Globally Appropriate Genome Reduced Killed Whole Bacterial HIV Vaccines
全球适用的基因组减少灭活全细菌 HIV 疫苗
基本信息
- 批准号:10672822
- 负责人:
- 金额:$ 56.53万
- 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:2023-03-13 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAdjuvantAnimal ModelAntibodiesAntibody Binding SitesAntibody FormationAntigensBacteriaBacterial VaccinesBindingBinding SitesBiological AssayBiomedical EngineeringBiomedical ResearchCellsCellular ImmunityChimeric ProteinsClinicalCold ChainsCombined VaccinesConsensusCoronavirusCryopreservationDNADNA biosynthesisDataDevelopmentDiseaseDoseEngineeringEnzyme-Linked Immunosorbent AssayEpidemicEscherichia coliEscherichia coli VaccinesExhibitsFamily suidaeFundingFutureGenomeGoalsHIVHIV AntigensHIV vaccineHIV-1HIV-1 vaccineHandHumanImmune responseImmunizeInactivated VaccinesIndustrializationInternationalKnowledgeLettersManufacturerMedicalMembraneModelingMonitorMonoclonal AntibodiesMusPeptide VaccinesPeptidesPhasePlasmidsPositioning AttributePreventive vaccineProductionProteinsRecombinantsRecording of previous eventsResearchRouteSafetyStructureStudy modelsSurfaceSystemT cell responseTechnology TransferTestingTrainingTranslatingVaccinatedVaccinationVaccine AntigenVaccine ProductionVaccinesViral AntigensViral Envelope ProteinsViral Fusion ProteinsVirusVirus DiseasesWhole Cell VaccineWorkantigen-specific T cellscell mediated immune responseclinical efficacycostdesignearly phase clinical trialforgivenesshigh rewardhigh riskimmunogenicityimprovedin vivo evaluationinnovationmanufacturing capabilitiesmeetingsmonomermouse modelneutralizing antibodyneutralizing monoclonal antibodiesnonhuman primatenovelnovel strategiesnovel vaccinesporcine epidemic diarrhea virusprophylacticresponsesafety assessmentskillssuccesssynthetic biologyvaccine candidatevaccine developmentvaccine immunogenicityvaccine platformvaccine response
项目摘要
A broad consensus regarding HIV vaccine development calls for engineering antigens that elicit production
of antibodies like the known Broadly Neutralizing (BN) Monoclonal Antibodies (MAbs). Two Env BN MAb
binding sites, the Membrane Proximal External Region (MPER) and Fusion Peptide (FP), are attractive targets
because they are linear peptides. We developed a new, low cost, globally appropriate vaccine platform: Killed
Whole Cell (KWC) Genome-Reduced E. coli (grEc), with vaccine antigens expressed on bacterial surfaces
using Gram- autotransporters. Using synthetic biology, testable vaccine candidates can be made in ~3 wks for
~$50 each. Vaccines made with the platform will cost ~$1/dose, can be produced in existing factories globally,
and have forgiving cold chain requirements. We made coronavirus FP vaccines using the KWC grEc platform
and showed clinical efficacy in an animal model. We propose to make KWC grEc HIV vaccines targeting
MPER and FP. Our preliminary data show that we can express HIV MPER and FP Ags with this approach and
elicit HIV neutralizing sera in mice using an MPER-derived Ag. We hypothesize that the KWC grEc platform,
targeting MPER and FP, will yield safe, effective, low cost, globally appropriate HIV vaccines.
In PHASE 1, Aim 1, we will synthesize DNAs encoding MPER and FP Ags, employing bioengineering
strategies to enhance Ag exposure and antigenicity. We will clone these DNAs into our expression plasmid and
transform into grEc to make KWC candidate vaccines. Using highly neutralizing and relatively non-neutralizing
MAbs, we will test candidate vaccines, selecting those that show the best difference in binding neutralizing vs.
less neutralizing MAbs for in vivo testing. In Aim 2, we will vaccinate mice to assess vaccine immunogenicity,
comparing the different candidate vaccines, alone and in combination, to identify the best vaccines and
dose/route/adjuvant using ELISAs, ELIspot assays, and PhenoSense neutralization assays against a
representative panel of viruses.
Decision Gate to progress to Phase 2: Production of a single or combination vaccine that elicits sera in
vaccinated mice yielding an IC50 >100 in the PhenoSense neutralization assay for ≥75% of mice immunized,
for ≥75% of HIV-1 Env reference strains, while sera from control immunized mice (mice immunized with
bacteria not expressing viral antigen) show no neutralization above baseline control.
In PHASE 2 we will, in Aim 3, conduct a non-human primate (NHP) model study to assess the safety,
immunogenicity, and ability to elicit a neutralizing Ab response by the vaccines. We expect that our vaccines
will induce specific HIV Ag-binding Abs, HIV antigen-specific T cell responses, and BN neutralizing Ab
responses in NHP, implying that the vaccine will be safe and effective in humans. KWC vaccines have a long
history, are inexpensive to make, and can be produced globally in existing facilities, we anticipate that our work
can be quickly translated into safe and effective, inexpensive, globally appropriate, prophylactic HIV vaccines.
关于HIV疫苗开发的广泛共识要求设计抗原以诱导生产
抗体,如已知的广谱中和(BN)单抗(MAb)。两个环境BN单抗
结合部位,膜近端外区(MPER)和融合肽(FP)是有吸引力的靶点
因为它们是线型多肽。我们开发了一种新的、低成本、全球适用的疫苗平台:KILL
全细胞(KWC)基因组减少型大肠杆菌(GREC),疫苗抗原在细菌表面表达
使用革兰氏自动转运器。使用合成生物学,可以在大约3周内制造出可测试的候选疫苗
~每个50美元。使用该平台生产的疫苗每剂成本约为1美元,可以在全球现有工厂生产,
并且有宽大的冷链要求。我们使用KWC grec平台制造了冠状病毒FP疫苗
并在动物模型上显示了临床疗效。我们建议使KWC grec HIV疫苗具有靶向
MPER和Fp。我们的初步数据表明,我们可以用这种方法表达HIV MPER和FP AGS
用MPER来源的抗原诱导小鼠的HIV中和血清。我们假设KWC GREC平台,
针对MPER和FP,将产生安全、有效、低成本、全球适用的艾滋病毒疫苗。
在第一阶段,目标1,我们将利用生物工程合成编码MPER和FP AGS的DNA
加强Ag暴露和抗原性的策略。我们将把这些DNA克隆到我们的表达载体中,
转化为GREC以制造KWC候选疫苗。使用高度中和和相对非中和
,我们将测试候选疫苗,选择那些在结合中和方面表现出最佳差异的疫苗。
用于体内测试的中和性较低的单抗。在目标2中,我们将给小鼠接种疫苗以评估疫苗的免疫原性,
比较不同的候选疫苗,单独和组合,以确定最好的疫苗和
使用ELISA、ELISPOT和PhenoSense中和试验的剂量/路线/佐剂
具有代表性的病毒小组。
进入第二阶段的决策之门:生产单一或联合疫苗,以诱导血清感染
在对≥的表观中和试验中,免疫小鼠产生IC50和GT;100的小鼠免疫75%,
对于75%的≥-1env参考毒株,而来自对照免疫小鼠(免疫小鼠)的血清
不表达病毒抗原的细菌)在基线对照上没有显示中和。
在第二阶段中,我们将在目标3中进行非人灵长类(NHP)模型研究,以评估安全性,
免疫原性,以及通过疫苗诱导中和抗体反应的能力。我们希望我们的疫苗
将诱导特定的HIV抗原结合抗体、HIV抗原特异性T细胞反应和BN中和抗体
NHP中的反应,这意味着该疫苗将在人类身上安全有效。KWC疫苗有很长的时间
历史,制造成本低,可以在全球现有设施中生产,我们预计我们的工作
可以迅速转化为安全有效、廉价、全球适用的预防性艾滋病毒疫苗。
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 }}
Steven L. Zeichner其他文献
Steven L. Zeichner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('Steven L. Zeichner', 18)}}的其他基金
Pilot Study of Rectal Microbial Biomarkers for Appendicitis Diagnosis
用于诊断阑尾炎的直肠微生物生物标志物的初步研究
- 批准号:
9064769 - 财政年份:2015
- 资助金额:
$ 56.53万 - 项目类别:
Development of an in vivo screening technology for cancer vaccine immunogens
癌症疫苗免疫原体内筛选技术的开发
- 批准号:
8508685 - 财政年份:2011
- 资助金额:
$ 56.53万 - 项目类别:
Development of an in vivo screening technology for cancer vaccine immunogens
癌症疫苗免疫原体内筛选技术的开发
- 批准号:
8304214 - 财政年份:2011
- 资助金额:
$ 56.53万 - 项目类别:
Development of an in vivo screening technology for cancer vaccine immunogens
癌症疫苗免疫原体内筛选技术的开发
- 批准号:
8080672 - 财政年份:2011
- 资助金额:
$ 56.53万 - 项目类别:
WIRB - AN OPEN-LABEL, MULTIPLE-DOSE, CROSS-OVER STUDY TO EVALUATE: HIV
WIRB - 一项开放标签、多剂量、交叉研究来评估:HIV
- 批准号:
8167327 - 财政年份:2010
- 资助金额:
$ 56.53万 - 项目类别:
IMPAACT P1066: A PHASE I/II MULTICENTER, OPEN-LABEL, NONCOMPARATIVE STUDY OF
IMPAACT P1066:I/II 期多中心、开放标签、非比较研究
- 批准号:
8167353 - 财政年份:2010
- 资助金额:
$ 56.53万 - 项目类别:
PACTG P1047 SAFETY AND IMMUNOGENICITY OF QUADRIVALENT HUMAN PAPILLOMA VIRUS
PACTG P1047 四价人乳头瘤病毒的安全性和免疫原性
- 批准号:
8167345 - 财政年份:2010
- 资助金额:
$ 56.53万 - 项目类别:
PACTG P1047 SAFETY AND IMMUNOGENICITY OF QUADRIVALENT HUMAN PAPILLOMA VIRUS
PACTG P1047 四价人乳头瘤病毒的安全性和免疫原性
- 批准号:
7951109 - 财政年份:2008
- 资助金额:
$ 56.53万 - 项目类别:
IMPAACT P1066: A PHASE I/II MULTICENTER, OPEN-LABEL, NONCOMPARATIVE STUDY OF
IMPAACT P1066:I/II 期多中心、开放标签、非比较研究
- 批准号:
7951122 - 财政年份:2008
- 资助金额:
$ 56.53万 - 项目类别:
相似海外基金
Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
- 批准号:
23K08213 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
- 批准号:
2881726 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
Studentship
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
- 批准号:
10735090 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
- 批准号:
10722146 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
- 批准号:
10935776 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
- 批准号:
10935796 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
- 批准号:
10935775 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
- 批准号:
10649041 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
- 批准号:
10735964 - 财政年份:2023
- 资助金额:
$ 56.53万 - 项目类别:














{{item.name}}会员




