Improving the Immune Response to Nanoparticle-Based SARS-CoV-2 Vaccines

改善基于纳米颗粒的 SARS-CoV-2 疫苗的免疫反应

• 批准号: 10648704
• 负责人: Szu-Wen Wang
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648704
• 关键词: 2019-nCoV; Adjuvant; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigen Presentation; Antigens; Biological Assay; Bolus Infusion; COVID-19 pandemic; COVID-19 vaccine; Cells; Communicable Diseases; Coronavirus; Encapsulated; Epitopes; Exposure to; Formulation; Health; Histologic; Human; Hydrogels; Immune; Immune response; Immunity; Immunization; In Vitro; Individual; Influenza; Injections; Kinetics; Libraries; Malignant Neoplasms; Measures; Mediating; Mus; Nature; Physiological; Polymers; Preventive vaccine; Protein Array; Protein Engineering; Proteins; SARS-CoV-2 variant; Secondary Immunization; Serum; Site; Surface; System; T cell response; T-Lymphocyte; Temperature; Testing; Time; Transition Temperature; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Virus; Work; biodegradable polymer; controlled release; cross reactivity; cytokine; design; efficacy evaluation; emerging pathogen; improved; in vivo; in vivo imaging system; nanolabel; nanoparticle; nanovaccine; neutralizing antibody; pandemic disease; particle; pathogen; receptor; receptor binding; response; synergism; vaccine delivery; vaccine development; vaccine effectiveness; vaccine formulation; vaccine strategy

PROJECT SUMMARY / ABSTRACT Vaccines have been very effective at protecting against infectious diseases that pose serious threats to human health. However, prophylactic vaccines can also be limited, particularly if antigenic drift occurs to create variants of the pathogen; this can result in vaccines losing potency over time, needing boosters to confer protection, and lower neutralization efficacy on emerging viral variants – consequences which are observed in the current COVID-19 pandemic. Recent studies have shown that the release kinetics of vaccines can be important in establishing lasting and efficacious immunity. In particular, extending the exposure to antigens can result in higher antibody titers and increased diversity of neutralizing antibodies that target a more diverse set of epitopes, relative to immune responses from conventional bolus vaccination. Furthermore, vaccines made from protein-based nanoparticles can elicit increased antibody production, broader antigen cross-reactivity, and a more balanced Th1/Th2 response. This study tests the hypothesis that the synergy in combining the effects of nanoparticle vaccines for effective antigen presentation, together with a slower release to give a longer exposure to the vaccine, will elicit increased durability of the immune response and a broader cross-reactivity for emerging viral variants. To test this hypothesis, we propose to encapsulate protein nanoparticle vaccines with a biodegradable PLGA-PEG-PLGA (PPP)-based polymer to modulate the kinetics of its release from an in vivo vaccine depot. This extended-release vaccine strategy will then be applied towards SARS-CoV-2. We will evaluate the durability of the proposed vaccine strategy’s potency and the breadth of cross-reactive immune responses toward the variants of SARS-CoV-2 and other types of coronaviruses. Our specific aims are to: (1) create controlled-release nanoparticle depot vaccines against SARS-CoV-2, and (2) determine the efficacy and immunological responses to these vaccine nanoparticles that are encapsulated by the polymeric depot. Because the design of these vaccines is modular and different antigens can be exchanged in a relatively straightforward approach, the successful implementation of this proposed strategy for coronavirus antigens could have broader applicability towards the development of vaccines for other infectious pathogens.

项目概要/摘要 疫苗在预防传染病方面非常有效 严重威胁人类健康。然而，预防性疫苗也可能受到限制，特别是 如果发生抗原漂移而产生病原体变异体；这可能会导致疫苗失效 随着时间的推移效力，需要增强剂来提供保护，并降低中和功效 新出现的病毒变种——在当前的 COVID-19 大流行中观察到的后果。 最近的研究表明，疫苗的释放动力学对于建立疫苗很重要 持久有效的免疫力。特别是，延长与抗原的接触可能会导致 更高的抗体滴度和增加的中和抗体多样性，针对更多样化的 与传统推注疫苗接种的免疫反应相关的一组表位。此外， 由蛋白质纳米颗粒制成的疫苗可以增加抗体的产生， 更广泛的抗原交叉反应性和更平衡的 Th1/Th2 反应。这项研究测试了 假设结合纳米颗粒疫苗对有效抗原的作用具有协同作用 呈现，加上较慢的释放以延长疫苗的暴露时间，将引起 提高免疫反应的持久性和对新兴病毒的更广泛的交叉反应 变种。 为了验证这一假设，我们建议将蛋白质纳米颗粒疫苗封装在 基于可生物降解的 PLGA-PEG-PLGA (PPP) 的聚合物来调节其释放动力学 来自体内疫苗库。随后将应用这种缓释疫苗策略 针对 SARS-CoV-2。我们将评估拟议疫苗策略效力的持久性 以及针对 SARS-CoV-2 和 SARS-CoV-2 变种的交叉反应免疫反应的广度 其他类型的冠状病毒。我们的具体目标是：（1）创建控释纳米颗粒 针对 SARS-CoV-2 的储库疫苗，以及 (2) 确定功效和免疫学 对这些被聚合物贮库封装的疫苗纳米粒子的反应。因为 这些疫苗的设计是模块化的，不同的抗原可以在相对的范围内交换。 简单的方法，成功实施了这一针对冠状病毒的拟议战略 抗原可以在开发其他传染性疫苗方面具有更广泛的适用性 病原体。