Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in infants and young children worldwide. Since infection induces only partial protection, it causes repeat infection and disease throughout life. Though a high priority for vaccine development no vaccine is yet available. The lack of success in developing a vaccine suggests novel strategies are needed to achieve success. Most of the focus for RSV subunit vaccines has been on the RSV F protein. The G protein of RSV: 1) causes inflammation that increases RSV disease and 2) provides binding to primary human airway epithelial cells to infect the cells at the primary site of infection in humans. Blocking G with antibodies prevents these effects in mice. Accordingly, inducing anti- G antibodies with a G immunogen in a vaccine, should improve both safety and efficacy. This proposal is designed to identify the optimal G protein construct to use with a pre-fusion stabilized F protein in an RSV vaccine for adults. This approach takes advantage of the pre-fusion F's ability to induce highly levels of broadly neutralizing antibodies and the G protein's ability to induce antibodies that both neutralize the virus and block RSV-induced host responses that cause disease. This proposal is built on the principal investigator's (PI's) work that 1) helped elucidate the disease caused by G, especially the central conserved domain of G (CCD-G), and 2) developed an RSV-based virus-like particle (VLP) platform for RSV vaccines. The RSV VLP platform should ~maintain the native structures of F and G to induce optimal immune responses. We propose to make and evaluate RSV VLPs with prefusion stabilized F plus different constructs of a group A, G protein or G protein peptides and a group B G protein or peptides with different adjuvants. We use the PI's mouse model of RSV disease to determine which VLP/adjuvant is most effective at inducing F and G neutralizing antibodies, preventing virus replication and disease in RSV-challenged mice, and fails to cause enhanced disease. These studies will identify the optimal F plus G vaccine to move toward licensure. This vaccine promises to be safer and more effective than existing RSV vaccines.
Public Health Relevance Statement: Narrative Respiratory Syncytial Virus Infection (RSV) is an extremely common virus that infects almost everyone more than once. Most people recover naturally after experiencing coughing and cold-like symptoms. But for premature babies and very young children with lung or heart problems, or elderly people, RSV can be life threatening. It has been difficult for scientists to make safe and effective vaccines that protect against RSV. The goal of this project is to develop and test a new type of RSV vaccine designed for adult and elderly patients.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Elderly; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Antibodies; Antigens; immunogen; Birth; Parturition; Western Blotting; Immunoblotting; Western Immunoblotting; protein blotting; Bronchiolitis; Cells; Cell Body; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Coughing; Cessation of life; Death; Disease; Disorder; Epithelial Cells; Genes; Goals; Heart; Hospitalization; Hospital Admission; Human; Modern Man; IgG1; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Immunity; Infant; Premature Infant; infants born premature; infants born prematurely; premature baby; premature infant human; preterm baby; preterm infant; preterm infant human; Infection; Inflammation; Licensure; Lung; Lung Respiratory System; pulmonary; Electron Microscopy; Mucous body substance; Mucus; mucous; Mus; Mice; Mice Mammals; Murine; Persons; Patents; Legal patent; Pathology; Peptides; Pneumonia; expectant mother; expecting mother; pregnant mothers; Pregnant Women; Proteins; Cotton Rats; RSV infection; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory Tract Diseases; Risk; Safety; Spleen Reticuloendothelial System; Spleen; Saccharose; Sucrose; Testing; Universities; Vaccines; Virus Diseases; Viral Diseases; viral infection; virus infection; virus-induced disease; Virus Replication; viral multiplication; viral replication; virus multiplication; Virus; Work; aluminum sulfate; Alum Adjuvant; alum; Respiratory syncytial virus RSV proteins; Respiratory syncytial virus proteins; GTP-Binding Proteins; G-Proteins; GTP-Regulatory Proteins; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; GTP-Binding Protein alpha Subunits, Gs; G(s), alpha Subunit; G(s), a Subunit; G(s)alpha; G(s)a; GTP-Binding Protein a Subunits, Gs; Gs alpha Family G-Protein; Gsa; Gas; Regulatory Ns Protein; Stimulatory Gs G-Protein; alpha Subunit Stimulatory GTP-Binding Protein; alpha-Gs; a-Gs; Respiratory syncytial virus RSV F proteins; Respiratory syncytial virus F protein; peptide G; laminin-binding peptide; synthetic laminin-binding peptide; base; improved; Site; Phase; Histologic; Histologically; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Viral Activity; Viral Function; Viral Physiology; Letters; Immunological response; host response; immune system response; immunoresponse; Immune response; Attenuated; Inflammatory; Life; Scientist; lower respiratory tract; Lower respiratory tract structure; neutralizing antibody; Best Practice Analysis; Benchmarking; experience; success; develop a vaccine; develop vaccines; development of a vaccine; vaccine development; preempt; Structure; novel; Reporting; Modeling; response; immunogenic; Subunit Vaccines; RSV Vaccines; Respiratory Syncytial Virus Vaccines; Formalin; Molecular Interaction; Binding; preventing; prevent; virus-like nanoparticles; viruslike particle; Virus-like particle; Dose; Symptoms; Data; Clinical Data; Small Business Technology Transfer Research; STTR; Vaccinated; Vaccine Design; Principal Investigator; Cardiac; Adjuvant; Development; developmental; pre-clinical; preclinical; virtual; novel virus; immunogenicity; design; designing; novel strategies; new approaches; novel approaches; novel strategy; older patient; elderly patient; 2 year old; 2 years of age; age 2 years; aged 2 years; aged two years; two year old; two years of age; airway epithelium; Respiratory Epithelium; Structure of respiratory epithelium; mouse model; murine model; commercialization; vaccine candidate; T cell response; Pulmonary Inflammation; Lung Inflammation; Pneumonitis; Antibody Response; adaptive immune response
