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1.
Vet Pathol ; : 3009858211057197, 2021 Dec 02.
Article in English | MEDLINE | ID: covidwho-1551143

ABSTRACT

The dramatic global consequences of the coronavirus disease 2019 (COVID-19) pandemic soon fueled quests for a suitable model that would facilitate the development and testing of therapies and vaccines. In contrast to other rodents, hamsters are naturally susceptible to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the Syrian hamster (Mesocricetus auratus) rapidly developed into a popular model. It recapitulates many characteristic features as seen in patients with a moderate, self-limiting course of the disease such as specific patterns of respiratory tract inflammation, vascular endothelialitis, and age dependence. Among 4 other hamster species examined, the Roborovski dwarf hamster (Phodopus roborovskii) more closely mimics the disease in highly susceptible patients with frequent lethal outcome, including devastating diffuse alveolar damage and coagulopathy. Thus, different hamster species are available to mimic different courses of the wide spectrum of COVID-19 manifestations in humans. On the other hand, fewer diagnostic tools and information on immune functions and molecular pathways are available than in mice, which limits mechanistic studies and inference to humans in several aspects. Still, under pandemic conditions with high pressure on progress in both basic and clinically oriented research, the Syrian hamster has turned into the leading non-transgenic model at an unprecedented pace, currently used in innumerable studies that all aim to combat the impact of the virus with its new variants of concern. As in other models, its strength rests upon a solid understanding of its similarities to and differences from the human disease, which we review here.

2.
Sci Adv ; 7(49): eabk0172, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1546430

ABSTRACT

Vaccines are instrumental and indispensable in the fight against the COVID-19 pandemic. Several recent SARS-CoV-2 variants are more transmissible and evade infection- or vaccine-induced protection. We constructed live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome and showed that the lead candidate, designated sCPD9, protects Syrian hamsters from a challenge with ancestral virus. Here, we assessed immunogenicity and protective efficacy of sCPD9 in the Roborovski dwarf hamster, a nontransgenic rodent species that is highly susceptible to SARS-CoV-2 and severe COVID-19­like disease. We show that a single intranasal vaccination with sCPD9 elicited strong cross-neutralizing antibody responses against four current SARS-CoV-2 variants of concern, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.1.28.1 (Gamma), and B.1.617.2 (Delta). The sCPD9 vaccine offered complete protection from COVID-19­like disease caused by the ancestral SARS-CoV-2 variant B.1 and the two variants of concern B.1.1.7 and B.1.351.

3.
Viruses ; 13(11)2021 11 16.
Article in English | MEDLINE | ID: covidwho-1524173

ABSTRACT

With the exception of inactivated vaccines, all SARS-CoV-2 vaccines currently used for clinical application focus on the spike envelope glycoprotein as a virus-specific antigen. Compared to other SARS-CoV-2 genes, mutations in the spike protein gene are more rapidly selected and spread within the population, which carries the risk of impairing the efficacy of spike-based vaccines. It is unclear to what extent the loss of neutralizing antibody epitopes can be compensated by cellular immune responses, and whether the use of other SARS-CoV-2 antigens might cause a more diverse immune response and better long-term protection, particularly in light of the continued evolution towards new SARS-CoV-2 variants. To address this question, we explored immunogenicity and protective effects of adenoviral vectors encoding either the full-length spike protein (S), the nucleocapsid protein (N), the receptor binding domain (RBD) or a hybrid construct of RBD and the membrane protein (M) in a highly susceptible COVID-19 hamster model. All adenoviral vaccines provided life-saving protection against SARS-CoV-2-infection. The most efficient protection was achieved after exposure to full-length spike. However, the nucleocapsid protein, which triggered a robust T-cell response but did not facilitate the formation of neutralizing antibodies, controlled early virus replication efficiently and prevented severe pneumonia. Although the full-length spike protein is an excellent target for vaccines, it does not appear to be the only option for future vaccine design.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Immunity, Cellular , Immunity, Humoral , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/immunology , Cricetinae , Female , Inflammation , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Phosphoproteins/genetics , Phosphoproteins/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology
4.
Nature ; 599(7884): 283-289, 2021 11.
Article in English | MEDLINE | ID: covidwho-1404888

ABSTRACT

Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. 1-4). Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and is accompanied by a senescence-associated secretory phenotype (SASP), which comprises pro-inflammatory cytokines, extracellular-matrix-active factors and pro-coagulatory mediators5-7. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. In vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, which mirrored hallmark features of COVID-19 such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade. Senolytics such as navitoclax and a combination of dasatinib plus quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-infected hamsters and mice. Our findings mark VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest that senolytic targeting of virus-infected cells is a treatment option against SARS-CoV-2 and perhaps other viral infections.


Subject(s)
COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cellular Senescence/drug effects , Molecular Targeted Therapy , SARS-CoV-2/pathogenicity , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Animals , COVID-19/complications , Cell Line , Cricetinae , Dasatinib/pharmacology , Dasatinib/therapeutic use , Disease Models, Animal , Female , Humans , Male , Mice , Quercetin/pharmacology , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thrombosis/complications , Thrombosis/immunology , Thrombosis/metabolism
5.
Cell Rep ; 36(5): 109493, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1328703

ABSTRACT

Safe and effective vaccines are urgently needed to stop the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We construct a series of live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome and assess their safety and efficacy in Syrian hamsters. Animals were vaccinated with a single dose of the respective recoded virus and challenged 21 days later. Two of the tested viruses do not cause clinical symptoms but are highly immunogenic and induce strong protective immunity. Attenuated viruses replicate efficiently in the upper but not in the lower airways, causing only mild pulmonary histopathology. After challenge, hamsters develop no signs of disease and rapidly clear challenge virus: at no time could infectious virus be recovered from the lungs of infected animals. The ease with which attenuated virus candidates can be produced and administered favors their further development as vaccines to combat the ongoing pandemic.


Subject(s)
COVID-19 Vaccines , COVID-19/immunology , COVID-19/prevention & control , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Animals , Chlorocebus aethiops , Gene Editing , Genome, Viral , Humans , Immunity , Mesocricetus , Mutation , Pandemics/prevention & control , Vaccines, Attenuated , Vero Cells , Virus Replication
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