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