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.

项目总结/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，预防性疫苗也可能是有限的，特别是 如果发生抗原漂移，产生病原体的变体;这可能导致疫苗丢失， 效力随着时间的推移，需要助推器，以提供保护，并降低中和效力 新出现的病毒变种--在当前的COVID-19大流行中观察到的后果。 最近的研究已经表明，疫苗的释放动力学在建立免疫应答中可能是重要的。 持久有效的免疫力。特别地，延长对抗原的暴露可导致 更高的抗体滴度和增加的中和抗体的多样性， 一组表位，相对于来自常规推注疫苗接种的免疫应答。此外，委员会认为， 由基于蛋白质的纳米颗粒制成的疫苗可以引起增加的抗体产生， 更广泛的抗原交叉反应性和更平衡的Th 1/Th 2应答。这项研究测试了 假设纳米颗粒疫苗与有效抗原的协同作用 介绍，连同较慢的释放，使更长的接触疫苗，将引起 增加免疫应答的持久性和对新出现的病毒的更广泛的交叉反应性 变体。 为了验证这一假设，我们建议用一种纳米颗粒包裹蛋白质纳米颗粒疫苗。 可生物降解的PLGA-PEG-PLGA（PPP）基聚合物，以调节其释放动力学 从体内疫苗库中提取这种延长释放的疫苗策略随后将被应用于 SARS-CoV-2。我们将评估拟议的疫苗战略效力的持久性 以及针对SARS-CoV-2变异体的交叉反应性免疫应答的广度， 其他类型的冠状病毒。我们的具体目标是：（1）制备控释纳米粒 针对SARS-CoV-2的储库疫苗，和（2）确定效力和免疫学 这些疫苗纳米颗粒被聚合物储库包封。因为 这些疫苗的设计是模块化的 简单的方法，成功实施这一拟议的冠状病毒战略， 抗原可能对其他传染性疾病的疫苗开发具有更广泛的适用性， 病原体