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Principal Investigator: Ursula Buchholz
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $227,201
Funding agency: National Institute of Allergy and Infectious Diseases
We previously constructed a first-generation construct called HPIV3-EbovZ GP, in which the complete genome of the JS strain of HPIV3 was modified by the addition of the Ebov GP gene in the third gene position, between the HPIV3 P and M genes. The JS strain is thought to be an attenuated HPIV3, based on previous clinical studies, although the basis of this attenuation is unknown. Ebov GP is the sole Ebov virion surface protein, the sole Ebov neutralization antigen, and the major protective antigen. The Ebov GP gene was engineered to have the appropriate HPIV3 transcription signals for it to be expressed as a separate mRNA by the HPIV3 polymerase. HPIV3-EbovZ GP was substantially immunogenic and protective when given to non-human primates by combined intranasal (IN) and intratracheal (IT) administration, even in animals previously infected with HPIV3. However, immunogenicity depended on IT delivery of vaccine: IN delivery alone was insufficient. This suggested that vector expression beyond the upper respiratory tract was necessary for immunogenicity. We had also explored delivery of the HPIV3-EbovZ GP construct by the aerosol route in rhesus macaques. The aerosol route was generally more immunogenic and protective than the combined IN/IT route. This induced generally higher serum and mucosal EBOV-specific IgG, IgA, and neutralizing antibody titers, as well as Ebov-specific cellular responses in the lungs, including polyfunctional CD8+ T cells and CD4+ T helper cells that were predominately Th1. In addition, the HPIV3-EbovZ GP vaccine induced more robust cell-mediated and humoral immune responses than an alphavirus vaccine delivered parenterally in parallel. One aerosol dose of HPIV3-EbovZ GP conferred 100% protection to macaques against EBOV challenge.
We performed (with clinical collaborators at the Johns Hopkins Bloomberg School of Public Health) an open-label phase 1 clinical trial to determine the safety, tolerability, and immunogenicity of HPIV3-EbovZ GP delivered IN in healthy adults in an inpatient setting (NCT025645750), which was intended to be a safety study prior to evaluating aerosol delivery. Ten subjects received two doses (4- to 8-week interval) of 6.0 log10 PFU of vaccine. The first dose was moderately infectious (7/10 subjects shed virus detected by qRT-PCR, mean peak titer 3.8 log10 genomic equivalents/ml, mean duration of shedding 7.9 days). Little shedding was detected after the second dose. A second cohort (n=20) received one of two planned doses of 7.0 log10 PFU of vaccine. Shedding was similar but of shorter duration (mean of 3.7 days). The vaccine was well tolerated, with the exception that asymptomatic ALT elevations were noted in 5 volunteers (3 mild, 2 moderate) in cohort 2 after vaccination and associated with shedding. All resolved by day 28. The study was halted due to these elevations of ALTs, but their significance is unclear. Because of this, this vaccine will not be administered further at this time. Induction of serum antibodies was poor (mucosal antibodies to be analyzed), but this was expected since, as noted above, we had previously observed that administration by the IN route alone was poorly immunogenic in rhesus monkeys.
We also developed a second-generation version of this vector, called HPIV3/delHNF/EbovZ-GP, in which the HPIV3 F and HN genes were deleted, leaving Ebov GP as the sole viral surface glycoprotein.
We have initiated a Phase 1 study to evaluate the safety, infectivity, and immunogenicity of this second-generation HPIV3/delHNF/EbovZ GP vaccine candidate when administered intranasally in healthy adults in an inpatient setting (NCT03462004). This vaccine candidate contains EbovZ GP as the sole envelope glycoprotein. Participants were randomly assigned to receive two doses of either 6.0 log10 PFU/mL of HPIV3/delHNF/EbovZ-GP vaccine or placebo. The first dose was given on Day 0 and the second dose was given 35 days later. Vaccine replication was evaluated by nasal wash and RT-qPCR and infectivity assays, and serum antibody responses will be measured. As expected, at the 6.0 log10 PFU dose, the HPIV3/delHNF/EbovZ-GP vaccine was marginally infectious, and adverse events were generally mild to moderate. The study product was deemed safe, and a higher dose of 7.0 log10 PFU may be evaluated in the future. Sample and data analysis is in progress, and a publication is in preparation.
Terms: <0-11 years old><21+ years old><7S Gamma Globulin><Adult><Adult Human><Adverse Experience><Adverse event><Aerosols><Alpha Virus><Animal Experiments><Animals><Antibodies><Antibody Response><Antibody titer measurement><Antigens><Assay><Attenuated><Avian Influenza A Virus><Avian Influenza Virus><Avian Orthomyxovirus Type A><Avian Paramyxovirus 1><Avian Paramyxoviruses><Avulavirus><Bioassay><Biological Assay><Blood Serum><Bovine Species><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CDC42 Homolog Gene><CDC42-Interacting Protein Gene><CIP4><Cattle><Cavia><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell Surface Antigens><Cell Surface Glycoproteins><Cells><Child><Child Youth><Children (0-21)><Chimera><Chimera organism><Clinical><Clinical Research><Clinical Study><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Coronavirus glycoprotein S><Coronavirus spike protein><Cytoplasm><Data Analyses><Data Analysis><Development><Dose><EBOV><EBOV GP><Early-Stage Clinical Trials><Ebola virus><Ebola virus GP gene product><Ebola virus envelope glycoprotein><Ebola-like Viruses><Effectiveness><Engineering><Family member><Fowl Plague Virus><Future><G25K Gene><GP Ebola virus><GP Gene><Gene Arrangement><Gene Order><Gene Position><Gene Transcription><Generations><Genes><Genetic Transcription><Genome><Genomics><Glycoproteins><Group A Arboviruses><Guinea Pigs><Guinea Pigs Mammals><HPIV1><HPIV3><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemadsorption Type 2 Virus><Hemadsorption Virus 1><Hemadsorption Virus 2><Human><Human Parainfluenza Virus 1><Human Parainfluenza Virus 3><IgA><IgG><Immune response><Immunity><Immunoglobulin A><Immunoglobulin G><Immunologic Surface Markers><Immunological Surface Markers><Immunological response><Inducer Cells><Inducer T-Lymphocytes><Infant><Infection><Influenza HA><Influenza Hemagglutinin><Inpatients><Intracellular Communication and Signaling><Intranasal Administration><Intranasal Drug Administration><Lung><Lung Respiratory System><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Measures><Mediating><Membrane Glycoproteins><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Mice><Mice Mammals><Modern Man><Modification><Mucosa><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Murine><Murine pneumonia virus><Mus><Myxovirus pestis galli><NIH><Nasal Lavage Fluid><Nasal Washing><Nasal Washings><National Institutes of Health><Newcastle disease virus><Non-Polyadenylated RNA><Para-Influenza Virus Type 1><Para-Influenza Virus Type 3><Paramyxoviridae><Paramyxovirus><Participant><Pathogenicity><Phase 1 Clinical Trials><Phase I Clinical Trials><Phase I Study><Placebos><Pneumonia Virus of Mice><Pneumoviridae><Pneumovirinae><Pneumovirus><Polymerase><Population><Preparation><Primates><Primates Mammals><Proteins><Public Health Schools><Publications><Pulmonary Body System><Pulmonary Organ System><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA><RNA Expression><RNA Gene Products><Randomized><Respiratory Epithelium><Respiratory System><Respiratory Tracts><Respiratory syncytial virus><Respiratory tract structure><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><Rodent><Rodentia><Rodents Mammals><Route><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-Related Coronavirus><Safety><Sampling><Scientific Publication><Serum><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Structure of respiratory epithelium><Surface Antigens><Surface Glycoproteins><Surface Proteins><System><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TRIP10><TRIP10 gene><Testing><Thyroid Hormone Receptor Interactor 10 Gene><Time><Transcription><United States National Institutes of Health><Upper respiratory tract><Vaccination><Vaccines><Viral><Viral Shedding><Viral Vaccines><Virion><Virus><Virus Particle><Virus Replication><Virus Shedding><Work><adulthood><airway epithelium><animal experiment><antibody titering><antigen based test><antigen test><attenuate><attenuates><attenuation><avian flu virus><avian paramyxovirus serotype 1><biological signal transduction><bird flu virus><bovid><bovine><cell culture><cell cultures><chimeras><cohort><coronavirus S protein><coronavirus spike glycoprotein><cow><data interpretation><deliver vaccines><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><emerging pathogen><experimental animal><experimental animals><expression vector><flu HA><flu hemagglutinin><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><kids><mRNA><neutralizing antibody><new pathogen><non-human primate><nonhuman primate><novel pathogen><open label><open label study><parainfluenza virus><parainfluenza virus type 1><parainfluenza virus type 3><pathogen><pathogenic virus><phase 1 study><phase I protocol><plasmid vaccine><preparations><pulmonary><qRTPCR><randomisation><randomization><randomly assigned><respiratory><respiratory pathogen><respiratory tract epithelium><response><reverse genetics><safety study><seropositive><severe acute respiratory syndrome-CoV><sham therapy><tissue tropism><upper airway tract><vaccine candidate><vaccine delivery><vaccine development><vector><vector vaccine><vector-based vaccine><viral detection><viral multiplication><viral pathogen><viral replication><virus detection><virus multiplication><virus pathogen><volunteer><youngster>