Development of polyvalent inactivated rhinovirus vaccine

多价灭活鼻病毒疫苗的研制

基本信息

批准号：
9342637
负责人：
Martin Lawrence Moore
金额：
$ 21.64万
依托单位：
MEISSA VACCINES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9342637
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Acute Acute Disease Address Adjuvant Adult Alhydrogel Alpha Cell Antibody Response Antigens Asthma Bacterial Artificial Chromosomes Biological Biological Assay Biotechnology Blood Circulation Capsid Capsid Proteins Cell Line Cells Chemistry Child Chronic Obstructive Airway Disease Clinical Common Cold Common Cold Virus Communicable Diseases Communities Complementary DNA Complex Complex Mixtures Cyclic GMP Data Development Disease Ensure Equilibrium Etiology Family Picornaviridae Formulation Future GPA33 gene Genetic Transcription Genome Goals Hospitalization Human Immunity In Vitro Laboratories Laboratory Study Length Liquid Chromatography Macaca mulatta Mass Spectrum Analysis Measurable Measures Medical Methods Mus Peptides Play Pneumonia Polyproteins Polyvalent Vaccine Preparation Procedures Process Proteins Proteomics Publishing Recombinants Recording of previous events Research Research Personnel Rhinovirus Role Seeds Series Serotyping Serum System T7 RNA polymerase Testing Time Transfection United States Universities Vaccines Virus Work aluminum sulfate assay development base cGMP production cost design high risk population immunogenicity in vitro Assay innovation monolayer neutralizing antibody nonhuman primate plasmid DNA product development research clinical testing scale up tandem mass spectrometry tissue culture vaccine development viral RNA

项目摘要

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.

人类鼻病毒（RV）是普通感冒的主要病因，是人类传染病。 RV不仅仅是令人讨厌的。这是社区获得性肺炎的主要原因在美国的儿童和成人中，在引发两种哮喘的加重方面发挥了重要作用和慢性阻塞性肺部疾病，每年每年产生数十亿美元的医疗费用高风险人群。几十年前，研究人员将灭活的房车确定为一种保护性疫苗，定义病毒中和抗体（NAB）作为防寒的保护和RV的估计持续时间使用单价灭活的RV免疫。但是，许多RV类型的共循环进一步劝阻疫苗开发。在1970年代，对人进行了10个灭活的RV疫苗，但只有三分之一疫苗菌株可诱导可测量的NAB，增强了RV疫苗发育的悲观情绪。然而，在此早期10值疫苗中，每个输入RSV型抗原的平均量较低。埃默里（Emory）的摩尔实验室最近公布说，针对许多RV类型的血清NAB可能是由多价灭活的RV诱导，通过简单增加每个RV的量疫苗中的抗原。在小鼠中使用多达25个价值的配方，在非人类灵长类动物中使用50个价值，灭活的RV疫苗免疫原性与足够数量的输入抗原有关。血清nab to 多价灭活的RV是特异性类型的，需要大量的价值（RV类型）。这些原理证明数据指向用于RV疫苗产品开发的可访问疫苗方法。高度多价疫苗的开发将需要克服化学，制造业的挑战和对照（CMC），例如识别和确保高度复杂的疫苗的效力和一致性混合物。有三种RV物种A，B和C，分别为83、32和55种。没有 RV抗原漂移的证据。 Meissa疫苗，Inc和Emory University最初将专注于最多普遍的RV类型，物种中的83种类型。为了平衡可管理的CMC研究与产品开发，我们最初的目标是生成28个价值的重组RV A疫苗。 28个价值RV A疫苗稍后可以对过程和控制进行缩放并适应更高的价值，或者开发作为三种28价疫苗的系列，以覆盖所有83 RV A血清型。在AIM 1中，我们将产生28 RV A 感染性克隆构建具有A10，A12，A15，A16，A19，A28，A29，A31， A32，A33，A34，A38，A40，A41，A49，A49，A53，A55，A56，A58，A59，A59，A60，A66，A68，A68，A75，A75，A78，A80，A85，A85或A96 并评估其在适合CGMP制造的细胞系中产生传染病的能力。在AIM 2中，我们将开发基于蛋白质组学的测定法，以识别和量化与28个相对应的独特肽 28价疫苗组成中的类型。该测定将用于测量高度的效力复杂的疫苗混合物，并评估有资格释放批次的能力。