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1.
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.
Methods Mol Biol ; 2410: 193-208, 2022.
Article in English | MEDLINE | ID: covidwho-1574895

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health emergency. Several vaccine candidates have been developed in response to the COVID-19 pandemic. One approach is to construct live-recombinant viruses expressing the SARS-CoV-2 spike protein (S) as vaccine candidates. The vesicular stomatitis virus (VSV) vector is a mature vaccine platform which was successfully developed as a vaccine against Ebola virus (EBOV), leading to its licensure by the Food and Drug Administration (FDA) in December 2019. Based on this work, we developed two live, replication-competent VSV-vectored vaccines against SARS-CoV-2: (1) a VSV expressing the S protein of SARS-CoV-2 and (2) a bivalent VSV expressing the S protein of SARS-CoV-2 and the glycoprotein (GP) of EBOV. This protocol describes the methodologies for the design, cloning, rescue, and preparation of these recombinant VSV vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , Vaccines, Synthetic , COVID-19/prevention & control , Ebolavirus/immunology , Humans , Pandemics , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Attenuated
4.
Front Immunol ; 12: 721328, 2021.
Article in English | MEDLINE | ID: covidwho-1435991

ABSTRACT

The unprecedented 2013-2016 West Africa Ebola outbreak accelerated several medical countermeasures (MCMs) against Ebola virus disease (EVD). Several investigational products (IPs) were used throughout the outbreak but were not conclusive for efficacy results. Only the Randomized Controlled Trial (RCT) on ZMapp was promising but inconclusive. More recently, during the second-largest Ebola outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo (DRC), four IPs, including one small molecule (Remdesivir), two monoclonal antibody (mAb) cocktails (ZMapp and REGN-EB3) and a single mAb (mAb114), were evaluated in an RCT, the Pamoja Tulinde Maisha (PALM) study. Two products (REGN-EB3 and mAb114) demonstrated efficacy as compared to the control arm, ZMapp. There were remarkably few side effects recorded in the trial. The FDA approved both medications in this scientifically sound study, marking a watershed moment in the field of EVD therapy. These products can be produced relatively inexpensively and can be stockpiled. The administration of mAbs in EVD patients appears to be safe and effective, while several critical knowledge gaps remain; the impact of early administration of Ebola-specific mAbs on developing a robust immune response for future Ebola virus exposure is unknown. The viral mutation escape, leading to resistance, presents a potential limitation for single mAb therapy; further improvements need to be explored. Understanding the contribution of Fc-mediated antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) of those approved mAbs is still critical. The potential merit of combination therapy and post-exposure prophylaxis (PEP) need to be demonstrated. Furthermore, the PALM trial has accounted for 30% of mortality despite the administration of specific treatments. The putative role of EBOV soluble Glycoprotein (sGP) as a decoy to the immune system, the virus persistence, and relapses might be investigated for treatment failure. The development of pan-filovirus or pan-species mAbs remains essential for protection. The interaction between FDA-approved mAbs and vaccines remains unclear and needs to be investigated. In this review, we summarize the efficacy and safety results of the PALM study and review current research questions for the further development of mAbs in pre-exposure or emergency post-exposure use.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , Ebolavirus/drug effects , Hemorrhagic Fever, Ebola/drug therapy , Hemorrhagic Fever, Ebola/virology , Animals , Antibodies, Monoclonal/pharmacology , Antigens, Viral/immunology , Antiviral Agents/pharmacology , Clinical Studies as Topic , Drug Approval , Drug Evaluation, Preclinical , Ebola Vaccines , Ebolavirus/immunology , Hemorrhagic Fever, Ebola/mortality , Hemorrhagic Fever, Ebola/prevention & control , Humans , Prognosis , Treatment Failure , Treatment Outcome , United States , United States Food and Drug Administration , Vaccination
7.
Science ; 372(6543): 738-741, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1180894

ABSTRACT

Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus/immunology , Immunologic Memory , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Child, Preschool , Cross Reactions , Ebolavirus/immunology , Female , Fetal Blood/immunology , Genes, Immunoglobulin , Humans , Immunoglobulin Class Switching , Immunoglobulin D/genetics , Immunoglobulin D/immunology , Immunoglobulin Heavy Chains/immunology , Immunoglobulin M/genetics , Immunoglobulin M/immunology , Infant , Lymph Nodes/immunology , Male , Middle Aged , Receptors, Antigen, B-Cell/immunology , Somatic Hypermutation, Immunoglobulin , Spleen/immunology , Young Adult
11.
Trends Biotechnol ; 38(9): 943-947, 2020 09.
Article in English | MEDLINE | ID: covidwho-597298

ABSTRACT

Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.


Subject(s)
Coronavirus Infections/prevention & control , Drug Approval/organization & administration , Hemorrhagic Fever, Ebola/prevention & control , Influenza, Human/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/biosynthesis , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Ebola Vaccines/administration & dosage , Ebola Vaccines/biosynthesis , Ebolavirus/drug effects , Ebolavirus/immunology , Ebolavirus/pathogenicity , Europe/epidemiology , Global Health/trends , Government Regulation , Hemorrhagic Fever, Ebola/epidemiology , Hemorrhagic Fever, Ebola/immunology , Hemorrhagic Fever, Ebola/virology , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/biosynthesis , Influenza, Human/epidemiology , Influenza, Human/immunology , Influenza, Human/virology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS Virus/drug effects , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2 , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/prevention & control , Severe Acute Respiratory Syndrome/virology , United States/epidemiology , Viral Vaccines/administration & dosage , Zika Virus/drug effects , Zika Virus/immunology , Zika Virus/pathogenicity , Zika Virus Infection/epidemiology , Zika Virus Infection/immunology , Zika Virus Infection/prevention & control , Zika Virus Infection/virology
12.
J Cell Mol Med ; 24(12): 6988-6999, 2020 06.
Article in English | MEDLINE | ID: covidwho-186413

ABSTRACT

Outbreaks of infections with viruses like Sars-CoV-2, Ebola virus and Zika virus lead to major global health and economic problems because of limited treatment options. Therefore, new antiviral drug candidates are urgently needed. The promising new antiviral drug candidate silvestrol effectively inhibited replication of Corona-, Ebola-, Zika-, Picorna-, Hepatis E and Chikungunya viruses. Besides a direct impact on pathogens, modulation of the host immune system provides an additional facet to antiviral drug development because suitable immune modulation can boost innate defence mechanisms against the pathogens. In the present study, silvestrol down-regulated several pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, CCL2, CCL18) and increased TNF-α during differentiation and activation of M1-macrophages, suggesting that the effects of silvestrol might cancel each other out. However, silvestrol amplified the anti-inflammatory potential of M2-macrophages by increasing expression of anti-inflammatory surface markers CD206, TREM2 and reducing release of pro-inflammatory IL-8 and CCL2. The differentiation of dendritic cells in the presence of silvestrol is characterized by down-regulation of several surface markers and cytokines indicating that differentiation is impaired by silvestrol. In conclusion, silvestrol influences the inflammatory status of immune cells depending on the cell type and activation status.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cytokines/genetics , Dendritic Cells/drug effects , Immunologic Factors/pharmacology , Macrophages/drug effects , Triterpenes/pharmacology , Betacoronavirus/growth & development , Betacoronavirus/immunology , Cell Differentiation/drug effects , Chikungunya virus/drug effects , Chikungunya virus/growth & development , Chikungunya virus/immunology , Cytokines/classification , Cytokines/immunology , Dendritic Cells/immunology , Dendritic Cells/virology , Ebolavirus/drug effects , Ebolavirus/growth & development , Ebolavirus/immunology , Gene Expression Profiling , Gene Expression Regulation/drug effects , Hepatitis E virus/drug effects , Hepatitis E virus/growth & development , Hepatitis E virus/immunology , Humans , Immunity, Innate/drug effects , Macrophages/immunology , Macrophages/virology , Organ Specificity , Picornaviridae/drug effects , Picornaviridae/growth & development , Picornaviridae/immunology , Primary Cell Culture , SARS-CoV-2 , Signal Transduction , Zika Virus/drug effects , Zika Virus/growth & development , Zika Virus/immunology
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