scholarly journals Optimization of Single-Dose VSV-Based COVID-19 Vaccination in Hamsters

2022 ◽  
Vol 12 ◽  
Author(s):  
Kyle L. O’Donnell ◽  
Chad S. Clancy ◽  
Amanda J. Griffin ◽  
Kyle Shifflett ◽  
Tylisha Gourdine ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Cell Response ◽  
Ebola Virus ◽  
Nk Cell ◽  
Protective Efficacy ◽  
Clinical Signs ◽  
Cost Effective ◽  
T Cell Response ◽  
Fast Acting

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.

scholarly journals Optimization of single dose VSV-based COVID-19 vaccination in hamsters

2021 ◽  
Author(s):  
Kyle L O'Donnell ◽  
Chad S Clancy ◽  
Amanda J Griffin ◽  
Kyle Shifflett ◽  
Tylisha Gourdine ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Cell Response ◽  
Ebola Virus ◽  
Nk Cell ◽  
Protective Efficacy ◽  
Clinical Signs ◽  
Cost Effective ◽  
T Cell Response ◽  
Fast Acting

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 the 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.

scholarly journals Heterologous Combination of ChAdOx1 and MVA Vectors Expressing Protein NS1 as Vaccination Strategy to Induce Durable and Cross-Protective CD8+ T Cell Immunity to Bluetongue Virus

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 346 ◽  
Author(s):  
Sergio Utrilla-Trigo ◽  
Luis Jiménez-Cabello ◽  
Ruymán Alonso-Ravelo ◽  
Eva Calvo-Pinilla ◽  
Alejandro Marín-López ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Cell Response ◽  
Bluetongue Virus ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ns1 Protein ◽  
Reassortant Strain

The sequence of non-structural protein NS1 of bluetongue virus (BTV), which contains immunodominant CD8+ T cell epitopes, is highly conserved among BTV serotypes, and has therefore become a major tool in the development of a universal BTV vaccine. In this work, we have engineered multiserotype BTV vaccine candidates based on recombinant chimpanzee adenovirus (ChAdOx1) and modified vaccinia virus Ankara (MVA) vectors expressing the NS1 protein of BTV-4 or its truncated form NS1-Nt. A single dose of ChAdOx1-NS1 or ChAdOx1-NS1-Nt induced a moderate CD8+ T cell response and protected IFNAR(-/-) mice against a lethal dose of BTV-4/MOR09, a reassortant strain between BTV-1 and BTV-4, although the animals showed low viremia after infection. Furthermore, IFNAR(-/-) mice immunized with a single dose of ChAdOx1-NS1 were protected after challenge with a lethal dose of BTV-8 in absence of viremia nor clinical signs. Additionally, the heterologous prime-boost ChAdOx1/MVA expressing NS1 or NS1-Nt elicited a robust NS1 specific CD8+ T cell response and protected the animals against BTV-4/MOR09 even 16 weeks after immunization, with undetectable levels of viremia at any time after challenge. Subsequently, the best immunization strategy based on ChAdOx1/MVA-NS1 was assayed in sheep. Non-immunized animals presented fever and viremia levels up to 104 PFU/mL after infection. In contrast, although viremia was detected in immunized sheep, the level of virus in blood was 100 times lower than in non-immunized animals in absence of clinical signs.

scholarly journals Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013–16 West Africa epidemic

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
T. R. W. Tipton ◽  
Y. Hall ◽  
J. A. Bore ◽  
A. White ◽  
L. S. Sibley ◽  
...  
Keyword(s):  
T Cell ◽  
West Africa ◽  
Cell Response ◽  
Ebola Virus ◽  
Medical Condition ◽  
Virus Disease ◽  
T Cell Response ◽  
Ebola Virus Disease ◽  
Cell Phenotype ◽  
T Cell Epitopes

AbstractZaireebolavirus (EBOV) is a highly pathogenic filovirus which can result in Ebola virus disease (EVD); a serious medical condition that presents as flu like symptoms but then often leads to more serious or fatal outcomes. The 2013–16 West Africa epidemic saw an unparalleled number of cases. Here we show characterisation and identification of T cell epitopes in surviving patients from Guinea to the EBOV glycoprotein. We perform interferon gamma (IFNγ) ELISpot using a glycoprotein peptide library to identify T cell epitopes and determine the CD4+ or CD8+ T cell component response. Additionally, we generate data on the T cell phenotype and measure polyfunctional cytokine secretion by these antigen specific cells. We show candidate peptides able to elicit a T cell response in EBOV survivors and provide inferred human leukocyte antigen (HLA) allele restriction. This data informs on the long-term T cell response to Ebola virus disease and highlights potentially important immunodominant peptides.

scholarly journals Chimeric Yellow Fever/Dengue Virus as a Candidate Dengue Vaccine: Quantitation of the Dengue Virus-Specific CD8 T-Cell Response

2000 ◽  
Vol 74 (17) ◽  
pp. 8094-8101 ◽  
Author(s):  
Robbert G. van der Most ◽  
Kaja Murali-Krishna ◽  
Rafi Ahmed ◽  
James H. Strauss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dengue Virus ◽  
Yellow Fever ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Protective Efficacy ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
E Proteins

ABSTRACT We have constructed a chimeric yellow fever/dengue (YF/DEN) virus, which expresses the premembrane (prM) and envelope (E) genes from DEN type 2 (DEN-2) virus in a YF virus (YFV-17D) genetic background. Immunization of BALB/c mice with this chimeric virus induced a CD8 T-cell response specific for the DEN-2 virus prM and E proteins. This response protected YF/DEN virus-immunized mice against lethal dengue encephalitis. Control mice immunized with the parental YFV-17D were not protected against DEN-2 virus challenge, indicating that protection was mediated by the DEN-2 virus prM- and E-specific immune responses. YF/DEN vaccine-primed CD8 T cells expanded and were efficiently recruited into the central nervous systems of DEN-2 virus challenged mice. At 5 days after challenge, 3 to 4% of CD8 T cells in the spleen were specific for the prM and E proteins, and 34% of CD8 T cells in the central nervous system recognized these proteins. Depletion of either CD4 or CD8 T cells, or both, strongly reduced the protective efficacy of the YF/DEN virus, stressing the key role of the antiviral T-cell response.

Enhanced T-cell response to mosquito extracts by NK cells in hypersensitivity to mosquito bites associated with EBV infection and NK cell lymphocytosis

2005 ◽  
Vol 96 (8) ◽  
pp. 519-526 ◽  
Author(s):  
Yoshiki Tokura ◽  
Hiroyuki Matsuoka ◽  
Chizuko Koga ◽  
Hideo Asada ◽  
Naohiro Seo ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Response ◽  
Nk Cell ◽  
T Cell Response ◽  
Ebv Infection

scholarly journals Single-Dose Nevirapine Exposure Affects T Cell Response and Cytokine Levels in HIV Type 1-Infected Women

2009 ◽  
Vol 25 (10) ◽  
pp. 1049-1053 ◽  
Author(s):  
Sharon Shalekoff ◽  
Stephen Meddows-Taylor ◽  
Diana B. Schramm ◽  
Glenda Gray ◽  
Gayle Sherman ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cytokine Levels ◽  
Single Dose Nevirapine ◽  
Hiv Type 1

scholarly journals 864 Identification of a novel allosteric oral Cbl-b inhibitor that augmented T cell response and enhanced NK cell killing in vitro and in vivo

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A905-A905
Author(s):  
Jun Kuai ◽  
Yingzhi Bi ◽  
Yilin Qi ◽  
Deborah Conrady ◽  
Rajiv Govindaraj ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Patients ◽  
Immune Suppression ◽  
Cell Response ◽  
Nk Cell ◽  
E3 Ligase ◽  
T Cell Response ◽  
Negative Regulator ◽  
Inactive Form

BackgroundImmunotherapies aiming to boost anti-tumor cell responses in cancer patients has been proven successful by checkpoint inhibitors targeting PD1 or CTLA-4, but the majority of cancer patients do not garner durable benefit. Co-stimulation through the CD28 pathway is one potential approach to maximize the benefits of immunotherapies. The E3 ubiquitin ligase Cbl-b (casitas b-lineage lymphoma proto-oncogene b) has been established as a master negative regulator of T-cells and NK cells and plays an important role in immune suppression. Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice resulted in CD8 T-cell-mediated rejection of primary tumors in several mouse models. Based on the overwhelming evidence supporting the role of Cbl-b in immune suppression, targeting Cbl-b with small molecule inhibitors is attractive for cancer immunotherapy.MethodsCbl-b is activated by tyrosine kinases and undergoes a large conformational change from closed inactive form to open active form. Historically, it had been difficult to identify inhibitors of Cbl-b. Through the utilization of our proprietary SpotFinder platform, a druggable phosphoregulatory pocket was identified in the inactive form of Cbl-b. Learnings from the platform allowed for the development of screening assays utilizing specifically designed protein constructs. Assays were developed to identify inhibitors that bind to the hotspot and lock Cbl-b in its inactive form.ResultsHere we report on a member of our lead series of inhibitors, a low nanomolar potent inhibitor identified via application of our SpotFinder platform. This inhibitor binds to the inactive form of Cbl-b, its binding mode in the identified hotspot confirmed by co-crystal structures. It inhibits the phosphorylation of Cbl-b by kinases, inhibits the E3 ligase activity of Cbl-b, promotes cytokine release and enhances T cell proliferation well as NK cell activation and killing. In vivo, our CBL-B inhibitors efficaciously augmented the T cell response in anti-CD3 treated mice.ConclusionsWe herein demonstrated the validation of our proprietary SpotFinder platform via the prediction and drugging of a regulatory hotspot on an important immune oncology target that has to date been very difficult to drug.

Immune activation after Regional Chemotherapy - NK-cell, CD4+ and CD8+ T-cell response

2020 ◽  
Vol 46 (2) ◽  
pp. e153-e154
Author(s):  
Kornelia Aigner ◽  
Stephan Drothler ◽  
Rita Schlaf ◽  
Karl Reinhard Aigner
Keyword(s):  
T Cell ◽  
Immune Activation ◽  
Cell Response ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Regional Chemotherapy ◽  
T Cell Response

scholarly journals Dimorphism in the TCRγ-chain repertoire defines 2 types of human immunity to Epstein-Barr virus

2020 ◽  
Vol 4 (7) ◽  
pp. 1198-1205 ◽  
Author(s):  
Zakia Djaoud ◽  
Peter Parham
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Nk Cell ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Γδ T Cell ◽  
Barr Virus ◽  
Group 2 ◽  
Group 1

Abstract Humans form 2 groups based on their innate immunity to Epstein-Barr virus (EBV). Group 1 makes a strong natural killer (NK)–cell and γδ T-cell response, whereas group 2 makes a strong NK-cell response, but a weak γδ T-cell response. To investigate the underlying basis for this difference in γδ T-cell immunity to EBV, we used next-generation sequencing to compare the γδ T-cell receptor (TCR) repertoires of groups 1 and 2. In the absence of EBV, group 1 TCRγ chains are enriched for complementarity determining region 3 (CDR3s) containing JγP, whereas group 2 TCRγ chains are enriched for CDR3s containing Jγ2. In group 1 donors, EBV activates many γδ T cells expressing Vγ9JγP, inducing proliferation that produces a large population of activated effector cells. The TCRs using Vγ9JγP are closely related to the TCRs of γδ T cells that respond to phosphoantigens. In group 2 donors, EBV activates a small subpopulation of γδ T cells, most expressing Vγ9JγP. In conclusion, we find that differences in the TCRγ-chain repertoire underlie the differential response of group 1 and group 2 to EBV.

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