Developing a Multi-epitope Pan-Coronavirus Vaccine
开发多表位泛冠状病毒疫苗
基本信息
- 批准号:10669702
- 负责人:
- 金额:$ 74.22万
- 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:2020-08-07 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAcute Respiratory Distress SyndromeAntibodiesAntigensAuthorization documentationB-LymphocytesBloodBody Weight decreasedBrainCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCOVID-19COVID-19 outbreakCOVID-19 severityCOVID-19 susceptibilityCXCL10 geneCXCL11 geneCXCL9 geneCellsCessation of lifeChinaChiropteraCoronavirusCoronavirus InfectionsCountryDataDevelopmentDiseaseDisease OutbreaksElderlyEpitheliumEpitopesFutureGoalsHLA A*0201 antigenHLA-DR AntigensHealthHistopathologyHumanHumanitiesImmune responseImmune systemImmunizationIndividualInflammatoryInflammatory ResponseInterventionLeadLegal patentLungMedicalMiddle East Respiratory SyndromeMiddle East Respiratory Syndrome CoronavirusMinority GroupsMucous MembraneOutcomePhase I Clinical TrialsPhenotypePneumoniaPreclinical TestingPredispositionPreparationProteinsProvinceRouteSARS coronavirusSARS-CoV-2 genomeSARS-CoV-2 infectionSafetySeasonsSevere Acute Respiratory SyndromeSpecificityStructure of parenchyma of lungSymptomsSystemT cell responseT-LymphocyteT-Lymphocyte EpitopesTestingTissuesTransgenesTransgenic MiceUnited StatesVaccinesVirus Diseasesauthoritybrain tissuechemokinecoronavirus diseasecoronavirus vaccinecytokine release syndromedesignfightinghuman coronavirusimmunogenicityimmunopathologyin vitro testingin vivo evaluationinnovationmouse modelnanoparticleneurotropicneutralizing antibodynovelnovel coronaviruspandemic diseasepre-clinicalpreventpromoterprophylacticprotective efficacyprototypepublic health emergencyself assemblyuniversal coronavirus vaccinevaccine candidatevaccine deliveryvaccine evaluationvector
项目摘要
SUMMARY
Humanity is confronting a pandemic caused by the new Corona Virus 2 (SARS-CoV-2) infection. Our long-
term goal is to develop a potent prophylactic pan-Coronavirus vaccine to stop/reduce past, current and
future Coronavirus infections and/or diseases. While SARS-CoV-2-induced antibody and CD4+ and CD8+
T cell responses are critical to reducing viral infection in the majority of asymptomatic individuals, an
excessive proinflammatory cytokine storm appears to lead to acute respiratory distress syndrome in many
symptomatic individuals. Major gaps: Identifying the epitope specificities, the phenotype and function of B
cells, CD4+ T cells and CD8+ T cells associated with “natural protection seen in asymptomatic individuals
(those who are infected, but never develop any major symptoms) should guide the development of a future
coronavirus vaccine. Preliminary Results: We have made significant progress in: (A) Identifying a priori
potential human B-cell, CD4+ and CD8+ T cell target epitopes from the whole SARS-CoV-2 genome; (B)
Identifying “universal” epitopes conserved and common between: (1) previous SARS and MERS
coronavirus outbreaks, (2) current 4388 SARS-CoV-2 strains that now circulate in the United States and
184 other countries; and (3) SARS-like coronavirus strains currently found in bats that have the potential
to produce future human outbreaks; (C) Applying our scalable self-assembling protein nanoparticles
(SAPNs) antigen delivery platform to produce prototype multi-epitope pan-Coronavirus vaccine
candidates, that incorporate conserved protective epitopes from human and bats Coronaviruses, and
demonstrated their B- and T-cell immunogenicity in HLA transgenic mice; and (D) Generating a novel
“humanized” susceptible HLA-DR/HLA-A*0201/hACE2 triple transgenic mouse model in which to test
these vaccine candidates. Our hypothesis is that one of our pan-Coronavirus vaccine candidates,
containing conserved “asymptomatic” SARS-CoV-2 B- and T-cell epitopes that are mainly recognized by
the immune system of “protected,” asymptomatic individuals would protect from SARS-CoV-2 infection and
disease, upon intranasal delivery. To test this hypothesis our Specific Aims are: Aim 1: To test in vitro the
antigenicity of conserved Coronavirus epitopes, we recently identified from the whole SARS-CoV-2
genome, using blood-derived antibodies, CD4+ T-cells and CD8+ T-cells from SARS-CoV-2-infected
symptomatic vs. asymptomatic individuals. The immunodominant conserved “asymptomatic” epitopes will
be identified and used in our multi-epitope pan-Coronavirus vaccine candidates. Aim 2: To test in vivo the
safety, immunogenicity, and protective efficacy of highly conserved multi-epitope pan-Coronavirus vaccine
candidates, delivered mucosally, to our novel “humanized” susceptible triple transgenic mouse model.
Successful completion of this preclinical vaccine project is expected to identify a broadly protective pan-
Coronavirus vaccine candidate that could quickly proceed into an FDA Phase 1 clinical trial.
摘要
人类正面临由新的冠状病毒2(SARS-CoV-2)感染引起的大流行。我们的长-
学期目标是开发一种有效的预防性泛冠状病毒疫苗,以阻止/减少过去、现在和
未来的冠状病毒感染和/或疾病。而SARS-CoV-2诱导的抗体和CD4+、CD8+
T细胞反应对于减少大多数无症状个体的病毒感染至关重要
过度的促炎细胞因子风暴似乎会导致许多人的急性呼吸窘迫综合征
有症状的个体。主要差距:确定B抗原表位的特异性、表型和功能
与无症状个体的自然保护相关的细胞、CD4+T细胞和CD8+T细胞
(那些感染了,但从未出现任何重大症状的人)应该指导未来的发展
冠状病毒疫苗。初步结果:我们在以下方面取得了重大进展:(A)确定先验
SARS-CoV-2全基因组潜在的人类B细胞、CD4+和CD8+T细胞靶位;
确定在以前的SARS和MERS之间保守和共同的“通用”表位:
冠状病毒暴发,(2)目前在美国传播的4388株SARS-CoV-2毒株,以及
184个其他国家;及(3)目前在蝙蝠身上发现的类似SARS冠状病毒株,这些病毒有可能
以产生未来的人类疫情;(C)应用我们的可伸缩自组装蛋白质纳米颗粒
(SAPN)抗原递送平台生产多表位泛冠状病毒疫苗原型
包含来自人类和蝙蝠冠状病毒的保守保护性表位的候选,以及
在人类白细胞抗原转基因小鼠中证明了它们的B细胞和T细胞免疫原性;以及(D)产生了一种新的
用于检测的“人源化”易感HLA-DR/HLA-A*0201/hACE2三重转基因小鼠模型
这些候选疫苗。我们的假设是,我们的泛冠状病毒候选疫苗之一,
含有保守的“无症状”SARS-CoV-2 B细胞和T细胞表位,主要由
受保护的、无症状的人的免疫系统将保护他们免受SARS-CoV-2感染和
疾病,在鼻腔分娩时。为了验证这一假设,我们的具体目标是:目标1:在体外测试
我们最近从SARS-CoV-2全病毒中鉴定的冠状病毒保守表位的抗原性
用SARS-CoV-2感染的血源性抗体、CD4+T细胞和CD8+T细胞提取基因组
有症状与无症状的个体。免疫显性保守的“无症状”表位将
将被识别并用于我们的多表位泛冠状病毒候选疫苗。目的2:在体内测试
高度保守的多表位泛冠状病毒疫苗的安全性、免疫原性和保护效果
我们的新型“人源化”易感三重转基因小鼠模型的候选基因。
这一临床前疫苗项目的成功完成预计将确定一种具有广泛保护性的PAN-
冠状病毒候选疫苗可能很快进入FDA第一阶段临床试验。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SARS-CoV-2 Envelope (E) Protein Binds and Activates TLR2 Pathway: A Novel Molecular Target for COVID-19 Interventions.
- DOI:10.3390/v14050999
- 发表时间:2022-05-08
- 期刊:
- 影响因子:0
- 作者:
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Lbachir BenMohamed其他文献
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{{ truncateString('Lbachir BenMohamed', 18)}}的其他基金
Developing a Multi-epitope Pan-Coronavirus Vaccine
开发多表位泛冠状病毒疫苗
- 批准号:
10171239 - 财政年份:2020
- 资助金额:
$ 74.22万 - 项目类别:
A Novel Prime/Pull Therapeutic Vaccine Strategy to Prevent Recurrent Genital Herpes
预防复发性生殖器疱疹的新型初免/拉动治疗疫苗策略
- 批准号:
10318146 - 财政年份:2020
- 资助金额:
$ 74.22万 - 项目类别:
A Novel Prime/Pull Therapeutic Vaccine Strategy to Prevent Recurrent Genital Herpes
预防复发性生殖器疱疹的新型初免/拉动治疗疫苗策略
- 批准号:
9913971 - 财政年份:2020
- 资助金额:
$ 74.22万 - 项目类别:
A Novel Prime/Pull Therapeutic Vaccine Strategy to Prevent Recurrent Genital Herpes
预防复发性生殖器疱疹的新型初免/拉动治疗疫苗策略
- 批准号:
10546435 - 财政年份:2020
- 资助金额:
$ 74.22万 - 项目类别:
Developing a Multi-epitope Pan-Coronavirus Vaccine
开发多表位泛冠状病毒疫苗
- 批准号:
10231272 - 财政年份:2020
- 资助金额:
$ 74.22万 - 项目类别:
A Novel Prime/Pull Therapeutic Vaccine Strategy to Prevent Recurrent Genital Herpes
预防复发性生殖器疱疹的新型初免/拉动治疗疫苗策略
- 批准号:
10083701 - 财政年份:2020
- 资助金额:
$ 74.22万 - 项目类别:
Developing a Multi-epitope Pan-Coronavirus Vaccine
开发多表位泛冠状病毒疫苗
- 批准号:
10454975 - 财政年份:2020
- 资助金额:
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10223136 - 财政年份:2019
- 资助金额:
$ 74.22万 - 项目类别:
Mucosal Chemokines and CD8+ T Cell Immunity to Genital Herpes
粘膜趋化因子和 CD8 T 细胞对生殖器疱疹的免疫
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10450154 - 财政年份:2019
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$ 74.22万 - 项目类别:
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9752627 - 财政年份:2016
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