scholarly journals Replicating bacterium-vectored vaccine expressing SARS-CoV-2 Membrane and Nucleocapsid proteins protects against severe COVID-19-like disease in hamsters

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Qingmei Jia ◽  
Helle Bielefeldt-Ohmann ◽  
Rachel M. Maison ◽  
Saša Masleša-Galić ◽  
Sarah K. Cooper ◽  
...  
Keyword(s):  
Weight Loss ◽  
Structural Proteins ◽  
High Dose ◽  
Lung Pathology ◽  
High Homology ◽  
Universal Vaccine ◽  
Nucleocapsid Proteins ◽  
Syrian Hamsters ◽  
Viral Loads ◽  
Vectored Vaccine

AbstractTo generate an inexpensive readily manufactured COVID-19 vaccine, we employed the LVS ΔcapB vector platform, previously used to generate potent candidate vaccines against Select Agent diseases tularemia, anthrax, plague, and melioidosis. Vaccines expressing SARS-CoV-2 structural proteins are constructed using the LVS ΔcapB vector, a highly attenuated replicating intracellular bacterium, and evaluated for efficacy in golden Syrian hamsters, which develop severe COVID-19-like disease. Hamsters immunized intradermally or intranasally with a vaccine co-expressing the Membrane and Nucleocapsid proteins and challenged 5 weeks later with a high dose of SARS-CoV-2 are protected against severe weight loss and lung pathology and show reduced viral loads in the oropharynx and lungs. Protection correlates with anti-Nucleocapsid antibody. This potent vaccine should be safe; inexpensive; easily manufactured, stored, and distributed; and given the high homology between Membrane and Nucleocapsid proteins of SARS-CoV and SARS-CoV-2, potentially serve as a universal vaccine against the SARS subset of pandemic causing β-coronaviruses.

scholarly journals Replicating bacterium-vectored vaccine expressing SARS-CoV-2 Membrane and Nucleocapsid proteins protects against severe COVID-19 disease in hamsters

2020 ◽  
Author(s):  
Qingmei Jia ◽  
Helle Bielefeldt-Ohmann ◽  
Rachel Maison ◽  
Saša Masleša-Galić ◽  
Richard Bowen ◽  
...  
Keyword(s):  
Severe Disease ◽  
High Dose ◽  
Lung Pathology ◽  
Universal Vaccine ◽  
Nucleocapsid Proteins ◽  
Golden Syrian Hamster ◽  
Viral Loads ◽  
Highly Correlated ◽  
Vectored Vaccine ◽  
Tularemia Vaccine

AbstractAn inexpensive readily manufactured COVID-19 vaccine that protects against severe disease is needed to combat the pandemic. We have employed the LVS ΔcapB vector platform, previously used successfully to generate potent vaccines against the Select Agents of tularemia, anthrax, plague, and melioidosis, to generate a COVID-19 vaccine. The LVS ΔcapB vector, a replicating intracellular bacterium, is a highly attenuated derivative of a tularemia vaccine (LVS) previously administered to millions of people. We generated vaccines expressing SARS-CoV-2 structural proteins and evaluated them for efficacy in the golden Syrian hamster, which develops severe COVID-19 disease. Hamsters immunized intradermally or intranasally with a vaccine co-expressing the Membrane (M) and Nucleocapsid (N) proteins, then challenged 5-weeks later with a high dose of SARS-CoV-2, were protected against severe weight loss and lung pathology and had reduced viral loads in the oropharynx and lungs. Protection by the vaccine, which induces murine N-specific interferon-gamma secreting T cells, was highly correlated with pre-challenge serum anti-N TH1-biased IgG. This potent vaccine against severe COVID-19 should be safe and easily manufactured, stored, and distributed, and given the high homology between MN proteins of SARS-CoV and SARS-CoV-2, has potential as a universal vaccine against the SARS subset of pandemic causing β-coronaviruses.

scholarly journals mRNA-1273 and Ad26.COV2.S vaccines protect against the B.1.621 variant of SARS-CoV-2

2021 ◽  
Author(s):  
Tamarand L Darling ◽  
Boaling Ying ◽  
Bradley Whitener ◽  
Laura VanBlargan ◽  
Traci L Bricker ◽  
...  
Keyword(s):  
Weight Loss ◽  
Animal Models ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Evasion ◽  
Lung Infection ◽  
High Dose ◽  
South American ◽  
Lung Pathology ◽  
Virus Challenge ◽  
Vectored Vaccine

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, viral variants with greater transmissibility or immune evasion properties have arisen, which could jeopardize recently deployed vaccine and antibody-based countermeasures. Here, we evaluated in mice and hamsters the efficacy of preclinical non-GMP Moderna mRNA vaccine (mRNA-1273) and the Johnson & Johnson recombinant adenoviral-vectored vaccine (Ad26.COV2.S) against the B.1.621 (Mu) South American variant of SARS-CoV-2, which contains spike mutations T95I, Y144S, Y145N, R346K, E484K, N501Y, D614G, P681H, and D950N. Immunization of 129S2 and K18-human ACE2 transgenic mice with mRNA-1273 vaccine protected against weight loss, lung infection, and lung pathology after challenge with B.1.621 or WA1/2020 N501Y/D614G SARS-CoV-2 strain. Similarly, immunization of 129S2 mice and Syrian hamsters with a high dose of Ad26.COV2.S reduced lung infection after B.1.621 virus challenge. Thus, immunity induced by mRNA-1273 or Ad26.COV2.S vaccines can protect against the B.1.621 variant of SARS-CoV-2 in multiple animal models.

scholarly journals Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2-Infected Syrian Hamsters

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Rebecca L. Brocato ◽  
Lucia M. Principe ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Janice A. Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Weight Loss ◽  
Animal Models ◽  
Adaptive Immunity ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Clinical Signs ◽  
High Dose ◽  
Syrian Hamsters ◽  
Neutralizing Monoclonal Antibody

ABSTRACT Animal models recapitulating human COVID-19 disease, especially severe disease, are urgently needed to understand pathogenesis and to evaluate candidate vaccines and therapeutics. Here, we develop novel severe-disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than those in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and was uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2 but also play an early role in protection from acute disease. IMPORTANCE Syrian hamsters are in use as a model of disease caused by SARS-CoV-2. Pathology is pronounced in the upper and lower respiratory tract, and disease signs and endpoints include weight loss and viral RNA and/or infectious virus in swabs and organs (e.g., lungs). However, a high dose of virus is needed to produce disease, and the disease resolves rapidly. Here, we demonstrate that immunosuppressed hamsters are susceptible to low doses of virus and develop more severe and prolonged disease. We demonstrate the efficacy of a novel neutralizing monoclonal antibody using the cyclophosphamide transient suppression model. Furthermore, we demonstrate that RAG2 knockout hamsters develop severe/fatal disease when exposed to SARS-CoV-2. These immunosuppressed hamster models provide researchers with new tools for evaluating therapies and vaccines and understanding COVID-19 pathogenesis.

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

2021 ◽  
Author(s):  
Sham Nambulli ◽  
Yufei Xiang ◽  
Natasha L. Tilston-Lunel ◽  
Linda J. Rennick ◽  
Zhe Sang ◽  
...  
Keyword(s):  
Weight Loss ◽  
Low Cost ◽  
Cost Effective ◽  
Therapeutic Interventions ◽  
Lung Pathology ◽  
Aerosol Delivery ◽  
Upper Airways ◽  
Novel Therapy ◽  
Syrian Hamsters ◽  
Effective Option

AbstractGlobally there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss 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 by 6 logs leading to drastically mitigated lung pathology and prevents viral pneumonia. 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.

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

2021 ◽  
Vol 7 (22) ◽  
pp. eabh0319
Author(s):  
Sham Nambulli ◽  
Yufei Xiang ◽  
Natasha L. Tilston-Lunel ◽  
Linda J. Rennick ◽  
Zhe Sang ◽  
...  
Keyword(s):  
Weight Loss ◽  
Low Cost ◽  
Cost Effective ◽  
Therapeutic Interventions ◽  
Lung Pathology ◽  
Aerosol Delivery ◽  
Upper Airways ◽  
Syrian Hamsters ◽  
Innovative Therapy ◽  
Effective Option

Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss 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 after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.

scholarly journals Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2 Infected Syrian Hamsters

2020 ◽  
Author(s):  
Rebecca Brocato ◽  
Lucia Principe ◽  
Robert Kimi ◽  
Xiankun Zeng ◽  
Janice Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Weight Loss ◽  
Animal Models ◽  
Adaptive Immunity ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Clinical Signs ◽  
Syrian Hamsters ◽  
Viral Loads ◽  
Neutralizing Monoclonal Antibody

Abstract Animal models recapitulating human COVID-19 disease, especially with severe disease, are urgently needed to understand pathogenesis and evaluate candidate vaccines and therapeutics. Here, we develop novel severe disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to SARS-CoV-2 by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2, but also play an early role in protection from acute disease.

scholarly journals The B.1.427/1.429 (epsilon) SARS-CoV-2 variants are more virulent than ancestral B.1 (614G) in Syrian hamsters

2021 ◽  
Author(s):  
Timothy Carroll ◽  
Douglas Fox ◽  
Neeltje van Doremalen ◽  
Erin Ball ◽  
Mary Kate Morris ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Severe Disease ◽  
Body Weight Loss ◽  
Relative Fitness ◽  
Lung Pathology ◽  
Upper Respiratory Tract ◽  
Hamster Model ◽  
Syrian Hamsters

As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel variant of concern (VOC) designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and shown to enhance infectivity in vitro and decrease antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both strains exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most body weight loss among all 3 lineages. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three strains. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the upper respiratory tract (URT) but not in the lungs. In multi-virus in-vivo competition experiments, we found that epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the URT gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) variants in hamsters. These results demonstrate enhanced virulence and high relative fitness of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) strain.

scholarly journals Single immunization with recombinant ACAM2000 vaccinia viruses expressing the spike and the nucleocapsid proteins protect hamsters against SARS-CoV-2 caused clinical disease

2021 ◽  
Author(s):  
Yvon Deschambault ◽  
Jessie Lynch ◽  
Bryce Warner ◽  
Kevin Tierney ◽  
Denise Huynh ◽  
...  
Keyword(s):  
Weight Loss ◽  
Recovery Time ◽  
Vaccine Candidate ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Hamster Model ◽  
Nucleocapsid Proteins ◽  
Viral Loads ◽  
Vaccinia Viruses ◽  
The Individual

SUMMARYIncreasing cases of SARS-CoV-2 breakthrough infections from immunization with predominantly spike protein based COVID-19 vaccines highlight the need for alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins in a novel vaccinia virus ACAM2000 platform (rACAM2000). Following a single intramuscular immunization, the rACAM2000 co-expressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and quicker recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titre and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that the rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate and further studies will investigate if the rACAM2000 vaccine candidate can induce a long lasting immunity against infection of SARS-CoV-2 variants of concern.

2016-P: High Dose DACRA Treatment Improves Glucose Homeostasis, without Additional Weight Loss

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 2016-P
Author(s):  
NINA SONNE ◽  
ANNA T. LARSEN ◽  
KIM V. ANDREASSEN ◽  
MORTEN ASSER KARSDAL ◽  
KIM HENRIKSEN
Keyword(s):  
Weight Loss ◽  
Glucose Homeostasis ◽  
High Dose ◽  
Additional Weight

scholarly journals Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kathryn A. Ryan ◽  
Kevin R. Bewley ◽  
Susan A. Fotheringham ◽  
Gillian S. Slack ◽  
Phillip Brown ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Viral Rna ◽  
Dose Titration ◽  
High Dose ◽  
Lung Pathology ◽  
Upper Respiratory Tract ◽  
Virus Shedding ◽  
Upper Respiratory ◽  
Dose Dependent ◽  
Titration Study

AbstractThere is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.

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