SBIR-STTR Award

Human Rhinoviruses (HRV) cause approximately one third of the 60 million cases of common cold each year in the US and therefore are one of the most economically important human diseases of developed countries. Although rhinoviruses are not generally considered killer viruses, more recent studies have shown that rhinoviruses are a significant source of hospitalization for those with asthma and chronic pulmonary diseases. The large number of HRV serotypes (>100) stand as a major barrier to vaccine development. However, three past and recent developments suggest that the design of a first generation rhinovirus vaccine may now be possible. First, in vitro evolutionary escape experiments indicate that both monoclonal and polyclonal antibodies made to the HRV capsid act similarly and repeatedly result in rather narrow and similar range of amino acid changes in the capsid of the virus. Second, serological mapping data suggest the host response is largely restricted to immunodominant epitopes located in the most highly variable regions of the capsid flanking the conserved cellular receptor-binding region. Third, a unique small panel of monoclonal antibodies has been shown to neutralize across multiple serotypes. Thus, it is possible that epitopes exist in the virus that can induce more broadly protective antibodies, but are not readily seen by the immune system. Finally, in preliminary studies with the related picornavirus of ungulates, Foot and Mouth Disease Virus, Immune Refocusing mutations introduced into just one of four immunodominant antigenic sites, the GH-loop of VP1, resulted in an antigen that stimulated cross-neutralizing antibodies. We propose 1) to design and produce a panel of HRV39 vaccine candidates with mutational changes to immunodominant epitopes; 2) to test the candidates for stimulation of cross-neutralizing antibodies; and 3) to investigate delivery systems for native- like capsid protein folding and efficient antigen presentation to the immune system.

Public Health Relevance:
Human rhinoviruses (HRVs) are a leading cause of the common cold and an increasingly recognized cause and/or exacerbater of asthma and chronic pulmonary disease. Due to the large number of serotypes, efforts to develop a vaccine have been discouraging. Recent advances in understanding how pathogens utilize highly variable antigenic sites to misdirect the immune system from responding to more highly conserved epitopes have led to the development of the Immune Refocusing Technology for novel vaccine design. We propose to apply this Technology to redirect the immune system to recognize cross-reactive epitopes on HRV39. Sera from mice immunized with the vaccine candidates will be assessed for enhanced cross-reactive antiviral activity against heterologous serotypes. The development of a broadly protective HRV vaccine would result in enormous improvements in health status and have an immediate impact on health-related economic savings.

Thesaurus Terms:
"3-D Analysis; 3-Dimensional Analysis; 3d Analysis; Aids Virus; Atgn; Acute Nasopharyngitis; Agreement; Amino Acid Sequence; Amino Acids; Antibodies; Antigen Presentation; Antigenic Determinants; Antigenic Determinants, Immunodominant; Antigens; Antiviral Agents; Antiviral Drugs; Antivirals; Assay; Asthma; Attenuated; B Blood Cells; B-Cells; B-Lymphocytes; Baculoviruses; Binding; Binding (Molecular Function); Binding Determinants; Bioassay; Biologic Assays; Biological Assay; Blood Serum; Bronchial Asthma; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; Cd54 (Icam 1); Cd54 Antigens; Capsid; Capsid Proteins; Cells; Chronic; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Coat Proteins; Collection; Common Cold; Data; Developed Countries; Developed Nations; Development; Economics; Engineering; Engineerings; Epitope Mapping; Epitopes; Escape Mutant; Event; Family Picornaviridae; Foot-And-Mouth Disease Virus; Funding; Future; Generations; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic Defect; Genetics-Mutagenesis; Glycoprotein Icam 1 (Human Clone Phrvr1 Deblocked Protein Moiety Reduced); Grant; Grippe; Hiv-1; Hiv-I; Hiv1; Hosp; Health Status; Hospitalization; Human; Human Immunodeficiency Virus 1; Human, General; Icam-1; Immune; Immune Response; Immune System; Immunity; Immunization; Immunodeficiency Virus Type 1, Human; Immunodominant Determinants; Immunodominant Domains; Immunodominant Epitopes; Immunodominant Regions; Immunodominant Sites; Immunoglobulin V; Immunoglobulin Variable Region; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; In Vitro; Inbred Icr Mice; Industrialized Countries; Industrialized Nations; Infection; Influenza; Insecta; Insects; Intercellular Adhesion Molecule 1; Invertebrates, Insects; Investments; Legal Patent; Length; Level Of Health; Licensing; Lung Diseases; Mammals, Mice; Man (Taxonomy); Man, Modern; Maps; Methods; Mice; Mice, Inbred Icr; Minority; Moab, Clinical Treatment; Molecular Biology, Mutagenesis; Molecular Interaction; Monoclonal Antibodies; Mouse Strains; Mouse, Icr; Murine; Mus; Mutagenesis; Mutation; Nih; National Institutes Of Health; National Institutes Of Health (U.S.); Patents; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Picornaviridae; Picornaviruses; Plasmids; Preparation; Production; Protein Structure, Primary; Proteins; Protocol; Protocols Documentation; Pulmonary Diseases; Pulmonary Disorder; Receptor Protein; Relative; Relative (Related Person); Respiratory Disease; Respiratory Disorder; Respiratory System Disease; Respiratory System Disorder; Rhinovirus; Savings; Sensitization, Immunologic; Sensitization, Immunological; Serologic; Serological; Serotyping; Serum; Services; Site; Source; Structural Models; Structure; Surface; System; System, Loinc Axis 4; Technology; Testing; Three-Dimensional Analysis; Ungulate; United States National Institutes Of Health; Vaccine Antigen; Vaccine Design; Vaccines; Variable Region; Variable Region, Ig; Viral; Viral Coat Proteins; Viral Outer Coat Protein; Virion; Virus; Virus Particle; Virus-Like Particle; Viruses, General; Work; Aminoacid; Base; Body System, Allergic/Immunologic; Clinical Investigation; Coat (Nonenveloped Virus); Cross Reactivity; Design; Designing; Experience; Experiment; Experimental Research; Experimental Study; Flexibility; Flu Infection; Gene Product; Genome Mutation; Host Response; Human T Cell Leukemia Virus Iii; Human T Lymphotropic Virus Iii; Human Disease; Immunogen; Immunogenic; Immunogenicity; Immunoresponse; Improved; Influenza Infection; Interest; Lung Disorder; Neutralizing Antibody; New Vaccines; Next Generation Vaccines; Novel; Novel Vaccines; Organ System, Allergic/Immunologic; Particle; Pathogen; Phase 2 Study; Polyclonal Antibody; Protein Folding; Protein Sequence; Prototype; Public Health Relevance; Receptor; Receptor Binding; Research Study; Response; Therapeutic Protein; Vaccine Candidate; Vaccine Development; Viruslike Particle"

Human rhinoviruses (HRV) are the leading cause of common colds and virus-induced exacerbation of asthma and chronic pulmonary diseases. In addition, HRV can cause severe lower respiratory tract infections in children, the elderly, and immune-compromised patients. The economic burden of the common cold is estimated to be about $40B each year in the US in terms of direct medical expenses and lost work and productivity and HRV accounts for more than half of these expenses. A reduction in the rate and severity of common colds would greatly reduce our healthcare burden and improve the quality of life for millions of individuals. Infection with HRV stimulates antibodies that can prevent re-infection by the same virus; however, the immune response is highly serotype-restricted and directed against only the homologous virus. Since there are over 100 serotypes of HRV-A and -B and 50 genotypes of HRV-C, humans typically suffer 2 or 3 HRV illnesses and several more asymptomatic infections each year. The large numbers of serotypes and the serotype-restricted immune responses have complicated the design of HRV vaccines. In a Phase I SBIR-AT grant, BMI produced a set of ten HRV-A antigens that stimulate significantly enhanced cross-serotype neutralizing antibodies. Using algorithms that included sequence alignments, in vitro and in vivo virus evolution studies, and structural epitope analyses, the sites that contribute to the serotype restricted responses were identified. The test antigens contained amino acid substitutions designed to reduce the antigenicity towards these genetically variable, serotype-restricted sites and to redirect immunity towards more highly conserved sites that had been less immunogenic, such as those in the receptor-binding site. Sera from rabbits immunized with the engineered antigens contained unprecedented levels of cross-neutralizing activity which are the direct correlate of protection from infection. Sera from the lead antigen, 39M7, neutralized 41 of the 61 serotypes of viruses tested including 13 of the HRV-B serotypes. The data have been reviewed by independent experts and represents ground-breaking advances in the design of vaccines that are able to stimulate broad immunity against multiple serotypes or strains of viruses. In thi SBIR-AT Phase II application, we propose to continue the development of the 39M7 lead candidate through pre-clinical studies. Our partner, C-PERL will produce 1-gram test lots of the VLP antigen using their innovative insect larva expression system to provide sufficient sample for process development. 1-gram near-GMP lots will be prepared in the final stages of process development and used to assess stimulation of cross-neutralizing antibodies as a function of dose, route, adjuvant, and excipients in non-GLP rabbit studies. cGMP material will be prepared, certified, and tested for immunogenicity and toxicity in mice and rabbits. Because of the specialized nature of the project, we have recruited consultants seasoned in GLP, cGMP, statistical analysis, and other regulatory affairs. The consultants will also assist in meetings wih the FDA and preparation of IND filings. We have also retained long-time collaborator, Dr. Ron Turner, a highly respected pediatric clinical scientist who, in the event of our continued success, will oversee future clinical studies at the University of Virginia. In summary, we have assembled a unique team with disruptive insights and innovative capabilities to develop a vaccine against a pathogen previously thought to be resistant to vaccine technologies. In the process, we have developed a coherent path towards the development and commercialization of a product that could make a significant impact on the overall health of our population while reducing this burden on our national healthcare system.

Public Health Relevance Statement:


Public Health Relevance:
Human rhinoviruses cause approximately 50% of all common colds which account for an economic burden of about $40B each year in the US. In a Phase I SBIR-AT project, BMI applied its proprietary Immune Refocusing Technology to design a set of 10 novel HRV antigens which were produced as recombinant HRV viruses and as baculovirus-expressed capsid/VLPs. Sera from rabbits immunized with the HRV antigens demonstrated unprecedented cross-neutralized activities. Sera from the best performing antigen neutralized 41 of 61 serotypes tested. We propose to follow up with a Phase II SBIR-AT study designed to develop the leading VLP antigen through pre-clinical studies so that FDA filings and Clinical Trials can be started to analyze the safety and immunogenicity of the vaccines in humans. If successful, the project will lead to the commercialization of the first effective vaccine against human rhinoviruses.

NIH Spending Category:
Biotechnology; Immunization; Infectious Diseases; Prevention; Vaccine Related

Project Terms:
Accounting; Adjuvant; Adult; Algorithms; Amino Acid Substitution; Animals; Antibodies; Antibody Response; antigen processing; Antigens; Asthma; Baculoviruses; base; Binding Sites; Biological Assay; Biological Preservation; Blood Cells; Blood Chemical Analysis; Blood Circulation; Buffers; Capsid; Capsid Proteins; cGMP production; Characteristics; Child; Childhood; Chromatography; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; commercialization; Common Cold; Common Cold Virus; Crude Extracts; Cyclic GMP; Data; design; Detergents; Development; Dose; Economic Burden; Elderly; Engineering; Epitopes; Event; Evolution; Excipients; Excision; Filtration; follow-up; Future; Genotype; GMP lots; Goals; Grant; Harvest; Health; health economics; Healthcare; Healthcare Systems; Histopathology; Hospitalization; Housing; Human; Immune; Immune response; Immunity; immunogenic; immunogenicity; improved; In Vitro; in vivo; Individual; Infection; innovation; Insecta; insight; Laboratories; Larva; Lead; Licensing; Lower Respiratory Tract Infection; Lung diseases; Mediating; Medical; meetings; Methods; Morbidity - disease rate; Movement; Mus; Mutation; Nature; neutralizing antibody; novel; Nucleic Acids; Oryctolagus cuniculus; pathogen; Patients; Performance; Phase; Population; Positioning Attribute; pre-clinical; preclinical study; Preparation; pressure; prevent; Procedures; Process; process optimization; Production; Productivity; protein folding; Proteins; Protocols documentation; quality assurance; Quality of life; receptor binding; Recombinants; Recruitment Activity; Regulatory Affairs; Research Design; Resistance; response; Rhinovirus; Route; Running; Safety; Sampling; Schedule; Scientist; Seasons; Sequence Alignment; Serotyping; Serum; Severities; Site; Small Business Innovation Research Grant; Staging; Structure; success; Sucrose; System; Technology; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Toxin; Universities; vaccine candidate; Vaccine Design; vaccine development; vaccine evaluation; Vaccines; Viral; Virginia; Virion; Virus; Virus Diseases; Virus-like particle; Work