Development of broadly-protective vaccines for influenza B viruses
开发针对乙型流感病毒的广泛保护性疫苗
基本信息
- 批准号:10206685
- 负责人:
- 金额:$ 22.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-25 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdjuvantAffectAlhydrogelAnimalsAntibodiesAntibody titer measurementAntigensAttenuated VaccinesBacteriophagesBiological AssayCD8-Positive T-LymphocytesCellsComplementControl AnimalDataDevelopmentEpidemicEpitopesFerretsFutureHemagglutininHumanImmune responseImmunityImmunizationImmunizeImmunologyInfectionInfluenza A Virus, H1N1 SubtypeInfluenza A Virus, H3N2 SubtypeInfluenza A virusInfluenza B VirusLeadLibrariesLung diseasesMapsMorbidity - disease rateMutagenesisMutationOrganPeptidesPhage DisplayPharmaceutical PreparationsPhasePopulationPropertyProteinsRecombinantsResearchSaint Jude Children&aposs Research HospitalSerumSpleenTestingUpdateVaccinatedVaccinationVaccinesVariantViral AntigensViral ProteinsVirusbasecross reactivitycytokinedesignexperimental studyimmunogenicityimprovedinfluenza virus straininfluenza virus vaccineinfluenzaviruslymph nodesmortalitymutantnanoparticlenovelnovel strategiesprotective efficacyrespiratoryresponsestemuniversal vaccinevaccine accessvaccine candidatevaccine efficacy
项目摘要
PROJECT SUMMARY
Influenza B viruses (IBV) cause annual epidemics with appreciable morbidity and mortality, but have been
understudied compared to influenza A viruses (IAV). Currently available vaccines for IBV and IAV are sub-
optimal and must be updated frequently due to the emergence of novel antigenic variants. To date, efforts to
develop broadly protective, potentially ‘universal’ vaccines have almost exclusively focused on IAV. RFA-AI-20-
003 therefore calls for the “development and/or characterization of IBV vaccine components that
complement existing lead IAV vaccine candidates”. In Aim 1 (R21 phase), we plan to develop broadly reactive
influenza B candidate vaccine viruses. Using mutagenesis approaches, we have already generated mutant
IBV hemagglutinins (HA, the major viral antigen) whose antigenic properties are in-between those of the two
major lineages of IBV. Thus, these antigens may elicit immune responses that confer protection against viruses
of both IBV lineages. Here, we plan to develop additional IBV HA mutants with potentially higher cross-reactivity
than that of our current candidates. In addition, we will establish an antigenic map for IBV HA to analyze the
antigenic properties of IBV HAs (antigenic maps are now widely used for IAV HAs, but have not been developed
for IBV HA). In Aim 2 (R33 phase), we will assess the immunogenicity of influenza B candidate vaccine
viruses. Briefly, the top 5 candidates from Aim 1 will be used to immunize ferrets. Immunization will be carried
out with adjuvanted, secreted IBV HA (sHA) mutants (thus eliminating the contribution of other IBV proteins to
immune responses), or with adjuvanted IBV HA presented on nanoparticles composed of a self-assembling
phage protein (generated by Dr. R. Kane, Georgia Tech). The sera from vaccinated ferrets will be tested for
reactivity with IBV HA antigens, and these data will be integrated into the antigenic map. Using an established
phage display approach, Dr. S. Khurana (Federal Drug Administration) will identify the epitopes targeted by the
antibodies elicited by our HA mutants. This analysis will allow us to identify antigens that elicit broadly reactive
antibodies that target conserved epitopes. Immunology studies will be carried out by Dr. P. Thomas, St. Jude
Children’s Research Hospital. On the basis of the data obtained in Aim 2, the top 2 IBV HA immunogens will be
used to assess the protective efficacy of influenza B candidate vaccine viruses (Aim 3, R33 phase). Ferrets
will be immunized as established in Aim 2 and challenged with IBVs representing both current lineages and an
ancestral virus (isolated before the separation of the lineages). Virus titers and immune responses will be
compared with those of control animals. We expect that a single immunization with the IBV HA mutants will elicit
more broadly protective immunity than a single immunization with wild-type IBV HA. In summary, upon
completion of both phases, we expect to have developed a novel strategy for the design of broadly protective
IBV vaccines, and to have demonstrated their broadly protective efficacy in ferrets.
项目总结
B型流感病毒(IBV)每年都会引起流行病,发病率和死亡率都很高,但一直以来
与甲型流感病毒(IAV)相比,研究不足。目前可用于IBV和IAV的疫苗是亚种
由于出现了新的抗原变异体,因此必须经常更新。到目前为止,努力
开发具有广泛保护性、可能“通用”的疫苗几乎完全集中在IAV上。RFA-AI-20-
因此,要求“开发和/或表征传染性支气管炎病毒疫苗成分
补充现有的主要IAV候选疫苗“。在目标1(R21阶段),我们计划发展广泛的反应性
B型流感候选疫苗病毒。使用突变方法,我们已经产生了突变
IBV血凝素(HA,主要病毒抗原),其抗原性介于两者之间
IBV的主要血统。因此,这些抗原可能会引发免疫反应,从而提供对病毒的保护。
两种传染性支气管炎病毒的血统。在这里,我们计划开发更多具有潜在更高交叉反应性的IBV HA突变体
比我们现在的候选人更多。此外,我们还将建立IBV HA的抗原图,以分析
IBV Has的抗原性(目前广泛用于IAV Has的抗原图,但尚未开发出来
对于IBV HA)。在目标2(R33阶段),我们将评估B型流感候选疫苗的免疫原性
病毒。简而言之,来自目标1的前5名候选人将用于免疫雪貂。将进行免疫接种
用佐剂分泌的IBV HA(Sa)突变体(从而消除了其他IBV蛋白对
免疫反应),或与佐剂IBV HA呈现在由自组装组成的纳米颗粒上
噬菌体蛋白(由佐治亚理工学院R.凯恩博士产生)。将对接种疫苗的雪貂的血清进行检测
与IBV HA抗原的反应,这些数据将被整合到抗原图中。使用已建立的
通过噬菌体展示方法,S.Khurana博士(联邦药物管理局)将确定
我们的血凝素突变体引发的抗体。这一分析将使我们能够识别引起广泛反应的抗原。
针对保守表位的抗体。免疫学研究将由圣犹大的P.Thomas博士进行
儿童研究医院。根据AIM 2中获得的数据,排名前两位的IBV HA免疫原将是
用于评估B型流感候选疫苗病毒(AIM 3,R33阶段)的保护效果。雪貂
将按照AIM 2中的规定进行免疫,并用代表当前血统和
祖传病毒(在分离谱系之前分离)。病毒滴度和免疫反应将是
与对照动物相比。我们预计,用IBV HA突变体进行一次免疫将导致
比用野生型IBV HA单一免疫更广泛的保护性免疫。总而言之,在
完成这两个阶段,我们预计将开发出一种新的战略,以设计广泛的保护
IBV疫苗,并已在雪貂身上证明了其广泛的保护效果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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YOSHIHIRO KAWAOKA其他文献
YOSHIHIRO KAWAOKA的其他文献
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{{ truncateString('YOSHIHIRO KAWAOKA', 18)}}的其他基金
Development of broadly-protective vaccines for influenza B viruses
开发针对乙型流感病毒的广泛保护性疫苗
- 批准号:
10821572 - 财政年份:2023
- 资助金额:
$ 22.78万 - 项目类别:
Development of broadly-protective vaccines for influenza B viruses
开发针对乙型流感病毒的广泛保护性疫苗
- 批准号:
10359831 - 财政年份:2021
- 资助金额:
$ 22.78万 - 项目类别:
COVID-19 comorbidity studies in Syrian hamster models
叙利亚仓鼠模型中的 COVID-19 合并症研究
- 批准号:
10450889 - 财政年份:2021
- 资助金额:
$ 22.78万 - 项目类别:
PanCorVac (Center for Pan-Coronavirus Vaccine Development)
PanCorVac(泛冠状病毒疫苗开发中心)
- 批准号:
10841731 - 财政年份:2021
- 资助金额:
$ 22.78万 - 项目类别:
COVID-19 comorbidity studies in Syrian hamster models
叙利亚仓鼠模型中的 COVID-19 合并症研究
- 批准号:
10285154 - 财政年份:2021
- 资助金额:
$ 22.78万 - 项目类别:
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