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.

项目摘要/摘要 疫苗在预防引起传染病方面一直非常有效。 对人类健康的严重威胁。然而，预防性疫苗也可能是有限的，尤其是 如果发生抗原漂移，产生病原体的变种；这可能导致疫苗丢失 效力随着时间的推移，需要助推器来提供保护，并降低中和效率 新出现的病毒变异--在当前的新冠肺炎大流行中观察到的后果。 最近的研究表明，疫苗的释放动力学在建立 持久有效的免疫力。特别是，延长接触抗原的时间可能会导致 更高的抗体效价和针对更多样化的中和抗体的多样性 相对于常规团注疫苗的免疫反应的一组表位。此外， 由基于蛋白质的纳米颗粒制成的疫苗可以诱导更多的抗体产生， 更广泛的抗原交叉反应，以及更平衡的Th1/Th2反应。这项研究测试了 假设在结合有效抗原的纳米颗粒疫苗的效果时的协同作用 展示，加上较慢的释放，使更长时间接触疫苗，将引发 提高免疫反应的持久性和对新出现的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包裹在 可生物降解PLGA-PEG-PLGA(PPP)聚合物对其释药动力学的调控 来自体内的疫苗仓库。然后将应用这种缓释疫苗策略 走向SARS-CoV-2。我们将评估拟议的疫苗策略的效力的持久性 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)创造可控释纳米粒 SARS-CoV-2疫苗仓库，以及(2)确定疫苗的效力和免疫学 对聚合物库包裹的这些疫苗纳米颗粒的反应。因为 这些疫苗的设计是模块化的，不同的抗原可以在相对较短的时间内交换 直截了当的方法，成功实施这一拟议的冠状病毒战略 抗原可在开发其他传染性疾病疫苗方面具有更广泛的适用性。 病原体。