Cross-Protective Multivalent Vaccine for Tick-Borne Flaviviruses

蜱传黄病毒交叉保护性多价疫苗

• 批准号: 10225429
• 负责人: DAVID E CLEMENTS
• 金额: $ 87.67万
• 依托单位: HAWAII BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225429
• 关键词: Adjuvant; Alkhurma Virus; Antibodies; Antibody titer measurement; Antigens; Area; Biological Assay; Biotechnology; Canada; Categories; Cells; Clinical Trials; Country; Cyclic GMP; Dengue Virus; Development; Disease; Dose; Ensure; Europe; European; Evaluation; Family; Feedback; Flaviviridae; Formulation; Geographic Distribution; Geographic Locations; Geography; Goals; Guidelines; Hawaii; Hemorrhage; Human; Human Resources; Immune response; Immunize; India; Infection; Infectious Diseases Research; Insecta; International; Kyasanur Forest disease virus; Medical; Middle East; Military Personnel; Mission; Modeling; Mus; National Institute of Allergy and Infectious Disease; Neurologic; North America; Oryctolagus cuniculus; Pathogenicity; Phase; Population; Positioning Attribute; Powassan virus; Process; Protein Subunits; Proteins; Recombinants; Research; Research Institute; Research Personnel; Risk; Role; Safety; Schedule; Serum; Strategic Planning; Switzerland; System; Technology; Testing; Texas; Tick-Borne Encephalitis; Tick-Borne Encephalitis Virus; Toxicity Tests; Toxicology; United States National Institutes of Health; Universities; Vaccination; Vaccine Antigen; Vaccine Production; Vaccines; Virus; West Nile virus; Work; base; clinical development; emerging pathogen; env Gene Products; first responder; global health; hemorrhagic fever virus; high risk; human pathogen; meetings; member; mosquito-borne; neutralizing antibody; potency testing; preclinical development; priority pathogen; research clinical testing; success; tick-borne flavivirus; vaccine candidate; vaccine development; vaccine safety

Project Summary/Abstract The NIH/NIAID 2017 Strategic Plan is specifically directed at promoting research that can provide solutions to mitigate the threat posed by emerging and re-emerging diseases. The tick-borne flavivirus (TBFV) group includes a number of important human pathogens that result in serious neurological or hemorrhagic diseases that are either Category B or C priority pathogens. The TBFVs are considered to be emerging or re-emerging pathogens due to increases in the number of human infections, the expansion of their geographic distribution, and emergence of new viruses. Additionally, the number of different viruses in the TBFV group poses challenges. There are two licensed Tick-borne encephalitis virus (TBEV) vaccines in Europe. These vaccines are based on the European strains of TBEV (TBEV-Eu), and while they provide some level of cross-neutralization, not all of the TBFV are covered. Furthermore, these vaccines are not licensed in the U.S. and are no longer available in Canada. The development of a multivalent vaccine that provides cross-protection against multiple pathogenic TBFVs would be of great value and is in line with the priorities of NIH/NIAID to develop multivalent and cross-protective technologies. We have demonstrated that two combinations of TBFV recombinant envelope subunit proteins (r80E) can provide protection against a diverse range of TBFV in a mouse challenge model. Additionally, passive transfer studies using serum from mice immunized with combinations of the r80E protein confirm the role of antibodies in protection against virus challenge. This Phase IIB application builds upon our initial efforts to develop a multivalent TBFV vaccine that provides broad cross-protection against viruses in this group. The proposed research aims to 1) optimizing the vaccine formulation; 2) produce pilot lots of the antigens; 3) conduct a pre-IND meeting with the FDA; and 4) conduct potency and toxicity testing to establish the suitability and safety of the final TBFV vaccine formulation. With the successful completion of these efforts, we will be positioned to advance a multicomponent TBFV vaccine into a cGMP manufacturing campaign and toward clinical evaluation.

项目总结/摘要 NIH/NIAID 2017年战略计划专门针对促进研究， 解决办法，以减轻新出现和重新出现的疾病构成的威胁。蜱传黄病毒 （TBFV）组包括许多重要的人类病原体，这些病原体导致严重的神经或 属于B或C类优先病原体的出血性疾病。TBFV被认为是 新出现或重新出现的病原体，由于人类感染人数的增加， 它们的地理分布和新病毒的出现。此外，不同病毒的数量 TBFV集团提出了挑战。有两种许可的蜱传脑炎病毒（TBEV）疫苗， 欧洲这些疫苗基于TBEV的欧洲株（TBEV-Eu），虽然它们提供了 一定程度的交叉中和，并不是所有的TBFV都被覆盖。此外，这些疫苗不是 在美国获得许可，在加拿大不再提供。多价疫苗的开发， 提供针对多种致病性TBFV的交叉保护将具有很大的价值，并且符合 NIH/NIAID开发多价和交叉保护技术的优先事项。我们已经证明 TBFV重组包膜亚单位蛋白（r80 E）的两种组合可以提供针对 不同范围的TBFV在小鼠攻击模型中。此外，使用血清的被动转移研究 来自用r80 E蛋白的组合免疫的小鼠的结果证实了抗体在保护中的作用 对抗病毒的挑战。该IIB期申请建立在我们开发多价 TBFV疫苗，提供广泛的交叉保护，防止病毒在这一组。拟议研究 目的是1）优化疫苗配方; 2）生产抗原的中试批次; 3）进行IND前 与FDA会面;以及4）进行效力和毒性测试，以确定 最终的TBFV疫苗制剂。随着这些努力的成功完成，我们将能够 将多组分TBFV疫苗推进cGMP生产活动并推向临床 评价

项目成果

Differences in Genetic Diversity of Mammalian Tick-Borne Flaviviruses.

• DOI: 10.3390/v15020281
• 发表时间: 2023-01-19
• 期刊: Viruses