Defining the protective efficacy of antibodies against the EBV gH/gL glycoprotein complex
定义针对 EBV gH/gL 糖蛋白复合物的抗体的保护功效
基本信息
- 批准号:10199986
- 负责人:
- 金额:$ 43.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-09 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAfricaAfrica South of the SaharaAgeAnimal ModelAnimalsAntibodiesAntibody ResponseAntibody-mediated protectionAreaB-Cell LymphomasB-LymphocytesBindingBlocking AntibodiesCell surfaceCellsCentral Nervous System LymphomaCessation of lifeClinicalComplement 3d ReceptorsComplement ReceptorComplexDataDevelopmentEpithelial CellsEpitopesEpstein-Barr Virus InfectionsEpstein-Barr Virus-Related Malignant NeoplasmGlycoproteinsGoalsHIVHIV-1Hodgkin DiseaseHumanHuman Herpesvirus 4ImmuneImmune responseImmunocompromised HostIn VitroIncidenceIndividualInfantInfectionInfectious MononucleosisLarge-Cell Immunoblastic LymphomaLeadLifeLinkLymphocryptovirusLymphomaLymphomagenesisMacacaMacaca mulattaMalignant NeoplasmsMediatingMembraneMembrane FusionModelingMonoclonal AntibodiesMusNasopharynxNon-Hodgkin&aposs LymphomaOralOrthologous GenePathologyPatientsPersonsPlayPrimary InfectionRecombinantsRelative RisksResearchResourcesRhesusRiskRoleSiteSourceSpecificitySubunit VaccinesTarget PopulationsTestingVaccine DesignVaccinesViralViral AntigensViral Load resultVirionVirusVirus LatencyWorkbasecell typecross reactivitydesignexperimental studyhuman modelhumanized mouseimmunogenicityimprovedinsightlarge cell Diffuse non-Hodgkin&aposs lymphomamembermouse modelneutralizing antibodynext generationnovel vaccinesoverexpressionpathogenphase II trialpreventprimary effusion lymphomaprotective efficacyreceptorscaffoldtumorvaccine developmentvaccine trialviral transmission
项目摘要
PROJECT SUMMARY/ABSTRACT
Epstein-Barr virus (EBV) is a nearly ubiquitous orally-transmitted pathogen for which there is no vaccine.
Following primary infection, most individuals carry the virus asymptomatically; however, unchecked infection in
immunocompromised individuals, such as those living with HIV-1/AIDS, can lead to the development of
lymphomas. These include Non-Hodgkin's Lymphomas such as plasmablastic lymphoma, primary central
nervous system lymphoma, primary effusion lymphoma and diffuse large B-cell lymphoma, as well as classic
Hodgkin's lymphoma. Overall, HIV-infected individuals have a 60–200-fold higher relative risk to develop Non-
Hodgkin's Lymphomas and an 8–10-fold higher relative risk to develop Hodgkin's Lymphoma compared to
uninfected individuals. Thus, a safe and effective vaccine that prevents EBV infection and/or eliminates the EBV-
associated component of risk could have a significant clinical benefit, particularly in resource-poor areas where
HIV-1 is endemic. Successful vaccines are usually protective because they elicit neutralizing antibodies. At
present it is not currently known whether pre-existing neutralizing antibodies can block EBV transmission. Since
both B cells and epithelial cells are present in the nasopharynx, a preventative EBV vaccine would likely need to
elicit antibodies that can block infection of both cell types. To date, subunit vaccine efforts focused on the gp350
glycoprotein which binds to complement receptors 1 and 2 and promotes attachment and internalization of virions
by B cells without mediating membrane fusion. A phase II trial of a gp350 vaccine reduced the incidence of
infectious mononucleosis but failed to protect against infection. Antibodies against gp350 can inhibit EBV
infection of B cells, but most epithelial cells do not express complement receptors. Thus, the inability of gp350
vaccines to protect against EBV infection may be due to their inability to elicit antibodies that neutralize EBV
infection of epithelial cells. We recently isolated a monoclonal antibody, AMMO1 that binds to the EBV gH/gL
glycoprotein complex, which is an important regulator of fusion between the host cell and viral membranes.
AMMO1 binds to gH/gL in a manner that disrupts membrane fusion and neutralizes EBV infection of both B and
epithelial cells demonstrating, in principle, that vaccine elicited gH/gL antibodies could be more efficacious than
those against gp350. The goal of this proposal is to define the protective capacity of AMMO1 and other anti-EBV
monoclonal antibodies against EBV infection in complementary animal models: humanized mice that harbor
human B cells and in infant rhesus macaques, which can be orally infected with the rhesus ortholog of EBV. We
will also evaluate the ability of several gH/gL-based vaccines to elicit neutralizing antibodies and compare these
gp350-based vaccines in relevant animal challenge models. These studies will delineate the role that antibodies
play in preventing EBV infection and inform vaccine development. Moreover, the proposed challenge studies in
infant macaques are highly relevant to the target-population in Sub-Sharan Africa where EBV infection normally
occurs in the first 3 years of life.
项目总结/摘要
EB病毒(EBV)是一种几乎无处不在的经口传播的病原体,目前尚无疫苗。
初次感染后,大多数人无症状地携带病毒;然而,
免疫功能低下的个体,如HIV-1/AIDS感染者,可能导致
淋巴瘤这些包括非霍奇金淋巴瘤,如浆母细胞淋巴瘤、原发性中央淋巴瘤、淋巴瘤和淋巴瘤。
神经系统淋巴瘤、原发性渗出性淋巴瘤和弥漫性大B细胞淋巴瘤,以及经典的
霍奇金淋巴瘤。总的来说,艾滋病毒感染者患非传染性疾病的相对风险要高出60-200倍。
霍奇金淋巴瘤和8-10倍高的相对风险发展霍奇金淋巴瘤相比,
未受感染的人。因此,预防EBV感染和/或消除EBV-1的安全和有效的疫苗,
风险的相关成分可能具有显著的临床益处,特别是在资源贫乏的地区,
HIV-1是地方病。成功的疫苗通常是保护性的,因为它们会引发中和抗体。在
目前尚不清楚预先存在的中和抗体是否可以阻断EBV传播。以来
B细胞和上皮细胞都存在于鼻咽部,预防性EBV疫苗可能需要
引发可以阻断两种细胞感染的抗体。到目前为止,亚单位疫苗的努力集中在gp 350上,
与补体受体1和2结合并促进病毒粒子附着和内化的糖蛋白
不介导膜融合的B细胞。gp 350疫苗的II期试验降低了
传染性单核细胞增多症,但未能防止感染。抗gp 350抗体可抑制EBV
感染B细胞,但大多数上皮细胞不表达补体受体。因此,gp 350不能
预防EBV感染的疫苗可能是由于它们不能引发中和EBV的抗体
上皮细胞感染。我们最近分离出一种单克隆抗体,AMMO 1,它与EBV gH/gL结合,
糖蛋白复合物,其是宿主细胞和病毒膜之间融合的重要调节剂。
AMMO 1以破坏膜融合并中和B和B区的EBV感染的方式结合gH/gL。
上皮细胞,原则上证明疫苗诱导的gH/gL抗体可能比
这些是针对GP 350的。该提案的目的是确定AMMO 1和其他抗EBV抗体的保护能力。
补充动物模型中抗EBV感染的单克隆抗体:携带EBV的人源化小鼠
人B细胞和幼年恒河猴中,其可以用EBV的恒河猴直系同源物口服感染。我们
我还将评估几种基于gH/gL的疫苗引发中和抗体的能力,并比较这些疫苗
在相关动物攻击模型中的基于gp 350的疫苗。这些研究将阐明抗体在
在预防EBV感染和疫苗开发方面发挥作用。此外,拟议的挑战研究,
幼年猕猴与非洲撒哈拉以南地区的目标人群高度相关,
发生在生命的前三年。
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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Andrew McGuire其他文献
Andrew McGuire的其他文献
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{{ truncateString('Andrew McGuire', 18)}}的其他基金
Development of an anti-idiotype based vaccine for respiratory syncytial virus
呼吸道合胞病毒抗独特型疫苗的研制
- 批准号:
10593361 - 财政年份:2021
- 资助金额:
$ 43.28万 - 项目类别:
Development of an anti-idiotype based vaccine for respiratory syncytial virus
呼吸道合胞病毒抗独特型疫苗的研制
- 批准号:
10414112 - 财政年份:2021
- 资助金额:
$ 43.28万 - 项目类别:
Development of an anti-idiotype based vaccine for respiratory syncytial virus
呼吸道合胞病毒抗独特型疫苗的研制
- 批准号:
10302873 - 财政年份:2021
- 资助金额:
$ 43.28万 - 项目类别:
Defining the protective efficacy of antibodies against the EBV gH/gL glycoprotein complex
定义针对 EBV gH/gL 糖蛋白复合物的抗体的保护功效
- 批准号:
10593368 - 财政年份:2019
- 资助金额:
$ 43.28万 - 项目类别:
Defining the protective efficacy of antibodies against the EBV gH/gL glycoprotein complex
定义针对 EBV gH/gL 糖蛋白复合物的抗体的保护功效
- 批准号:
10455109 - 财政年份:2019
- 资助金额:
$ 43.28万 - 项目类别:
Defining the protective efficacy of antibodies against the EBV gH/gL glycoprotein complex
定义针对 EBV gH/gL 糖蛋白复合物的抗体的保护功效
- 批准号:
10669738 - 财政年份:2019
- 资助金额:
$ 43.28万 - 项目类别:
Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1
评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗
- 批准号:
10300442 - 财政年份:2018
- 资助金额:
$ 43.28万 - 项目类别:
Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1
评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗
- 批准号:
10062817 - 财政年份:2018
- 资助金额:
$ 43.28万 - 项目类别:
Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1
评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗
- 批准号:
10540731 - 财政年份:2018
- 资助金额:
$ 43.28万 - 项目类别:
Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1
评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗
- 批准号:
10593447 - 财政年份:2018
- 资助金额:
$ 43.28万 - 项目类别:
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