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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (12)

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SARS-CoV-2 Proteins
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    One dose of COVID-19 MESHD nanoparticle vaccine REVC-128 provides protection against SARS-CoV-2 challenge at two weeks post immunization

    Authors: Maggie Gu; Jonathan L Torres; Jack Greenhouse; Shannon Wallace; Chi-I Chiang; Abigail M Jackson; Maciel Porto; Swagata Kar; Yuxing Li; Andrew B Ward; Yimeng Wang

    doi:10.1101/2021.04.02.438218 Date: 2021-04-02 Source: bioRxiv

    A COVID-19 MESHD vaccine with capability to induce early protection is needed to efficiently eliminate viral spread. Here, we demonstrate the development of a nanoparticle vaccine candidate, REVC-128, in which multiple trimeric spike ectodomain subunits with glycine (G) at position 614 were multimerized onto a nanoparticle. In-vitro characterization of this vaccine confirms its structural and antigenic integrity. In-vivo immunogenicity evaluation in mice indicates that a single dose of this vaccine induces potent serum neutralizing antibody titer at two weeks post immunization, which is significantly higher than titer induced by trimeric spike protein PROTEIN without nanoparticle presentation. The comparison of serum binding to spike subunits between animals immunized by spike with and without nanoparticle presentation indicates that nanoparticle prefers the display of spike RBD (Receptor-Binding Domain) over S2 subunit, likely resulting in a more neutralizing but less cross-reactive antibody response. Moreover, a Syrian golden hamster in-vivo model for SARS-CoV-2 virus challenge was implemented at two weeks post a single dose of REVC-128 immunization. The results show that vaccination protects hamsters against SARS-CoV-2 virus challenge with evidence of steady body weight, suppressed viral loads and alleviation of tissue damage (lung and nares) for protected animals, compared with ~10% weight loss MESHD, higher viral loads and tissue damage in unprotected animals. Furthermore, the data show that vaccine REVC-128 is thermostable at up to 37 degree for at least 4 weeks. These findings, along with a long history of safety for protein vaccines, suggest that the REVC-128 is a safe, stable and efficacious single-shot vaccine candidate to induce the earliest protection against SARS-CoV-2 infection MESHD.

    A protective broadly cross-reactive human antibody defines a conserved site of vulnerability on beta-coronavirus spikes

    Authors: Panpan Zhou; Meng Yuan; Ge Song; Nathan Beutler; Namir Shaabani; Deli Huang; Wan-ting He; Xueyong Zhu; Sean Callaghan; Peter Yong; Fabio Anzanello; Linghang Peng; James Ricketts; Mara Parren; Elijah Garcia; Stephen A. Rawlings; Davey M. Smith; David Nemazee; John R. Teijaro; Thomas Rogers; Ian A. Wilson; Dennis R. Burton; Raiees Andrabi

    doi:10.1101/2021.03.30.437769 Date: 2021-03-31 Source: bioRxiv

    We recently described CC40.8 bnAb from a COVID-19 MESHD donor that exhibits broad reactivity with human {beta}-CoVs. Here, we show that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab HGNC with a SARS-CoV-2 S2 stem-peptide at 1.6 A resolution and found that the peptide adopts a mainly helical structure. Conserved residues in {beta}-CoVs interact with the antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibits in vivo protective efficacy against SARS-CoV-2 challenge in a hamster model with reduction in weight loss MESHD and lung viral titers. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 MESHD infection and therefore their elicitation may require rational vaccine strategies. Overall, our study describes a new target on CoV spikes for protective antibodies that may facilitate the development of pan-{beta}-CoV vaccines.

    A lipid nanoparticle RBD-hFc mRNA vaccine protects hACE2 HGNC transgenic mice against lethal SARS-CoV-2 infection MESHD

    Authors: Uri Elia; Shahar Rotem; Srinivas Ramishetti; David Gur; Moshe Aftalion; Adi Bercovich-Kinori; Ron Alcalay; Efi Makdasi; Theodor Chitlaru; Ronit Rosenfeld; Tomer Israely; Sharon Melamed; Inbal Abutbul Ionita; Dganit Danino; Dan Peer; Ofer Cohen

    doi:10.1101/2021.03.29.436639 Date: 2021-03-29 Source: bioRxiv

    The current global COVID-19 pandemic MESHD led to an unprecedented effort to develop effective vaccines against SARS-CoV-2. mRNA vaccines were developed very rapidly during the last year, and became the leading immunization platform against the virus, with highly promising phase-3 results and remarkable efficacy data. Since most animal models are not susceptible to SARS CoV-2 infection MESHD, pre-clinical studies are often limited to infection-prone animals such as hamsters and non-human primates. In these animal models, SARS-CoV-2 infection MESHD results in viral replication and a mild disease disease MESHD. Therefore, the protective efficacy of the vaccine in these animals is commonly evaluated by its ability to elicit immunologic responses, diminish viral replication and prevent weight loss MESHD. Our lab recently reported the design of a SARS-CoV-2 human Fc-conjugated receptor-binding domain (RBD-hFc) mRNA vaccine delivered via lipid nanoparticles (LNPs). These experiments demonstrated the development of a robust and specific immunologic response in RBD-hFc mRNA- vaccinated BALB/c mice. In the current study, we evaluated the protective effect of this RBD-hFc mRNA vaccine by employing the K18- hACE2 HGNC mouse model. We report that administration of RBD-hFc mRNA vaccine to K18- hACE2 HGNC mice led to a robust humoral response comprised of both binding and neutralizing antibodies. In accordance with the recorded immunologic immune response, 70% of vaccinated mice were protected against a lethal dose (3000 plaque forming units) of SARS-CoV-2, while all control animals succumbed to infection. To the best of our knowledge, this is the first non-replicating mRNA vaccine study reporting protection of K18- hACE2 HGNC against a lethal SARS-CoV-2 infection MESHD.

    A novel soluble ACE2 HGNC protein totally protects from lethal disease caused by SARS-CoV-2 infection MESHD

    Authors: Luise Hassler; Jan Wysocki; Ian Gelarden; Anastasia Tomatsidou; Haley Gula; Vlad Nicoleascu; Glenn Randall; Jack Henkin; Anjana Yeldandi; Daniel Batlle

    doi:10.1101/2021.03.12.435191 Date: 2021-03-15 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 HGNC ( ACE2 HGNC), which is membrane bound, as its initial cell contact receptor preceding viral entry. Here we report a human soluble ACE2 HGNC variant fused with a 5kD albumin binding domain (ABD) and bridged via a dimerization motif hinge-like 4-cysteine dodecapeptide, which we term ACE2 HGNC 1-618-DDC-ABD. This protein is enzymatically active, has increased duration of action in vivo conferred by the ABD-tag, and displays 20-30-fold higher binding affinity to the SARS-CoV-2 receptor binding domain than its des-DDC monomeric form ( ACE2 HGNC 1-618-ABD) due to DDC-linked dimerization. ACE2 1-618-DDC-ABD was administered for 3 consecutive days to transgenic k18- hACE2 HGNC mice, a model that develops lethal SARS-CoV-2 infection MESHD, to evaluate the preclinical preventative/ therapeutic value for COVID-19 MESHD. Mice treated with ACE2 1-618-DDC-ABD developed a mild to moderate disease for the first few days assessed by a clinical score and modest weight loss MESHD. The untreated control animals, by contrast, became severely ill and had to be sacrificed by day 6/7 and lung histology revealed extensive pulmonary alveolar hemorrhage MESHD and mononuclear infiltrates. At 6 days, mortality was totally prevented in the treated group, lung histopathology was improved and viral titers markedly reduced. This demonstrates for the first time in vivo the preventative/ therapeutic potential of a novel soluble ACE2 protein in a preclinical animal model.

    Phodopus roborovskii SH101 as a systemic infection MESHD model of SARS-CoV-2

    Authors: Chongkai Zhai; Mingda Wang; Hea-Jong Chung; Md. Mehedi Hassan; Seungkoo Lee; Hyeon-Jin Kim; Seong-Tshool Hong

    doi:10.1101/2021.03.10.434891 Date: 2021-03-11 Source: bioRxiv

    Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 MESHD is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 MESHD representing most aspects of the clinical manifestations of COVID-19 MESHD with systemic symptoms. Here we report that a hamster strain of Phodopus roborovskii SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection MESHD upon SARS-CoV-2 infection MESHD as in the case of the human counterpart, unlike current COVID-19 MESHD animal models. P. roborovskii SH101 post-infection of SARS-CoV-2 MESHD represented most clinical symptoms of COVID-19 MESHD such as snuffling, dyspnea MESHD, cough, labored breathing MESHD, hunched posture, progressive weight loss MESHD, and ruffled fur, in addition to high fever MESHD following shaking chills. Histological examinations also revealed a serious right-predominated pneumonia MESHD as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 MESHD cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection MESHD in human, this hamster model seems to provide an ideal tool to investigate COVID-19 MESHD.

    The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2

    Authors: Andrea L Cathcart; Colin Havenar-Daughton; Florian A Lempp; Daphne Ma; Michael Schmid; Maria L Agostini; Barbara Guarino; Julia Di iulio; Laura Rosen; Heather Tucker; Joshua Dillen; Sambhavi Subramanian; Barbara Sloan; Siro Bianchi; Jason Wojcechowskyj; Jiayi Zhou; Hannah Kaiser; Arthur Chase; Martin Montiel-Ruiz; Nadine Czudnochowski; Elisabetta Cameroni; Sarah Ledoux; Christophe Colas; Leah Soriaga; Amalio Telenti; Seungmin Hwang; Gyorgy Snell; Herbert W Virgin; Davide Corti; Christy M Hebner

    doi:10.1101/2021.03.09.434607 Date: 2021-03-10 Source: bioRxiv

    VIR-7831 and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein PROTEIN of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2). VIR-7831 and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV MESHD) survivor. Both mAbs contain an LS mutation in the Fc region to prolong serum half-life and potentially enhance distribution to the respiratory mucosa. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection MESHD. VIR-7831 and VIR-7832 potently neutralize live wild-type SARS-CoV-2 in vitro as well as pseudotyped viruses encoding spike protein PROTEIN from the B.1.1.7, B.1.351 and P.1 variants. In addition, they retain activity against monoclonal antibody resistance mutations that confer reduced susceptibility to currently authorized mAbs. The VIR-7831/VIR-7832 epitope does not overlap with mutational sites in the current variants of concern and continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept concept wildtype SARS-CoV-2 infection MESHD model, animals treated with VIR-7831 had less weight loss MESHD, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that VIR-7831 and VIR-7832 are promising new agents in the fight against COVID-19 MESHD.

    Engineered SARS-CoV-2 receptor binding domain improves immunogenicity in mice and elicits protective immunity in hamsters

    Authors: Neil C Dalvie; Sergio A Rodriguez-Aponte; Brittany L Hartwell; Lisa H Tostanoski; Andrew M Biedermann; Laura E Crowell; Kawaljit Kaur; Ozan Kumru; Lauren Carter; Jingyou Yu; Aiquan Chang; Katherine McMahan; Thomas Courant; Celia Lebas; Ashley A Lemnios; Kristen A Rodrigues; Murillo Silva; Ryan S Johnston; Christopher A Naranjo; Mary Kate Tracey; Joseph R Brady; Charles A Whittaker; Dongsoo Yun; Swagata Kar; Maciel Porto; Megan Lok; Hanne Andersen; Mark G Lewis; Kerry R Love; Danielle L Camp; Judith Maxwell Silverman; Harry Kleanthous; Sangeeta B Joshi; David B Volkin; Patrice M Dubois; Nicolas Collin; Neil P King; Dan H Barouch; Darrell J Irvine; J Christopher Love

    doi:10.1101/2021.03.03.433558 Date: 2021-03-04 Source: bioRxiv

    Global containment of COVID-19 MESHD still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing costs. These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2. Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss MESHD in hamsters upon viral challenge.

    Low-dose lung radiotherapy for COVID-19 MESHD lung disease MESHD: a pre-clinical efficacy study in a bleomycin model of pneumonitis MESHD.

    Authors: Mark R Jackson; Katrina Stevenson; Sandeep K Chahal; Emer Curley; George Finney; Rodrigo Gutierrez-Quintana; Evarest Onwubiko; Angelika F Rupp; Karen Strathdee; Megan KL MacLeod; Charles McSharry; Anthony J Chalmers

    doi:10.1101/2021.03.03.433704 Date: 2021-03-03 Source: bioRxiv

    Purpose: Low-dose whole lung radiotherapy ( LDLR HGNC) has been proposed as a treatment for patients with acute respiratory distress syndrome MESHD associated with SARS-CoV-2 infection MESHD and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling and mechanisms of action. Materials and methods: Female C57BL/6 mice were treated with intranasal bleomycin sulphate (7.5 or 11.25 units/kg, day 0) then exposed to whole lung radiation therapy (0.5, 1.0, 1.5 Gy or sham, day 3). Bodyweight was measured daily and lung tissue harvested for histology and flow cytometry on day 10. Computed tomography (CT) lung imaging was performed pre-radiation (day 3) and pre-endpoint (day 10). Results: Bleomycin caused pneumonitis MESHD of variable severity which correlated with weight loss MESHD. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight; many of these mice exhibited less severe histopathological lung changes. Mice experiencing moderate initial weight loss MESHD were more likely to respond to LDLR than those experiencing severe initial weight loss MESHD. LDLR (1.0 Gy) significantly reduced bleomycin induced increases in interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids. Pre-radiation, bleomycin treated mice exhibited significantly higher percentages of non-aerated lung in left than right lungs; LDLR (1.0 Gy) prevented further reductions in aerated lung volume in right but not left lungs. LDLR doses of 0.5 and 1.5 Gy did not modulate bodyweight or flow cytometric readouts of bleomycin pneumonitis MESHD. Conclusions: Our data support the concept that LDLR can ameliorate acute inflammatory lung injury MESHD, identify 1.0 Gy as the most effective dose and provide preliminary evidence that it is more effective in the context of moderate than severe pneumonitis MESHD. Mechanistically, LDLR significantly suppressed bleomycin induced accumulation of interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids in the lung.

    Comparison of the pathogenicity and virus shedding of SARS CoV-2 VOC 202012/01 and D614G variant in hamster model

    Authors: Sreelekshmy Mohandas; Pragya D Yadav; Dimpal Nyayanit; Gururaj Deshpande; Anita Shete Aich; Gajanan Sapkal; Sanjay Kumar; Rajlaxmi Jain; Manoj Kadam; Abhimanyu Kumar; Deepak Y Patil; Prasad Sarkale; Pranita Gawande; Priya Abraham

    doi:10.1101/2021.02.25.432136 Date: 2021-02-25 Source: bioRxiv

    The emergence of SARS-CoV-2 variants has posed a serious challenge to public health system and vaccination programs across the globe. We have studied the pathogenicity and virus shedding pattern of the SARS-CoV-2 VOC 202012/01 and compared with D614G variant in Syrian hamsters. VOC 202012/01 could produce disease in hamsters characterized by body weight loss MESHD and respiratory tract tropism MESHD but mild lung pathology. Further, we also documented that neutralizing antibodies developed against VOC 202012/01 could equally neutralize D614G variant. Higher load of VOC 202012/01 in the nasal wash specimens was observed during the first week of infection outcompeting the D614G variant. The findings suggest increased fitness of VOC 202012/01 to the upper respiratory tract which could lead to higher transmission. Further investigations are needed to understand the transmissibility of new variants.

    Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections MESHD in Syrian hamsters at ultra-low doses

    Authors: Sham Nambulli; Yufei Xiang; Natasha L Tilston-Lunel; Linda J Rennick; Zhe Sang; William B Klimstra; Douglas S Reed; Nicholas A Crossland; Yi Shi; Paul W Duprex

    doi:10.1101/2021.02.23.432569 Date: 2021-02-23 Source: bioRxiv

    Globally there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 MESHD ( COVID-19 MESHD). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 MESHD disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection MESHD. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss MESHD and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals weight loss post-infection and decreases lung viral titers MESHD by 6 logs leading to drastically mitigated lung pathology and prevents viral pneumonia MESHD. Combined with the marked stability and low production cost, this novel therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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