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1.
Vaccines (Basel) ; 10(2)2022 Feb 14.
Article in English | MEDLINE | ID: covidwho-1699506

ABSTRACT

The emergence of rapidly spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a major challenge to the ability of vaccines and therapeutic antibodies to provide immunity. These variants contain mutations of specific amino acids that might impede vaccine efficacy. BriLife® (rVSV-ΔG-spike) is a newly developed SARS-CoV-2 vaccine candidate currently in phase II clinical trials. It is based on a replication-competent vesicular stomatitis virus (VSV) platform. The rVSV-ΔG-spike contains several spontaneously acquired spike mutations that correspond to SARS-CoV-2 variants' mutations. We show that human sera from BriLife® vaccinees preserve comparable neutralization titers towards alpha, gamma, and delta variants and show less than a three-fold reduction in the neutralization capacity of beta and omicron compared to the original virus. Taken together, we show that human sera from BriLife® vaccinees overall maintain a neutralizing antibody response against all tested variants. We suggest that BriLife®-acquired mutations may prove advantageous against future SARS-CoV-2 VOCs.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-304759

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause for the ongoing COVID-19 pandemic1. The continued spread of SARS-CoV-2 along with the imminent flu season increase the probability of influenza-SARS-CoV-2 dual infection which might result in a severe disease. In this study, we examined the disease outcome of influenza A virus (IAV) and SARS-CoV-2 co-infection in K18-hACE2 mice. Our data indicates that IAV-infected mice are more susceptible to develop severe disease upon co-infection with SARS-CoV-2 two days post influenza infection. This co-infection results in severe morbidity and nearly uniform fatality as compared to the non-fatal influenza disease, or the partial fatality of SARS-CoV-2 alone. Co-infection was associated with elevated influenza viral load in respiratory organs. Remarkably, prior immunity to influenza, but not to SARS-CoV-2, prevented the severe disease and mortality. These data provide an experimental support that flu intervention by prior vaccination may be valuable in reducing the risk of sever Flu - SARS-CoV-2 comorbidity, and highlight the importance of vaccination.

3.
Arch Toxicol ; 96(3): 859-875, 2022 03.
Article in English | MEDLINE | ID: covidwho-1634984

ABSTRACT

rVSV-ΔG-SARS-CoV-2-S is a clinical stage (Phase 2) replication competent recombinant vaccine against SARS-CoV-2. To evaluate the safety profile of the vaccine, a series of non-clinical safety, immunogenicity and efficacy studies were conducted in four animal species, using multiple doses (up to 108 Plaque Forming Units/animal) and dosing regimens. There were no treatment-related mortalities or any noticeable clinical signs in any of the studies. Compared to unvaccinated controls, hematology and biochemistry parameters were unremarkable and no adverse histopathological findings. There was no detectable viral shedding in urine, nor viral RNA detected in whole blood or serum samples seven days post vaccination. The rVSV-ΔG-SARS-CoV-2-S vaccination gave rise to neutralizing antibodies, cellular immune responses, and increased lymphocytic cellularity in the spleen germinal centers and regional lymph nodes. No evidence for neurovirulence was found in C57BL/6 immune competent mice or in highly sensitive type I interferon knock-out mice. Vaccine virus replication and distribution in K18-human Angiotensin-converting enzyme 2-transgenic mice showed a gradual clearance from the vaccination site with no vaccine virus recovered from the lungs. The nonclinical data suggest that the rVSV-ΔG-SARS-CoV-2-S vaccine is safe and immunogenic. These results supported the initiation of clinical trials, currently in Phase 2.


Subject(s)
COVID-19 Vaccines/toxicity , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Cricetinae , Female , Membrane Glycoproteins/genetics , Mesocricetus , Mice , Mice, Inbred C57BL , Rabbits , Swine , Vaccination , Vaccines, Synthetic/toxicity , Viral Envelope Proteins/genetics
4.
Viruses ; 14(2)2022 01 19.
Article in English | MEDLINE | ID: covidwho-1625815

ABSTRACT

SARS-CoV-2, a member of the coronavirus family, is the causative agent of the COVID-19 pandemic. Currently, there is still an urgent need in developing an efficient therapeutic intervention. In this study, we aimed at evaluating the therapeutic effect of a single intranasal treatment of the TLR3/MDA5 synthetic agonist Poly(I:C) against a lethal dose of SARS-CoV-2 in K18-hACE2 transgenic mice. We demonstrate here that early Poly(I:C) treatment acts synergistically with SARS-CoV-2 to induce an intense, immediate and transient upregulation of innate immunity-related genes in lungs. This effect is accompanied by viral load reduction, lung and brain cytokine storms prevention and increased levels of macrophages and NK cells, resulting in 83% mice survival, concomitantly with long-term immunization. Thus, priming the lung innate immunity by Poly(I:C) or alike may provide an immediate, efficient and safe protective measure against SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , COVID-19/prevention & control , Immunity, Innate , Poly I-C/immunology , Poly I-C/therapeutic use , SARS-CoV-2/drug effects , Toll-Like Receptor 3/agonists , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Disease Models, Animal , Female , Humans , Lung/immunology , Lung/virology , Mice , Mice, Transgenic , SARS-CoV-2/immunology , Toll-Like Receptor 3/immunology , Viral Load/drug effects
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293181

ABSTRACT

BriLife® (rVSV- ΔG-spike) is a SARS-CoV-2 vaccine candidate based on vesicular stomatitis virus (VSV) platform. We show that sera from BriLife® vaccinees maintain neutralization capacity against alpha, beta, gamma and delta SARS-CoV-2 variants. BriLife® spontaneously-acquired spike mutations, corresponding with key SARS-CoV-2 variants mutations, may contribute to its efficacy against SARS-CoV-2 variants.

6.
Front Bioeng Biotechnol ; 9: 737627, 2021.
Article in English | MEDLINE | ID: covidwho-1477802

ABSTRACT

The COVID-19 pandemic initiated a worldwide race toward the development of treatments and vaccines. Small animal models included the Syrian golden hamster and the K18-hACE2 mice infected with SARS-CoV-2 to display a disease state with some aspects of human COVID-19. A group activity of animals in their home cage continuously monitored by the HCMS100 (Home cage Monitoring System 100) was used as a sensitive marker of disease, successfully detecting morbidity symptoms of SARS-CoV-2 infection in hamsters and in K18-hACE2 mice. COVID-19 convalescent hamsters rechallenged with SARS-CoV-2 exhibited minor reduction in group activity compared to naive hamsters. To evaluate the rVSV-ΔG-spike vaccination efficacy against SARS-CoV-2, we used the HCMS100 to monitor the group activity of hamsters in their home cage. A single-dose rVSV-ΔG-spike vaccination of the immunized group showed a faster recovery than the nonimmunized infected hamsters, substantiating the efficacy of rVSV-ΔG-spike vaccine. HCMS100 offers nonintrusive, hands-free monitoring of a number of home cages of hamsters or mice modeling COVID-19.

7.
Nat Commun ; 12(1): 5819, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1454763

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. The continued spread of SARS-CoV-2 increases the probability of influenza/SARS-CoV-2 coinfection, which may result in severe disease. In this study, we examine the disease outcome of influenza A virus (IAV) and SARS-CoV-2 coinfection in K18-hACE2 mice. Our data indicate enhance susceptibility of IAV-infected mice to developing severe disease upon coinfection with SARS-CoV-2 two days later. In contrast to nonfatal influenza and lower mortality rates due to SARS-CoV-2 alone, this coinfection results in severe morbidity and nearly complete mortality. Coinfection is associated with elevated influenza viral loads in respiratory organs. Remarkably, prior immunity to influenza, but not to SARS-CoV-2, prevents severe disease and mortality. This protection is antibody-dependent. These data experimentally support the necessity of seasonal influenza vaccination for reducing the risk of severe influenza/COVID-19 comorbidity during the COVID-19 pandemic.


Subject(s)
COVID-19/immunology , COVID-19/virology , Coinfection/immunology , Coinfection/virology , Immunity , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Viral/immunology , COVID-19/pathology , Cell Line , Disease Models, Animal , Female , Humans , Inflammation/genetics , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Mice, Transgenic , Up-Regulation/genetics , Viral Load/immunology
8.
Cell Rep ; 35(13): 109305, 2021 06 29.
Article in English | MEDLINE | ID: covidwho-1260679

ABSTRACT

The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes.


Subject(s)
Antigens, Viral/immunology , COVID-19/immunology , COVID-19/virology , Peptides/immunology , SARS-CoV-2/immunology , Antigen Presentation , Antigens, Viral/metabolism , COVID-19 Vaccines , Cell Line , Epitopes, T-Lymphocyte/immunology , HEK293 Cells , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Humans , Peptidomimetics , SARS-CoV-2/genetics , T-Lymphocytes
9.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1125261

ABSTRACT

Modified vaccinia virus Ankara (MVA) is a replication-restricted smallpox vaccine, and numerous clinical studies of recombinant MVAs (rMVAs) as vectors for prevention of other infectious diseases, including COVID-19, are in progress. Here, we characterize rMVAs expressing the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Modifications of full-length S individually or in combination included two proline substitutions, mutations of the furin recognition site, and deletion of the endoplasmic retrieval signal. Another rMVA in which the receptor binding domain (RBD) is flanked by the signal peptide and transmembrane domains of S was also constructed. Each modified S protein was displayed on the surface of rMVA-infected cells and was recognized by anti-RBD antibody and soluble hACE2 receptor. Intramuscular injection of mice with the rMVAs induced antibodies, which neutralized a pseudovirus in vitro and, upon passive transfer, protected hACE2 transgenic mice from lethal infection with SARS-CoV-2, as well as S-specific CD3+CD8+IFNγ+ T cells. Antibody boosting occurred following a second rMVA or adjuvanted purified RBD protein. Immunity conferred by a single vaccination of hACE2 mice prevented morbidity and weight loss upon intranasal infection with SARS-CoV-2 3 wk or 7 wk later. One or two rMVA vaccinations also prevented detection of infectious SARS-CoV-2 and subgenomic viral mRNAs in the lungs and greatly reduced induction of cytokine and chemokine mRNAs. A low amount of virus was found in the nasal turbinates of only one of eight rMVA-vaccinated mice on day 2 and none later. Detection of low levels of subgenomic mRNAs in turbinates indicated that replication was aborted in immunized animals.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Genetic Vectors/genetics , SARS-CoV-2/immunology , Vaccines, DNA/immunology , Vaccinia virus/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Specificity/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/genetics , Disease Models, Animal , Gene Expression , Humans , Immunization , Immunization, Passive , Immunoglobulin G/immunology , Mice , Mice, Transgenic , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Vaccines, DNA/administration & dosage , Vaccines, DNA/genetics
10.
J Biol Chem ; 296: 100470, 2021.
Article in English | MEDLINE | ID: covidwho-1101336

ABSTRACT

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Dioxanes/pharmacology , Glucosyltransferases/antagonists & inhibitors , Glycosphingolipids/antagonists & inhibitors , Influenza A Virus, H1N1 Subtype/drug effects , Pyrrolidines/pharmacology , Quinuclidines/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/virology , Carbamates/chemical synthesis , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/virology , Chlorocebus aethiops , Clinical Trials, Phase III as Topic , Dioxanes/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gene Expression Regulation , Glucosyltransferases/genetics , Glucosyltransferases/metabolism , Glycosphingolipids/biosynthesis , Host-Pathogen Interactions/genetics , Humans , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/drug therapy , Influenza, Human/enzymology , Influenza, Human/virology , Madin Darby Canine Kidney Cells , Pyrrolidines/chemical synthesis , Quinuclidines/chemical synthesis , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Signal Transduction , Vero Cells , Virus Replication/drug effects
11.
Nat Commun ; 11(1): 6402, 2020 12 16.
Article in English | MEDLINE | ID: covidwho-983658

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 imposes an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we show the development of a replication competent recombinant VSV-∆G-spike vaccine, in which the glycoprotein of VSV is replaced by the spike protein of SARS-CoV-2. In-vitro characterization of this vaccine indicates the expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in-vivo model for COVID-19 is implemented. We show that a single-dose vaccination results in a rapid and potent induction of SARS-CoV-2 neutralizing antibodies. Importantly, vaccination protects hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss, and  alleviation of the extensive tissue damage and viral loads in lungs and nasal turbinates. Taken together, we suggest the recombinant VSV-∆G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Vesicular stomatitis Indiana virus/immunology , Animals , Antibodies, Viral/immunology , Antigens, Viral/immunology , Body Weight , COVID-19/virology , Cell Line , Cricetinae , Disease Models, Animal , Dose-Response Relationship, Immunologic , Genome, Viral , Lung/pathology , Lung/virology , Mice, Inbred C57BL , Mutation/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/ultrastructure , Vaccination , Viral Load
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