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

• 批准号: 10716190
• 负责人: Roger LE GRAND
• 金额: $ 52.99万
• 依托单位: OSIVAX SAS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10716190
• 关键词: Adjuvant; Animals; Antibodies; Antibody Response; Antigen Targeting; Antigens; Avian Influenza; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cessation of life; Clinical; Conduct Clinical Trials; Dose; Effectiveness; Elements; Exposure to; Future; Glycoproteins; Grant; Hospitalization; Human; Immune response; Immunity; Immunization; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Length; Membrane Proteins; Modeling; Monkeys; Mus; Mutation; National Institute of Allergy and Infectious Disease; Nucleoproteins; Pathogenicity; Patients; Persons; Phase; Populations at Risk; Recombinant Proteins; Research Design; Respiratory Disease; Seasons; Structure; Surface; Surface Antigens; T cell response; T-Lymphocyte; Technology; Testing; Update; Vaccination; Vaccines; Virus; age group; arm; cost; cost estimate; cross reactivity; current pandemic; global health; high risk; immunogenic; immunogenicity; improved; influenza outbreak; influenza virus strain; influenza virus vaccine; new pandemic; nonhuman primate; novel; novel strategies; pandemic disease; pandemic influenza; pandemic potential; prevent; protective efficacy; research and development; seasonal influenza; technology platform; universal influenza vaccine; vaccine development

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 此外，流感大流行是一种长期威胁，是呼吸道疾病的主要原因。 目前的疫苗可能会在 6 个月内导致全球超过 3000 万人死亡。 针对不断变化的表面蛋白的反应，需要每年更新。 当流行病毒与疫苗病毒不匹配时，感染率可能低至 10-20%。 疫苗具有高度毒株特异性，它们对新型大流行毒株提供的保护非常有限。 预防未来未知的季节性或大流行性流感病毒株的最佳方法是使用有效的疫苗 对抗尽可能广泛的菌株——希望具有普遍功效，它必须针对一种抗原。 在所有流感毒株和亚型中高度保守的核蛋白（NP）非常保守。 A 株内（高达 95%）暴露前患者体内存在的 NP 特异性 T 细胞与 >70% 的减少相关。 甲型流感——大流行性和季节性流感因此，我们对抗T细胞免疫。 NP 对流感（包括大流行毒株）具有广谱（可能是普遍的）功效。 Osivax 提出了一种基于其专有平台技术oligoDOM®的新颖方法，以生成 使用该技术，Osivax 开发了具有改善的体液和细胞免疫原性的七聚体抗原。 OVX836：一种重组蛋白，其中 H1N1 流感病毒株的全长 NP 序列为 与oligoDOM®融合，产生高、持久、剂量依赖性的体液和T细胞反应。 在小鼠中，导致针对同源和异源的致命攻击的交叉保护功效 这一功效在 2017 年进行的两项 2a 期临床试验中得到了临床证实。 异源 H1N1 和 H3N2 毒株占主导地位的流感季节，其功效范围为 75-80%，符合 WHO/NIAID 流感疫苗的理想功效目标。 OVX836优于其他疫苗的地方在于它具有通用性、多季节性和毒株依赖性。 与现有疫苗相比，所有三种免疫手段——CD8+ T 细胞、CD4+ T 细胞和抗体—— 主要依赖于针对极易发生突变的表面抗原的抗体反应。 该项目旨在证明 OVX836 针对两种异源流感病毒所提供的广泛保护作用 enza A 菌株——即曾经流行但现在季节性的 pH1N1（具体目标 #1）和 H5N1，一种高度 具有大流行潜力的致病菌株（具体目标#2）——在非人类灵长类动物（NHP）挑战模型中。 虽然幼稚感染模型更简单、更方便，但感染前模型可能更好地模仿 因此，为了验证感染前模型，我们建议评估保护作用。 通过评估免疫应答，OVX836 在未感染和感染前的 NHP 中产生免疫反应。 我们还将进一步研究我们疫苗的作用机制并确定潜在的 保护的相关性有待在人类中进一步评估。