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Principal Investigator: Ursula Buchholz
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $698,609
Funding agency: National Institute of Allergy and Infectious Diseases
We are developing paramyxovirus vectored vaccines for intranasal immunization against SARS-CoV-2. These vectors express immunogenic versions of the SARS-CoV-2 S protein and are designed to be highly attenuated in humans while maintaining a high level of immunogenicity at the primary sites of infection of SARS-CoV-2. The viral vectors are designed to replicate in the superficial layers of the respiratory epithelium, inducing local mucosal and systemic innate immunity, virus-neutralizing serum antibodies, and CD8+ and CD4+ T cells. In 2021, we characterized vaccine candidates in cell culture and in animal models.
Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. No SARS-CoV-2 vaccines are available for young children. In 2021, we developed live intranasal vector vaccine candidates for infants and children against coronavirus disease-2019 (COVID-19) based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as the empty vector B/HPIV3 control in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2-neutralizing antibodies (12-fold higher) and serum IgG and IgA to SARS-CoV-2 S protein (13-fold and 5-fold) and receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to high titers in lungs and nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P-immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S or B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. Characterization of correlates of protection in rhesus macaques is ongoing. Based on our results, B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2. Clinical trial material of this vaccine candidate is being manufactured under cGMP for evaluation of safety and immunogenicity in a Phase 1 study.
Single-dose vaccines with the ability to restrict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the respiratory tract are needed for all age groups, aiding efforts towards control of COVID-19. In addition to the B/HPIV3/S-2P candidate described above, we are developing vector vaccine candidates based on vector platforms without pre-existing anti-vector immunity in humans. Preclinical characterizations in vitro and in vivo are ongoing.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><21+ years old><7S Gamma Globulin><Adult><Adult Human><African Green Monkey><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Response><Attenuated><B.1.1.7><B.1.351><Birth><Blood Serum><Body Tissues><Body Weight decreased><Bovine Species><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 antigen><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cattle><Cell Culture Techniques><Child><Child Youth><Childhood><Children (0-21)><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical Research><Clinical Study><Clinical Trials><CoV-2><CoV2><Complementary DNA><Cricetinae><Cyclic GMP><Development><Disease Outbreaks><Dose><Engineering><Evaluation><Exhibits><Green Monkey><Guanosine Cyclic Monophosphate><HPIV3><Hamsters><Hamsters Mammals><Hemadsorption Virus 1><Human><Human Parainfluenza Virus 3><IgA><IgG><Immunity><Immunization><Immunize><Immunoglobulin A><Immunoglobulin G><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunostimulation><In Vitro><Infant><Infection><Innate Immunity><LYT3><Lung><Lung Respiratory System><M mulatta><M. mulatta><Macaca mulatta><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Nasal><Nasal Passages Nose><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nose><Outbreaks><Para-Influenza Virus Type 3><Paramyxoviridae><Paramyxovirus><Parturition><Phase><Phase I Study><Pneumoviridae><Pneumovirinae><Pneumovirus><Population><Protein Engineering><Proteins><Pulmonary Body System><Pulmonary Organ System><Recovery><Respiratory Epithelium><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><Rhesus Macaque><Rhesus Monkey><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 B.1.1.7><SARS-CoV-2 B.1.351><SARS-CoV-2 S protein><SARS-CoV-2 antigen><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 antigen><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-CoV2 vaccine><SARS-Related Coronavirus><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><Safety><Serum><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><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 CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><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 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><Site><South Africa variant><South African variant><Structure of respiratory epithelium><System><T cell response><T4 Cells><T4 Lymphocytes><Tissues><Transmission><U.K. variant><UK variant><United Kingdom variant><Vaccines><Viral Vector><Virus><Weight Loss><Weight Reduction><Wuhan coronavirus><access to vaccination><access to vaccines><adulthood><age group><base><body weight loss><bovid><bovine><cDNA><cGMP><cell culture><cohort><conformation><conformational state><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antigen><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 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><cow><design><designing><developmental><genetic protein engineering><hCoV19><immunogenic><immunogenicity><improved><in vivo><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><lead candidate><model of animal><model organism><nCoV2><neutralizing antibody><non-human primate><nonhuman primate><parainfluenza virus><parainfluenza virus type 3><pathogen><pediatric><phase 1 study><plasmid vaccine><pre-clinical><preclinical><protective efficacy><protein design><pulmonary><receptor binding><receptor bound><respiratory virus><response><reverse genetics><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 antigen><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome-CoV><transmission process><vaccination access><vaccination availability><vaccine access><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 availability><vaccine candidate><vaccine for novel coronavirus><vector><vector vaccine><vector-based vaccine><wt-loss><youngster>