A multivalent prophylactic and therapeutic vaccine against EBV infection and EBV-associated malignancies
针对 EBV 感染和 EBV 相关恶性肿瘤的多价预防性和治疗性疫苗
基本信息
- 批准号:10247243
- 负责人:
- 金额:$ 85.86万
- 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:2020-09-08 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdolescentAdultAnimal ModelAnimalsAntibodiesAntibody ResponseAntibody titer measurementAntigensAutoimmunityB-LymphocytesBloodCellsChildhoodChronic DiseaseClinical TrialsComplexDevelopmentDiseaseDoseEBV-associated diseaseEnsureEnzyme-Linked Immunosorbent AssayEpithelial CellsEpstein-Barr Virus InfectionsEpstein-Barr Virus-Related Malignant NeoplasmExhibitsGardasilGlycoproteinsGoalsHIVHumanHuman Herpesvirus 4Human PapillomavirusIatrogenesisImmuneImmune responseImmunizationImmunizeImmunocompetentImmunocompromised HostImmunoglobulin GImmunosuppressionIn VitroIndividualInfantInfectionInfection preventionInfectious MononucleosisInvestigational New Drug ApplicationKnowledgeLymphocryptovirusLymphomaLymphoproliferative DisordersMacaca mulattaMalignant NeoplasmsMeasuresMediatingModelingModified Vaccinia Virus AnkaraMorbidity - disease rateMusMyeloid CellsOncogenicOncogenic VirusesOralOrthologous GeneOryctolagus cuniculusPeripheral Blood Mononuclear CellPhase I/II Clinical TrialPopulationPreventivePreventive vaccinePrimary InfectionPropertyRegimenResearchRhesusRiskSIVSalivaSplenocyteStructureSubunit VaccinesT-LymphocyteTestingTimeVaccinesViralViral AntigensViral GenomeViral ProteinsVirusVirus DiseasesVirus SheddingVirus-like particleWild Type Mouseacute symptombasecell typechronic infectionclinically relevantco-infectiondesigngerm free conditionglobal healthhuman modelhumanized mouseimmunogenicimmunogenicityin vivoinnovationlymph nodesmortalitymouse modelneutralizing antibodynovel strategiespersistent EBV infectionpost-transplantpre-clinicalpreclinical trialpreventprophylacticresponsesuccesstherapeutic vaccinevaccine candidatevaccine developmentvaccine efficacyvaccine evaluationvaccine trialvectorviral DNA
项目摘要
ABSTRACT: Epstein-Barr virus (EBV) represents a major global health problem, as it is associated with
infectious mononucleosis in adolescents and >200,000 pediatric and adult cancer cases worldwide each year.
Despite the high morbidity and mortality associated with EBV infection, there is no licensed prophylactic EBV
vaccine. Thus, a safe and effective EBV prophylactic vaccine is urgently needed. To date, no vaccine
candidate has elicited neutralizing antibodies (nAbs) to completely block EBV infection in vivo. Approaches to
EBV vaccine development have been limited in part by the oncogenic potential of the viral genome and a lack
of animal models to test vaccine candidates. This proposed project will use a novel strategy to develop a safe
and effective vaccine candidate that incorporates up to five EBV glycoproteins into a single Epstein-Barr virus-
like particle (EBV-LP). The EBV glycoproteins gp350, gB, gp42, and gH/gL complex, which are essential for
EBV attachment, fusion, and entry into host cells, are attractive targets for provoking a humoral/antibody-
mediated response. Our group and others have shown that antibodies to these glycoproteins neutralize viral
infection in vitro and in vivo. Thus, their inclusion is critical for developing an effective prophylactic vaccine that
protects against viral infection. To our knowledge, this combination of EBV antigens has not been tested in pre-
clinical or clinical trials. We will generate EBV-LPs containing combinations of up to five glycoproteins using
modified vaccinia Ankara virus. We will determine the efficacy of the EBV-LPs to generate nAb responses in
wild-type mice, then test the ability of these antibodies to neutralize >90% of EBV infection of human epithelial
and B cells in vitro and to prevent infection of human B cells in vivo in a humanized mouse model (Aim 1).
Because EBV is human-tropic, we will use the EBV-homologous rhesus lymphocryptovirus (rhLCV) as a
surrogate virus to study vaccine efficacy in vivo in rhesus macaques (RM), considered the most relevant
animal model that recapitulates key features of human EBV infection. Importantly, RM orally inoculated with
rhLCV exhibit acute symptoms and viral shedding similar to EBV+ humans, as well as development of
lymphoma after persistent infection under immunosuppression. We will evaluate the ability of our EBV-LP-
based or analogous rhLCV-LP-based vaccines to elicit nAbs that can prevent or limit infection, with no/low EBV
DNA in blood, splenocytes, or lymph nodes, and absence of EBV+ cancer in immunocompetent and
immunocompromised RM, compared to well-characterized EBV gp350-based vaccines (Aim 2). Our central
hypothesis is that EBV-LPs/rhLCV-LPs will generate protective anti-EBV/rhLCV glycoprotein nAb responses
to prevent EBV/rhLCV infection in vitro and in vivo. We expect our approach to provide a path to an
investigational new drug application for a prophylactic EBV vaccine. We will also define, for the first time, the
minimum EBV/rhLCV glycoproteins required to elicit sterilizing nAbs in vitro and in vivo. This will advance our
long-term goal of developing vaccines that prevent EBV infection and EBV-associated diseases and cancers.
摘要: EB 病毒(EBV)是一个重大的全球健康问题,因为它与
每年全世界有超过 200,000 例青少年传染性单核细胞增多症和儿童和成人癌症病例。
尽管 EBV 感染相关的发病率和死亡率很高,但目前还没有获得许可的预防性 EBV 药物
疫苗。因此,迫切需要一种安全有效的EBV预防疫苗。迄今为止,还没有疫苗
候选者已引发中和抗体(nAb)以完全阻断体内 EBV 感染。接近
EB 病毒疫苗的开发部分受到病毒基因组致癌潜力和缺乏
用于测试候选疫苗的动物模型。该拟议项目将使用一种新颖的策略来开发安全的
以及将多达 5 种 EBV 糖蛋白整合到单一 Epstein-Barr 病毒中的有效候选疫苗
类似颗粒(EBV-LP)。 EBV 糖蛋白 gp350、gB、gp42 和 gH/gL 复合物,对于
EBV 附着、融合和进入宿主细胞是激发体液/抗体的有吸引力的目标
介导的反应。我们的小组和其他人已经证明,这些糖蛋白的抗体可以中和病毒
体外和体内感染。因此,将它们纳入其中对于开发有效的预防性疫苗至关重要
防止病毒感染。据我们所知,这种 EBV 抗原组合尚未经过预测试。
临床或临床试验。我们将使用以下方法生成包含最多五种糖蛋白组合的 EBV-LP
改良痘苗安卡拉病毒。我们将确定 EBV-LP 产生 nAb 反应的功效
野生型小鼠,然后测试这些抗体中和 > 90% 的人类上皮细胞 EBV 感染的能力
和 B 细胞在体外,并在人源化小鼠模型中预防体内人类 B 细胞的感染(目标 1)。
由于 EBV 是人类嗜性病毒,我们将使用 EBV 同源恒河猴淋巴隐病毒 (rhLCV) 作为
替代病毒在恒河猴(RM)体内研究疫苗功效,被认为是最相关的
概括人类 EBV 感染主要特征的动物模型。重要的是,RM口服接种
rhLCV 表现出与 EBV+ 人类类似的急性症状和病毒脱落,以及发展为
免疫抑制下持续感染后的淋巴瘤。我们将评估我们的 EBV-LP 的能力-
基于或类似的基于 rhLCV-LP 的疫苗,可引发可预防或限制感染的 nAb,且无/低 EBV
血液、脾细胞或淋巴结中存在 DNA,且免疫功能正常且不存在 EBV+ 癌症
与充分表征的基于 gp350 的 EBV 疫苗相比,免疫功能低下的 RM(目标 2)。我们的中央
假设 EBV-LPs/rhLCV-LPs 将产生保护性抗 EBV/rhLCV 糖蛋白 nAb 反应
预防 EBV/rhLCV 体外和体内感染。我们希望我们的方法能够提供一条通往
预防性 EBV 疫苗的研究性新药申请。我们还将首次定义
体外和体内引发灭菌 nAb 所需的最低 EBV/rhLCV 糖蛋白。这将推进我们的
开发预防 EBV 感染以及 EBV 相关疾病和癌症的疫苗的长期目标。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Javier Gordon Ogembo其他文献
Correction: HPV genotyping by L1 amplicon sequencing of archived invasive cervical cancer samples: a pilot study
- DOI:
10.1186/s13027-024-00589-0 - 发表时间:
2024-06-19 - 期刊:
- 影响因子:2.800
- 作者:
Charles D. Warden;Preetam Cholli;Hanjun Qin;Chao Guo;Yafan Wang;Chetan Kancharla;Angelique M. Russell;Sylvana Salvatierra;Lorraine Z. Mutsvunguma;Kerin K. Higa;Xiwei Wu;Sharon Wilczynski;Raju Pillai;Javier Gordon Ogembo - 通讯作者:
Javier Gordon Ogembo
Javier Gordon Ogembo的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Javier Gordon Ogembo', 18)}}的其他基金
Unmasking the roles of viral glycoproteins in oral transmission of KSHV
揭示病毒糖蛋白在 KSHV 口腔传播中的作用
- 批准号:
10623087 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
KSHV Subunit Vaccine Candidates to Elicit Potent Humoral Immune Reponses against KSHV Infection
KSHV 亚单位候选疫苗可引发针对 KSHV 感染的有效体液免疫反应
- 批准号:
10376277 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
Unmasking the roles of viral glycoproteins in oral transmission of KSHV
揭示病毒糖蛋白在 KSHV 口腔传播中的作用
- 批准号:
10318876 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
Unmasking the roles of viral glycoproteins in oral transmission of KSHV
揭示病毒糖蛋白在 KSHV 口腔传播中的作用
- 批准号:
10474478 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
KSHV Subunit Vaccine Candidates to Elicit Potent Humoral Immune Reponses against KSHV Infection
KSHV 亚单位候选疫苗可引发针对 KSHV 感染的有效体液免疫反应
- 批准号:
10559659 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
Unmasking the roles of viral glycoproteins in oral transmission of KSHV
揭示病毒糖蛋白在 KSHV 口腔传播中的作用
- 批准号:
10737872 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
Unmasking the roles of viral glycoproteins in oral transmission of KSHV
揭示病毒糖蛋白在 KSHV 口腔传播中的作用
- 批准号:
10627167 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
Unmasking the roles of viral glycoproteins in oral transmission of KSHV
揭示病毒糖蛋白在 KSHV 口腔传播中的作用
- 批准号:
10599690 - 财政年份:2021
- 资助金额:
$ 85.86万 - 项目类别:
Characterization of Epstein-Barr virus monoclonal antibodies as tools for diagnosing and prevention of EBV infection in transplant settings
EB 病毒单克隆抗体作为移植环境中诊断和预防 EBV 感染工具的表征
- 批准号:
9797160 - 财政年份:2018
- 资助金额:
$ 85.86万 - 项目类别:
A novel VLP vaccine to prevent EBV infection and EBV - associated malignancies
一种预防 EBV 感染和 EBV 相关恶性肿瘤的新型 VLP 疫苗
- 批准号:
9302981 - 财政年份:2017
- 资助金额:
$ 85.86万 - 项目类别:
相似海外基金
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The impact of changes in social determinants of health on adolescent and young adult mental health during the COVID-19 pandemic: A longitudinal study of the Asenze cohort in South Africa
COVID-19 大流行期间健康社会决定因素的变化对青少年和年轻人心理健康的影响:南非 Asenze 队列的纵向研究
- 批准号:
10755168 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
A Priority Setting Partnership to Establish a Patient, Caregiver, and Clinician-identified Research Agenda for Adolescent and Young Adult Cancer in Canada
建立优先合作伙伴关系,以建立患者、护理人员和临床医生确定的加拿大青少年和年轻人癌症研究议程
- 批准号:
480840 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Miscellaneous Programs
Incidence and Time on Onset of Cardiovascular Risk Factors and Cardiovascular Disease in Adult Survivors of Adolescent and Young Adult Cancer and Association with Exercise
青少年和青年癌症成年幸存者心血管危险因素和心血管疾病的发病率和时间以及与运动的关系
- 批准号:
10678157 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Fertility experiences among ethnically diverse adolescent and young adult cancer survivors: A population-based study
不同种族青少年和年轻成年癌症幸存者的生育经历:一项基于人群的研究
- 批准号:
10744412 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Treatment development for refractory leukemia using childhood/adolescent, and young adult leukemia biobank
利用儿童/青少年和青年白血病生物库开发难治性白血病的治疗方法
- 批准号:
23K07305 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular design of Two-Way Player CAR-T cells to overcome disease/antigen heterogeneity of childhood, adolescent, and young adult cancers
双向 CAR-T 细胞的分子设计,以克服儿童、青少年和年轻成人癌症的疾病/抗原异质性
- 批准号:
23H02874 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Effects of adolescent social isolation on adult decision making and corticostriatal circuitry
青少年社会隔离对成人决策和皮质纹状体回路的影响
- 批准号:
10756652 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Adolescent trauma produces enduring disruptions in sleep architecture that lead to increased risk for adult mental illness
青少年创伤会对睡眠结构产生持久的破坏,从而导致成人精神疾病的风险增加
- 批准号:
10730872 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:
Using Tailored mHealth Strategies to Promote Weight Management among Adolescent and Young Adult Cancer Survivors
使用量身定制的移动健康策略促进青少年和年轻癌症幸存者的体重管理
- 批准号:
10650648 - 财政年份:2023
- 资助金额:
$ 85.86万 - 项目类别:














{{item.name}}会员




