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.

摘要 流感是呼吸道疾病的主要原因。此外，流感大流行是一种常年的威胁， 可能会在6个月内导致全球3000万人死亡。目前的疫苗产生一种抗体免疫反应 应对表面蛋白质，这些蛋白质不断变化，需要每年更新。此外，它们的有效性-- 当流行病毒与疫苗病毒不匹配时，NESS可能低至10-20%。作为季节性流感 疫苗具有高度的毒株特异性，对新的大流行毒株提供的保护非常有限。 预防未知的未来季节性或大流行流感的最好方法是接种有效的疫苗。 针对尽可能广泛的菌株--最好是普遍有效。要做到这一点，它必须针对一种抗原。 这在所有流感毒株和亚型中都是高度保守的。核蛋白(NP)非常保守 在A-菌株中(高达95%)。暴露前患者中存在的NP特异性T细胞与&gt；70%的减少相关- 甲型流感--大流行和季节性感染。因此，我们假设T细胞免疫是针对 NP将对流感具有广谱(可能是普遍的)疗效，包括大流行毒株。 Osivax提出了一种基于其专有平台技术OlioDOM®的新方法，以生成 具有改进的体液和细胞免疫原性的七聚体抗原。使用这项技术，Osivax开发- OVX836：一种重组蛋白，其中H1N1流感毒株的全长NP序列是 已融合到寡聚DOM®。OVX836可产生高、持久且剂量依赖的体液和T细胞应答 在小鼠身上，导致对致死攻击的交叉保护效力，既有同源的也有异源的- 甲型和乙型流感病毒株。年进行的两个2a期临床试验证实了这一疗效。 异源H1N1和H3N1毒株占主导地位的流感季节，其效力在 75-80%，符合世卫组织/NIAID流感疫苗的期望疗效目标。的主要优势 与其他疫苗相比，OVX836具有通用性、多季节和不受毒株影响的特点。此外，它还能刺激 所有三种免疫手臂-CD8+T细胞，CD4+T细胞和抗体-与现有的疫苗形成对比，后者 主要依赖于对极易发生突变的表面抗原的抗体反应。 本项目旨在演示OVX836针对两种异源影响提供的广泛保护- Enza A-毒株--即曾经的大流行但现在是季节性的H1N1(特定目标1)和H5N1，一种高度 具有大流行潜力的致病菌株(特定目标2)--在非人灵长类(NHP)挑战模型中。 虽然幼稚的感染模型更简单、更方便，但预先感染的模型可能更好地模拟 人类的状况。因此，为了验证感染前模型，我们建议评估保护 以及OVX836在幼稚和感染前的NHP中产生的免疫应答。通过评估免疫反应- 我们还将进一步研究我们的疫苗的作用机制，并确定潜在的 在人类身上保护的相关性有待进一步评估。