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，流感大流行是一种长期威胁， 可能在6个月内导致全球超过3000万人死亡。目前的疫苗产生抗体免疫反应， 对抗不断变化的表面蛋白质，需要每年更新。此外，其有效的- 当循环病毒与疫苗病毒不匹配时，Ness可低至10-20%。作为季节性流感 疫苗是高度株特异性的，它们对新的大流行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 针对尽可能广泛的菌株-优选地具有普遍功效。要做到这一点，它必须针对抗原 在所有流感病毒株和亚型中高度保守。核蛋白（NP）是非常保守的 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>70%的减少相关。 甲型流感-大流行性和季节性。因此，我们假设T细胞免疫针对 NP将对流感具有广谱（可能是普遍的）效力，包括大流行毒株。 Osivax提出了一种基于其专有平台技术oligoDOM®的新方法， 具有改善的体液和细胞免疫原性的七聚体抗原。利用这项技术，Osivax开发- oped OVX 836：一种重组蛋白，其中H1N1流感病毒株的全长NP序列被 与oligoDOM®融合。OVX 836产生高、持久和剂量依赖性的体液和T细胞应答 在小鼠中，导致对同源和异源In-A的致死性攻击的交叉保护功效。 流感病毒A型和B型菌株。这一功效在期间进行的两项2a期临床试验中得到了临床证实 流感季节，其中异源H1N1和H3 N2毒株占主导地位，疗效范围为 75- 80%，符合WHO/NIAID对流感疫苗的预期有效性目标。的主要优点 OVX 836与其他疫苗相比，它具有通用性，多季节性和菌株独立性。此外，它刺激 免疫的所有三个分支-CD 8 + T细胞，CD 4 + T细胞和抗体-与现有的疫苗相比， 主要依赖于针对高度倾向于突变的表面抗原的抗体应答。 该项目旨在证明OVX 836对两种异源感染的保护范围， enza A-菌株-即曾经大流行但现在是季节性的pH 1 N1（特定目标#1）和H5 N1， 具有大流行潜力的致病菌株（特定目标#2）-在非人灵长类动物（NHP）攻毒模型中。 虽然初始感染模型更简单，更方便，但感染前模型可能更好地模拟感染模型。 人类的状况因此，为了验证预感染模型，我们建议评估保护 以及OVX 836在未感染和感染前NHP中赋予的免疫应答。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， 保护的相关因素，以进一步评估在人类。