Improved Influenza Vaccine Efficacy Through Infection Mimicry

通过感染模拟提高流感疫苗的功效

• 批准号: 10112817
• 负责人: Kathryn Kosuda
• 金额: $ 99.99万
• 依托单位: VAXESS TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112817
• 关键词: Address; Affinity; Age-Months; Animal Model; Antibodies; Antibody Response; Antigen Presentation; Antigens; Benchmarking; Biocompatible Materials; Body Temperature; Bolus Infusion; CD8B1 gene; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinic; Clinical; Data; Dermis; Detection; Development; Devices; Disease; Engineering; Exposure to; Ferrets; Fibroins; Formulation; Generations; Goals; Gold; Histopathology; Hospitalization; Human; Immune; Immune response; Immune system; Immunization; Immunize; Immunoglobulin G; Immunologics; Individual; Infection; Influenza; Influenza vaccination; Injections; Interferon Type II; Intramuscular Injections; Kinetics; Knowledge; Leucocytic infiltrate; Lung; Manufacturer Name; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Mutation; Outcome; Patients; Perception; Phase; Phase I Clinical Trials; Population; Positioning Attribute; Proteins; Public Health; Risk Assessment; Rodent; ST14 gene; Safety; Seasons; Serum; Silk; Skin; Source; Structure of germinal center of lymph node; Symptoms; System; T cell response; T-Lymphocyte; Technology; Time; Toxic effect; Translations; Vaccine Antigen; Vaccines; Viral; Virus; Work; World Health Organization; anti-influenza; base; burden of illness; clinically relevant; combat; compliance behavior; design; flu; immunogenicity; improved; in vivo; influenza infection; influenza virus vaccine; influenzavirus; intradermal injection; lymph nodes; manufacturability; meetings; mimicry; mouse model; prevent; primary outcome; protective efficacy; response; seasonal influenza; trafficking; universal vaccine; vaccine delivery; vaccine efficacy; vaccine response

Project Summary/Abstract The World Health Organization estimates that influenza viruses cause serious illness in 3 to 5 million people and up to 650,000 deaths globally each year. While seasonal vaccines to prevent influenza infection are available, frequent mutations in the virus require manufacturers to guess which strains will circulate each season and reformulate vaccine on an annual basis. As a result, the public health impact of seasonal vaccines is limited due to challenges with product efficacy (estimated at 36% for the 2017-18 season). This challenge highlights the critical need for improving current influenza vaccines through strategies to both improve humoral responses (onset, magnitude, and breadth) and generate additional responses such as mucosal immunity and CD4/CD8 cellular responses. Our technology focuses on engineering the sustained release of seasonal influenza vaccines to mimic infection kinetics over 1-2 weeks, providing greater breadth of anti-influenza antibodies and inducing T cell responses. This is accomplished through the use of silk fibroin biomaterial in a microneedle array format that can be easily administered to the skin. The design of the microneedles is such that after a brief 5 minute wear time, the silk microneedle tips are released from the patch and are embedded in the dermis. These silk tips have been engineered to both stabilize vaccine antigens at body temperature while slowly releasing this payload over 1-2 weeks. Our central hypotheses include: (1) sustained antigen presentation mimicking natural infection kinetics can enhance influenza vaccine responses, including greater breadth of protection, and (2) microneedle delivery could simplify patient administration while also improving antigen delivery to immune cells in the skin. These hypotheses are supported by our preliminary data with this strategy, demonstrating significant improvements to the humoral and cellular responses elicited by influenza vaccination. As such, we aim to advance our product towards the clinic through further optimization of the composition of our silk microneedles and by demonstrating their immunogenicity, manufacturability, and safety in IND-enabling studies. Successful completion of our objectives will position the technology for a Phase I clinical trial with the ultimate goal of reducing the global burden of influenza.

项目总结/摘要 世界卫生组织估计，流感病毒导致300万至500万人严重患病， 全球每年有多达65万人死亡。虽然有预防流感感染的季节性疫苗， 病毒的频繁变异要求制造商猜测每个季节会传播哪些毒株， 每年重新配制疫苗。因此，季节性疫苗对公共卫生的影响有限， 产品功效的挑战（2017-18赛季估计为36%）。这一挑战凸显了 迫切需要通过改善体液应答和免疫应答的策略来改善当前的流感疫苗 （发作、幅度和宽度），并产生额外的反应，如粘膜免疫和CD 4/CD 8 细胞反应。我们的技术专注于设计季节性流感疫苗的持续释放 在1-2周内模拟感染动力学，提供更广泛的抗流感抗体，并诱导T 细胞反应。这是通过使用微针阵列形式的丝素蛋白生物材料来实现的， 可以容易地施用于皮肤。微针的设计使得在短暂的5分钟佩戴后， 随着时间的推移，丝微针尖端从贴片释放并嵌入真皮中。这些丝尖 被设计成在体温下稳定疫苗抗原，同时缓慢释放这种有效载荷， 1-2周我们的中心假设包括：（1）持续的抗原呈递模拟自然感染 动力学可以增强流感疫苗的反应，包括更大的保护范围，以及（2）微针 递送可以简化患者给药，同时还改善抗原向皮肤中免疫细胞的递送。 这些假设得到了我们使用这种策略的初步数据的支持，证明了显著的 流感疫苗接种引起的体液和细胞反应的改善。因此，我们的目标是 通过进一步优化蚕丝微针的成分，将我们的产品推向临床 并通过在IND使能研究中证明其免疫原性、可生产性和安全性。成功 我们目标的完成将使该技术进入I期临床试验，最终目标是 减轻全球流感负担。