Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Toxicol Pathol ; 50(3): 280-293, 2022 04.
Article in English | MEDLINE | ID: covidwho-1673709

ABSTRACT

Coronavirus disease 2019 (COVID-19) in humans has a wide range of presentations, ranging from asymptomatic or mild symptoms to severe illness. Suitable animal models mimicking varying degrees of clinical disease manifestations could expedite development of therapeutics and vaccines for COVID-19. Here we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulted in subclinical disease in rhesus macaques with mild pneumonia and clinical disease in Syrian hamsters with severe pneumonia. SARS-CoV-2 infection was confirmed by formalin-fixed, paraffin-embedded (FFPE) polymerase chain reaction (PCR), immunohistochemistry, or in situ hybridization. Replicating virus in the lungs was identified using in situ hybridization or virus plaque forming assays. Viral encephalitis, reported in some COVID-19 patients, was identified in one macaque and was confirmed with immunohistochemistry. There was no evidence of encephalitis in hamsters. Severity and distribution of lung inflammation were substantially more in hamsters compared with macaques and exhibited vascular changes and virus-induced cytopathic changes as seen in COVID-19 patients. Neither the hamster nor macaque models demonstrated evidence for multisystemic inflammatory syndrome (MIS). Data presented here demonstrate that macaques may be appropriate for mechanistic studies of mild asymptomatic COVID-19 pneumonia and COVID-19-associated encephalitis, whereas Syrian hamsters may be more suited to study severe COVID-19 pneumonia.


Subject(s)
COVID-19 , Encephalitis , Animals , COVID-19 Vaccines , Cricetinae , Disease Models, Animal , Encephalitis/pathology , Humans , Lung/pathology , Macaca mulatta , Mesocricetus , SARS-CoV-2
3.
Commun Biol ; 4(1): 290, 2021 03 05.
Article in English | MEDLINE | ID: covidwho-1118820

ABSTRACT

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.


Subject(s)
COVID-19/immunology , Cell Degranulation , Interferons/physiology , Neutrophils/physiology , SARS-CoV-2 , Aged , Animals , CD36 Antigens/physiology , COVID-19/etiology , Collagen/metabolism , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Lung/metabolism , Macaca mulatta , Male , Middle Aged , Receptors, Notch/physiology , Signal Transduction/physiology , Transforming Growth Factor beta/physiology , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/physiology
4.
Nature ; 592(7853): 283-289, 2021 04.
Article in English | MEDLINE | ID: covidwho-1101660

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).


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Disease Models, Animal , SARS-CoV-2/immunology , Aging/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, Viral/chemistry , Antigens, Viral/genetics , Antigens, Viral/immunology , BNT162 Vaccine , COVID-19/blood , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , Cell Line , Clinical Trials as Topic , Female , Humans , Immunization, Passive , Internationality , Macaca mulatta/immunology , Macaca mulatta/virology , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Multimerization , RNA, Viral/analysis , Respiratory System/immunology , Respiratory System/virology , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Solubility , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccination , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/chemistry , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
5.
Nat Microbiol ; 6(1): 73-86, 2021 01.
Article in English | MEDLINE | ID: covidwho-989838

ABSTRACT

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.


Subject(s)
COVID-19/veterinary , Callithrix/immunology , Lung/immunology , Macaca mulatta/immunology , Monkey Diseases/virology , Papio/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Animals , Antibodies, Viral/immunology , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid , COVID-19/diagnostic imaging , COVID-19/immunology , COVID-19/pathology , Female , Humans , Immunity, Cellular/immunology , Immunoglobulin G/immunology , Inflammation/pathology , Lung/virology , Male , Monkey Diseases/immunology , Myeloid Cells/immunology , Viral Load , Virus Shedding
6.
Nat Commun ; 11(1): 6122, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-952011

ABSTRACT

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Disease Models, Animal , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , Brain/immunology , Brain/pathology , Brain/virology , COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Disease Susceptibility , Genetic Predisposition to Disease , Keratin-18/genetics , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Mortality , Promoter Regions, Genetic/genetics , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , Virus Diseases/immunology , Virus Diseases/pathology
7.
Science ; 370(6520): 1110-1115, 2020 11 27.
Article in English | MEDLINE | ID: covidwho-840630

ABSTRACT

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/therapy , Animals , COVID-19/prevention & control , Drug Combinations , Macaca mulatta , Mesocricetus
SELECTION OF CITATIONS
SEARCH DETAIL