Development of the first HRV vaccine

描述（由申请方提供）：人鼻病毒（HRV）是普通感冒和病毒诱导的哮喘和慢性肺部疾病恶化的主要原因。此外，HRV可导致儿童、老年人和免疫功能低下患者严重的下呼吸道感染。在美国，普通感冒的经济负担估计每年约为400亿美元，包括直接医疗费用和工作损失和生产力损失，而HRV占这些费用的一半以上。降低普通感冒的发病率和严重程度将大大减轻我们的医疗负担，提高数百万人的生活质量。HRV感染可刺激抗体，防止同一病毒再次感染;然而，免疫反应是高度限制型的，仅针对同源病毒。由于存在超过100种血清型的HRV-A和-B以及50种基因型的HRV-C，因此人类通常每年遭受2或3种HRV疾病和几种更多的无症状感染。大量的血清型和限制型免疫应答使HRV疫苗的设计复杂化。在I期SBIR-AT资助中，BMI产生了一组10种HRV-A抗原，其刺激显著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， 确定了有限的答复。测试抗原含有氨基酸取代，其设计用于降低对这些遗传可变的、多态性限制性位点的抗原性，并将免疫重定向至免疫原性较低的更高度保守的位点，例如受体结合位点中的那些。来自用工程抗原免疫的兔的血清含有前所未有的水平的交叉中和活性，这与保护免受感染直接相关。来自主要抗原39 M7的血清中和了61种检测的病毒血清型中的41种，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，这些疫苗能够刺激对多种血清型或病毒株的广泛免疫。 在本次SBIR-AT II期申请中，我们建议通过临床前研究继续开发39 M7候选电极导线。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抗原试验批次，为工艺开发提供足够的样品。1-将在工艺开发的最后阶段制备100克接近GMP批次，并用于评估非GLP家兔研究中作为剂量、给药途径、佐剂和辅料函数的交叉中和抗体刺激。cGMP材料将在小鼠和家兔中制备、认证和检测免疫原性和毒性。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的会议和IND申请的准备。我们还聘请了长期合作者罗恩特纳博士，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，以开发针对先前被认为对疫苗技术具有抗性的病原体的疫苗。在这个过程中，我们已经制定了一条连贯的道路，以开发和商业化的产品，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。

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.