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.

项目总结 无乳链球菌，通常被称为B组链球菌(GBS)，是新生儿的主要病因 全世界的脑膜炎和败血症以及妊娠和非妊娠的侵袭性疾病的病原体 成年人。GBS新生儿疾病表现为早发，定义为出生后头六天内的疾病，或 晚发型，定义为出生后第一周的疾病；这两种疾病都有生命危险。在一些 例如，早发性疾病可以通过产中预防性使用抗生素来预防；然而，这种治疗 该战略对低收入和中等收入国家是不现实的，也不能预防晚发性疾病或~3.5 每年有100万早产和6万死产可归因于GBS。从分子上讲，GBS产生十种不同的 荚膜多糖，其中五种(Ia、Ib、II、III和V型)与97%的侵袭性 新生儿GBS疾病事件。此外，以前的研究已经证明，胎盘转移 母体抗体能够保护新生儿免受侵袭性GBS感染。因此，针对这些的疫苗 五种血清型具有较高的社会和商业价值。为了研制针对GBS的有效疫苗 胶囊，多糖必须共价连接到免疫原性载体蛋白上，产生什么 称为结合疫苗。结合疫苗被认为是迄今为止最有效的疫苗之一，如 它们具有高度的保护性，并在所有年龄段都能产生免疫记忆。然而，他们的合成 是复杂的，昂贵的，不利于所有的多糖，这阻碍了小说的发展 结合疫苗对抗像GBS这样威胁生命的细菌。作为替代制造平台， VaxNewMo正在开发使用创新的体内结合技术的结合疫苗，该技术 消除了对目前用于合成这些化合物的复杂的化学结合方法的依赖 疫苗。因此，使用VaxNewMo专有的生物结合酶技术，我们将产生最多 广泛覆盖针对导致97%新生儿的五种最流行的GBS血清型的GBS疫苗 侵袭性疾病事件。本应用程序第一阶段的拟议研究将集中于(目标1)开发五个 GBS囊膜多糖在大肠杆菌中的可伸缩重组表达 与VaxNewMo的结合酶技术相结合，研制出首个抗病毒生物结合疫苗 GBS。随后(目标2)我们将演示单价GBS生物结合疫苗是 在免疫原性上不逊于传统制备的化学GBS结合疫苗。我们还将 通过提供初步的免疫原性数据，展示VaxNewMo生物结合平台的多功能性 在五价GBS生物结合物上。最后，我们将通过确定细菌负荷来测试免疫力的相关性 和/或从接种疫苗的小鼠出生的感染了GBS的新生幼崽的存活率。我们第二阶段资金的下一步 将开发和优化大规模GBS生物结合疫苗的纯化方案 并为Fast Track FDA批准提供足够的安全性、耐受性和免疫原性数据。