Toward a universal influenza virus vaccine based on live attenuated NS1-deleted influenza viruses

开发基于 NS1 缺失减毒活流感病毒的通用流感病毒疫苗

• 批准号: 10534661
• 负责人: Adolfo Garcia-Sastre
• 金额: $ 112.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-07 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534661
• 关键词: 1918 influenza pandemic; Acceleration; Address; Adjuvant; Animal Model; Anniversary; Antibodies; Antibody Response; Antibody titer measurement; Antibody-mediated protection; Antigens; Attenuated; Biotechnology; Cellular Immunity; Clinic; Clinical Trials; Data; Development; Documentation; Epitopes; Excision; Family suidae; Fc Receptor; Ferrets; Future; GMP lots; Generations; Genes; Grant; Head; Hemagglutinin; Human; Immune; Immune response; Immunity; Immunization; Influenza A Virus, H1N1 Subtype; Influenza A virus; Influenza B Virus; Influenza Hemagglutinin; Influenza vaccination; Licensing; Monitor; Mus; Phase; Phase I Clinical Trials; Phenotype; Production; Property; Proteins; Public Health; Recombinants; Safety; Seasons; Severities; Testing; Time; Toxic effect; Toxicology; Vaccination; Vaccines; Virus; Virus Diseases; antagonist; attenuation; clinical development; clinical investigation; clinical lot; cross immunity; cross reactivity; experimental study; immunogenic; immunogenicity; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; lead candidate; manufacturability; manufacture; medical schools; neutralizing antibody; new pandemic; pandemic influenza; pandemic potential; pandemic virus; phase 1 study; pre-clinical; preclinical development; preclinical study; prevent; research clinical testing; response; reverse genetics; seasonal influenza; universal influenza vaccine; vaccination strategy; vaccine platform

Influenza viruses continue to pose a significant threat to global public health. Consequently, there is a vitally important need to generate new influenza virus vaccines and innovative vaccination strategies. The development of a long-lived broadly-protective influenza virus vaccine would have a tremendous impact on worldwide efforts to control influenza viruses. The purpose of this application is to accelerate the development of a universal influenza virus vaccine through the preclinical development of two lead candidate components of such a vaccine. Since our initial discovery that sequential immunization with influenza vaccines based on chimeric HAs induce broad protection against diverse influenza virus strains in animal models, we have moved into Phase 1 clinical trials that investigate the safety and immunogenicity of inactivated adjuvanted and cold-adapted live attenuated influenza A virus vaccines containing chimeric group 1 influenza virus HAs. Such vaccines induce protective immunity in mice, ferrets and pigs against all group 1 influenza A virus, including H1, H2 and H5 viruses. Protection correlates with the induction of high levels of cross-reactive Fc-receptor engaging antibodies against the conserved group 1 HA stalk. If any of these vaccination strategies are successful in humans, addition of group 2 influenza A and influenza B chimeric HAs would result in protection against any type, subtype and strain of influenza virus. This “universal flu vaccine” would eliminate the need for annual influenza virus vaccination and prevent future influenza pandemics. In the current application we propose to generate GMP clinical lots and IND-enabling information to subsequently perform human clinical trials with a highly immunogenic vaccine platform expressing chimeric HAs based on live attenuated delNS1 influenza viruses. In contrast to the cold-adapted influenza vaccines, delNS1 influenza vaccines are highly immunostimulatory due to the removal of the immune antagonist gene NS1. For the purpose of this grant, our group at Icahn School of Medicine at Mount Sinai, which pioneered the use of chimeric HAs for universal influenza virus vaccination, has partnered with Vivaldi, a biotechnology company that has delNS1-based influenza virus vaccines under clinical development. At the end of our proposal, we will have generated two GMP lots of delNS1-based group 1 chimeric HA influenza virus vaccines ready for clinical investigation. These lots will be used after completion of our grant for sequential immunizations in humans to obtain their safety and immunogenicity profiles. Moreover, we anticipate that human influenza virus challenge studies after vaccination with inactivated, cold-adapted and delNS1-based chimeric HA vaccines will differentiate the vaccine platform among these three resulting in best levels of protection. The best platform will be used as the basis for further clinical development and incorporation of group 1, group 2 and influenza B chimeric HAs to protect against all possible influenza viruses.

流感病毒继续对全球公共卫生构成重大威胁。因此，有一个至关重要的 因此，迫切需要研制新的流感病毒疫苗和创新的疫苗接种战略。的 开发一种长寿命的广泛保护性流感病毒疫苗将对 全世界努力控制流感病毒。这项申请的目的是为了加快发展 通过临床前开发两种主要候选成分， 这样的疫苗。自从我们最初发现， 嵌合HA在动物模型中诱导了对不同流感病毒株的广泛保护，我们已经 进入1期临床试验，研究灭活疫苗的安全性和免疫原性。 含有嵌合组1的佐剂化和冷适应的减毒活甲型流感病毒疫苗 流感病毒HAs这种疫苗在小鼠、雪貂和猪中诱导针对所有第1组的保护性免疫 甲型流感病毒，包括H1、H2和H5病毒。保护与诱导高水平的 针对保守组1HA茎的交叉反应性Fc受体接合抗体。如果任何这些 疫苗接种策略在人类中是成功的，添加组2甲型流感和B流感嵌合HA 将导致针对任何类型、亚型和流感病毒株的保护。这种“通用流感疫苗” 将消除每年接种流感病毒疫苗的需要，并预防未来的流感大流行。在 当前的应用程序，我们建议生成GMP临床批次和IND使能信息， 用表达嵌合HA的高免疫原性疫苗平台进行人类临床试验， 减毒的delNSl活流感病毒。与冷适应性流感疫苗相比，delNS1流感疫苗可以用于预防流感。 疫苗由于去除了免疫拮抗剂基因NS1而具有高度免疫刺激性。为 为了达到这个目的，我们在西奈山伊坎医学院的研究小组率先使用了 用于通用流感病毒疫苗接种的嵌合HA已经与生物技术公司Vivaldi合作 该公司正在临床开发基于delNS1的流感病毒疫苗。在我们的建议的最后，我们 将生产两批基于delNS 1的组1嵌合HA流感病毒疫苗 用于临床研究。这些批次将在我们的赠款完成后用于连续免疫接种， 以获得其安全性和免疫原性特征。此外，我们预计人类流感病毒 用灭活的、冷适应的和基于delNS1的嵌合HA疫苗接种后的攻击研究将 在这三种疫苗平台之间进行区分，以获得最佳保护水平。最好的平台将 用作进一步临床开发和纳入1型、2型和B型流感病毒的基础 嵌合HA以保护免受所有可能的流感病毒。

项目成果

Interferon mediated prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine lacking non-structural protein 1.

• DOI: 10.1038/s41598-021-01780-8
• 发表时间: 2021-11-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Rathnasinghe R;Salvatore M;Zheng H;Jangra S;Kehrer T;Mena I;Schotsaert M;Muster T;Palese P;García-Sastre A
• 通讯作者: García-Sastre A

Group 1 and group 2 hemagglutinin stalk antibody response according to age.

• DOI: 10.3389/fimmu.2023.1194073
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Sanchez-de Prada, Laura;Sanz-Munoz, Ivan;Sun, Weina;Palese, Peter;de Lejarazu, Raul Ortiz;Eiros, Jose Maria;Garcia-Sastre, Adolfo;Aydillo, Teresa
• 通讯作者: Aydillo, Teresa

Prophylactic Protection Against Respiratory Viruses Conferred by a Prototype Live Attenuated Influenza Virus Vaccine.

原型减毒流感病毒疫苗可预防呼吸道病毒。

• DOI: 10.21203/rs.3.rs-668116/v1
• 发表时间: 2021
• 期刊: Research square
• 作者: Rathnasinghe,Raveen;Salvatore,Mirella;Zheng,Hongyong;Jangra,Sonia;Kehrer,Thomas;Mena,Ignacio;Schotsaert,Michael;Muster,Thomas;Palese,Peter;García-Sastre,Adolfo
• 通讯作者: García-Sastre,Adolfo