Development of the first HRV vaccine

开发第一种 HRV 疫苗

• 批准号: 8714104
• 负责人: GREGORY John TOBIN
• 金额: $ 92.31万
• 依托单位: BIOLOGICAL MIMETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714104
• 关键词: Accounting; Adjuvant; Adult; Algorithms; Amino Acid Substitution; Animals; Antibodies; Antibody Formation; Antigens; Asthma; Baculoviruses; Binding Sites; Biological Assay; Biological Preservation; Blood Cells; Blood Chemical Analysis; Blood Circulation; Buffers; Capsid; Capsid Proteins; Characteristics; Child; Childhood; Chromatography; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Trials; Common Cold; Common Cold Virus; Crude Extracts; Cyclic GMP; Data; Detergents; Development; Dose; Economic Burden; Elderly; Engineering; Epitopes; Event; Evolution; Excipients; Excision; Filtration; Future; GMP lots; Genotype; Goals; Grant; Harvest; Health; Healthcare; Healthcare Systems; Histopathology; Hospitalization; Housing; Human; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Insecta; Laboratories; Larva; Lead; Licensing; Lower Respiratory Tract Infection; Lung diseases; Mediating; Medical; Methods; Morbidity - disease rate; Movement; Mus; Mutation; Nature; Nucleic Acids; Oryctolagus cuniculus; Patients; Performance; Phase; Population; Positioning Attribute; Preparation; Procedures; Process; Production; Productivity; Proteins; Protocols documentation; Quality of life; Recombinants; Recruitment Activity; Regulatory Affairs; Research Design; Resistance; Rhinovirus; Route; Running; Safety; Sampling; Schedule; Scientist; Seasons; Sequence Alignment; Serotyping; Serum; Severities; Site; Small Business Innovation Research Grant; Staging; Structure; Sucrose; System; Technology; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Toxin; Universities; Vaccine Design; Vaccines; Viral; Virginia; Virion; Virus; Virus Diseases; Virus-like particle; Work; antigen processing; base; cGMP production; commercialization; design; follow-up; health economics; immunogenic; immunogenicity; improved; in vivo; innovation; insight; meetings; neutralizing antibody; novel; pathogen; pre-clinical; preclinical study; pressure; prevent; process optimization; protein folding; public health relevance; quality assurance; receptor binding; response; success; vaccine candidate; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：人类鼻病毒（HRV）是普通感冒以及病毒引起的哮喘和慢性肺部疾病恶化的主要原因。此外，HRV还可引起儿童、老年人和免疫功能低下患者的严重下呼吸道感染。在美国，就直接医疗费用以及工作和生产力损失而言，普通感冒每年造成的经济负担估计约为 $40B，HRV 占这些费用的一半以上。普通感冒的发病率和严重程度的降低将大大减轻我们的医疗负担并改善数百万人的生活质量。 HRV 感染会刺激抗体产生，从而防止同一病毒再次感染；然而，免疫反应受到血清型的高度限制，并且仅针对同源病毒。由于HRV-A和-B有超过100种血清型以及HRV-C有50种基因型，因此人类每年通常会罹患2或3种HRV疾病以及数种更多的无症状感染。大量的血清型和血清型限制的免疫反应使 HRV 疫苗的设计变得复杂。在 I 期 SBIR-AT 资助中，BMI 生产了一组 10 种 HRV-A 抗原，可刺激显着增强的跨血清型中和抗体。使用包括序列比对、体外和体内病毒进化研究以及结构表位分析在内的算法，确定有助于血清型的位点 确定了有限的反应。测试抗原含有氨基酸取代，旨在降低对这些遗传变异、血清型限制位点的抗原性，并将免疫重定向至免疫原性较低的高度保守的位点，例如受体结合位点中的位点。用工程抗原免疫的兔子的血清含有前所未有的交叉中和活性水平，这与免受感染的保护直接相关。主要抗原 39M7 的血清中和了所测试的 61 种病毒血清型中的 41 种，其中包括 13 种 HRV-B 血清型。这些数据已经过独立专家的审查，代表了疫苗设计方面的突破性进展，能够刺激针对多种血清型或病毒株的广泛免疫力。 在SBIR-AT II期申请中，我们建议通过临床前研究继续开发39M7先导候选药物。我们的合作伙伴 C-PERL 将使用其创新的昆虫幼虫表达系统生产 1 克 VLP 抗原测试批次，为工艺开发提供足够的样本。 1 克近 GMP 批次将在工艺开发的最后阶段制备，并用于评估非 GLP 兔子研究中作为剂量、途径、佐剂和赋形剂函数的交叉中和抗体的刺激作用。 cGMP 材料将在小鼠和兔子中进行制备、认证和免疫原性和毒性测试。由于该项目的专业性，我们聘请了在GLP、cGMP、统计分析和其他法规事务方面经验丰富的顾问。顾问还将协助与 FDA 举行会议并准备 IND 备案。我们还保留了长期合作者 Ron Turner 博士，他是一位备受尊敬的儿科临床科学家，如果我们继续取得成功， 将监督弗吉尼亚大学未来的临床研究。 总之，我们组建了一支具有颠覆性见解和创新能力的独特团队，以开发针对以前被认为对疫苗技术具有抗性的病原体的疫苗。在此过程中，我们制定了一条连贯的产品开发和商业化道路，该产品可以对我们人口的整体健康产生重大影响，同时减轻我们国家医疗保健系统的负担。