A molecularly targeted pre- and post-exposure vaccine for anthrax

炭疽暴露前和暴露后分子靶向疫苗

• 批准号: 8781529
• 负责人: JON OSCHERWITZ
• 金额: $ 26.02万
• 依托单位: VLP BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781529
• 关键词: Adjuvant; Adverse effects; Aerosols; Alhydrogel; Animal Model; Anthrax Vaccines; Anthrax disease; Antibodies; Antigens; Bacillus anthracis; Benchmarking; Biothrax; Breathing; Clinical; Collaborations; Development; Dose; Drug Formulations; Engineering; Epitopes; Evaluation; Event; Exposure to; Foundations; General Population; Health; Human; Immune Sera; Immunity; Immunization; In Vitro; Incidence; Individual; Injection of therapeutic agent; Institute of Medicine (U.S.); Lead; Lethal Dose 50; Licensing; Mediating; Metric; Military Personnel; Mus; Oryctolagus cuniculus; Peptides; Population; Protocols documentation; Qualifying; Reproduction spores; Risk; Serum; Site; Specificity; Technology; Testing; Toxin; Vaccination; Vaccines; Virus-like particle; aerosolized; anthrax lethal factor; base; comparative; immunogenic; immunogenicity; in vivo; member; neutralizing antibody; next generation; nonhuman primate; novel; novel vaccines; phase 2 study; vaccine development

DESCRIPTION (provided by applicant): We have shown that immunization of rabbits with multiple antigenic peptides (MAPs) displaying sequence from domain 2 of protective antigen (PA) elicit antibodies specific for a linear determinant within the 2?2-2?3 loop of PA, that mediate potent neutralization of lethal toxin (LeTx) in vitro. We have now shown in two separate large studies that antibodies against this site, referred to as the loop neutralizing determinant (LND), can mediate complete protection of rabbits from an aerosolized spore inhalation challenge with a 200 LD50-targeted dose of B. anthracis Ames strain. LND-specific antibody is not present in rabbit PA-antiserum and more importantly, is not present in AVA-vaccinee sera. The LND specificity, therefore, is non-overlapping with the specificities present in PA antisera, and therefore represents a unique and novel specificity for development of a stand-alone or adjunctive vaccine for anthrax. We have now developed an optimized highly immunogenic LND-VLP vaccine using our novel proprietary platform technology which incorporates the vaccine target sequence into highly immunogenic virus like particles. This new LND vaccine, when formulated with human use adjuvants, has the potential to elicit potent and rapid protective immunity against anthrax with only one or two injections. In the current project, we will further optimize the LND-VLP vaccine through insertion of a second linear neutralizing epitope we have identified in lethal factor, to establish additional critical redundancy and increased potency in a new bivalent LND-LF-VLP vaccine, which promises to be a safe and strategic new pre- and post-exposure vaccine for anthrax.

描述（由申请人提供）：我们已经证明，用显示保护性抗原（PA）结构域 2 序列的多种抗原肽（MAP）对兔子进行免疫，可引发对 2?2-2?3 环内的线性决定簇具有特异性的抗体。 PA，在体外介导致命毒素 (LeTx) 的有效中和。我们现在在两项独立的大型研究中表明，针对该位点的抗体（称为环中和决定簇 (LND)）可以介导完全保护兔子免受 200 LD50 目标剂量炭疽芽孢杆菌 Ames 雾化孢子吸入攻击的影响拉紧。 LND 特异性抗体不存在于兔 PA 抗血清中，更重要的是，也不存在于 AVA 疫苗血清中。因此，LND 特异性与 PA 抗血清中存在的特异性不重叠，因此代表了开发炭疽独立疫苗或辅助疫苗的独特且新颖的特异性。我们现在使用我们新颖的专有平台技术开发了一种优化的高免疫原性 LND-VLP 疫苗，该技术将疫苗靶序列整合到高免疫原性病毒样颗粒中。这种新型 LND 疫苗与人类使用的佐剂配制在一起，只需注射一到两次，就有可能引发针对炭疽的强大而快速的保护性免疫力。在当前的项目中，我们将通过插入我们在致死因子中确定的第二个线性中和表位来进一步优化 LND-VLP 疫苗，以建立额外的关键冗余并增强疫苗的效力。 新型二价 LND-LF-VLP 疫苗，有望成为一种安全且具有战略意义的新型炭疽暴露前和暴露后疫苗。