against Lambda and B. 1.1.519 variants and against USA-WA1/2020 are equivalent. The susceptibility of Delta plus, Lambda, and other variants to neutralization by the sera indicates that antigenic change has not led to virus escape from vaccine-elicited neutralizing antibodies and supports ongoing mass immunization with BNT162b2 to control the variants and to minimize the emergence of new variants.
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- 2021
28. Distinct neutralizing kinetics and magnitudes elicited by different SARS-CoV-2 variant spikes
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Scott C. Weaver, Jianying Liu, Yang Liu, Jing Zou, Ping Ren, Xuping Xie, and Pei Yong Shi
- Subjects
Vaccination ,Titer ,Immunization ,Mutant ,biology.protein ,Alpha (ethology) ,Heterologous ,Biology ,biochemical phenomena, metabolism, and nutrition ,Neutralizing antibody ,Virology ,Neutralization ,Article - Abstract
The rapid evolution of SARS-CoV-2 mandates a better understanding of cross-protection between variants after vaccination or infection, but studies directly evaluating such cross-protection are lacking. Here we report that immunization with different variant spikes elicits distinct neutralizing kinetics and magnitudes against other SARS-CoV-2 variants. After immunizing hamsters with wild-type or mutant SARS-CoV-2 bearing variant spikes from Alpha, Beta, Gamma, or Epsilon, the animals developed faster and greater neutralization activities against homologous SARS-CoV-2 variants than heterologous variants, including Delta. The rank of neutralizing titers against different heterologous variants varied, depending on the immunized variant spikes. The differences in neutralizing titers between homologous and heterologous variants were as large as 62-, 15-, and 9.7-fold at days 14, 28, and 45 post-immunization, respectively. Nevertheless, all immunized hamsters were protected from challenges with all SARS-CoV-2 variants, including those exhibiting the lowest neutralizing antibody titers. The results provide insights into the COVID-19 vaccine booster strategies.
- Published
- 2021
29. Author response: Inhibition of SARS-CoV-2 polymerase by nucleotide analogs from a single-molecule perspective
- Author
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Mona Seifert, Lawrence Harris, Robert N. Kirchdoerfer, Pei Yong Shi, Subhas C. Bera, James M. Wood, Steven C. Almo, Bruno Canard, Jamie J. Arnold, Xiangzhi Meng, Flavia S. Papini, Hongjie Xia, Martin Depken, Thi-Tuyet-Nhung Le, Craig E. Cameron, Ashleigh Shannon, Tyler L. Grove, Yan Xiang, David Dulin, and Pauline van Nies
- Subjects
chemistry.chemical_classification ,biology ,Chemistry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Perspective (graphical) ,biology.protein ,Nucleotide ,Virology ,Response inhibition ,Polymerase - Published
- 2021
30. Rational design of West Nile virus vaccine through large replacement of 3′ UTR with internal poly(A)
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Jing Liu, Zhiming Yuan, Ya-Nan Zhang, Yuan Shaopeng, Cheng-Lin Deng, Qiu-Yan Zhang, Xiao-Dan Li, Bo Zhang, Hong-Qing Zhang, Pei Yong Shi, Han-Qing Ye, Fang Yu, Zhan Shunli, Gao Lei, Na Li, and Xiang-Yue Zeng
- Subjects
Untranslated region ,Medicine (General) ,live‐attenuated vaccine ,viruses ,Immunology ,QH426-470 ,Biology ,Antibodies, Viral ,Article ,UTR ,Mice ,R5-920 ,Immune system ,flavivirus ,Chlorocebus aethiops ,Genetics ,West Nile Virus ,Animals ,West Nile Virus Vaccines ,3' Untranslated Regions ,Vero Cells ,Pathogen ,internal poly(A) ,Attenuated vaccine ,virus diseases ,Outbreak ,Articles ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Virology ,Microbiology, Virology & Host Pathogen Interaction ,Vaccination ,Flavivirus ,Vero cell ,Molecular Medicine ,Poly A ,West Nile Fever - Abstract
The genus Flavivirus comprises numerous emerging and re‐emerging arboviruses causing human illness. Vaccines are the best approach to prevent flavivirus diseases. But pathogen diversities are always one of the major hindrances for timely development of new vaccines when confronting unpredicted flavivirus outbreaks. We used West Nile virus (WNV) as a model to develop a new live‐attenuated vaccine (LAV), WNV‐poly(A), by replacing 5ʹ portion (corresponding to SL and DB domains in WNV) of 3ʹ‐UTR with internal poly(A) tract. WNV‐poly(A) not only propagated efficiently in Vero cells, but also was highly attenuated in mouse model. A single‐dose vaccination elicited robust and long‐lasting immune responses, conferring full protection against WNV challenge. Such “poly(A)” vaccine strategy may be promising for wide application in the development of flavivirus LAVs because of its general target regions in flaviviruses., West Nile virus (WNV) is one of the many members of the genus Flavivirus known to cause human diseases. Here we present a novel live attenuated WNV vaccine, WNV‐poly(A), that protects against WNV infections in a mouse model.
- Published
- 2021
31. One mucosal administration of a live attenuated recombinant COVID-19 vaccine protects nonhuman primates from SARS-CoV-2
- Author
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Yang Liu, Daniel Valentin, Robert Jordan, Melissa H. Bloodworth, Roderick S. Tang, Shannon I. Phan, Christopher C. Stobart, Jack Greenhouse, Aditya Garg, Xing Cheng, Tatyana Orekov, Swagata Kar, Laurent Pessaint, Hanne Leth Andersen, Mariana F. Tioni, R. Stokes Peebles, Pei Yong Shi, Martin L. Moore, Danlu Wu, Angie Silva Pena, and Xuping Xie
- Subjects
Attenuated vaccine ,biology ,business.industry ,viruses ,RNA virus ,Entry into host ,biology.organism_classification ,Virology ,Virus ,law.invention ,Viral envelope ,law ,biology.protein ,Recombinant DNA ,Medicine ,Nasal administration ,Antibody ,business - Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 global pandemic. Vaccines are needed to control the disease and bring an end to the pandemic. SARS-CoV-2 is an enveloped RNA virus that relies on its trimeric surface glycoprotein, spike, for entry into host cells. Here we describe the COVID-19 vaccine candidate MV-014-212, a live attenuated, recombinant human respiratory syncytial virus (RSV) expressing a chimeric SARS-CoV-2 spike as the only viral envelope protein. MV-014-212 was attenuated and immunogenic in African green monkeys (AGMs). One mucosal administration of MV-014-212 in AGMs protected against SARS-CoV-2 challenge, reducing the peak shedding of SARS-CoV-2 in the nose by more than 200-fold. MV-014-212 elicited mucosal immunity in the nose and neutralizing antibodies in serum that exhibited cross neutralization against two virus variants of concern. Intranasally delivered, live attenuated vaccines such as MV-014-212 entail low-cost manufacturing suitable for global deployment. MV-014-212 is currently in phase I clinical trials as a single-dose intranasal COVID-19 vaccine.
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- 2021
32. Ecology and transmission of a dengue virus serotype 4 identified in wild Aedes aegypti in Florida
- Author
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Heather Coatsworth, Xuping Xie, Jasmine B. Ayers, Christy M. Waits, Rhoel R. Dinglasan, Caroline J. Stephenson, and Pei Yong Shi
- Subjects
Serotype ,biology ,Transmission (medicine) ,viruses ,fungi ,Aedes aegypti ,Dengue virus ,biology.organism_classification ,medicine.disease_cause ,medicine.disease ,Virology ,Virus ,Dengue fever ,biology.animal ,Vector (epidemiology) ,Manatee ,medicine - Abstract
1AbstractDengue virus is the most prevalent mosquito-borne virus, causing approximately 390 million infections and 25,000 deaths per year. Aedes aegypti, the primary mosquito vector of dengue virus, is well established throughout the state of Florida, USA. Autochthonous transmission of dengue virus to humans in Florida has been increasing since 2009, alongside consistent importation of dengue cases. However, most cases of first infection with dengue are asymptomatic and the virus can be maintained in mosquito populations, complicating surveillance and leading to an underestimation of disease risk. Metagenomic sequencing of Aedes aegypti mosquitoes in Manatee County, Florida revealed the presence of dengue virus serotype 4 (DENV-4) genomes in mosquitoes from multiple trapping sites over 2 years, in the absence of a human DENV-4 index case and even though a locally acquired case of DENV-4 has never been reported in Florida. This finding suggested that: i) DENV-4 may circulate amongst humans undetected, ii) the virus was being maintained in the mosquito population, or iii) the detected complete genome sequence may not represent a viable virus. This study demonstrates that an infectious clone generated from the Manatee County DENV-4 (DENV-4M) sequence is capable of infecting mammalian and insect tissue culture systems, as well as adult female Aedes aegypti mosquitoes when fed in a blood meal. However, the virus is subject to a dose dependent infection barrier in mosquitoes, and has a kinetic delay compared to a phylogenetically related wild-type (WT) control virus from a symptomatic child, DENV-4H (strain Homo sapiens/Haiti-0075/2015, GenBank accession MK514144.1). DENV-4M disseminates from the midgut to the ovary and saliva at 14 days post-infection. Viral RNA was also detectable in the adult female offspring of DENV-4M infected mosquitoes. These results demonstrate that the virus is capable of infecting vector mosquitoes, is transmissible by bite, and is vertically transmitted, indicating a mechanism for maintenance in the environment without human-mosquito transmission. These findings suggest undetected human-mosquito transmission and/or long-term maintenance of the virus in the mosquito population is occurring in Florida, and underscore the importance of proactive surveillance for viruses in mosquitoes.Graphical AbstractIn order to better assess the public health risk posed by a detection of DENV-4 RNA in Manatee County, FL Aedes aegypti, we produced an infectious clone using the sequence from the wild-caught mosquitoes and characterized it via laboratory infections of mosquitoes and mosquito tissues.
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- 2021
33. Mucosal vaccination induces protection against SARS-CoV-2 in the absence of detectable neutralizing antibodies
- Author
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Jiaren Sun, Renee L Hajnik, Lynn Soong, Pei Yong Shi, Awadalkareem Adam, Haitao Hu, Grace H. Rafael, Jing Zou, Hongjie Xia, Chaojie Zhong, Binbin Wang, Tian Wang, Yuejin Liang, Alan D.T. Barrett, Scott C. Weaver, and Xiaofang Wang
- Subjects
viruses ,Immunology ,Inflammation ,Brief Communication ,Antigen ,Immunity ,medicine ,Pharmacology (medical) ,Vector (molecular biology) ,skin and connective tissue diseases ,RC254-282 ,Pharmacology ,Vaccines ,biology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC581-607 ,respiratory system ,biochemical phenomena, metabolism, and nutrition ,Virology ,respiratory tract diseases ,Biological sciences ,Immunization ,biology.protein ,Infectious diseases ,Nasal administration ,medicine.symptom ,Antibody ,Immunologic diseases. Allergy ,business ,Viral load - Abstract
A candidate multigenic SARS-CoV-2 vaccine based on an MVA vector expressing both viral N and S proteins (MVA-S + N) was immunogenic, and induced T-cell responses and binding antibodies to both antigens but in the absence of detectable neutralizing antibodies. Intranasal immunization with the vaccine diminished viral loads and lung inflammation in mice after SARS-CoV-2 challenge, which correlated with the T-cell response induced by the vaccine in the lung, indicating that T-cell immunity is also likely critical for protection against SARS-CoV-2 infection in addition to neutralizing antibodies.
- Published
- 2021
34. Allosteric inhibitors of the main protease of SARS-CoV-2
- Author
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Subodh Kumar Samrat, Jimin Xu, Xuping Xie, Eleonora Gianti, Haiying Chen, Jing Zou, Jason G. Pattis, Khaled Elokely, Hyun Lee, Zhong Li, Michael L. Klein, Pei-Yong Shi, Jia Zhou, and Hongmin Li
- Subjects
Molecular Docking Simulation ,Pharmacology ,Cysteine Endopeptidases ,SARS-CoV-2 ,Virology ,Humans ,Protease Inhibitors ,Molecular Dynamics Simulation ,Viral Nonstructural Proteins ,Antiviral Agents ,Coronavirus 3C Proteases ,Peptide Hydrolases ,COVID-19 Drug Treatment - Abstract
SARS-CoV-2 has raised the alarm to search for effective therapy for this virus. To date several vaccines have been approved but few available drugs reported recently still need approval from FDA. Remdesivir was approved for emergency use only. In this report, the SARS-CoV-2 3CLpro was expressed and purified. By using a FRET-based enzymatic assay, we have screened a library consisting of more than 300 different niclosamide derivatives and identified three molecules JMX0286, JMX0301, and JMX0941 as potent allosteric inhibitors against SARS-CoV-2 3CLpro, with IC
- Published
- 2022
35. Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection
- Author
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Jared Pitts, Darius Babusis, Meghan S. Vermillion, Raju Subramanian, Kim Barrett, Diane Lye, Bin Ma, Xiaofeng Zhao, Nicholas Riola, Xuping Xie, Adriana Kajon, Xianghan Lu, Roy Bannister, Pei-Yong Shi, Maria Toteva, Danielle P. Porter, Bill J. Smith, Tomas Cihlar, Richard Mackman, and John P. Bilello
- Subjects
Pharmacology ,Adenosine ,SARS-CoV-2 ,Virology ,Chlorocebus aethiops ,Animals ,Humans ,Antiviral Agents ,Pandemics ,COVID-19 Drug Treatment - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.
- Published
- 2022
36. An Interview with Pei-Yong Shi, PhD
- Author
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Pei Yong Shi
- Subjects
2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,COVID-19 ,Cell Biology ,History, 20th Century ,Virology ,History, 21st Century ,Spike Glycoprotein, Coronavirus ,Medicine ,Cytokines ,Humans ,business ,Pandemics - Published
- 2021
37. Author Correction: A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19
- Author
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Tomas Cihlar, John P. Bilello, Camila R. Fontes-Garfias, Mini Balakrishnan, Xianwen Zhang, Kumari G. Lokugamage, Chien Te K. Tseng, Vineet D. Menachery, Antonio E. Muruato, Xuping Xie, Pei Yong Shi, Jing Zou, Shinji Makino, Jianying Liu, and Ping Ren
- Subjects
2019-20 coronavirus outbreak ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Science ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,General Physics and Astronomy ,General Chemistry ,Virology ,General Biochemistry, Genetics and Molecular Biology ,Neutralization ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Anti infectives ,Medicine ,business - Abstract
The original version of this Article contained an error in the Acknowledgements, which incorrectly listed the NIH grant ‘AI142759’. This has been corrected in both the PDF and HTML versions of the Article. © The Author(s) 2021.
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- 2021
38. Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants
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Amarendra, Pegu, Sarah E, O'Connell, Stephen D, Schmidt, Sijy, O'Dell, Chloe A, Talana, Lilin, Lai, Jim, Albert, Evan, Anderson, Hamilton, Bennett, Kizzmekia S, Corbett, Britta, Flach, Lisa, Jackson, Brett, Leav, Julie E, Ledgerwood, Catherine J, Luke, Mat, Makowski, Martha C, Nason, Paul C, Roberts, Mario, Roederer, Paulina A, Rebolledo, Christina A, Rostad, Nadine G, Rouphael, Wei, Shi, Lingshu, Wang, Alicia T, Widge, Eun Sung, Yang, John H, Beigel, Barney S, Graham, John R, Mascola, Mehul S, Suthar, Adrian B, McDermott, Nicole A, Doria-Rose, Jae, Arega, Wendy, Buchanan, Mohammed, Elsafy, Binh, Hoang, Rebecca, Lampley, Aparna, Kolhekar, Hyung, Koo, Catherine, Luke, Mamodikoe, Makhene, Seema, Nayak, Rhonda, Pikaart-Tautges, Janie, Russell, Elisa, Sindall, Pratap, Kunwar, Evan J, Anderson, Amer, Bechnak, Mary, Bower, Andres F, Camacho-Gonzalez, Matthew, Collins, Ana, Drobeniuc, Venkata Viswanadh, Edara, Srilatha, Edupuganti, Katharine, Floyd, Theda, Gibson, Cassie M Grimsley, Ackerley, Brandi, Johnson, Satoshi, Kamidani, Carol, Kao, Colleen, Kelley, Hollie, Macenczak, Michele Paine, McCullough, Etza, Peters, Varun K, Phadke, Nadine, Rouphael, Erin, Scherer, Amy, Sherman, Kathy, Stephens, Mehgan, Teherani, Jessica, Traenkner, Juton, Winston, Inci, Yildirim, Lee, Barr, Joyce, Benoit, Barbara, Carste, Joe, Choe, Maya, Dunstan, Roxanne, Erolin, Jana, Ffitch, Colin, Fields, Lisa A, Jackson, Erika, Kiniry, Susan, Lasicka, Stella, Lee, Matthew, Nguyen, Stephanie, Pimienta, Janice, Suyehira, Michael, Witte, Nedim Emil, Altaras, Andrea, Carfi, Marjorie, Hurley, Rolando, Pajon, Wellington, Sun, Tal, Zaks, Rhea N, Coler, Sasha E, Larsen, Kathleen M, Neuzil, Lisa C, Lindesmith, David R, Martinez, Jennifer, Munt, Michael, Mallory, Caitlin, Edwards, Ralph S, Baric, Nina M, Berkowitz, Eli A, Boritz, Kevin, Carlton, Pamela, Costner, Adrian, Creanga, Daniel C, Douek, Martin, Gaudinski, Ingelise, Gordon, LaSonji, Holman, Kwanyee, Leung, Bob C, Lin, Mark K, Louder, Kaitlyn M, Morabito, Laura, Novik, Sarah, O'Connell, Marcelino, Padilla, Phillip A, Swanson, Yi, Zhang, James D, Chappell, Mark R, Denison, Tia, Hughes, Xiaotao, Lu, Andrea J, Pruijssers, Laura J, Stevens, Christine M, Posavad, Michael, Gale, Vineet, Menachery, and Pei-Yong, Shi
- Subjects
Adult ,2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Time Factors ,Adolescent ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunization, Secondary ,Alpha (ethology) ,Cross Reactions ,Antibodies, Viral ,Article ,Young Adult ,Immunogenicity, Vaccine ,Immune system ,Humans ,Medicine ,Beta (finance) ,Aged ,Immune Evasion ,Messenger RNA ,Multidisciplinary ,biology ,SARS-CoV-2 ,business.industry ,Immunogenicity ,Antibody titer ,COVID-19 ,Middle Aged ,Virology ,Antibodies, Neutralizing ,Vaccination ,Immunization ,Immunology ,biology.protein ,Antibody ,business ,2019-nCoV Vaccine mRNA-1273 - Abstract
SARS-CoV-2 mutations may diminish vaccine-induced protective immune responses, and the durability of such responses has not been previously reported. Here, we present a comprehensive assessment of the impact of variants B.1.1.7, B.1.351, P.1, B.1.429, and B.1.526 on binding, neutralizing, and ACE2-blocking antibodies elicited by the vaccine mRNA-1273 over seven months. Cross-reactive neutralizing responses were rare after a single dose of mRNA-1273. At the peak of response to the second dose, all subjects had robust responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of mRNA-1273. Across all assays, B.1.351 had the greatest impact on antibody recognition, and B.1.1.7 the least. These data complement ongoing studies of clinical protection to inform the potential need for additional boost vaccinations., One-Sentence Summary: Most mRNA-1273 vaccinated individuals maintained binding and functional antibodies against SARS-CoV-2 variants for 6 months.
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- 2021
39. Neutralization of SARS-CoV-2 variants B.1.617.1 and B.1.525 by BNT162b2-elicited sera
- Author
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David K. C. Cooper, Scott C. Weaver, Ugur Sahin, Philip R. Dormitzer, Mark Cutler, Hongjie Xia, Alexander Muik, Hui Cai, Jing Zou, Pei Yong Shi, Jianying Liu, Kathrin U. Jansen, Yang Liu, Xuping Xie, and Kena A. Swanson
- Subjects
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Biology ,Virology ,Neutralization - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve around the world, generating new variants that are of concern based on their potential for altered transmissibility, pathogenicity, and coverage by vaccines and therapeutics. Here we report that 20 BNT162b2 vaccine-elicited human sera neutralize engineered SARS-CoV-2 with a USA-WA1/2020 genetic background (a virus strain isolated in January 2020) and spike glycoproteins from the newly emerged B.1.617.1 (first identified in India) or B.1.525 (first identified in Nigeria) lineages. Geometric mean plaque reduction neutralization titers against the variant viruses, particularly the B.1.617.1 variant, are lower than the titer against USA-WA1/2020 virus, but all sera tested neutralize the variant viruses at titers of at least 40. The susceptibility of the newly emerged B.1.617.1 and B.1.525 variants to BNT162b2 vaccine-elicited neutralization supports mass immunization as a central strategy to end the COVID-19 pandemic across geographies.
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- 2021
40. In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains
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Baoling Ying, Pei Yong Shi, Spencer Stumpf, W. Blaine Stine, Charles Y. Chiu, James Brett Case, Davide Corti, Mehul S. Suthar, Sean P. J. Whelan, Laura A. VanBlargan, Lindsay Droit, Raul Andino, Adrianus C. M. Boon, Daved H. Fremont, Seth J. Zost, Miguel Garcia Knight, Zhuoming Liu, Rita E. Chen, Xuping Xie, Traci L. Bricker, Ali H. Ellebedy, John M. Errico, Michael S. Diamond, Lisa A. Purcell, Ishmael D. Aziati, Tamarand L. Darling, David Wang, Pavlo Gilchuk, Meredith E. Davis-Gardner, Scott A. Handley, Swathi Shrihari, James E. Crowe, Emma S. Winkler, and Astha Joshi
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Male ,Antibodies, Viral ,Transgenic ,Mice ,Monoclonal ,Chlorocebus aethiops ,antibodies ,Viral ,Neutralizing ,Lung ,Multidisciplinary ,Serine Endopeptidases ,Antibodies, Monoclonal ,Spike Glycoprotein ,Infectious Diseases ,Spike Glycoprotein, Coronavirus ,Pneumonia & Influenza ,Female ,Angiotensin-Converting Enzyme 2 ,Antibody ,Post-Exposure Prophylaxis ,Infection ,Biotechnology ,Genetically modified mouse ,General Science & Technology ,medicine.drug_class ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Mice, Transgenic ,Biology ,Monoclonal antibody ,Antibodies ,Article ,Vaccine Related ,Neutralization Tests ,In vivo ,Biodefense ,medicine ,Animals ,Humans ,Potency ,variations ,Gene ,Vero Cells ,Mesocricetus ,SARS-CoV-2 ,Prevention ,COVID-19 ,Pneumonia ,biology.organism_classification ,Antibodies, Neutralizing ,Virology ,In vitro ,Coronavirus ,Emerging Infectious Diseases ,Cell culture ,Vero cell ,biology.protein ,SARS-CoV-2 variant strains ,Pre-Exposure Prophylaxis ,Immunization - Abstract
Rapidly-emerging variants jeopardize antibody-based countermeasures against SARS-CoV-2. While recent cell culture experiments have demonstrated loss of potency of several anti-spike neutralizing antibodies against SARS-CoV-2 variant strains1-3, the in vivo significance of these results remains uncertain. Here, using a panel of monoclonal antibodies (mAbs) corresponding to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron, and Lilly we report the impact on protection in animals against authentic SARS-CoV-2 variants including WA1/2020 strains, a B.1.1.7 isolate, and chimeric strains with South African (B.1.351) or Brazilian (B.1.1.28) spike genes. Although some individual mAbs showed reduced or abrogated neutralizing activity against B.1.351 and B.1.1.28 viruses with E484K spike protein mutations in cell culture, low prophylactic doses of mAb combinations protected against infection in K18-hACE2 transgenic mice, 129S2 immunocompetent mice, and hamsters without emergence of resistance. Two exceptions were mAb LY-CoV555 monotherapy which lost all protective activity in vivo, and AbbVie 2B04/47D11, which showed partial loss of activity. When administered after infection as therapy, higher doses of mAb cocktails protected in vivo against viruses displaying a B.1.351 spike gene. Thus, many, but not all, of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing SARS-CoV-2 variant strains.
- Published
- 2021
41. BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants
- Author
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Scott C. Weaver, Jianying Liu, Jing Zou, Hongjie Xia, Philip R. Dormitzer, Kena A. Swanson, Mark Cutler, David A. Cooper, Alexander Muik, Ugur Sahin, Yang Liu, Hui Cai, Pei Yong Shi, Xuping Xie, and Kathrin U. Jansen
- Subjects
0301 basic medicine ,COVID-19 Vaccines ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,030106 microbiology ,Antibodies, Viral ,Neutralization ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Neutralization Tests ,Pandemic ,Chlorocebus aethiops ,Animals ,Humans ,030212 general & internal medicine ,Vero Cells ,BNT162 Vaccine ,chemistry.chemical_classification ,Vaccines, Synthetic ,Multidisciplinary ,biology ,SARS-CoV-2 ,COVID-19 ,Virology ,Antibodies, Neutralizing ,Titer ,chemistry ,Spike Glycoprotein, Coronavirus ,Vero cell ,biology.protein ,Antibody ,Glycoprotein - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve around the world, generating new variants that are of concern on the basis of their potential for altered transmissibility, pathogenicity, and coverage by vaccines and therapeutic agents1–5. Here we show that serum samples taken from twenty human volunteers, two or four weeks after their second dose of the BNT162b2 vaccine, neutralize engineered SARS-CoV-2 with a USA-WA1/2020 genetic background (a virus strain isolated in January 2020) and spike glycoproteins from the recently identified B.1.617.1, B.1.617.2, B.1.618 (all of which were first identified in India) or B.1.525 (first identified in Nigeria) lineages. Geometric mean plaque reduction neutralization titres against the variant viruses—particularly the B.1.617.1 variant—seemed to be lower than the titre against the USA-WA1/2020 virus, but all sera tested neutralized the variant viruses at titres of at least 1:40. The susceptibility of the variant strains to neutralization elicited by the BNT162b2 vaccine supports mass immunization as a central strategy to end the coronavirus disease 2019 (COVID-19) pandemic globally. Samples of serum from individuals immunized with the BNT162b2 vaccine show neutralization activity against engineered SARS-CoV-2s bearing the spike mutations from B.1.617 and other variants.
- Published
- 2021
42. An intranasal vaccine durably protects against SARS-CoV-2 variants in mice
- Author
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David T. Curiel, Pei Yong Shi, Daved H. Fremont, Baoling Ying, Igor P. Dmitriev, Galit Alter, Saravanan Raju, Matthew J. Gorman, Rita E. Chen, Elena A. Kashentseva, Swathi Shrihari, Michael S. Diamond, Lucas J. Adams, Ahmed O. Hassan, and Dansu Yuan
- Subjects
biology ,Effector ,business.industry ,Vaccine efficacy ,Virology ,Neutralization ,Vaccination ,medicine.anatomical_structure ,Immunization ,biology.protein ,Medicine ,Nasal administration ,Bone marrow ,Antibody ,business - Abstract
SARS-CoV-2 variants that attenuate antibody neutralization could jeopardize vaccine efficacy and the end of the COVID-19 pandemic. We recently reported the protective activity of a single-dose intranasally-administered spike protein-based chimpanzee adenovirus-vectored vaccine (ChAd-SARS-CoV-2-S) in animals, which has advanced to human trials. Here, we assessed its durability, dose-response, and cross-protective activity in mice. A single intranasal dose of ChAd-SARS-CoV-2-S induced durably high neutralizing and Fc effector antibody responses in serum and S-specific IgG and IgA secreting long-lived plasma cells in the bone marrow. Protection against a historical SARS-CoV-2 strain was observed across a 100-fold vaccine dose range and over a 200-day period. At 6 weeks or 9 months after vaccination, serum antibodies neutralized SARS-CoV-2 strains with B.1.351 and B.1.1.28 spike proteins and conferred almost complete protection in the upper and lower respiratory tracts after challenge. Thus, in mice, intranasal immunization with ChAd-SARS-CoV-2-S provides durable protection against historical and emerging SARS-CoV-2 strains.
- Published
- 2021
43. A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope
- Author
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Emma S. Winkler, Brian O. Smith, Lindsay Droit, Saravanan Raju, Adrian Creanga, Pei Yong Shi, Scott A. Handley, Rita Chen, James E. Crowe, Andrianus Boon, Bradley Whitener, Pavlo Gilchuk, Amarendra Pegu, Daved H. Fremont, Dong-Mei Wang, Zhuoming Liu, Ishmael D. Aziati, Lucas J. Adams, Laura A. VanBlargan, Whelan Spj, Michael P. Diamond, Haiyong Zhao, and James Brett Case
- Subjects
Genetically modified mouse ,biology ,medicine.drug_class ,In vivo ,biology.protein ,medicine ,Antibody ,Receptor ,Monoclonal antibody ,Inhibitory postsynaptic potential ,Virology ,Epitope ,Virus - Abstract
SUMMARYWith the emergence of SARS-CoV-2 variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here we developed a panel of neutralizing anti-SARS-CoV-2 mAbs that bind the receptor binding domain of the spike protein at distinct epitopes and block virus attachment to cells and its receptor, human angiotensin converting enzyme-2 (hACE2). While several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by historical SARS-CoV-2 strains, others induced escape variantsin vivoand lost activity against emerging strains. We identified one mAb, SARS2-38, that potently neutralizes all SARS-CoV-2 variants of concern tested and protects mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engages a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of inhibitory antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.
- Published
- 2021
44. Susceptibility to SARS-CoV-2 of Cell Lines and Substrates Commonly Used to Diagnose and Isolate Influenza and Other Viruses
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Azaibi Tamin, Naomi Dybdahl-Sissoko, David E. Wentworth, Xiaoyu Fan, Hong Pang, Malania M. Wilson, Li Wang, Gaston Bonenfant, Nannan Jiang, Jessica Ciomperlik-Patton, Natalie J. Thornburg, Pei Yong Shi, Michael Currier, John R. Barnes, Bin Zhou, Ray Campagnoli, Jennifer L Harcourt, Jimma Liddell, Gloria Larson, Jaber Hossain, and Dan Cui
- Subjects
Epidemiology ,viruses ,ACE2 ,Infectious and parasitic diseases ,RC109-216 ,cell lines ,medicine.disease_cause ,Mice ,0302 clinical medicine ,030212 general & internal medicine ,Receptor ,skin and connective tissue diseases ,Original Research ,Mutation ,Susceptibility to SARS-CoV-2 of Cell Lines and Substrates Commonly Used to Diagnose and Isolate Influenza and Other Viruses ,CATS ,virus diseases ,Infectious Diseases ,coronavirus disease ,Angiotensin-converting enzyme 2 ,Spike Glycoprotein, Coronavirus ,Medicine ,influenza ,MDCK ,spike protein substitution ,Microbiology (medical) ,Cell type ,030231 tropical medicine ,Biology ,Peptidyl-Dipeptidase A ,Cell Line ,03 medical and health sciences ,respiratory infections ,Dogs ,angiotensin-converting enzyme 2 ,Influenza, Human ,medicine ,Animals ,Humans ,Tropism ,severe acute respiratory syndrome coronavirus ,SARS-CoV-2 ,Research ,fungi ,COVID-19 ,Virology ,zoonoses ,body regions ,Cell culture ,Cats ,Trans-acting - Abstract
Co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses has been reported. We evaluated cell lines commonly used to isolate viruses and diagnose related diseases for their susceptibility to SARS-CoV-2. Although multiple kidney cell lines from monkeys were susceptible to SARS-CoV-2, we found many cell types derived from humans, dogs, minks, cats, mice, and chicken were not. We analyzed MDCK cells, which are most commonly used for surveillance and study of influenza viruses, and found that they were not susceptible to SARS-CoV-2. The low expression level of the angiotensin converting enzyme 2 receptor and lower receptor affinity to SARS-CoV-2 spike, which could be overcome by overexpression of canine angiotensin converting enzyme 2 in trans, strengthened the cellular barrier to productive infection. Moreover, a D614G mutation in the spike protein did not appear to affect SARS-CoV-2 cell tropism. Our findings should help avert inadvertent propagation of SARS-CoV-2 from diagnostic cell lines.
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- 2021
45. Genetic and biochemical characterizations of Zika virus NS2A protein
- Author
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Xianwen Zhang, Jing Zou, Pei Yong Shi, Hongjie Xia, Xinwen Chen, Chao Shan, and Xuping Xie
- Subjects
Epidemiology ,viruses ,Immunology ,Viral Nonstructural Proteins ,Endoplasmic Reticulum ,Virus Replication ,Microbiology ,Article ,Cell Line ,Zika virus ,03 medical and health sciences ,membrane topology ,Virology ,Drug Discovery ,Humans ,030304 developmental biology ,0303 health sciences ,flavivirus replication ,biology ,Zika Virus Infection ,030306 microbiology ,Virus Assembly ,food and beverages ,Zika Virus ,General Medicine ,biology.organism_classification ,flavivirus NS2A ,3. Good health ,virion assembly ,Infectious Diseases ,Virion assembly ,Membrane topology ,Molecular mechanism ,Parasitology - Abstract
Zika virus (ZIKV) can cause devastating congenital Zika syndromes in pregnant women and Guillain-Barre syndrome in adults. Understanding the molecular mechanism of ZIKV replication is essential for antiviral and vaccine development. Here we report the structural and functional characterization of ZIKV NS2A protein. Biochemical structural probing suggests that ZIKV NS2A has a single segment that traverses the ER membrane and six segments that peripherally associate with the ER membrane. Functional analysis has defined distinct NS2A residues essential for viral RNA synthesis or virion assembly. Only the virion assembly-defective mutants, but not the RNA synthesis-defective mutants, could be rescued through trans complementation with a wide-type NS2A protein. These results suggest that the NS2A molecules in virion assembly complex could be recruited in trans, whereas the NS2A molecules in viral replication complex must be recruited in cis. Together with previous results, we propose a flavivirus assembly model where NS2A plays a central role in modulating viral structural and nonstructural proteins as well as genomic RNA during virion assembly.
- Published
- 2019
46. Neutralization and durability of 2 or 3 doses of the BNT162b2 vaccine against Omicron SARS-CoV-2
- Author
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Hongjie Xia, Jing Zou, Chaitanya Kurhade, Hui Cai, Qi Yang, Mark Cutler, David Cooper, Alexander Muik, Kathrin U. Jansen, Xuping Xie, Kena A. Swanson, and Pei-Yong Shi
- Subjects
Vaccines, Synthetic ,SARS-CoV-2 ,Virology ,COVID-19 ,Humans ,Parasitology ,mRNA Vaccines ,Antibodies, Viral ,Antibodies, Neutralizing ,Microbiology ,BNT162 Vaccine - Abstract
Two doses of the BNT162b2 mRNA vaccine are highly effective against SARS-CoV-2. Here, we tested the antibody neutralization against Omicron SARS-CoV-2 after 2 and 3 doses of BNT162b2. Serum from vaccinated individuals was serially tested for its ability to neutralize wild-type SARS-CoV-2 (USA-WA1/2020) and an engineered USA-WA1/2020 bearing the Omicron spike glycoprotein. At 2 or 4 weeks post dose 2, the neutralization geometric mean titers (GMTs) against the wild-type and Omicron-spike viruses were 511 and 20, respectively; at 1 month post dose 3, the neutralization GMTs increased to 1,342 and 336; and at 4 months post dose 3, the neutralization GMTs decreased to 820 and 171. The data support a 3-dose vaccination strategy and provide a glimpse into the durability of the neutralization response against Omicron.
- Published
- 2022
47. A single-dose plasmid-launched live-attenuated Zika vaccine induces protective immunity
- Author
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Huanle Luo, Tian Wang, Antonio E. Muruato, Xuping Xie, Jing Zou, Pei Yong Shi, Chao Shan, and Scott C. Weaver
- Subjects
Male ,0301 basic medicine ,Research paper ,live-attenuated vaccine ,Antibodies, Viral ,Zika virus ,Mice ,Immunogenicity, Vaccine ,0302 clinical medicine ,flavivirus ,Pregnancy ,Chlorocebus aethiops ,Gene Order ,Testis ,Vaccines, DNA ,Medicine ,030212 general & internal medicine ,Neutralizing antibody ,Antigens, Viral ,Attenuated vaccine ,biology ,Zika Virus Infection ,General Medicine ,3. Good health ,Vaccination ,Female ,Plasmids ,DNA vaccine ,Genome, Viral ,Vaccines, Attenuated ,General Biochemistry, Genetics and Molecular Biology ,Virus ,DNA vaccination ,03 medical and health sciences ,Neutralization Tests ,Immunity ,Animals ,Humans ,Seroconversion ,Vero Cells ,business.industry ,Viral Vaccines ,Antibodies, Neutralizing ,Virology ,Infectious Disease Transmission, Vertical ,Disease Models, Animal ,HEK293 Cells ,030104 developmental biology ,Immunization ,biology.protein ,business - Abstract
Background Vaccines are the most effective means to fight and eradicate infectious diseases. Live-attenuated vaccines (LAV) usually have the advantages of single dose, rapid onset of immunity, and durable protection. DNA vaccines have the advantages of chemical stability, ease of production, and no cold chain requirement. The ability to combine the strengths of LAV and DNA vaccines may transform future vaccine development by eliminating cold chain and cell culture with the potential for adventitious agents. Methods A DNA-launched LAV was developed for ZIKV virus (ZIKV), a pathogen that recently caused a global public health emergency. The cDNA copy of a ZIKV LAV genome was engineered into a DNA plasmid. The DNA-LAV plasmid was delivered into mice using a clinically proven device TriGrid™ to launch the replication of LAV. Findings A single-dose immunization as low as 0.5 μg of DNA-LAV plasmid conferred 100% seroconversion in A129 mice. All seroconverted mice developed sterilizing immunity, as indicated by no detectable infectious viruses and no increase of neutralizing antibody titers after ZIKV challenge. The immunization also elicited robust T cell responses. In pregnant mice, the DNA-LAV vaccination fully protected against ZIKV-induced disease and maternal-to-fetal transmission. High levels of neutralizing activities were detected in fetal serum, indicating maternal-to-fetal humoral transfer. In male mice, a single-dose vaccination completely prevented testis infection, injury, and oligospermia. Interpretation The remarkable simplicity and potency of ZIKV DNA-LAV warrant further development of this vaccine candidate. The DNA-LAV approach may serve as a universal vaccine platform for other plus-sense RNA viruses. Fund National Institute of Health, Kleberg Foundation , Centers for Disease Control and Prevention , University of Texas Medical Branch.
- Published
- 2018
48. SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans
- Author
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Michael K. Klebert, Tingting Lei, Alem Haile, Sharlene A. Teefey, Pei Yong Shi, Florian Krammer, Wooseob Kim, Teresa Suessen, Michael S. Diamond, James Brett Case, Aaron J. Schmitz, Xuping Xie, Adriana M Rauseo, Ali H. Ellebedy, Rita Chen, Mahima Thapa, Jane A. O’Halloran, Rachel M. Presti, Jackson S. Turner, William D. Middleton, Fatima Amanat, and Elizaveta Kalaidina
- Subjects
Messenger RNA ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Medicine ,business ,Virology - Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)-based vaccines are ~95% effective in preventing coronavirus disease 2019. However, the dynamics of antibody secreting plasmablasts (PBs) and germinal centre (GC) B cells induced by these vaccines in SARS-CoV-2 naïve and antigen-experienced humans remains unclear. Here we examined peripheral blood and/or lymph node (LN) antigen-specific B cell responses in 32 individuals who received two doses of BNT162b2, an mRNA-based vaccine encoding the full-length SARS-CoV-2 spike (S) gene. Circulating IgG- and IgA-secreting PBs targeting the S protein peaked one week after the second immunization then declined and were undetectable three weeks later. PB responses coincided with maximal levels of serum anti-S binding and neutralizing antibodies to a historical strain as well as emerging variants, especially in individuals previously infected with SARS-CoV-2, who produced the most robust serological responses. Fine needle aspirates of draining axillary LNs identified GC B cells that bind S protein in all participants sampled after primary immunization. GC responses increased after boosting and were detectable in two distinct LNs in several participants. Remarkably, high frequencies of S-binding GC B cells and PBs were maintained in draining LNs for up to seven weeks after first immunization, with a substantial fraction of the PB pool class-switched to IgA. GC B cell-derived monoclonal antibodies predominantly targeted the RBD, with fewer clones binding to the N-terminal domain or shared epitopes within the S proteins of human betacoronaviruses OC43 and HKU1. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a robust and persistent GC B cell response that engages pre-existing as well as new B cell clones, which enables generation of high-affinity, broad, and durable humoral immunity.
- Published
- 2021
49. SARS-CoV-2 variants show resistance to neutralization by many monoclonal and serum-derived polyclonal antibodies
- Author
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Xuping Xie, Xianwen Zhang, Davide Corti, Daved H. Fremont, Pei Yong Shi, Jianying Liu, Laura VanBlargan, Wooseob Kim, Stephen Tahan, James Brett Case, Lindsay Droit, Andrianus Boon, Parakkal Deepak, Herbert W. Virgin, John M. Errico, Michael S. Diamond, Yang Liu, Dora Pinto, James E. Crowe, Alfred H.J. Kim, Ali H. Ellebedy, Emma S. Winkler, Aaron J. Schmitz, Jackson S. Turner, Rita Chen, Mahima Thapa, Jane A. O’Halloran, Rachel M. Presti, Naveenchandra Suryadevara, Pavlo Gilchuk, and David Wang
- Subjects
biology ,medicine.drug_class ,Monoclonal antibody ,Virology ,Assay Standardization ,COVID-19 ,Antibody-based Countermeasures ,Pseudoviruses, Chimeric Washington Strain ,South African Spike Gene ,Vaccine Efficacy ,Article ,Neutralization ,Virus ,law.invention ,Polyclonal antibodies ,law ,Monoclonal ,medicine ,biology.protein ,Recombinant DNA ,Antibody ,Neutralizing antibody - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 106 million people and causing 2.3 million deaths. The rapid deployment of antibody-based countermeasures has provided hope for curtailing disease and ending the pandemic1. However, the emergence of rapidly-spreading SARS-CoV-2 variants in the United Kingdom (B.1.1.7), South Africa (B.1.351), and elsewhere with mutations in the spike protein has raised concern for escape from neutralizing antibody responses and loss of vaccine efficacy based on preliminary data with pseudoviruses2-4. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera, and human sera from recipients of the Pfizer-BioNTech (BNT162b2) mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, a chimeric Washington strain with a South African spike gene (Wash SA-B.1.351), and isogenic recombinant variants with designed mutations or deletions at positions 69-70, 417, 484, 501, and/or 614 of the spike protein. Several highly neutralizing mAbs engaging the receptor binding domain (RBD) or N-terminal domain (NTD) lost inhibitory activity against Wash SA-B.1.351 or recombinant variants with an E484K spike mutation. Most convalescent sera and virtually all mRNA vaccine-induced immune sera tested showed markedly diminished neutralizing activity against the Wash SA-B.1.351 strain or recombinant viruses containing mutations at position 484 and 501. We also noted that cell line selection used for growth of virus stocks or neutralization assays can impact the potency of antibodies against different SARS-CoV-2 variants, which has implications for assay standardization and congruence of results across laboratories. As several antibodies binding specific regions of the RBD and NTD show loss-of-neutralization potency in vitro against emerging variants, updated mAb cocktails, targeting of highly conserved regions, enhancement of mAb potency, or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.
- Published
- 2021
50. Glucagon-like peptide-2 receptor is a receptor for tick-borne encephalitis virus to infect nerve cells
- Author
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Jiekai Chen, Rongjuan Pei, Yun Wang, Jielin Tang, Xiaoli Xiong, Min Yang, Xinwen Chen, Yuan Zhou, Jun He, Qi Yang, He Zhao, Jizheng Chen, and Pei-Yong Shi
- Subjects
Tick-borne encephalitis virus ,Nerve cells ,Biology ,Receptor ,biology.organism_classification ,Virology ,Glucagon-Like Peptide-2 Receptor - Abstract
Tick-borne encephalitis virus (TBEV) is a tick-borne flavivirus that causes severe encephalitis disease1,2. Host proteins required for TBEV entry remain largely unknown3. Here we performed a genome-wide CRISPR-Cas9 knockout screen and identified G-protein-coupled receptor glucagon-like peptide-2 receptor (GLP2R) as a receptor for TBEV to infect nerve cells. Knockdown or knockout of GLP2R reduced TBEV infection of different nerve cells; trans supply of GLP2R restored viral infection. GLP2R directly binds to viral envelope domain III through its extracellular loop 1 (ECL1). TBEV infection can be blocked by the ECL1 peptide, a functional ligand to GLP2R, or GLP2R antibodies. GLP2R-deficient mice were generated to validate the role of GLP2R in TBEV infection and pathogenesis. Wild-type mice succumbed to TBEV infection and developed >107 TCID50 (median tissue culture infectious dose) virus per gram of brain tissue. In contrast, all GLP2R-deficient mice survived TBEV infection without detectable infectious virus in brain. Altogether, our results support GLP2R as a receptor for TBEV to infect nerve cells.
- Published
- 2021
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