Document text
Principal Investigator: Ursula Buchholz
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $2,955,452
Funding agency: National Institute of Allergy and Infectious Diseases
We are developing parainfluenza virus- and pneumovirus-vectored vaccines for intranasal immunization against SARS-CoV-2. These viral vectors are designed to be highly attenuated in humans. They replicate to low levels in the superficial layers of the respiratory epithelium, and are optimized to induce strong local mucosal and systemic immune responses to the SARS-CoV-2 spike protein S, the major protective antigen of SARS-CoV-2.
Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. A pediatric COVID vaccine for intranasal immunization would have the potential to reduce the burden of COVID illness while also restricting SARS-CoV-2 transmission. We developed bivalent vaccine candidates to protect infants and children against coronavirus disease-2019 (COVID-19) and parainfluenza virus type 3, another major cause of pediatric respiratory illness. These candidates are based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the prefusion-stabilized SARS-CoV-2 spike protein (S). Previously, we showed that prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P (expressing the S-2P stabilized version of the S protein) induced high levels of serum SARS-CoV-2-neutralizing antibodies, as well as S-specific IgA and IgG.
In FY 2023, we continued the development of these B/HPIV3 vectors. To further improve the immunogenicity, we generated B/HPIV3/S-6P, expressing a further-stabilized version of the S protein (S-6P, described by Hsieh et al., PMID 32703906). Indeed, intranasal immunization of hamsters with B/HPIV3/S-6P reproducibly elicited significantly higher levels of serum anti-S IgG and IgA to the receptor binding domain (RBD) than B/HPIV3/S-2P; hamster sera efficiently neutralized variants of concern (VoCs), including Omicron variants. B/HPIV3/S-2P and B/HPIV3/S-6P immunization protected hamsters against weight loss and lung inflammation following SARS-CoV-2 challenge with the vaccine-matched strain WA1/2020 or VoCs B.1.1.7/Alpha or B.1.351/Beta and induced near-sterilizing immunity. Three weeks post-challenge, B/HPIV3/S-2P and B/HPIV3/S-6P-immunized hamsters exhibited a robust anamnestic serum antibody response with increased neutralizing potency to VoCs, including Omicron sublineages. B/HPIV3/S-6P also primed for stronger anamnestic antibody responses after challenge with WA1/2020 than B/HPIV3/S-2P. (Liu X, Park HS, Matsuoka Y, Santos C, Yang L, Luongo C, Moore IN, Johnson RF, Garza NL, Zhang P, Lusso P, Best SM, Buchholz UJ, Le Nouen C. PLoS pathogens. 2023;19(6):e1011057. Epub 20230623. PMCID: PMC10325082.)
B/HPIV3/S-6P was further evaluated in a preclinical study in rhesus macaques. We found that a single intranasal/intratracheal dose of B/HPIV3/S-6P induced strong S-specific airway mucosal IgA and IgG responses. High levels of S-specific antibodies were also induced in serum, which efficiently neutralized SARS-CoV-2 variants of concern of alpha, beta, and delta lineages, while their ability to neutralize Omicron sub-lineages was lower. Furthermore, B/HPIV3/S-6P induced robust systemic and pulmonary S-specific CD4+ and CD8+ T cell responses, including tissue-resident memory cells in the lungs. Following challenge, SARS-CoV-2 replication was undetectable in airways and lung tissues of immunized macaques. Based on these results, B/HPIV3/S-6P was selected for evaluation of safety and immunogenicity in a Phase 1 study. (Le Nouen C, Nelson CE, Liu X, Park HS, Matsuoka Y, Luongo C, Santos C, Yang L, Herbert R, Castens A, Moore IN, Wilder-Kofie T, Moore R, Walker A, Zhang P, Lusso P, Johnson RF, Garza NL, Via LE, Munir S, Barber DL, Buchholz UJ. Cell. 2022;185(25):4811-25 e17. Epub 20221110. PMCID: PMC9684001)
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><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><21+ years old><5 year old><5 years of age><7S Gamma Globulin><Acute Laryngotracheo-Bronchitis Virus><Acute Laryngotracheobronchitis Virus><Adult><Adult Human><Airway mucosa><Antibodies><Antibody Response><Attenuated><B.1.1.529><B.1.1.7><B.1.351><Barbering><Blood Serum><Body Tissues><Body Weight decreased><Bovine Species><CA virus><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID><COVID-19><COVID-19 S protein><COVID-19 antibody><COVID-19 antigen><COVID-19 immunity><COVID-19 infection><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 transmission><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID-19 virus transmission><COVID19><COVID19 S protein><COVID19 immunity><COVID19 infection><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cattle><Cell Body><Cells><Child><Child Youth><Childhood><Children (0-21)><Clinical Research><Clinical Study><CoV disease><CoV-2><CoV2><Cofactor Protein S><Complement><Complement Proteins><Complementary DNA><Cricetinae><Croup-Associated Virus><Development><Disease><Disorder><Dose><Engineering><Evaluation><Exhibits><Generations><HPIV2><HPIV3><Hamsters><Hamsters Mammals><Hemadsorption Virus 1><Human><Human Parainfluenza Virus 2><Human Parainfluenza Virus 3><IgA><IgG><Immune response><Immunity><Immunization><Immunize><Immunoglobulin A><Immunoglobulin G><Immunological response><In Vitro><Infant><Infection><Injectable><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Memory><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Immune Responses><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Murine pneumonia virus><Omicron variant><Para-Influenza Virus Type 2><Para-Influenza Virus Type 3><Parainfluenza Virus Type 2><Paramyxoviridae><Paramyxovirus><Phase><Phase I Study><Pneumonia Virus of Mice><Pneumonitis><Pneumoviridae><Pneumovirinae><Pneumovirus><Protein S><Proteins><Pulmonary Body System><Pulmonary Inflammation><Pulmonary Organ System><Recovery><Reproducibility><Respiratory Epithelium><Respiratory Mucosa><Respiratory System><Respiratory Tracts><Respiratory tract structure><Rhesus Macaque><Rhesus Monkey><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.529><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 immunity><SARS-CoV-2 infection><SARS-CoV-2 omicron><SARS-CoV-2 omicron variant><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 transmission><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 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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 immunity><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><South Africa strain><South Africa variant><South African strain><South African variant><Structure of parenchyma of lung><Structure of respiratory epithelium><System><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Tissues><Transmission><U.K. variant><UK strain><UK variant><United Kingdom variant><Vaccine Design><Vaccines><Viral Vector><Vitamin K-Dependent Protein S><Weight Loss><Weight Reduction><Wuhan coronavirus><adulthood><age 5 years><airway epithelium><anti-IgG><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><attenuate><attenuates><body weight loss><bovid><bovine><cDNA><community spread><community transmission><community-level spread><community-level transmission><corona virus disease><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 antigen><coronavirus disease 2019 immunity><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 transmission><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cow><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><five year old><five years of age><hCoV19><host response><immune system response><immunity against COVID-19><immunity against COVID19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><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><kids><lead candidate><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><manufacture><mucosal vaccine><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing antibody><non-human primate><nonhuman primate><omicron variant of COVID-19><omicron variant of SARS-CoV-2><parainfluenza virus><parainfluenza virus type 3><pathogen><pediatric><phase 1 study><plasmid vaccine><pre-clinical study><preclinical study><programs><protective efficacy><pulmonary><receptor binding><receptor bound><respiratory><respiratory tract epithelium><respiratory virus><response><reverse genetics><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.1.1.529><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><severe acute respiratory syndrome coronavirus 2 transmission><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><symptomatic COVID-19><symptomatic COVID19><symptomatic coronavirus disease 2019><thymus derived lymphocyte><translational goal><translational mission><transmission process><transmitted COVID-19><transmitted SARS-CoV-2><transmitted coronavirus disease 2019><transmitted severe acute respiratory syndrome coronavirus 2><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><vaccine response><vaccine responsiveness><vaccine-induced response><variants of concern><vector><vector vaccine><vector-based vaccine><wt-loss><youngster>