Document text
Principal Investigator: Andrea Marzi
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $222,715
Funding agency: National Institute of Allergy and Infectious Diseases
1. Intranasal single-dose vaccination with VSV-based COVID-19 vaccines protects rodents from disease
We designed, cloned, and recovered two replication-competent VSV-based vaccines encoding the SARS-CoV-2 spike protein either alone (VSV-SARS2) or in combination with the EBOV GP (VSV-SARS2-EBOV). EBOV GP was included to enable ACE2-independent vaccine replication in the host and to possibly expand target cell tropism. We vaccinated hamsters by the intranasal (IN) or intramuscular (IM) routes 28 days prior to challenge with four SARS-CoV-2 VOC: the ancestral, alpha, beta, and delta variants. IN vaccination with either the VSV-SARS2 or VSV-SARS2-EBOV resulted in the highest protective efficacy, as demonstrated by decreased virus shedding and lung viral load in vaccinated hamsters. Histopathologic analysis of the lungs revealed the least amount of lung damage in the IN-vaccinated animals regardless of the challenge virus. In addition, IN-vaccination resulted in protection within 10 days and the animals did not show any clinical or significant histopathologic signs of COVID-19 pneumonia when challenged with the ancestral SARS-CoV-2 strain or the alpha or beta variants (ODonnell et al., Frontiers in Immunology 2021; ODonnell et al., Vaccines 2022).
In FY23, we showed that a VSV-based vaccine expressing the SARS-CoV-2 S plus the conserved nucleocapsid (N) protein was protective in a hamster challenge model when a single dose was administered 28 or 10 days prior to challenge, respectively. In this study, only IN vaccination resulted in protection against challenge with multiple VOC highlighting that the addition of the N protein indeed improved protective efficacy. This data demonstrates the ability of a VSV-based dual-antigen vaccine to reduce viral shedding and protect from disease caused by SARS-CoV-2 VOC (ODonnell et al. Front Immunol 2022).
Furthermore, we conducted an over 12-month long vaccine durability study in mice. The study has been completed, data analysis is ongoing and revealed that vaccine-mediated protection wanes around 6-9 months after vaccination with total IgG and neutralizing antibody titers decreasing. Studies investigating the cellular response are ongoing (ODonnell et al. manuscript in preparation).
Ongoing studies also investigate early immune responses after vaccination in the mouse model with the aim to decipher mechanisms contributing to the fast onset of protection (Anhalt et al., unpublished data).
2. VSV-SARS2-EBOV protected NHPs within 10 days when administered IM but not IN
We vaccinated NHPs with a single dose of 107 PFU of the vaccine by the IM or IN route, while NHPs vaccinated IN or IM with 107 PFU VSV-EBOV served as controls. Challenge with SARS-CoV-2 WA1 by multiple routes as described previously occurred 10 days later. At 7 days after challenge, all NHPs were euthanized for sample collection. NHPs IM-vaccinated with VSV-SARS2-EBOV were protected within 10 days and did not show signs of COVID-19 pneumonia. In contrast, IN vaccination resulted in limited immunogenicity and enhanced COVID-19 pneumonia compared to controls. The IN-vaccinated NHPs exhibited lung lesions and presented with more lung infiltrates compared to the IM and control groups at the time of euthanasia (Furuyama et al., mBio 2022).
3. SARS-CoV-2 VOC infection induces similar disease but distinct humoral responses and transcriptomic changes in Syrian golden hamsters
Following the discovery of SARS-CoV-2 and its rapid spread throughout the world, new viral variants of concern (VOC) have emerged. There is a critical need to understand the impact of the emerging variants on host response and disease dynamics to facilitate the development of vaccines and therapeutics. Syrian golden hamsters are the leading small animal model that recapitulates key aspects of severe COVID-19. We performed intranasal inoculation of SARS-CoV-2 into hamsters with the ancestral virus (nCoV-WA1-2020) or VOC first identified in the United Kingdom (B.1.1.7, alpha) and South Africa (B.1.351, beta) and analyzed viral loads and host responses. Similar gross and histopathologic pulmonary lesions were observed after infection with all three variants. Although differences in viral genomic copy numbers were noted in the lungs and oral swabs of challenged animals, infectious titers in the lungs were comparable between the variants. Antibody neutralization capacities varied, dependent on the original challenge virus and cross-variant protective capacity. Transcriptional profiling of lung samples 4 days post-challenge (DPC) was performed in collaboration with Dr. Ilehm Messaoudi and indicated significant induction of antiviral pathways in response to all three challenges with a more robust inflammatory signature in response to B.1.1.7 infection. Furthermore, no additional mutations in the spike protein were detected at 4 DPC. Although disease severity and viral shedding were not significantly different, the emerging VOC induced distinct humoral responses and transcriptional profiles compared to the ancestral virus. These observations suggest potential differences in acute early responses or alterations in immune modulation by VOC (ODonnell et al., eBioMedicine 2021).
4. Analysis of human COVID-19 serum samples
In order to expand our understanding of human cytokine responses during COVID-19, we analyzed human serum samples collected over time from patients from Indiana (collaboration with Dr. Ryan Relich). SARS-CoV-2 infection results in a variety of clinical symptoms ranging from no or mild to severe disease. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 isolate had detectable but limited neutralizing antibodies against the emerging SARS-CoV-2 Alpha, Beta and Delta variants. This study highlights the potential of re-infection for recovered COVID-19 patients (Griffin et al., Sci Rep 2021).
In FY22, we also supported a study by Prof. Ayato Takada (Hokkaido University, Japan) exploring the potential risks of antibody-dependent enhancement (ADE) in COVID-19. Clinical importance of ADE is unclear since the proposed ADE mechanism mostly depends on the Fc receptor (FcR) expressed exclusively on immune cells which are not primary targets of SARS-CoV-2. We show that SARS-CoV-2 utilizes at least two distinct ADE mechanisms, FcR-mediated and FcR-independent complement component C1q-mediated pathways. We found that both FcR- and C1q-mediated ADE activities were detectable in the sera of acute and convalescent COVID-19 patients at a high rate. Although neutralizing activity was also detected, it was counteracted by ADE at subneutralizing conditions in the presence of FcR or C1q. Considering the ubiquity of C1q and its cellular receptors, our data suggest that C1q-mediated ADE may more likely occur in respiratory epithelial cells, which SARS-CoV-2 primarily infects (Okuya et al., Microbiology Spectrum 2022).
5. Protection from COVID-19 by nanobodies
In FY23, we conducted collaborative studies on the development of SARS-CoV-2-specific nanobodies in collaboration with Dr. Charles K.F. Chan at Stanford university. He is exploring nanobodies as a therapeutic approach against respiratory diseases and COVID-19 was used as a proof-of-concept virus. Intranasal or aerosol administration of the nanobody before intranasal SARS-CoV-2 infection protected the majority of hamsters from severe disease (ODonnell et al. unpublished data). This approach is currently under investigation for respiratory syncytial virus.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><7S Gamma Globulin><ACE2><Acute><Aerosols><Animal Model><Animal Models and Related Studies><Animals><Antibody Response><Antibody titer measurement><Antibody-Dependent Enhancement><B.1.1.7><B.1.351><B.1.617.2><Blood Plasma><Blood Serum><C1 q><C1q><COVID associated pneumonia><COVID crisis><COVID epidemic><COVID induced pneumonia><COVID infected patient><COVID pandemic><COVID patient><COVID pneumonia><COVID positive patient><COVID related pneumonia><COVID-19><COVID-19 S protein><COVID-19 associated pneumonia><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced pneumonia><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 pneumonia><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related pneumonia><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cell Body><Cells><Chemotactic Cytokines><Clinical><CoV emergence><CoV-2><CoV2><Collaborations><Complement><Complement 1q><Complement C1q><Complement Proteins><Control Groups><Cricetinae><Data><Data Analyses><Data Analysis><Data Set><Delta variant><Development><Disease><Disorder><Dose><EBOV><EBOV GP><Ebola virus><Ebola virus GP gene product><Ebola virus envelope glycoprotein><Ebola-like Viruses><Epithelial Cells><Euthanasia><Exhibits><Expression Signature><Fc Receptor><GP Ebola virus><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Genetic Alteration><Genetic Change><Genetic defect><Golden Hamsters><Golden Syrian Hamsters><Hamsters><Hamsters Mammals><Homologous Chemotactic Cytokines><Human><IgG><Immune><Immune response><Immunes><Immunobiology><Immunoglobulin G><Immunological response><Immunology><Immunomodulation><Immunophysiology><Indiana><Infection><Infiltration><Inflammatory><Innate Immune Response><Intercrines><Intramuscular><Investigation><Japan><Knowledge><Lung><Lung Respiratory System><Lung damage><Manuscripts><Mediating><Mercy Killing><Mesocricetus auratus><Mice><Mice Mammals><Microbiology><Modeling><Modern Man><Molecular Virology><Murine><Mus><Mutation><Nature><Nucleocapsid><Oral><Pathogenesis><Pathway interactions><Patients><Plasma><Plasma Serum><Play><Preparation><Proteins><Receptor Protein><Research><Respiratory Disease><Respiratory Epithelium><Respiratory System Disease><Respiratory System Disorder><Respiratory syncytial virus><Reticuloendothelial System, Serum, Plasma><Risk><Rodent Diseases><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.7><SARS-CoV-2 B.1.351><SARS-CoV-2 B.1.617.2><SARS-CoV-2 S protein><SARS-CoV-2 alpha><SARS-CoV-2 associated pneumonia><SARS-CoV-2 beta><SARS-CoV-2 delta><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced pneumonia><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 pneumonia><SARS-CoV-2 positive patient><SARS-CoV-2 related pneumonia><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Sampling><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Severities><Severity of illness><South Africa><South Africa strain><South Africa variant><South African strain><South African variant><Structure of respiratory epithelium><Swab><Symptoms><Syrian Hamsters><Testing><Therapeutic><Time><Transcript Expression Analyses><Transcript Expression Analysis><Tropism><U.K. variant><UK strain><UK variant><United Kingdom><United Kingdom variant><Universities><VSV><Vaccinated><Vaccination><Vaccine Antigen><Vaccines><Variant><Variation><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Viral Shedding><Virus><Virus Diseases><Virus Shedding><Wuhan coronavirus><airway epithelium><analyze gene expression><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody receptor><antibody titering><chemoattractant cytokine><chemokine><cohort><compare to control><comparison control><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated pneumonia><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced pneumonia><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 pneumonia><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease associated pneumonia><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease induced pneumonia><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease pneumonia><coronavirus disease positive patient><coronavirus disease related pneumonia><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 pneumonia><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><cytokine><data interpretation><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease severity><ebolavirus><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><frontier><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><genome mutation><hCoV19><host response><immune modulation><immune regulation><immune system response><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung injury><lung lesion><model of animal><mouse model><murine model><nCoV><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><nanobodies><nanobody><neutralizing antibody><new CoV><new corona virus><new coronavirus><non-human primate><nonhuman primate><novel CoV><novel corona virus><novel coronavirus><outcome following vaccination><outcome following vaccine><pandemic><pandemic disease><pathogenic virus><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome coronavirus 2><preparations><protective allele><protective efficacy><protective variant><pulmonary><pulmonary damage><pulmonary injury><pulmonary lesion><pulmonary tissue damage><pulmonary tissue injury><receptor><respiratory tract epithelium><response><result following vaccination><result following vaccine><sample collection><sdAb><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 B.1.1.7><severe acute respiratory syndrome coronavirus 2 B.1.351><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 associated pneumonia><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced pneumonia><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 pneumonia><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related pneumonia><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single domain antibodies><specimen collection><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptomics><vaccination outcome><vaccination result><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine development><vaccine for novel coronavirus><vaccine outcome><vaccine result><variants of concern><viral genomics><viral infection><viral pathogen><virus genomics><virus infection><virus pathogen><virus-induced disease>