Novel delivery platform and antigen design for an effective COVID-19 vaccine

用于有效的 COVID-19 疫苗的新型递送平台和抗原设计

• 批准号: 10669131
• 负责人: SURESH K MITTAL
• 金额: $ 76.42万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669131
• 关键词: 1918 influenza pandemic; 2019-nCoV; Adenovirus Vector; Adenoviruses; Affinity; Amino Acids; Animal Model; Antibody Response; Antibody-Dependent Enhancement; Antigens; Antiviral Agents; Autophagocytosis; B-Lymphocytes; COVID-19; COVID-19 pandemic; COVID-19 severity; COVID-19 susceptibility; COVID-19 vaccine; Cattle; Cessation of life; China; Chiroptera; Coronavirus; Coronavirus Infections; Coughing; Country; Development; Dose; Dryness; Elderly; Equilibrium; Feline Coronavirus; Ferrets; Fever; Glycoproteins; Health Personnel; Human; Immune response; Immune system; Immunity; Immunization; Immunocompetence; Incubated; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N2 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Intervention; Lung; Malaise; Mediating; Membrane; Memory; Memory B-Lymphocyte; Mesocricetus auratus; Middle East Respiratory Syndrome Coronavirus; Morbidity - disease rate; Mucous Membrane; Multiple Organ Failure; Mus; Myalgia; Mycobacterium tuberculosis; N-terminal; Names; Natural Immunity; Nucleoproteins; Outcome; Peptides; Pneumonia; Population; Proteins; Rapid diagnostics; Recombinant Vaccines; Reporting; Respiratory Failure; Risk; Role; SARS coronavirus; SARS-CoV-2 antigen; SARS-CoV-2 genome; SARS-CoV-2 immunity; SARS-CoV-2 infection; Secondary Immunization; Septic Shock; Severe Acute Respiratory Syndrome; Symptoms; System; T cell response; T-Lymphocyte; Time; Training; Transgenic Mice; United States; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Virus; Work; adaptive immunity; cell mediated immune response; delivery vehicle; design; diagnostic assay; emerging pathogen; flu; genome analysis; high risk; humanized monoclonal antibodies; immunogenic; immunogenicity; influenzavirus; mortality; multiple myeloma M Protein; novel; novel coronavirus; novel vaccines; pandemic disease; protective efficacy; vaccine delivery; vaccine development; vaccine formulation; vaccine platform; vaccine-induced antibodies; vector; viral transmission; 1918 influenza pandemic; 2019-nCoV; Adenovirus Vector; Adenoviruses; Affinity; Amino Acids; Animal Model; Antibody Response; Antibody-Dependent Enhancement; Antigens; Antiviral Agents; Autophagocytosis; B-Lymphocytes; COVID-19; COVID-19 pandemic; COVID-19 severity; COVID-19 susceptibility; COVID-19 vaccine; Cattle; Cessation of life; China; Chiroptera; Coronavirus; Coronavirus Infections; Coughing; Country; Development; Dose; Dryness; Elderly; Equilibrium; Feline Coronavirus; Ferrets; Fever; Glycoproteins; Health Personnel; Human; Immune response; Immune system; Immunity; Immunization; Immunocompetence; Incubated; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N2 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Intervention; Lung; Malaise; Mediating; Membrane; Memory; Memory B-Lymphocyte; Mesocricetus auratus; Middle East Respiratory Syndrome Coronavirus; Morbidity - disease rate; Mucous Membrane; Multiple Organ Failure; Mus; Myalgia; Mycobacterium tuberculosis; N-terminal; Names; Natural Immunity; Nucleoproteins; Outcome; Peptides; Pneumonia; Population; Proteins; Rapid diagnostics; Recombinant Vaccines; Reporting; Respiratory Failure; Risk; Role; SARS coronavirus; SARS-CoV-2 antigen; SARS-CoV-2 genome; SARS-CoV-2 immunity; SARS-CoV-2 infection; Secondary Immunization; Septic Shock; Severe Acute Respiratory Syndrome; Symptoms; System; T cell response; T-Lymphocyte; Time; Training; Transgenic Mice; United States; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Virus; Work; adaptive immunity; cell mediated immune response; delivery vehicle; design; diagnostic assay; emerging pathogen; flu; genome analysis; high risk; humanized monoclonal antibodies; immunogenic; immunogenicity; influenzavirus; mortality; multiple myeloma M Protein; novel; novel coronavirus; novel vaccines; pandemic disease; protective efficacy; vaccine delivery; vaccine development; vaccine formulation; vaccine platform; vaccine-induced antibodies; vector; viral transmission

PROJECT SUMMARY For effective management of the COVID-19 pandemic and its second wave, the design and implementation of multiple intervention approaches are crucial. They include the development of effective antivirals, high-affinity SARS-CoV-2-neuralizing human or humanized monoclonal antibodies, rapid diagnostic assays, immunogenic and protective vaccines, strategies to mitigate virus transmissibility, and enhancing capacity related to trained medical personnel, facilities, and supplies. Due to the possibility of antibody-dependent enhancement (ADE) of COVID-19, vaccine efforts should consider the use of a novel vaccine platform and design of a relevant antigen strategy. It is essential to note that the elderly are the most vulnerable segment of the population that is at a higher risk of COVID-19 severity; the vaccine development efforts should, therefore, consider the decline in the immune competence in the elderly. We have developed a novel replication-defective (E1 & E3 deleted) bovine adenovirus (Ad) type 3 (BAd3)- based vaccine platform, which is better than the currently available Ad vector systems for providing heterologous influenza protection with dose sparing and is not impacted by the pre-existing human Ad vector immunity. Recently, we have revealed that the BAd vaccine platform provides the expression of significantly higher levels of the immunogen and innate and adaptive immunity-related factors compared to that of human Ad vectors in mice. This work suggests that the BAd vector system could serve as an excellent delivery vehicle for the development of recombinant vaccines against emerging pathogens for the elderly and other segments of the population. We have also identified a 22 amino acid residues Autophagy-Inducing Peptide (AIP) C5 (AIP-C5) from the CFP10 protein of M. tuberculosis that enhances robust T cell immune responses in mice to NP of H7N9 influenza virus when delivered through an Ad vector. It conferred complete protection against H1N1, H3N2, H5N2, H7N9, and H9N2 influenza viruses. The proposal is based on the hypothesis that immunization with the autophagy-inducing replication-deficient BAd vector expressing relevant antigen/s of SARS-CoV-2 will strengthen an effective mucosal (lung) and systemic anti-COVID-19 immunity. Under Aim 1, we will evaluate the immunogenicity and protective efficacy of a novel vaccine platform and antigen design in animal models for developing an effective COVID-19 vaccine. Whereas under Aim 2, we will investigate the vaccine-induced antibody-dependent enhancement (ADE) of SARS-CoV-2 infection, the quality of memory innate, B and T cell responses, and the durability of protective immunity in the best animal model. We believe that the use of a unique nonhuman Ad vaccine platform and novel antigen design containing AIP-C5 will yield an effective COVID-19 vaccine for all segments of the population. This effort will be of significant value to effectively flatten the COVID- 19 pandemic's trajectory and its second wave.

项目摘要 为了有效地管理Covid-19的大流行及其第二波，设计和实施 多种干预方法至关重要。其中包括开发有效抗病毒药，高亲和力 SARS-COV-2神经化的人或人源性单克隆抗体，快速诊断测定，免疫原性 以及保护性疫苗，减轻病毒传播的策略以及增强与受过训练有关的能力 医务人员，设施和用品。由于可能需要抗体依赖性增强（ADE） COVID-19，疫苗工作应考虑使用新型疫苗平台和相关抗原的设计 战略。必须注意的是，老年人是人口中最脆弱的部分 COVID-19严重程度的较高风险；因此，疫苗开发工作应考虑到下降 老年人的免疫能力。 我们已经开发了一种新颖的复制缺陷（E1和E3删除）牛腺病毒（AD）3型（BAD3） - 基于基于的疫苗平台，它比当前可用的AD矢量系统更好 剂量保留的流感保护，不受先前存在的人类AD载体免疫的影响。 最近，我们透露，不良疫苗平台提供了明显更高水平的表达 与人类AD向量相比，免疫原，先天和适应性免疫相关的因素 老鼠。这项工作表明，不良向量系统可以成为 针对老年人和其他部分的重组疫苗开发重组疫苗 人口。我们还确定了22个氨基酸残基自噬诱导肽（AIP）C5（AIP-C5） 从结核分枝杆菌的CFP10蛋白中，增强了小鼠对H7N9 NP的稳健T细胞免疫反应 流感病毒通过AD载体传递。它授予了针对H1N1，H3N2的完全保护 H5N2，H7N9和H9N2流感病毒。 该提案基于以下假设：自噬诱导复制缺陷的免疫 表达SARS-COV-2相关抗原/s的不良向量将增强有效的粘膜（肺）和 全身性抗旋转-19免疫力。在AIM 1下，我们将评估免疫原性和保护性 新型疫苗平台和抗原设计在动物模型中的功效，以开发有效 2019冠状病毒病疫苗。而在AIM 2下，我们将研究疫苗诱导的抗体依赖性 SARS-COV-2感染的增强（ADE），记忆先天，B和T细胞反应的质量以及 最好的动物模型中保护性免疫的耐用性。我们相信使用独特 非人类广告疫苗平台和包含AIP-C5的新型抗原设计将产生有效的Covid-19 所有人口部分的疫苗。这项努力将有效地弄平covid-将具有重要的价值 19大流行的轨迹及其第二波。