Development of the first HRV vaccine

描述(申请人提供)：人类鼻病毒(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的患者严重的下呼吸道感染。据估计，在美国，普通感冒每年造成的经济负担约为400亿美元，包括直接医疗费用以及工作和生产力损失，而HRV占这些费用的一半以上。普通感冒发病率和严重程度的降低将极大地减轻我们的医疗负担，并提高数百万人的生活质量。感染HRV可以刺激抗体，防止再次感染相同的病毒；然而，免疫反应是高度血清型限制的，只针对同源病毒。由于有100多种HRV-A和-B血清类型和50种HRV-C基因类型，人类通常每年都会患上2到3种HRV疾病，并有更多的无症状感染。大量的血清型和血清型限制性的免疫反应使HRV疫苗的设计变得复杂。在第一阶段SBIR-AT赠款中，BMI生产了一组10种HRV-A抗原，这些抗原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的算法，对血清型有贡献的位置 鉴定出限制性反应。测试抗原包含氨基酸替换，旨在降低对这些遗传可变的、血清型受限的位点的抗原性，并将免疫重定向到免疫原性较低的高度保守的部位，如受体结合部位。用基因工程抗原免疫的兔血清含有前所未有的交叉中和活性，这与保护免受感染直接相关。来自前导抗原39M7的血清中和了61个血清型中的41个，其中包括13个HRV-B血清型。这些数据经过了独立专家的审查，代表了疫苗设计方面的突破性进展，这些疫苗能够激发对多种血清型或毒株的广泛免疫力。在此次SBIR-AT第二阶段应用中，我们建议通过临床前研究继续开发39M7领先候选药物。我们的合作伙伴C-Perl将使用他们创新的昆虫幼虫表达系统生产1克测试批次的VLP抗原，为工艺开发提供足够的样本。1克近GMP批次将在过程开发的最后阶段制备，并用于评估交叉中和抗体在非GLP兔研究中作为剂量、路线、佐剂和辅料的函数的刺激作用。CGMP材料将被制备、认证，并在小鼠和兔子身上进行免疫原性和毒性测试。由于项目的专业性，我们聘请了在普洛斯、cGMP、统计分析和其他监管事务方面经验丰富的顾问。顾问还将协助与FDA的会议和准备IND文件。我们还聘请了长期合作伙伴罗恩·特纳医生，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，我们已经组建了一个独特的团队，具有颠覆性的洞察力和创新能力，以开发一种针对一种以前被认为对疫苗技术具有抵抗力的病原体的疫苗。在这个过程中，我们制定了一条连贯的道路，以开发一种可以对我国人口的整体健康产生重大影响的产品，并将其商业化，同时减轻我们国家医疗保健系统的这一负担。

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.