Adenovirus-vectored RSV vaccine not inhibited by maternal immunity

描述（由申请人提供）：RSV是导致幼儿下呼吸道疾病和住院的主要病毒原因，但目前还没有批准的疫苗。绝大多数感染RSV的儿童患有轻度上呼吸道感染;然而，在20-30%的RSV感染儿童中发生严重下呼吸道感染，导致美国每年> 130，000例儿科住院。鉴于RSV相关的住院、发病率和死亡率的程度，RSV疫苗的开发是高度优先的公共卫生事项。失败的RSV疫苗，如福尔马林灭活病毒，减毒病毒和纯化蛋白亚单位疫苗的历史清楚地表明需要一种新的疫苗设计。幸运的是，基于对天然RSV感染的免疫生物学、失败的疫苗以及安全有效的被动免疫疗法Synagistm的理解，出现了新的疫苗设计。新疫苗设计的重点是诱导中和抗体的保护和细胞溶解细胞反应，以清除感染。该SBIR的策略是根据最近腺病毒载体疫苗在RSV动物模型中的保护作用以及对预先存在的免疫力作为有效和安全免疫的障碍的认识而制定的。GenVec使用复制缺陷型腺病毒载体疫苗治疗RSV的策略是基于临床证明的腺病毒载体疫苗诱导抗体、CD 8 + T细胞和Th 1型应答的能力。这些考虑导致了以下基本假设：新生儿对疫苗载体和RSV的母体免疫力可以通过疫苗设计来规避。我们已经鉴定了一种非人腺病毒载体SAV 7，其已被证明在RSV保护的动物模型中具有与Ad 5载体相当的功效。人类群体应该对非人腺病毒载体是幼稚的。我们将能够在临床前模型中快速测试母体免疫假设，并获得阳性结果，进而进行人体临床测试。我们在RSV动物模型、腺病毒载体疫苗方面的经验以及与RSV研究领域的领导者Barney Graham、VRC、NIAID的合作增加了我们成功的可能性。该项目的目的是验证非人腺病毒载体的低人血清阳性率，并在体内评估（棉鼠模型）预先存在的免疫力对疫苗载体诱导的RSV免疫应答的影响。将对人腺病毒免疫和被动RSV抗体免疫进行建模。成功完成目标并证明预先存在的免疫力对SAV 7 RSV疫苗载体的免疫原性无影响将证明该项目继续进行至II期是合理的。第二阶段的关键方面将是候选疫苗的临床前测试，适用于在两个月以下的婴儿中诱导针对RSV的保护，随后是临床材料的cGMP生产。我们估计，在第一阶段完成后，将该产品投入临床试验所需的额外时间和资金为3 年和500万美元。

DESCRIPTION (provided by applicant): RSV is the leading viral cause of lower respiratory illness and hospitalization in young children, yet there isn't an approved vaccine. The vast majority of children infected with RSV suffer from a mild upper respiratory tract infection; however, severe lower respiratory infection develops in 20-30% of RSV-infected children, resulting in >130,000 pediatric hospitalizations annually in the United States. Given the degree of RSV-associated hospitalizations, morbidity, and mortality, the development of an RSV vaccine is a high public health priority. The history of failed RSV vaccines, such as formalin-inactivated virus, attenuated viruses, and purified protein subunit vaccines clearly shows the need for a new vaccine design. Fortunately, there are new vaccine designs based on understanding the immunobiology of natural RSV infection, the failed vaccines, and the safe and effective passive immunotherapy Synagistm. The new vaccine designs focus on inducing neutralizing antibodies for protection and cytolytic cellular responses to clear infection. The strategy for this SBIR was formulated on the recent demonstration of protection in animal models of RSV by adenoviral vector vaccines and the recognition of pre-existing immunity as an impediment to effective and safe immunization. GenVec's strategy to use a replication-defective adenovirus vectored vaccine for RSV is based on the clinically proven capability of adenovirus vectored vaccines to induce antibody, CD8+ T-cell, and Th1 type responses. These considerations resulted in the underlying hypothesis that maternal immunity in the neonate to both the vaccine vector and RSV can be circumvented by vaccine design. We have identified a non-human adenovirus vector, SAV7, that has been demonstrated to have comparable efficacy to Ad5 vectors in animal models of RSV protection. The human population should be na¿ve to the non-human adenovirus vector. We will be able to rapidly test the maternal immunity hypothesis in preclinical models, and with positive results, advance to human clinical testing. Our probability of success is increased by our experience with key RSV animal models, adenoviral vector vaccines, and our collaboration with a leader in the field of RSV research, Barney Graham, VRC, NIAID. The aims of the project are the verification of low human seroprevalence of the non-human adenovirus vectors and in vivo assessment (cotton rat model) of the effect of pre-existing immunity on vaccine vector-induced immune responses to RSV. Both human adenovirus immunity and passive RSV antibody immunity will be modeled. Successful completion of the aims and demonstration of no effect of pre-existing immunity on the immunogenicity of the SAV7 RSV vaccine vector will justify continuing the project to Phase II. Key aspects of Phase II would be pre-clinical testing of candidate vaccines in regimens appropriate for inducing protection against RSV in infants less than two months old and, subsequently, cGMP manufacture of clinical material. We estimate the additional time and funding necessary to bring this product to clinical testing after the completion of Phase I to be 3 years and 5 million dollars.