Adjuvanted Recombinant Candidates to Prime / Boost COVID-19 RNA Vaccines

带佐剂的重组候选物可用于启动/增强 COVID-19 RNA 疫苗

• 批准号: 10325834
• 负责人: DARRICK Albert CARTER
• 金额: $ 24.3万
• 依托单位: PAI LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325834
• 关键词: Adjuvanted; Recombinant; Candidates; Prime; Boost

PROJECT SUMMARY Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in late 2019 causing Coronavirus Disease 2019 (COVID-19) and within months became a worldwide pandemic - as of the writing of this proposal, at least 82.5M people have been infected and more than 1.8M have died in addition to having a significant impact on the worldwide economy. Multiple vaccines are in development for COVID-19 and two of these have been awarded emergency use approval from the US FDA based on RNA platforms. With our partners at HDT Bio Corp. we are soon to enter phase I clinical trials with an RNA-based vaccine, HDT-301. While the development and deployment of these vaccines is exciting and has moved with unprecedented speed, it is unclear how durable the immune responses will be and whether or not they will induce broad protection against emerging strains. Therefore, the ability to boost these vaccines should be investigated to determine if a prime / boost regimen can be deployed in the face of waning immunity or newly emerging viral variants like the recently identified UK strain. As next generation candidates we are now producing 4 different adjuvants containing a non-GLA based TLR4 active ingredient derived from MPL referred to as 3D(6acyl)-PHAD (“3D-PHAD”). These adjuvants are called AlT4™, EmT4™, LiT4™, and MiT4. In this proposal, we will test each of these adjuvants in combination with recombinant Covid-19 spike protein in mice as adjuvanted protein vaccines and as RNA vaccine boosters. Following immunization with protein / adjuvant, potential protection against multiple Covid-19 spike protein variants will be confirmed using both ELISA and viral neutralization assays. Lead combinations will then be tested using a prime-boost strategy using a proprietary mRNA prime vaccination with HDT-301 followed by a adjuvanted protein boost. Specifically, we propose to (1) Down-select a lead adjuvant in mice and (2) Determine protection from Covid-19 using an RNA prime protein boost immunization strategy. When this research is completed, we will have protocols and data supporting the use of these vaccines in further studies in higher animal models leading to human trials as the data warrant.

项目摘要 严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）于2019年底出现，导致冠状病毒 疾病2019（COVID-19），并在几个月内成为一个世界性的大流行病-截至本提案的写作， 至少有8250万人被感染，180多万人死亡， 全球经济的影响。目前正在开发多种针对COVID-19的疫苗，其中两种已被 基于RNA平台获得了美国FDA的紧急使用批准。与HDT Bio的合作伙伴 Corp.我们很快将进入基于RNA的疫苗HDT-301的I期临床试验。虽然发展 这些疫苗的部署是令人兴奋的，并以前所未有的速度进行，目前还不清楚这些疫苗的持久性 免疫应答将是什么以及它们是否将诱导针对新出现的菌株的广泛保护。 因此，应研究加强这些疫苗的能力，以确定初免/加强方案是否可以 在面对免疫力下降或新出现的病毒变种（如最近发现的英国毒株）时， 作为下一代候选物，我们现在生产4种不同的佐剂，其含有基于非GLA的TLR 4 衍生自MPL的活性成分称为3D（6酰基）-PHAD（"3D-PHAD"）。这些佐剂被称为 AlT4 ™、EmT4 ™、LiT4 ™和MiT4。在本提案中，我们将测试这些佐剂中的每一种与以下物质的组合： 重组Covid-19刺突蛋白在小鼠中作为佐剂蛋白疫苗和RNA疫苗加强剂。 蛋白/佐剂免疫后，对多种Covid-19刺突蛋白的潜在保护作用 将使用ELISA和病毒中和测定来确认变体。然后，将电极导线组合 使用引发-加强策略进行测试，使用专有的mRNA引发疫苗接种HDT-301，然后用免疫球蛋白免疫。 佐剂蛋白增强。具体而言，我们建议（1）在小鼠中向下选择一种主要佐剂，以及（2）确定 使用RNA引发蛋白加强免疫策略预防Covid-19。当这项研究 完成后，我们将有协议和数据支持这些疫苗在更高的研究中的使用。 动物模型导致人体试验的数据保证。