Development of polyvalent inactivated rhinovirus vaccine

人鼻病毒（RV）是普通感冒的主要病原体，也是导致人类免疫性疾病的主要原因。 人类传染病RV不仅仅是一个麻烦。它是社区获得性肺炎的主要原因 在美国的儿童和成人中， 和慢性阻塞性肺病，导致数十亿美元的医疗费用，每年在这些 高危人群。几十年前，研究人员将灭活RV确定为一种保护性疫苗， 病毒中和抗体（nAb）作为预防感冒的相关因素，以及RV的估计持续时间 使用单价灭活RV的免疫。然而，许多RV类型的共同流通进一步阻碍了 疫苗研发。上世纪70年代，一种10价灭活RV疫苗曾在人群中进行过试验，但只有三分之一的人接种了疫苗。 的疫苗株诱导可测量的nAb，加强了对RV疫苗开发的悲观情绪。然而，在这方面， 该早期10价疫苗中每种输入RSV型抗原的平均量较低。 埃默里大学的摩尔实验室最近发表了针对许多RV类型的血清nAb可以被 通过简单地增加每种RV的量，用明矾佐剂的多价灭活RV诱导 疫苗中的抗原使用在小鼠中高达25价和在非人灵长类动物中高达50价的制剂， RV灭活疫苗的免疫原性与足够数量的输入抗原有关。血清nAb 多价灭活RV是类型特异性的，需要大量的价数（RV类型）。这些 原理验证数据指向用于RV疫苗产品开发的易处理的疫苗方法。 高度多价疫苗的开发将需要克服化学、制造、 和控制（CMC），如鉴定和确保高度复杂疫苗的效力和一致性 混合物。RV有A、B、C三种，分别有83、32、55个型。没有 RV抗原漂移的证据。Meissa Vaccines，Inc和Emory大学最初将专注于最 RV的主要类型为A.为了平衡可管理的CMC研究与产品 为了进一步开发，我们的初步目标是产生28价重组RV A疫苗。28价RV A疫苗 工艺和控制可以在以后按比例放大并适应更高的化合价，或者可替代地， 作为一个系列的三个28价疫苗，以覆盖所有83个RV A血清型。在目标1中，我们将生成28个RV A 携带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 并评价它们在适于cGMP生产的细胞系中产生感染性病毒的能力。在目标2中， 将开发一种基于蛋白质组学的测定方法，以鉴定和定量对应于28种 28价疫苗组合物中的类型。该测定法将被用于测量高浓度的 复杂的疫苗混合物，并评估放行批次的合格能力。

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.