Document text
Principal Investigator: Ursula Buchholz
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $321,289
Funding agency: National Institute of Allergy and Infectious Diseases
We are developing paramyxovirus vectored vaccines for intranasal immunization against SARS-CoV-2. The vaccine vectors express prefusion-stabilized 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 replicate in the superficial layers of the respiratory epithelium, inducing strong local mucosal and systemic immune responses to the SARS-CoV-2 S protein, including virus-neutralizing serum antibodies, and a systemic and mucosal response of multifunctional SARS-CoV-2 S-specific CD8+ and CD4+ T cells.
Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. 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 prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced high levels of serum SARS-CoV-2-neutralizing antibodies, and serum IgA and IgG to SARS-CoV-2 S protein. Serum 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 4.5 log10 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 6.6 log10 TCID50/g in lungs and 7 log10 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-2P-immunized hamsters, infectious SARS-CoV-2 challenge virus was undetectable in nasal tissues and lungs; immunization with B/HPIV3/S-2P protected against weight loss after SARS-CoV-2 challenge. Based on these results, B/HPIV3 expressing a prefusion-stabilized version of the S protein is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2 (Liu X, Luongo C, Matsuoka Y, Park HS, Santos C, Yang L, Moore IN, Afroz S, Johnson RF, Lafont BAP, Martens C, Best SM, Munster VJ, Holly J, Yewdell JW, Le Nouen C, Munir S, Buchholz UJ. A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters. Proceedings of the National Academy of Sciences of the United States of America. 2021;118(50)). Clinical trial material of the lead B/HPIV3-based vaccine candidate was manufactured under cGMP for evaluation of safety and immunogenicity in a Phase 1 study.
Single-dose vaccines with the ability to restrict 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, including avian paramyxovirus type 3 (APMV3). In a preclinical study, we found that APMV3 expressing the prefusion-stabilized S-6P version of the S protein (APMV3/S-6P) replicated to high titers in embryonated chicken eggs and was genetically stable. In hamsters, a single intranasal dose of APMV3/S-6P induced strong serum IgG and IgA responses to the S protein and its receptor-binding domain, and strong serum neutralizing antibody responses to the vaccine-matched SARS-CoV-2 isolate WA1/2020 (lineage A). Sera from APMV3/S-6P-immunized hamsters also efficiently neutralized Alpha and Beta variants of concern. Immunized hamsters challenged with WA1/2020 did not exhibit the weight loss and lung inflammation observed in empty vector-immunized controls; SARS-CoV-2 replication in the upper and lower respiratory tract of immunized animals was low or undetectable compared to the substantial replication in controls. Thus, a single intranasal dose of APMV3/S-6P was highly immunogenic and protective against SARS-CoV-2 challenge, suggesting that APMV3/S-6P is suitable for clinical development (Park HS, Matsuoka Y, Luongo C, Yang L, Santos C, Liu X, Ahlers LRH, Moore IN, Afroz S, Johnson RF, Lafont BAP, Dorward DW, Fischer ER, Martens C, Samal SK, Munir S, Buchholz UJ, Le Nouen C. Intranasal immunization with avian paramyxovirus type 3 expressing SARS-CoV-2 spike protein protects hamsters against SARS-CoV-2. NPJ Vaccines. 2022;7(1):72).
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><5 year old><5 years of age><7S Gamma Globulin><Adult><Adult Human><Americas><Animals><Antibodies><Antibody Response><Attenuated><Avian Paramyxoviruses><Avulavirus><B.1.1.7><B.1.351><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><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID-19><COVID-19 S protein><COVID-19 antibody><COVID-19 antigen><COVID-19 infection><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 S protein><COVID19 infection><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cattle><Child><Child Youth><Childhood><Children (0-21)><Clinical Research><Clinical Study><Clinical Trials><CoV-2><CoV2><Complementary DNA><Cricetinae><Cyclic GMP><Dose><Engineering><Evaluation><Exhibits><Guanosine Cyclic Monophosphate><HPIV3><Hamsters><Hamsters Mammals><Hemadsorption Virus 1><Holly><Human><Human Parainfluenza Virus 3><IgA><IgG><Immune response><Immunity><Immunization><Immunize><Immunoglobulin A><Immunoglobulin G><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><In Vitro><Infant><Infection><LYT3><Lead><Lower respiratory tract structure><Lung><Lung Inflammation><Lung Respiratory System><Martens><Martes><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Immune Responses><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Nasal><Nasal Passages Nose><National Academy of Sciences><Nose><Para-Influenza Virus Type 3><Paramyxoviridae><Paramyxovirus><Pb element><Phase><Phase I Study><Pneumonitis><Pneumoviridae><Pneumovirinae><Pneumovirus><Protein Engineering><Proteins><Pulmonary Body System><Pulmonary Inflammation><Pulmonary Organ System><Recovery><Respiratory Epithelium><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><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 S protein><SARS-CoV-2 alpha><SARS-CoV-2 antibody><SARS-CoV-2 antigen><SARS-CoV-2 beta><SARS-CoV-2 infection><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 antibody><SARS-CoV2 antigen><SARS-CoV2 infection><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 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><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 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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><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 strain><South Africa variant><South African strain><South African variant><Structure of respiratory epithelium><System><T cell response><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Tissues><Transmission><U.K. variant><UK strain><UK variant><United Kingdom variant><United States National Academy of Sciences><Vaccines><Viral Vector><Virus><Weight Loss><Weight Reduction><Wuhan coronavirus><Yang><adulthood><age 5 years><age group><airway epithelium><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to SARS-CoV2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><base><body weight loss><bovid><bovine><cDNA><cGMP><chicken egg><clinical development><conformation><conformational state><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 antigen><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cow><develop a vaccine><develop vaccines><development of a vaccine><five year old><five years of age><genetic protein engineering><hCoV19><heavy metal Pb><heavy metal lead><host response><immune system response><immunogenic><immunogenicity><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><insight><interest><lead candidate><lower respiratory tract><mucosal vaccine><nCoV2><neutralizing antibody><non-human primate><nonhuman primate><parainfluenza virus><parainfluenza virus type 3><pathogen><pediatric><phase 1 study><plasmid vaccine><pre-clinical study><preclinical study><protective efficacy><protein design><pulmonary><receptor binding><receptor bound><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 antibody><severe acute respiratory syndrome coronavirus 2 antigen><tissue culture><translational goal><translational mission><transmission process><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 candidate><vaccine development><vaccine for novel coronavirus><variants of concern><vector><vector vaccine><vector-based vaccine><wt-loss><youngster>