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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336025

ABSTRACT

Vaccines are a cornerstone in COVID-19 pandemic management. Here, we compare immune responses to and preclinical efficacy of the mRNA vaccine BNT162b2, an adenovirus-vectored spike vaccine, and the live-attenuated-virus vaccine candidate sCPD9 after single and double vaccination in Syrian hamsters. All regimens containing sCPD9 showed superior efficacy. The robust immunity elicited by sCPD9 was evident in a wide range of immune parameters after challenge with heterologous SARS-CoV-2 including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue. Our results demonstrate that use of live-attenuated vaccines may offer advantages over available COVID-19 vaccines, specifically when applied as booster, and may provide a solution for containment of the COVID-19 pandemic.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-322925

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has precipitated an unprecedented and yet unresolved crisis worldwide. Different mammals are susceptible to SARS-CoV-2;however, no species examined so far develops robust clinical disease that mirrors severe human cases or allows testing of vaccines and drugs under conditions of severe disease. Here, we compare the susceptibility of three dwarf hamster species (Phodopus spp.) to SARS-CoV-2 and introduce the Roborovski dwarf hamster (P. roborovskii) as a highly susceptible COVID-19 model with consistent and fulminant clinical signs. Particularly, this species shows SARS-CoV-2-induced severe acute diffuse alveolar damage and hyaline microthrombi in the lungs, changes described in patients who succumbed to the infection, but so far not reproduced in any experimentally infected animal. We therefore propose the Roborovski dwarf hamster as an ideal model to examine the efficacy and safety of live attenuated vaccine candidates and novel therapeutics, particularly for their use in highly susceptible individuals.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295313

ABSTRACT

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. The unconventionally secreted ORF8 recognizes the IL17RA receptor of macrophages and induces cytokine release. However, conventionally secreted ORF8 cannot bind to IL17RA due to N-linked glycosylation. Furthermore, we found that Yip1 interacting factor homolog B (YIF1B) is a channel protein that translocates unglycosylated ORF8 into vesicles for unconventional secretion. Blocking the unconventional secretion of ORF8 via a YIF1B knockout in hACE2 mice attenuates inflammation and yields delayed mortality following SARS-CoV-2 challenge.

4.
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.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293622

ABSTRACT

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. The unconventionally secreted ORF8 recognizes the IL17RA receptor of macrophages and induces cytokine release. However, conventionally secreted ORF8 cannot bind to IL17RA due to N-linked glycosylation. Furthermore, we found that Yip1 interacting factor homolog B (YIF1B) is a channel protein that translocates unglycosylated ORF8 into vesicles for unconventional secretion. Blocking the unconventional secretion of ORF8 via a YIF1B knockout in hACE2 mice attenuates inflammation and yields delayed mortality following SARS-CoV-2 challenge.

6.
Mol Inform ; 40(9): e2100031, 2021 09.
Article in English | MEDLINE | ID: covidwho-1351262

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to be a global threat, causing millions of deaths worldwide. SARS-CoV-2 is an enveloped virus with spike (S) glycoproteins conferring binding to the host cell's angiotensin-converting enzyme 2 (ACE2), which is critical for cellular entry. The host range of the virus extends well beyond humans and non-human primates. Natural and experimental infections have confirmed the high susceptibility of cats, ferrets, and Syrian hamsters, whereas dogs, mice, rats, pigs, and chickens are refractory to SARS-CoV-2 infection. To investigate the underlying reason for the variable susceptibility observed in different species, we have developed molecular descriptors to efficiently analyse dynamic simulation models of complexes between SARS-CoV-2 S and ACE2. Our extensive analyses represent the first systematic structure-based approach that allows predictions of species susceptibility to SARS-CoV-2 infection.


Subject(s)
SARS-CoV-2/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , Cats , Dogs , Ferrets , Haplorhini , Humans , Mesocricetus , Mice , Molecular Dynamics Simulation , Rats , SARS-CoV-2/metabolism , Species Specificity , Swine
7.
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
9.
Cell Rep ; 33(10): 108488, 2020 12 08.
Article in English | MEDLINE | ID: covidwho-938810

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated an unprecedented and yet-unresolved health crisis worldwide. Different mammals are susceptible to SARS-CoV-2; however, few species examined so far develop robust clinical disease that mirrors severe human cases or allows testing of vaccines and drugs under conditions of severe disease. Here, we compare the susceptibilities of three dwarf hamster species (Phodopus spp.) to SARS-CoV-2 and introduce the Roborovski dwarf hamster (P. roborovskii) as a highly susceptible COVID-19 model with consistent and fulminant clinical signs. Particularly, only this species shows SARS-CoV-2-induced severe acute diffuse alveolar damage and hyaline microthrombi in the lungs, changes described in patients who succumbed to the infection but not reproduced in any experimentally infected animal. Based on our findings, we propose the Roborovski dwarf hamster as a valuable model to examine the efficacy and safety of vaccine candidates and therapeutics, particularly for use in highly susceptible individuals.


Subject(s)
COVID-19/virology , Disease Models, Animal , Lung/virology , Phodopus/virology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/pathology , COVID-19/physiopathology , Lung/pathology , Lung/physiopathology , Pulmonary Alveoli/physiopathology , Pulmonary Alveoli/virology , SARS-CoV-2/genetics
10.
Viruses ; 12(7):779, 2020.
Article | WHO COVID | ID: covidwho-650369

ABSTRACT

In late 2019, an outbreak of a severe respiratory disease caused by an emerging coronavirus, SARS-CoV-2, resulted in high morbidity and mortality in infected humans. Complete understanding of COVID-19, the multi-faceted disease caused by SARS-CoV-2, requires suitable small animal models, as does the development and evaluation of vaccines and antivirals. Since age-dependent differences of COVID-19 were identified in humans, we compared the course of SARS-CoV-2 infection in young and aged Syrian hamsters. We show that virus replication in the upper and lower respiratory tract was independent of the age of the animals. However, older hamsters exhibited more pronounced and consistent weight loss. In situ hybridization in the lungs identified viral RNA in bronchial epithelium, alveolar epithelial cells type I and II, and macrophages. Histopathology revealed clear age-dependent differences, with young hamsters launching earlier and stronger immune cell influx than aged hamsters. The latter developed conspicuous alveolar and perivascular edema, indicating vascular leakage. In contrast, we observed rapid lung recovery at day 14 after infection only in young hamsters. We propose that comparative assessment in young versus aged hamsters of SARS-CoV-2 vaccines and treatments may yield valuable information, as this small-animal model appears to mirror age-dependent differences in human patients.

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