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Open accessJournal ArticleDOI: 10.1128/MBIO.02648-20

Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model.

02 Mar 2021-Mbio (American Society for Microbiology)-Vol. 12, Iss: 2, pp 02
Abstract: The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the prime target for vaccine development. The spike protein mediates both binding to host cells and membrane fusion and is also so far the only known viral target of neutralizing antibodies. Coronavirus spike proteins are large trimers that are relatively unstable, a feature that might be enhanced by the presence of a polybasic cleavage site in SARS-CoV-2 spike. Exchange of K986 and V987 for prolines has been shown to stabilize the trimers of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus spike proteins. Here, we test multiple versions of a soluble spike protein for their immunogenicity and protective effect against SARS-CoV-2 challenge in a mouse model that transiently expresses human angiotensin-converting enzyme 2 via adenovirus transduction. Variants tested include spike proteins with a deleted polybasic cleavage site, proline mutations, or a combination thereof, besides the wild-type protein. While all versions of the protein were able to induce neutralizing antibodies, only the antigen with both a deleted cleavage site and the K986P and V987P (PP) mutations completely protected from challenge in this mouse model.IMPORTANCE A vaccine for SARS-CoV-2 is urgently needed. A better understanding of antigen design and attributes that vaccine candidates need to have to induce protective immunity is of high importance. The data presented here validate the choice of antigens that contain the PP mutations and suggest that deletion of the polybasic cleavage site may lead to a further-optimized design.

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Topics: Coronavirus (56%)
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20 results found


Open accessJournal ArticleDOI: 10.1126/SCIADV.ABE8065
19 Feb 2021-Science Advances
Abstract: Multiple preventive vaccines are being developed to counter the coronavirus disease 2019 pandemic. The leading candidates have now been evaluated in nonhuman primates (NHPs) and human phase 1 and/or phase 2 clinical trials. Several vaccines have already advanced into phase 3 efficacy trials, while others will do so before the end of 2020. Here, we summarize what is known of the antibody and T cell immunogenicity of these vaccines in NHPs and humans. To the extent possible, we compare how the vaccines have performed, taking into account the use of different assays to assess immunogenicity and inconsistencies in how the resulting data are presented. We also review the outcome of challenge experiments with severe acute respiratory syndrome coronavirus 2 in immunized macaques, while noting variations in the protocols used, including but not limited to the virus challenge doses. Press releases on the outcomes of vaccine efficacy trials are also summarized.

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Topics: Vaccine efficacy (55%), Immunogenicity (52%)

50 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2021.01.035
04 Mar 2021-Cell
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.

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Topics: Immunity (51%), Neutralizing antibody (51%)

41 Citations


Open accessJournal ArticleDOI: 10.1007/S11908-021-00752-3
Abstract: The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected lives of billions of individuals, globally. There is an urgent need to develop interventions including vaccines to control the ongoing pandemic. Development of tools for fast-tracked testing including small and large animal models for vaccine efficacy analysis, assays for immunogenicity assessment, critical reagents, international biological standards, and data sharing allowed accelerated development of vaccines. More than 300 vaccines are under development and 9 of them are approved for emergency use in various countries, with impressive efficacy ranging from 50 to 95%. Recently, several new SARS-CoV-2 variants have emerged and are circulating globally, and preliminary findings imply that some of them may escape immune responses against previous variants and diminish efficacy of current vaccines. Most of these variants acquired new mutations in their surface protein (Spike) which is the antigen in most of the approved/under development vaccines. In this review, we summarize novel and traditional approaches for COVID-19 vaccine development including inactivated, attenuated, nucleic acid, vector and protein based. Critical assessment of humoral and cell-mediated immune responses induced by vaccines has shown comparative immunogenicity profiles of various vaccines in clinical phases. Recent reports confirmed that some currently available vaccines provide partial to complete protection against emerging SARS-CoV-2 variants. If more mutated variants emerge, current vaccines might need to be updated accordingly either by developing vaccines matching the circulating strain or designing multivalent vaccines to extend the breadth.

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Topics: Vaccine efficacy (56%)

23 Citations


Open accessJournal ArticleDOI: 10.1038/S41467-021-24909-9
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected at least 180 million people since its identification as the cause of the current COVID-19 pandemic. The rapid pace of vaccine development has resulted in multiple vaccines already in use worldwide. The contemporaneous emergence of SARS-CoV-2 ‘variants of concern’ (VOC) across diverse geographic locales underscores the need to monitor the efficacy of vaccines being administered globally. All WHO designated VOC carry spike (S) polymorphisms thought to enable escape from neutralizing antibodies. Here, we characterize the neutralizing activity of post-Sputnik V vaccination sera against the ensemble of S mutations present in alpha (B.1.1.7) and beta (B.1.351) VOC. Using de novo generated replication-competent vesicular stomatitis virus expressing various SARS-CoV-2-S in place of VSV-G (rcVSV-CoV2-S), coupled with a clonal 293T-ACE2 + TMPRSS2 + cell line optimized for highly efficient S-mediated infection, we determine that only 1 out of 12 post-vaccination serum samples shows effective neutralization (IC90) of rcVSV-CoV2-S: B.1.351 at full serum strength. The same set of sera efficiently neutralize S from B.1.1.7 and exhibit only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of some emergent SARS-CoV-2 variants may benefit from updated vaccines. Here, the authors characterize the neutralization capacity of post-Sputnik V vaccination sera against SARS-CoV-2 variants of concern B.1.1.7 (alpha) and B.1.351 (beta), showing the latter to exhibit resistance to neutralization in vitro.

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Topics: Vaccination (51%), Neutralization (50%)

18 Citations


Open accessPosted ContentDOI: 10.1101/2021.03.31.21254660
03 Apr 2021-medRxiv
Abstract: The novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia outbreak in Wuhan, China Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2 'variants of concern' (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B117 (501YV1) and B1351 (501YV2) Using a replication-competent EGFP-reporter vesicular stomatitis virus (VSV) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV-G, and coupled with a clonal HEK-293T ACE2 TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that only 1 out of 12 serum samples from a cohort of recipients of the Gamaleya Sputnik V Ad26 / Ad5 vaccine showed effective neutralization (IC90) of rcVSV-CoV2-S: B1351 at full serum strength The same set of sera efficiently neutralized S from B117 and showed only moderately reduced activity against S carrying the E484K substitution alone Taken together, our data suggest that control of some emergent SARS-CoV-2 variants may benefit from updated vaccines

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Topics: Betacoronavirus (52%)

16 Citations


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48 results found


Open accessJournal ArticleDOI: 10.1056/NEJMOA2001017
Na Zhu1, Dingyu Zhang, Wenling Wang1, Xingwang Li2  +15 moreInstitutions (3)
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

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Topics: Coronavirus (57%), Betacoronavirus (56%)

15,285 Citations


Open accessJournal ArticleDOI: 10.1038/S41586-020-2012-7
Peng Zhou1, Xing-Lou Yang1, Xian Guang Wang2, Ben Hu1  +25 moreInstitutions (3)
03 Feb 2020-Nature
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.

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Topics: Coronavirus (67%), Betacoronavirus (54%), Deltacoronavirus (51%) ... read more

12,056 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2020.02.052
16 Apr 2020-Cell
Abstract: The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Topics: Proteases (52%)

10,193 Citations


Open accessJournal ArticleDOI: 10.1038/S41586-020-2008-3
Fan Wu1, Su Zhao2, Bin Yu3, Yan-Mei Chen1  +17 moreInstitutions (4)
03 Feb 2020-Nature
Abstract: Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health1–3. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China5. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans. Phylogenetic and metagenomic analyses of the complete viral genome of a new coronavirus from the family Coronaviridae reveal that the virus is closely related to a group of SARS-like coronaviruses found in bats in China.

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Topics: Coronavirus (62%), Betacoronavirus (59%), Zika virus disease (54%) ... read more

6,266 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.ABB2507
13 Mar 2020-Science
Abstract: The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.

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5,197 Citations


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