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1.
Vaccines (Basel) ; 10(3)2022 Mar 12.
Article in English | MEDLINE | ID: covidwho-1742755

ABSTRACT

The continued progression of the COVID-19 pandemic can partly be attributed to the ability of SARS-CoV-2 to mutate and introduce new viral variants. Some of these variants with the potential to spread quickly and conquer the globe are termed variants of concern (VOC). The existing vaccines implemented on a global scale are based on the ancestral strain, which has resulted in increased numbers of breakthrough infections as these VOC have emerged. It is imperative to show protection against VOC infection with newly developed vaccines. Previously, we evaluated two vesicular stomatitis virus (VSV)-based vaccines expressing the SARS-CoV-2 spike protein alone (VSV-SARS2) or in combination with the Ebola virus glycoprotein (VSV-SARS2-EBOV) and demonstrated their fast-acting potential. Here, we prolonged the time to challenge; we vaccinated hamsters intranasally (IN) or intramuscularly 28 days prior to infection with three SARS-CoV-2 VOC-the Alpha, Beta, and Delta variants. IN vaccination with either the VSV-SARS2 or VSV-SARS2-EBOV resulted in the highest protective efficacy as demonstrated by decreased virus shedding and lung viral load of vaccinated hamsters. Histopathologic analysis of the lungs revealed the least amount of lung damage in the IN-vaccinated animals regardless of the challenge virus. This data demonstrates the ability of a VSV-based vaccine to not only protect from disease caused by SARS-CoV-2 VOC but also reduce viral shedding.

2.
Front Immunol ; 12: 788235, 2021.
Article in English | MEDLINE | ID: covidwho-1650090

ABSTRACT

The ongoing COVID-19 pandemic has resulted in global effects on human health, economic stability, and social norms. The emergence of viral variants raises concerns about the efficacy of existing vaccines and highlights the continued need for the development of efficient, fast-acting, and cost-effective vaccines. Here, we demonstrate the immunogenicity and protective efficacy of two vesicular stomatitis virus (VSV)-based vaccines encoding the SARS-CoV-2 spike protein either alone (VSV-SARS2) or in combination with the Ebola virus glycoprotein (VSV-SARS2-EBOV). Intranasally vaccinated hamsters showed an early CD8+ T cell response in the lungs and a greater antigen-specific IgG response, while intramuscularly vaccinated hamsters had an early CD4+ T cell and NK cell response. Intranasal vaccination resulted in protection within 10 days with hamsters not showing clinical signs of pneumonia when challenged with three different SARS-CoV-2 variants. This data demonstrates that VSV-based vaccines are viable single-dose, fast-acting vaccine candidates that are protective from COVID-19.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Ebolavirus/immunology , Pandemics/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Vesicular stomatitis Indiana virus/immunology , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Ebolavirus/genetics , Female , Humans , Immunogenicity, Vaccine , Immunoglobulin G/blood , Immunoglobulin G/immunology , Male , Plasmids , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes/immunology , Treatment Outcome , Vero Cells , Vesicular stomatitis Indiana virus/genetics
3.
EBioMedicine ; 73: 103675, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1596532

ABSTRACT

BACKGROUND: Following the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid spread throughout the world, new viral variants of concern (VOC) have emerged. There is a critical need to understand the impact of the emerging variants on host response and disease dynamics to facilitate the development of vaccines and therapeutics. METHODS: Syrian golden hamsters are the leading small animal model that recapitulates key aspects of severe coronavirus disease 2019 (COVID-19). We performed intranasal inoculation of SARS-CoV-2 into hamsters with the ancestral virus (nCoV-WA1-2020) or VOC first identified in the United Kingdom (B.1.1.7, alpha) and South Africa (B.1.351, beta) and analyzed viral loads and host responses. FINDINGS: Similar gross and histopathologic pulmonary lesions were observed after infection with all three variants. Although differences in viral genomic copy numbers were noted in the lungs and oral swabs of challenged animals, infectious titers in the lungs were comparable between the variants. Antibody neutralization capacities varied, dependent on the original challenge virus and cross-variant protective capacity. Transcriptional profiling of lung samples 4 days post-challenge (DPC) indicated significant induction of antiviral pathways in response to all three challenges with a more robust inflammatory signature in response to B.1.1.7 infection. Furthermore, no additional mutations in the spike protein were detected at 4 DPC. INTERPRETATIONS: Although disease severity and viral shedding were not significantly different, the emerging VOC induced distinct humoral responses and transcriptional profiles compared to the ancestral virus. These observations suggest potential differences in acute early responses or alterations in immune modulation by VOC. FUNDING: Intramural Research Program, NIAID, NIH; National Center for Research Resources, NIH; National Center for Advancing Translational Sciences, NIH.


Subject(s)
COVID-19/pathology , SARS-CoV-2/isolation & purification , Transcriptome , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/virology , Cricetinae , Dendritic Cells/cytology , Dendritic Cells/metabolism , Disease Models, Animal , Female , Immunity, Humoral , Lung/metabolism , Lung/pathology , Lung/virology , Mesocricetus , Mouth/pathology , Mouth/virology , Nucleocapsid Proteins/metabolism , RNA, Viral/analysis , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
4.
Vet Pathol ; 59(4): 673-680, 2022 07.
Article in English | MEDLINE | ID: covidwho-1582697

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emergent, amphixenotic infection that resulted in a pandemic declaration in March 2020. A rapid search for appropriate animal models of this newly emergent viral respiratory disease focused initially on traditional nonhuman primate research species. Nonhuman primate models have previously been shown to be valuable in evaluation of emerging respiratory coronaviruses with pandemic potential (ie, SARS-CoV and Middle East respiratory syndrome coronavirus). In this article, we review the pulmonary histopathologic characteristics and immunohistochemical evaluation of experimental SARS-CoV-2 infection in the rhesus macaque, pigtail macaque, African green monkey, and squirrel monkey. Our results indicate that all evaluated nonhuman primate species developed variably severe histopathologic changes typical of coronavirus respiratory disease characterized by interstitial pneumonia with or without syncytial cell formation, alveolar fibrin, and pulmonary edema that progressed to type II pneumocyte hyperplasia. Lesion distribution was multifocal, frequently subpleural, and often more severe in lower lung lobes. However, squirrel monkeys showed the least severe and least consistent lesions of the evaluated nonhuman primates. Additionally, our results highlight the disparate physical relationship between viral antigen and foci of pulmonary lesions. While classic respiratory coronaviral lesions were observed in the lungs of all nonhuman primates evaluated, none of the primates exhibited severe lesions or evidence of diffuse alveolar damage and therefore are unlikely to represent the severe form of SARS-CoV-2 infection observed in fatal human cases.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19/veterinary , Chlorocebus aethiops , Lung/pathology , Macaca mulatta , Pandemics/veterinary
5.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1565893

ABSTRACT

In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer nonspecific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here, we demonstrate that intravenous, but not subcutaneous, inoculation of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 (SCV2) and results in reduced viral loads in non-transgenic animals infected with an α variant. The observed increase in host resistance was associated with reductions in SCV2-induced tissue pathology, inflammatory cell recruitment, and cytokine production that multivariate analysis revealed as only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and ensuing immunopathology. While intravenous BCG vaccination is not a clinically acceptable practice, our findings provide an experimental model for identifying mechanisms by which nonspecific stimulation of the pulmonary immune response promotes host resistance to SCV2 lethality.


Subject(s)
BCG Vaccine/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Administration, Intravenous , Angiotensin-Converting Enzyme 2/metabolism , Animals , Chemokines/metabolism , Humans , Inflammation/pathology , Mice, Inbred C57BL , Mice, Transgenic , Viral Load
6.
Nat Commun ; 12(1): 4985, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361633

ABSTRACT

Transmission of SARS-CoV-2 is driven by contact, fomite, and airborne transmission. The relative contribution of different transmission routes remains subject to debate. Here, we show Syrian hamsters are susceptible to SARS-CoV-2 infection through intranasal, aerosol and fomite exposure. Different routes of exposure present with distinct disease manifestations. Intranasal and aerosol inoculation causes severe respiratory pathology, higher virus loads and increased weight loss. In contrast, fomite exposure leads to milder disease manifestation characterized by an anti-inflammatory immune state and delayed shedding pattern. Whereas the overall magnitude of respiratory virus shedding is not linked to disease severity, the onset of shedding is. Early shedding is linked to an increase in disease severity. Airborne transmission is more efficient than fomite transmission and dependent on the direction of the airflow. Carefully characterized SARS-CoV-2 transmission models will be crucial to assess potential changes in transmission and pathogenic potential in the light of the ongoing SARS-CoV-2 evolution.


Subject(s)
COVID-19/transmission , Fomites , Administration, Intranasal , Aerosols , Animals , COVID-19/blood , COVID-19/virology , Cytokines/blood , Female , High-Throughput Nucleotide Sequencing , Lung/virology , Mesocricetus , Nasal Cavity/virology , Particle Size , RNA, Viral/genetics , Respiratory System/virology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Vaccination , Virus Replication , Virus Shedding
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