Engineering Protein Antigens and their Presentation from Multivalent Scaffolds
工程蛋白质抗原及其从多价支架的呈现
基本信息
- 批准号:10582942
- 负责人:
- 金额:$ 85.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-07 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntibodiesAntibody ResponseAntigensAvian Influenza A VirusB-Cell Antigen ReceptorCoronavirusDevelopmentEconomic BurdenEngineeringEnsureEpidemicEpitopesFemaleFerretsFlavivirusGlycoproteinsHeadHealthHemagglutininHumanImmune responseImmunizeImmunodominant EpitopesImmunologyInfectionInfluenzaInfluenza A virusInfluenza vaccinationLicensingLigandsLocationLongevityMembraneModelingMusMutationPlayProtein EngineeringProteinsPublic HealthResearchResearch Project GrantsRoleTestingTherapeuticVaccinationVaccine DesignVaccinesViralVirionVirusVirus-like particleWorkdesignendosome membraneexperienceglobal healthimmunogenicityin vivoinfluenza infectioninfluenza virus vaccineinfluenzavirusmalenanoscaleneutralizing antibodynovelpandemic diseasepandemic influenzapandemic potentialpandemic viruspathogenprophylacticresponsescaffoldseasonal influenzauniversal influenza vaccinevaccine accessvaccine developmentvaccine efficacy
项目摘要
The objective of the proposed work is to develop a vaccine that provides broad protection against group 1
influenza A viruses – a group that includes the 1918, 1957-1958, and 2009 pandemic viruses, as well as avian
influenza “viruses of concern” – by eliciting a robust and durable immune response targeting the highly
conserved membrane-proximal stalk domain of hemagglutinin (HA). The project will test the hypothesis that
the combination of shielding the variable head domain of HA, refocusing the immune response to the highly
conserved stalk domain by controlling the orientation of HA, and multivalent presentation, will provide broad,
durable, and robust protection against group 1 influenza A viruses. Influenza represents a serious global health
problem, with seasonal influenza virus infections imposing significant health and economic burdens, and
pandemics caused by novel influenza viruses representing an even more serious threat. Licensed vaccines
induce an immune response that primarily targets the head domain of HA, which is highly variable in
sequence. As a result, the immune response to influenza vaccination is narrow and strain-specific and would
provide little protection against potential pandemic influenza viruses. While “broadly neutralizing” antibodies
targeting the highly conserved stalk domain of HA are prophylactically and therapeutically protective against
influenza virus challenges in vivo, such antibodies are not elicited effectively in natural infections or by licensed
influenza vaccines. The immunosubdominance of the HA stalk domain may result from its membrane-proximal
location, with interactions of B-cell receptors with conserved stalk epitopes being blocked by steric hindrance
on virions which are densely packed with glycoproteins. Indeed, we have recently shown that tuning the
orientation of HA to enhance the accessibility of stalk epitopes results in an enhanced protective stalk-directed
immune response. Furthermore, we have demonstrated an approach (tethered antigenic suppression) for
suppressing the immune response to the head domain of HA and refocusing the immune response on desired
epitopes (such as the stalk). We have also designed vaccines that elicit a robust protective antibody response
against a variety of antigens, including HA, by displaying them multivalently from virus-like particles. The first
aim of the proposed work is to engineer and test novel HA antigen designs to provide an enhanced stalk-
directed immune response. We will shield the head domain of HA to suppress its immunogenicity and will tune
the orientation of the head-shielded HA to increase the accessibility of the stalk domain and enhance its
immunogenicity. We will also investigate the ability to further increase the breadth of protection by using
engineered HA antigens that incorporate stalk domains from different viral subtypes. The second aim is to
characterize the breadth and the longevity of the anti-stalk response induced by vaccination in mice. The third
aim is to characterize immunogenicity and vaccine efficacy in naïve and pre-immunized, male and female
ferrets.
拟议工作的目标是开发一种疫苗,提供广泛的保护,对第1组
甲型流感病毒--包括1918年、1957-1958年和2009年大流行病毒,以及禽流感病毒
流感“关注的病毒”-通过引发针对高度
血凝素(HA)的保守的近膜柄结构域。该项目将测试假设,
屏蔽HA的可变头部结构域、将免疫应答重新聚焦于高度免疫应答的组合,
保守的茎域通过控制HA的方向和多价呈递,将提供广泛的,
持久和强大的保护,对1组甲型流感病毒。流感是一种严重的全球健康问题,
问题,季节性流感病毒感染造成重大健康和经济负担,
由新型流感病毒引起的大流行构成了更为严重的威胁。许可的疫苗
诱导主要靶向HA头部结构域的免疫应答,
顺序因此,对流感疫苗接种的免疫应答是狭窄的和株特异性的,
对潜在的大流行性流感病毒几乎没有提供保护。虽然“广泛中和”抗体
靶向HA的高度保守的茎结构域是抗HA的免疫和治疗保护性的。
在体内流感病毒攻击中,这样的抗体在自然感染中或通过许可的免疫抑制剂不能有效地引发。
流感疫苗。HA茎区的免疫亚显性可能是由于其近膜区的免疫亚显性。
位置,B细胞受体与保守茎表位的相互作用被空间位阻阻断
病毒粒子上的糖蛋白。事实上,我们最近已经表明,调整
HA的定向增强茎表位的可及性导致增强的保护性茎定向
免疫反应此外,我们已经证明了一种方法(系留抗原抑制),
抑制对HA头部结构域的免疫应答,并将免疫应答重新聚焦于所需的HA头部结构域,
表位(如茎)。我们还设计了能引发强烈保护性抗体反应的疫苗
针对多种抗原,包括HA,通过从病毒样颗粒多价展示它们。第一
所提出的工作的目的是工程化和测试新的HA抗原设计,以提供增强的茎-
定向免疫反应我们将屏蔽HA的头部结构域以抑制其免疫原性,并将进行调整
头部屏蔽HA的取向,以增加茎域的可及性并增强其
免疫原性我们还将研究通过使用
工程化HA抗原,其并入来自不同病毒亚型的茎域。第二个目标是
表征小鼠中疫苗接种诱导的抗茎应答的广度和寿命。第三
目的是描述初次和免疫前男性和女性的免疫原性和疫苗有效性
雪貂
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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Ravi S. Kane其他文献
Multivalent S2 subunit vaccines provide broad protection against Clade 1 sarbecoviruses in female mice
多价 S2 亚单位疫苗为雌性小鼠提供了针对第 1 群沙贝科病毒的广泛保护
- DOI:
10.1038/s41467-025-55824-y - 发表时间:
2025-01-07 - 期刊:
- 影响因子:15.700
- 作者:
Peter J. Halfmann;Raj S. Patel;Kathryn Loeffler;Atsuhiro Yasuhara;Lee-Ann Van De Velde;Jie E. Yang;Jordan Chervin;Chloe Troxell;Min Huang;Naiying Zheng;Elizabeth R. Wright;Paul G. Thomas;Patrick C. Wilson;Yoshihiro Kawaoka;Ravi S. Kane - 通讯作者:
Ravi S. Kane
Enzyme-based formulations for decontamination: current state and perspectives
- DOI:
10.1007/s00253-013-4797-x - 发表时间:
2013-03-10 - 期刊:
- 影响因子:4.300
- 作者:
Navdeep Grover;Cerasela Zoica Dinu;Ravi S. Kane;Jonathan S. Dordick - 通讯作者:
Jonathan S. Dordick
Facile generation of drug-like conformational antibodies specific for amyloid fibrils
针对淀粉样纤维的类药物构象抗体的简便生成
- DOI:
10.1038/s41589-025-01881-9 - 发表时间:
2025-04-29 - 期刊:
- 影响因子:13.700
- 作者:
Alec A. Desai;Jennifer M. Zupancic;Hanna Trzeciakiewicz;Julia E. Gerson;Kelly N. DuBois;Mary E. Skinner;Lisa M. Sharkey;Nikki McArthur;Sean P. Ferris;Nemil N. Bhatt;Emily K. Makowski;Matthew D. Smith;Hongwei Chen;Jie Huang;Cynthia Jerez;Yun-Huai Kuo;Ravi S. Kane;Nicholas M. Kanaan;Henry L. Paulson;Peter M. Tessier - 通讯作者:
Peter M. Tessier
Ravi S. Kane的其他文献
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{{ truncateString('Ravi S. Kane', 18)}}的其他基金
Design and Evolution of Polyvalent Domain Antibodies Specific for Tau Aggregates
Tau 聚集体特异性多价域抗体的设计和进化
- 批准号:
10585480 - 财政年份:2018
- 资助金额:
$ 85.2万 - 项目类别:
Engineering Nanoscale Aptamer-based Biomaterials that Target Cellular Receptors
针对细胞受体的工程纳米适体生物材料
- 批准号:
9112133 - 财政年份:2015
- 资助金额:
$ 85.2万 - 项目类别:
Optogenetic Characterization and Control of Stem Cell Signaling
干细胞信号传导的光遗传学表征和控制
- 批准号:
8674874 - 财政年份:2014
- 资助金额:
$ 85.2万 - 项目类别:
Optogenetic Characterization and Control of Stem Cell Signaling
干细胞信号传导的光遗传学表征和控制
- 批准号:
9208064 - 财政年份:2014
- 资助金额:
$ 85.2万 - 项目类别:
Optogenetic Characterization and Control of Stem Cell Signaling
干细胞信号传导的光遗传学表征和控制
- 批准号:
9000181 - 财政年份:2014
- 资助金额:
$ 85.2万 - 项目类别:
Engineering Nanoscale Aptamer-based Biomaterials that Target Cellular Receptors
针对细胞受体的工程纳米适体生物材料
- 批准号:
8523855 - 财政年份:2012
- 资助金额:
$ 85.2万 - 项目类别:
Engineering Nanoscale Aptamer-based Biomaterials that Target Cellular Receptors
针对细胞受体的工程纳米适体生物材料
- 批准号:
8345177 - 财政年份:2012
- 资助金额:
$ 85.2万 - 项目类别:
Engineering Nanoscale Aptamer-based Biomaterials that Target Cellular Receptors
针对细胞受体的工程纳米适体生物材料
- 批准号:
8711082 - 财政年份:2012
- 资助金额:
$ 85.2万 - 项目类别:
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