Development of an mRNA-Based Therapeutic HIV/AIDS Vaccine
开发基于 mRNA 的治疗性 HIV/AIDS 疫苗
基本信息
- 批准号:10364654
- 负责人:
- 金额:$ 82.38万
- 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:2020-03-05 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAntigensB-LymphocytesBloodCD8-Positive T-LymphocytesCellular ImmunityClinicalClinical ResearchClinical assessmentsCollaborationsDNADataDevelopmentDisease ProgressionDisease remissionDoseEconomic BurdenEnsureEpitope MappingEpitopesFrequenciesGAG GeneGenerationsGenesGermanyGoalsHIVHIV InfectionsHIV vaccineHealthHumanImmuneImmune responseImmunityImmunologicsIndividualInfectionInjectionsInterceptLeadLifeLife ExpectancyLymphoid TissueMacaca mulattaMeasurableMediatingMessenger RNAPatientsPeptidesPersonsPlasmaPositioning AttributePrimary InfectionPrognosisRNARNA vaccineRecrudescencesRegimenRelapseRiskRouteSIVSIV VaccinesSiteSocietiesSpecificityStainsT cell responseT-Lymphocyte EpitopesTechnologyTherapeuticTimeVaccinatedVaccinationVaccine DesignVaccine TherapyVaccinesViralViral Load resultViral reservoirVirusVirus DiseasesVirus ReplicationWithdrawalanti-CD20antiretroviral therapyantiviral immunitybasebiopharmaceutical industryclinically translatablecohortcytokinedesignexperimental studyimmunogenicimprovedlymph nodesnovel therapeutic interventionpreventresponsesafety and feasibilitytherapeutic vaccinetherapy designtooltositumomabvaccination protocolvaccination schedulevaccination strategyvaccine efficacyvaccine platformvectorvector controlvector vaccineviral rebound
项目摘要
PROJECT SUMMARY
Although the advent of combination antiretroviral therapy (cART) has dramatically improved the prognosis of
people living with human immunodeficiency virus (HIV), cART alone cannot eradicate the infection and,
therefore, daily treatment must be maintained for life to prevent relapse of uncontrolled viral replication and
resumption of disease progression. However, lifelong treatment entails both health risks to treated individuals
and a significant economic burden to society. As such, there is a pressing need to develop novel therapeutic
interventions to cure HIV. Since most examples of stringent, long-term, spontaneous and vaccine-associated
immune control of HIV and simian immunodeficiency virus (SIV) infection are either known, or strongly suspected
to be CD8+ T cell-mediated, therapeutic strategies designed to exploit CD8+ T cell immunity hold great promise
for achieving durable control of virus replication in the absence of cART, often referred to as a “functional cure”.
However, in most people, naturally occurring CD8+ T cell responses induced by HIV infection are often
ineffective at controlling the virus. As such, any HIV cure strategy based on enhancing CD8+ T cell immunity
would need to elicit immune responses that are qualitatively and/or quantitatively different from those that
emerge during primary infection and are subsequently maintained during cART. In addition, in the setting of cure
where the rebound-competent viral reservoir is systemically distributed, having high frequencies of effector-
differentiated and functionally potent anti-viral CD8+ T cell responses pre-positioned in sites of potential viral
rebound (even in immune privileged sites such as B cell follicles) at the time of cART cessation is likely to be
critical for achieving durable post-cART viral control. In this project, we will determine whether a therapeutic
vaccination strategy that utilizes the messenger ribonucleic acid (mRNA)-based vaccine platform RNActive,
can enhance cellular immunity in SIV-infected rhesus macaques (RM) on cART and establish high-level, long-
term control of SIV replication after cART cessation. The choice of this vector is based on preliminary data
demonstrating RNActivevaccines with SIV gene inserts (mRNA/SIV) are highly immunogenic in RM, with the
capacity to elicit potent, systemically distributed, SIV-specific CD8+ T cells with broad epitope recognition. Here
we will assess whether mRNA/SIV vaccination alone or in combination with anti-CD20 B cell depletion (to disrupt
B cell follicles) can facilitate immediate interception of rebounding viral reservoirs to facilitate durable control of
SIV replication after cART cessation. Any finding of vaccine efficacy in this project will provide strong impetus
for clinical assessment of the RNActiveplatform in cART-suppressed HIV+ patients and potentially lead to a
clinically translatable therapeutic approach to achieve HIV infection remission off cART.
项目概要
尽管联合抗逆转录病毒疗法(cART)的出现极大地改善了患者的预后
对于感染人类免疫缺陷病毒 (HIV) 的人,仅使用 cART 无法根除感染,并且
因此,必须终生维持日常治疗,以防止不受控制的病毒复制复发和
然而,终身治疗会给接受治疗的个体带来两种健康风险。
以及给社会带来巨大的经济负担,因此迫切需要开发新的治疗方法。
由于大多数严格的、长期的、自发的和与疫苗相关的例子。
HIV 和猿猴免疫缺陷病毒 (SIV) 感染的免疫控制要么是已知的,要么是强烈怀疑的
由于 CD8+ T 细胞介导,旨在利用 CD8+ T 细胞免疫的治疗策略前景广阔
在没有 cART 的情况下实现病毒复制的持久控制,通常被称为“功能性治愈”。
然而,在大多数人中,由 HIV 感染诱导的自然发生的 CD8+ T 细胞反应通常是
因此,任何基于增强 CD8+ T 细胞免疫的 HIV 治疗策略都无效。
需要引发与那些在质量和/或数量上不同的免疫反应
在原发感染期间出现,随后在 cART 期间维持。此外,在治愈过程中。
其中具有反弹能力的病毒库是系统性分布的,具有高频率的效应子
预先定位在潜在病毒位点的分化且功能有效的抗病毒 CD8+ T 细胞反应
cART 停止时的反弹(甚至在 B 细胞滤泡等免疫特权部位)很可能是
对于实现持久的 cART 后病毒控制至关重要。在这个项目中,我们将确定是否有一种治疗方法。
利用基于信使核糖核酸 (mRNA) 的疫苗平台 RNActive 的疫苗接种策略,
可以增强 CART 感染 SIV 的恒河猴 (RM) 的细胞免疫,并建立高水平、长期
cART 停止后 SIV 复制的期限控制 该载体的选择基于初步数据。
证明带有 SIV 基因插入 (mRNA/SIV) 的 RNActive 疫苗在 RM 中具有高度免疫原性,
能够引发有效的、系统性分布的、具有广泛表位识别的 SIV 特异性 CD8+ T 细胞。
我们将评估是否单独进行 mRNA/SIV 疫苗接种或与抗 CD20 B 细胞耗竭相结合(以破坏
B细胞滤泡)可以促进立即拦截反弹的病毒库,从而促进持久控制
cART 停止后 SIV 的复制。该项目中疫苗功效的任何发现都将提供强大的推动力。
用于对 cART 抑制的 HIV+ 患者的 RNAactive 平台进行临床评估,并可能导致
通过 cART 实现 HIV 感染缓解的临床可转化治疗方法。
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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Afamefuna Okoye其他文献
Afamefuna Okoye的其他文献
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{{ truncateString('Afamefuna Okoye', 18)}}的其他基金
Optimizing the Depletion of innate immune Effector Cells in Nonhuman Primates
优化非人灵长类动物先天免疫效应细胞的消耗
- 批准号:
10646290 - 财政年份:2022
- 资助金额:
$ 82.38万 - 项目类别:
Optimizing the Depletion of innate immune Effector Cells in Nonhuman Primates
优化非人灵长类动物先天免疫效应细胞的消耗
- 批准号:
10546827 - 财政年份:2022
- 资助金额:
$ 82.38万 - 项目类别:
Targeting the HIV/SIV reservoir at time of ART initiation
在开始 ART 时针对 HIV/SIV 病毒库
- 批准号:
10222532 - 财政年份:2020
- 资助金额:
$ 82.38万 - 项目类别:
Targeting the HIV/SIV reservoir at time of ART initiation
在开始 ART 时针对 HIV/SIV 病毒库
- 批准号:
10101853 - 财政年份:2020
- 资助金额:
$ 82.38万 - 项目类别:
Targeting the HIV/SIV reservoir at time of ART initiation
在开始 ART 时针对 HIV/SIV 病毒库
- 批准号:
10443751 - 财政年份:2020
- 资助金额:
$ 82.38万 - 项目类别:
Development of an mRNA-Based Therapeutic HIV/AIDS Vaccine
开发基于 mRNA 的治疗性 HIV/AIDS 疫苗
- 批准号:
10005745 - 财政年份:2020
- 资助金额:
$ 82.38万 - 项目类别:
Targeting the HIV/SIV reservoir at time of ART initiation
在开始 ART 时针对 HIV/SIV 病毒库
- 批准号:
10658852 - 财政年份:2020
- 资助金额:
$ 82.38万 - 项目类别:
Development of an mRNA-Based Therapeutic HIV/AIDS Vaccine
开发基于 mRNA 的治疗性 HIV/AIDS 疫苗
- 批准号:
10585914 - 财政年份:2020
- 资助金额:
$ 82.38万 - 项目类别:
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