Pan-lyssavirus therapeutics and mechanisms of protection against lyssaviruses
泛狂犬病病毒疗法和抗狂犬病病毒的保护机制
基本信息
- 批准号:10311511
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimalsAntibodiesAntibody-mediated protectionApplications GrantsBiological AssayBiological ProductsChiropteraCommunicable DiseasesCompetitive BindingComplementDataDiseaseDisease OutbreaksEnzyme-Linked Immunosorbent AssayEpitope MappingEscape MutantExploratory/Developmental Grant for Diagnostic Cancer ImagingFundingGenerationsGlycoproteinsGoalsHarvestHumanHybridomasImmune responseImmunityImmunizeInfectionInterventionKnowledgeLyssavirusMediatingModelingMokola virusMonoclonal AntibodiesMusMutationNatural Killer CellsPathway interactionsPersonsPhagocytosisPropertyRabiesRabies virusRecombinantsSerumSpleenSuggestionTestingTherapeuticTransgenic MiceVaccinatedVaccinesViralVirusVisitantibody-dependent cell cytotoxicitycross reactivitydesignimmunogenicityin vivoneutralizing antibodyneutralizing monoclonal antibodiesnovelreceptor bindingresponseseroconversion
项目摘要
Abstract
Rabies disease is nearly 100% lethal in the absence of treatment, killing an estimated 59,000 people annually.
When vaccines are properly administered, they are highly efficacious, making them one of the most economically
high-impact interventions among infectious diseases. About 30,000 people receive post-exposure treatment in
the USA annually indicating the need for treatment options against RABV. Of note, fifteen rabies-related viruses
(lyssaviruses) are similarly lethal, but divergent enough to evade protection from current vaccines and biologics,
which are based on the classical rabies virus (RABV).
We previously designed a structurally-informed chimeric glycoprotein (G) to incorporate large ectodomain
regions of two divergent lyssaviruses, RABV and Mokola virus (MOKV). In vivo, this vaccine elicited neutralizing
antibodies against both RABV and MOKV and protected against challenge with viruses containing MOK G or
RABV G. Based on knowledge of the RABV G, these preliminary data suggest that i) the chimeric G includes
important antigenic regions from both RABV and MOKV and that ii) the elicited antibodies should protect against
challenge. Moreover, some data also raised the compelling suggestion that antibody mechanisms in addition to
neutralization may contribute to protection.
Three independent but complementary aims are proposed to take the discoveries of the R21 to the next level.
The first Aim will investigate the immunogenicity and protective quality of a chimeric G lyssavirus vaccine against
a panel of different lyssaviruses of importance. Aim 2 examines antigenic regions of non-RABV lyssavirus
glycoproteins (G) and delineate the antigenic regions on the lyssavirus Gs by isolating and characterizing
neutralizing monoclonal antibodies (mAbs). The dogma for protection against RABV is that neutralizing
antibodies are necessary and sufficient. This has not been studies for non-RABV lyssaviruses and is not
completely supported by preliminary data from our previous study. Therefore, Aim 3 will revisit the mechanism
of protection against Lyssaviruses in pre- and post-exposure applications and redefine the function of
neutralizing and non-neutralizing antibodies for protection from rabies.
抽象的
如果不接受治疗,狂犬病几乎 100% 致死,每年估计有 59,000 人死亡。
如果疫苗接种得当,它们会非常有效,使其成为最经济的疫苗之一
传染病的高影响力干预措施。大约 30,000 人接受暴露后治疗
美国每年都表明需要针对 RABV 的治疗方案。值得注意的是,十五种与狂犬病相关的病毒
(狂犬病毒)同样具有致命性,但差异足以逃避当前疫苗和生物制剂的保护,
它们基于经典狂犬病病毒(RABV)。
我们之前设计了一种结构知情的嵌合糖蛋白(G)来整合大的胞外域
两种不同的狂犬病病毒(RABV 和 Mokola 病毒(MOKV))的区域。在体内,这种疫苗引发了中和
针对 RABV 和 MOKV 的抗体,并防止含有 MOK G 或 MOK G 的病毒的攻击
RABV G。基于对 RABV G 的了解,这些初步数据表明 i) 嵌合 G 包括
RABV 和 MOKV 的重要抗原区域,并且 ii) 引发的抗体应防止
挑战。此外,一些数据还提出了令人信服的建议,即抗体机制除了
中和可能有助于保护。
提出了三个独立但互补的目标,将 R21 的发现提升到一个新的水平。
第一个目标将研究嵌合 G 狂犬病病毒疫苗的免疫原性和保护质量
一组不同的重要狂犬病病毒属病毒。目标 2 检查非 RABV 狂犬病病毒的抗原区域
糖蛋白 (G) 并通过分离和表征来描绘狂犬病病毒 G 上的抗原区域
中和单克隆抗体(mAb)。预防 RABV 的教条是中和
抗体是必要且充分的。这还没有针对非 RABV 狂犬病病毒进行过研究,也不是
我们之前研究的初步数据完全支持。因此,Aim 3将重新审视该机制
在暴露前和暴露后应用中对狂犬病病毒的保护,并重新定义其功能
用于预防狂犬病的中和和非中和抗体。
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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Matthias Johannes Schnell其他文献
High Seroprevalence of Antibodies to Avian Influenza Viruses among Wild Waterfowl in Alaska: Implications for Surveillance
阿拉斯加野生水禽中禽流感病毒抗体的高血清阳性率:对监测的影响
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:3.7
- 作者:
H. Wilson;Jeffery S. Hall;P. Flint;J. Christian Franson;C. Ely;J. Schmutz;M. D. Samuel;Matthias Johannes Schnell - 通讯作者:
Matthias Johannes Schnell
Matthias Johannes Schnell的其他文献
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{{ truncateString('Matthias Johannes Schnell', 18)}}的其他基金
Toward a protective Covid-19 vaccine utilizing an established vector platform
利用已建立的载体平台开发保护性 Covid-19 疫苗
- 批准号:
10170820 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Pan-lyssavirus therapeutics and mechanisms of protection against lyssaviruses
泛狂犬病病毒疗法和抗狂犬病病毒的保护机制
- 批准号:
10078258 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Pan-lyssavirus therapeutics and mechanisms of protection against lyssaviruses
泛狂犬病病毒疗法和抗狂犬病病毒的保护机制
- 批准号:
9905663 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Training grant on Vaccines and Immunotherapies for Infectious Diseases and Cancer
传染病和癌症疫苗和免疫疗法培训补助金
- 批准号:
10465086 - 财政年份:2018
- 资助金额:
$ 39万 - 项目类别:
Training grant on Vaccines and Immunotherapies for Infectious Diseases and Cancer
传染病和癌症疫苗和免疫疗法培训补助金
- 批准号:
10201425 - 财政年份:2018
- 资助金额:
$ 39万 - 项目类别:
Development of a single-dose rabies virus vaccine
单剂量狂犬病病毒疫苗的研制
- 批准号:
10054163 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
Preclinical characterization of a multivalent killed Filovirus/Rabies vaccine
多价灭活丝状病毒/狂犬病疫苗的临床前表征
- 批准号:
8790424 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
Preclinical characterization of a multivalent killed Filovirus/Rabies vaccine
多价灭活丝状病毒/狂犬病疫苗的临床前表征
- 批准号:
9205480 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
Preclinical characterization of a multivalent killed Filovirus/Rabies vaccine
多价灭活丝状病毒/狂犬病疫苗的临床前表征
- 批准号:
8994257 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
Preclinical characterization of a multivalent killed Filovirus/Rabies vaccine
多价灭活丝状病毒/狂犬病疫苗的临床前表征
- 批准号:
8496399 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
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