Development of a bioconjugate vaccine against Group B Streptococcus

针对 B 族链球菌的生物结合疫苗的开发

• 批准号: 9890994
• 负责人: Mario Feldman
• 金额: $ 28.01万
• 依托单位: VAXNEWMO, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-12 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890994
• 关键词: Adult; Antibiotic Prophylaxis; Antibiotic Therapy; Bacteria; Biological; Biological Products; Birth; Bypass; Carbohydrates; Carrier Proteins; Characteristics; Chemicals; Clinical; Complex; Conjugate Vaccines; Contracts; Country; Data; Dependence; Developed Countries; Development; Disease; Enzymes; Epitopes; Escherichia coli; Event; Funding; Glucose; Human; Immunity; Immunoglobulin G; Immunologic Memory; Income; Infant; Intervention; Late-Onset Disorder; Legal patent; Life; Link; Maternal antibody; Measures; Meta-Analysis; Methods; Mind; Modeling; Molecular; Mus; Neonatal; Neonatal meningitis; Newborn Infant; Onset of illness; Pharmacologic Substance; Phase; Polysaccharides; Pregnant Women; Premature Birth; Process; Production; Proteins; Protocols documentation; Recombinants; Research; Risk; Safety; Serotyping; Shigella dysenteriae; Site; Streptococcal Infections; Streptococcal Vaccines; Streptococcus Group B; Synthesis Chemistry; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccine Production; Vaccines; World Health Organization; age group; capsule; chemical conjugate; chemical group; cost; early onset; fetal; glycosylation; immunogenic; immunogenicity; in vivo; innovation; interest; intrapartum; low and middle-income countries; maternal risk; neonatal death; neonatal infection; neonatal sepsis; neonate; next generation; novel; placental transfer; pregnant; prevent; prophylactic; prototype; pup; stillbirth; success; sugar; transmission process; treatment strategy; vaccine development

PROJECT SUMMARY Streptococcus agalactiae, commonly referred to as Group B Streptococcus (GBS), is a leading cause of neonatal meningitis and sepsis worldwide as well as an agent of invasive disease in both pregnant and non-pregnant adults. GBS neonatal disease manifests as early onset, defined as disease within the first six days after birth, or late onset, defined as disease occurring after the first week of life; both of which are life threatening. In some instances, early onset disease is preventable with intrapartum antibiotic prophylaxis; however, this treatment strategy is not practical for low- and middle-income countries nor does it prevent late onset disease or the ~3.5 million preterm and 60,000 stillbirths attributed to GBS each year. Molecularly, GBS produces one of ten different capsular polysaccharides, five of which (serotype Ia, Ib, II, III, and V) are associated with 97% of all invasive neonatal GBS disease events. In addition, previous studies have demonstrated that placental transfer of maternal antibodies are able protect neonates from invasive GBS infection. Therefore, a vaccine targeting these five serotypes is of high societal and commercial value. In order to make an efficacious vaccine targeting GBS capsules, the polysaccharide must be covalently linked to an immunogenic carrier protein generating what’s termed a conjugate vaccine. Conjugate vaccines are considered some of the most effective vaccines to date, as they are highly protective and generate immunological memory across all age groups. However, their synthesis is complex, costly, and not conducive for all polysaccharides, which has hindered development of novel conjugate vaccines against life threatening bacteria like GBS. As an alternative manufacturing platform, VaxNewMo is developing conjugate vaccines using an innovative in vivo conjugation technology, which eliminates the dependency on intricate chemical conjugation methods currently employed to synthesize these vaccines. Using VaxNewMo’s proprietary bioconjugating enzyme technology, we will therefore generate the most broadly covering GBS vaccine against five of the most prevalent GBS serotypes causing 97% of all neonatal invasive disease events. The proposed research in this phase I application will focus on (Aim 1) developing five glycoengineered strains of E. coli for the scalable, recombinant expression of GBS capsular polysaccharides in conjunction with VaxNewMo’s conjugating enzyme technology, generating the first bioconjugate vaccine against GBS. Subsequently (Aim 2) we will demonstrate that a monovalent GBS bioconjugate vaccine is immunogenically non-inferior to a traditionally prepared chemical GBS conjugate vaccine. We will also demonstrate the versatility of VaxNewMo’s bioconjugating platform by providing preliminary immunogenicity data on a pentavalent GBS bioconjugate. Last, we will test for correlates of immunity by determining bacterial burden and/or survival of newborn pups infected with GBS born from vaccinated mice. Our next step for Phase II funding will be to develop and optimize a purification protocol for large scale quantities of GBS bioconjugate vaccines and provide sufficient safety, tolerability and immunogenicity data for Fast Track FDA approval.

项目摘要 链球菌agalactiae，通常称为B组链球菌（GBS），是新生儿的主要原因 全球脑膜炎和败血症以及怀孕和非怀孕的侵入性疾病的药物 成年人。 GBS新生儿疾病表现为早期发病，在出生后的头六天内定义为疾病，或 发病迟到，被定义为生命的第一周后发生的疾病；两者都威胁生命。在某些人中 实例，可以通过预防性抗生素预防预防早期发作。但是，这种治疗方法 对于低收入和中等收入国家而言，策略是不切实际的，也不会预防迟发疾病或〜3.5 每年GBS归因于GBS，百万早产和60,000个死产。 GB分子产生了十种不同的一种 囊状多糖，其中五种（血清型IA，IB，II，III和V）与所有侵入性的97％相关 新生儿GBS疾病事件。此外，先前的研究表明 孕产妇抗体能够保护新生儿免受侵入性GBS感染。因此，针对这些的疫苗 五种血清型具有很高的社会和商业价值。为了制造有效的疫苗靶向GB 胶囊，多糖必须与免疫原性蛋白蛋白共价链接 称为共轭疫苗。共轭疫苗被认为是迄今为止的一些最有效的疫苗 它们受到高度保护，并在所有年龄组中产生免疫记忆。但是，它们的合成 对于所有多糖而言，复杂，昂贵且不导电，这阻碍了新颖的发展 结合疫苗，以防止像GB一样威胁生命的细菌。作为替代制造平台， VaxNewmo正在使用创新的体内共轭技术开发共轭疫苗，该技术是 消除对当前用于合成这些复杂化学共轭方法的依赖性 疫苗。因此，使用VaxNewmo的专有生物偶联酶技术，我们将产生最多的 与最普遍的GBS血清型中的五种GBS疫苗广泛覆盖GBS疫苗，造成97％的新生儿 侵入性疾病事件。 I阶段I申请中的拟议研究将重点放在（AIM 1）开发五个 大肠杆菌的糖化菌株，用于在GBS囊囊多糖中可扩展的重组表达 与VaxNewmo的共轭酶技术结合，生成第一种生物偶联物疫苗 GBS。随后（AIM 2）我们将证明单价GBS生物偶联疫苗是 从传统制备的化学GBS结合疫苗中进行免疫原性。我们也会 通过提供初步的免疫原性数据来证明VaxNewmo的生物偶联平台的多功能性 在Pentavalent GBS Bioconjugate上。最后，我们将通过确定细菌伯嫩测试免疫的相关性 和/或新生幼崽感染了来自接种疫苗的小鼠的GB的生存。我们的下一步资金 将开发和优化大规模GBS BioconJugate疫苗的纯化方案 并提供足够的安全性，耐受性和免疫原性数据，以快速跟踪FDA批准。