Broad spectrum protection and immune responses induced by an NP-based universal influenza vaccine in heterologous NHP challenge model
基于 NP 的通用流感疫苗在异源 NHP 攻击模型中诱导的广谱保护和免疫反应
基本信息
- 批准号:10716190
- 负责人:
- 金额:$ 52.99万
- 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:2023-09-26 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAnimalsAntibodiesAntibody ResponseAntigen TargetingAntigensAvian InfluenzaCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCessation of lifeClinicalConduct Clinical TrialsDoseEffectivenessElementsExposure toFutureGlycoproteinsGrantHospitalizationHumanImmune responseImmunityImmunizationInfectionInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A Virus, H3N2 SubtypeInfluenza A Virus, H5N1 SubtypeInfluenza A virusLengthMembrane ProteinsModelingMonkeysMusMutationNational Institute of Allergy and Infectious DiseaseNucleoproteinsPathogenicityPatientsPersonsPhasePopulations at RiskRecombinant ProteinsResearch DesignRespiratory DiseaseSeasonsStructureSurfaceSurface AntigensT cell responseT-LymphocyteTechnologyTestingUpdateVaccinationVaccinesVirusage grouparmcostcost estimatecross reactivitycurrent pandemicglobal healthhigh riskimmunogenicimmunogenicityimprovedinfluenza outbreakinfluenza virus straininfluenza virus vaccinenew pandemicnonhuman primatenovelnovel strategiespandemic diseasepandemic influenzapandemic potentialpreventprotective efficacyresearch and developmentseasonal influenzatechnology platformuniversal influenza vaccinevaccine development
项目摘要
ABSTRACT
Influenza is a major cause of respiratory disease. Moreover, an influenza pandemic is a perennial threat, which
may lead to >30 million deaths worldwide within 6 months. Current vaccines generate an antibody immune re-
sponse against surface proteins, which change constantly, requiring annual updates. Moreover, their effective-
ness may be as low as 10-20% when circulating viruses do not match the vaccine viruses. As seasonal influenza
vaccines are highly strain-specific, they would provide very limited protection against novel pandemic strains.
The best way to prevent an unknown future seasonal or pandemic influenza strain is with a vaccine with efficacy
against as broad a range of strains as possible – preferably universal efficacy. To do so, it must target an antigen
that is highly conserved among all influenza strains and subtypes. Nucleoprotein (NP) is very well conserved
within A-strains (up to 95%). NP-specific T-cells present in patients before exposure correlate with >70% reduc-
tion in influenza A – both pandemic and seasonal. Therefore, we hypothesize that T-cell immunization against
NP would have broad-spectrum (possibly universal) efficacy against influenza, including pandemic strains.
Osivax is proposing a novel approach based on its proprietary platform technology, oligoDOM®, to generate
heptameric antigens with improved humoral and cellular immunogenicity. Using this technology, Osivax devel-
oped OVX836: a recombinant protein in which the full-length NP sequence of an H1N1 influenza strain was
fused to oligoDOM®. OVX836 generates high, long-lasting, and dose-dependent humoral and T-cell responses
in mice, leading to cross-protective efficacy against lethal challenge by both homologous and heterologous in-
fluenza A- and B-strains. This efficacy was confirmed clinically in two Phase 2a clinical trials conducted during
influenza seasons in which heterologous H1N1 and H3N2 strains were dominant, with efficacy in the range of
75-80%, in line with the WHO/NIAID aspirational efficacy target for influenza vaccines. The main advantage of
OVX836 over other vaccines is that it is universal, multi-season and strain-independent. Moreover, it stimulates
all three arms of immunity – CD8+ T-cells, CD4+ T-cells and antibodies – in contrast to existing vaccines, which
rely mostly on an antibody response against surface antigens that are highly prone to mutations.
This project aims to demonstrate the breadth of protection conferred by OVX836 against two heterologous influ-
enza A-strains – namely the once pandemic but now seasonal pH1N1 (Specific Aim #1) and H5N1, a highly
pathogenic strain with pandemic potential (Specific Aim #2) – in a non-human primate (NHP) challenge model.
While a naïve infection model is simpler and more convenient, a pre-infected model is likely to better mimic the
human condition. Therefore, in order to validate a pre-infection model, we propose to evaluate the protection
and immune response conferred by OVX836 in naïve and pre-infected NHPs. By evaluating the immune re-
sponses in NHPs we will also further investigate the mechanism of action of our vaccine and identify potential
correlates of protection to be further evaluated in human.
抽象的
流感是呼吸道疾病的主要原因。而且,影响者是多年生威胁,
在6个月内可能导致全球3000万人死亡。电流疫苗会产生抗体免疫抗性
对表面蛋白质的赞助商,该蛋白会不断变化,需要年度更新。而且,他们的有效
当循环病毒与疫苗病毒不匹配时,NES可能会低至10-20%。作为季节性影响
疫苗是高度应变特异性的,它们将提供非常有限的保护,以防止新的大流行菌株。
防止未知的未来季节性或大流行影响力菌株的最佳方法是轻松
反对尽可能广泛的菌株 - 优先的通用效率。为此,它必须针对抗原
核蛋白(NP)非常保守
在A-strains内(最高95%)。暴露之前,患者中存在NP特异性的T细胞,与降低> 70%相关 -
影响力和季节性的影响力。因此,我们假设T细胞免疫反对
NP将具有针对影响的影响的广谱(可能是普遍)的效率,包括大流行菌株。
Osivax正在根据其专有平台技术Poligodom®提出一种新颖的方法,以生成
具有改善的体液和细胞免疫原性的肝素抗原。使用这项技术,Osivax Devel-
OPED OVX836:一种重组蛋白,其中H1N1影响力的全长NP序列为
融合到寡头®。 OVX836产生高,持久和剂量依赖性的体液和T细胞反应
在小鼠中,通过同源和异源性内的攻击致命挑战,从而产生交叉保护效率
Fluenza a-和b-strains。在两期2A期临床试验中进行了临床证实。
流感季节,异源H1N1和H3N2菌株占主导地位,效率在范围内
75-80%,与WHO/NIAID的障碍效率目标一致。主要优势
其他疫苗的OVX836是它是通用的,多季节的和不依赖应变的。而且,它刺激了
与现有的疫苗相反,所有三个免疫力 - CD8+ T细胞,CD4+ T细胞和抗体
主要依靠对表面抗原的抗体反应,该反应高度容易突变。
该项目旨在证明OVX836对两种异源影响的保护广度 -
Enza a-strains - 即曾经大流行,但现在季节性的PH1N1(特定目标#1)和H5N1,高度
在非人类灵长类动物(NHP)挑战模型中,具有大流行潜力的致病菌株(特定目标#2)。
虽然幼稚的感染模型更简单,更方便,但预感染的模型可能会更好地模仿
人类状况。因此,为了验证感染模型,我们建议评估保护
OVX836在幼稚和预感染的NHP中赋予的免疫响应。通过评估免疫 -
NHP中的赞助商我们还将进一步研究疫苗的作用机理并确定潜力
在人类中进一步评估保护的相关性。
项目成果
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