Development of polyvalent inactivated rhinovirus vaccine

人鼻病毒(RV)是引起普通感冒的主要病原体，也是人类患感冒的主要原因。 人类传染病。房车不仅仅是一种麻烦。它是社区获得性肺炎的一个主要原因。 在美国的儿童和成人中，它在引发两种哮喘的恶化方面发挥着重要作用 以及慢性阻塞性肺疾病，每年在这些地区造成数十亿美元的医疗费用 高危人群。几十年前，研究人员将灭活轮状病毒确定为保护性疫苗，定义为 病毒中和抗体(NAB)作为预防感冒和估计轮状病毒持续时间的相关性 使用单价灭活房车进行免疫。然而，许多房车类型的联合循环受到了进一步的阻碍 疫苗研发。20世纪70年代，一种10价灭活轮状病毒疫苗在人体内进行了测试，但只有三分之一 疫苗株中可产生可测量的NAB，加强了对RV疫苗发展的悲观情绪。然而， 在这种早期的10价疫苗中，每个输入的RSV型抗原的平均数量很低。 埃默里的摩尔实验室最近发表了针对许多RV类型的血清NAB可以是 多价灭活房车辅以明矾诱导，简单增加每辆房车数量 疫苗中的抗原。在老鼠身上使用25价的配方，在非人类灵长类动物中使用50价的配方， 灭活轮状病毒疫苗的免疫原性与足够的输入抗原有关。血清NAB至 多价灭活轮状病毒是特定类型的，需要大量的价态(RV类型)。这些 原则证明数据表明，轮状病毒疫苗产品开发是一种易于处理的疫苗方法。 高度多价疫苗的开发将需要克服化学、制造、 和控制(CMC)，例如识别和确保高度复杂疫苗的效力和一致性 混合物。轮状病毒有A、B、C三种，分别为83、32、55种。没有 RV抗原漂移的证据。Meissa Vaccines，Inc.和埃默里大学最初将专注于 流行的轮状病毒类型，A种内的83种类型，以平衡可管理的CMC研究和产品 在研发过程中，我们的最初目标是生产28价重组轮状病毒A疫苗。28价轮状病毒A疫苗 过程和控制可以在以后扩大规模并适应更高的价态，或者也可以开发 作为一系列的三种28价疫苗，覆盖所有83个轮状病毒A血清型。在目标1中，我们将产生28 RV A 含有A10、A12、A15、A16、A19、A28、A29、A31、 A32、A33、A34、A38、A40、A41、A49、A53、A55、A56、A58、A59、A60、A66、A68、A75、A78、A80、A85或A96 并评估它们在适合制造cGMP的细胞系中产生传染性病毒的能力。在目标2中，我们 将开发一种基于蛋白质组学的分析方法，以识别和量化与28个蛋白质组中的每一个对应的独特多肽 28价疫苗组合物中的类型。这一检测方法将被用来测量一种高度的 复杂的疫苗混合物，并接受能力评估，以获得放行批次的资格。

Human rhinovirus (RV) is the predominant etiological agent of the common cold and the leading cause of human infectious disease. RV is more than a nuisance. It is a major cause of community-acquired pneumonia in children and adults in the United States and plays a major role in triggering exacerbations of both asthma and chronic obstructive pulmonary disease, resulting in billions of dollars in medical costs every year in these high-risk populations. Decades ago, researchers identified inactivated RV as a protective vaccine, defined virus-neutralizing antibodies (nAb) as a correlate of protection against colds, and estimated duration of RV immunity using monovalent inactivated RV. However, co-circulation of many RV types discouraged further vaccine development. A 10-valent inactivated RV vaccine was tested in people in the 1970s, but only one-third of the vaccine strains induced measurable nAb, reinforcing pessimism for RV vaccine development. However, the average amount of each input RSV type antigen in this early 10-valent vaccine was low. The Moore laboratory at Emory recently published that serum nAb against many RV types can be induced by polyvalent inactivated RV adjuvanted with alum by simply increasing the amount of each RV antigen in the vaccine. Using formulations up to 25-valent in mice and 50-valent in non-human primates, inactivated RV vaccine immunogenicity was related to sufficient quantity of input antigens. Serum nAb to polyvalent inactivated RV were type-specific, necessitating a high number of valences (RV types). These proof-of-principle data point to a tractable vaccine approach for RV vaccine product development. Highly polyvalent vaccine development will require overcoming challenges in chemistry, manufacturing, and controls (CMC), such as identifying and ensuring potency and consistency of highly complex vaccine mixtures. There are three RV species, A, B, and C, with 83, 32, and 55 types, respectively. There is no evidence of RV antigenic drift. Meissa Vaccines, Inc and Emory University will initially focus on the most prevalent RV types, the 83 types within species A. In order to balance manageable CMC research with product development, our initial goal is to generate a 28-valent recombinant RV A vaccine. A 28-valent RV A vaccine process and control can later be either scaled up and adapted to higher valency or, alternatively, be developed as a series of three 28-valent vaccines, to cover all 83 RV A serotypes. In Aim 1, we will generate 28 RV A infectious clone constructs harboring the capsid proteins of types A10, A12, A15, A16, A19, A28, A29, A31, A32, A33, A34, A38, A40, A41, A49, A53, A55, A56, A58, A59, A60, A66, A68, A75, A78, A80, A85, or A96 and evaluate their ability to produce infectious virus in a cell line suitable for cGMP manufacturing. In Aim 2, we will develop a proteomics-based assay to identify and quantify unique peptides corresponding to each of the 28 types in the 28-valent vaccine composition. This assay will be advanced for measuring potency of a highly complex vaccine mixture and be assessed for ability to be qualified for releasing lots.