Induction of cross C. trachomatis serovar protection utilizing a polyvalent nanoparticle vaccine.

利用多价纳米颗粒疫苗诱导交叉沙眼衣原体血清型保护。

• 批准号: 10458656
• 负责人: Matthew Adrian Coleman
• 金额: $ 38.33万
• 依托单位: LAWRENCE LIVERMORE NATIONAL SECURITY, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458656
• 关键词: Abdominal Pain; Acute; Adjuvant; Animals; Antibiotics; Antibodies; Antigens; Area; Bioinformatics; Blindness; C3H/HeN Mouse; Cells; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Chronic; Classification; Complex; Country; DNA; DNA sequencing; Data; Disease; Ectopic Pregnancy; Embryo; Engineering; Eye Infections; Female; Fertility; Genital; Genitalia; Goals; Health; Human; Immune response; Immunization; Immunize; Immunologic Memory; Immunology; In Vitro; Infection; Infertility; Length; Licensure; Lipoproteins; Lymphogranuloma Venereum; Mediating; Membrane Proteins; Messenger RNA; Modeling; Molecular Conformation; Mucous Membrane; Mus; Partner in relationship; Pathogenesis; Pathology; Pelvic Inflammatory Disease; Peptides; Phylogenetic Analysis; Polyvalent Vaccine; Production; Proteins; RNA; Recombinant Vaccines; Recombinants; Research Project Grants; Respiratory System; Respiratory Tract Infections; Route; Safety; Serology; Serum; Severities; Sexual Transmission; Sexually Transmitted Diseases; Subunit Vaccines; T-Lymphocyte; Testing; Time; Trachoma; Trees; Vaccinated; Vaccination; Vaccine Production; Vaccines; Vagina; Woman; base; chlamydia vaccine; chronic abdominal pain; clinically relevant; cytokine; effectiveness evaluation; gastrointestinal system; genital infection; health economics; immunogenicity; long-term sequelae; major outer membrane protein; male; men; nano; nanolipoprotein particles; nanoparticle; nonhuman primate; particle; pathogenic bacteria; pregnant; reproductive tract; respiratory challenge; scaffold; scale up; socioeconomics; vaccination outcome; vaccine effectiveness; vaccine formulation; vaccine trial

ABSTRACT Throughout the world Chlamydia trachomatis (Ct) is the most common sexually transmitted bacterial pathogen. In countries with poor sanitary conditions ocular infections with Ct can result in trachoma, the most frequent cause of preventable blindness worldwide. Based on protection and serological studies in mice Ct is classified into 15 major serovars of which eight account for most of the sexually transmitted infections (STI). In men and women, the majority of genital Ct infections are asymptomatic and therefore not treated. Even in symptomatic cases unless therapy is implemented in a timely and correct manner long-term sequelae including pelvic inflammatory disease (PID), chronic abdominal pain, ectopic pregnancy and infertility can occur. Thus, vaccination is the best approach to control chlamydial infections. In this Project we want to test the hypothesis that a subunit vaccine formulated with Ct antigens elicits robust immune responses and induces cross-serovar protection in female mice against a genital challenge. To accomplish this goal we are going to test, in C3H/HeN female mice, vaccines formulated with the Ct major outer membrane protein (MOMP) and the polymorphic membrane proteins (Ppms). MOMP, MOMP peptides, MOMP DNA and RNA, from Ct senior serovars, will be formulated and delivered using Nano-Scaffold-Based Nano Lipoprotein Particles (NLP). Immunization with native MOMP will help guide the production of these vaccine constructs. To enhance protection in the genital tract, mice will be vaccinated by mucosal and systemic routes using adjuvants. Following vaccination, mucosal and systemic cellular and humoral immune responses will be determined and correlated with protection. Vaccinated animals will be challenged transcervically with the eight most clinically relevant Ct serovars. Protection against infection will be assessed by determining the number of mice with positive vaginal cultures, the total number of positive vaginal cultures, the length of time mice shed and the severity of vaginal shedding. To determine protection against long-term sequelae vaccinated and challenged female mice will subsequently be caged with proven male breeder mice and fertility and upper genital pathology, including hydrosalpinx formation, will be evaluated. If we cannot obtain a robust, broad cross-serovar protection by vaccinating only with MOMP, we will test a polyvalent vaccine with MOMP in combination with Ppm C, G or H using NLP. To ascertain the neutral, additive, synergistic, or antagonistic effects of each antigen, following vaccination, immune responses to each antigen will be characterized and the data will be correlated with protection. Our goal is to engineer a safe Nano-Scaffold-Based subunit vaccine that protects mice against a genital challenge with the Ct serovars that infect the human genital tract. At the end of this project protective vaccine constructs will be ready for scale-up production and human implementation. An efficacious vaccine against Ct will have a broad worldwide health and socioeconomic impact.

摘要 沙眼衣原体（Ct）是世界上最常见的性传播细菌 病原体在卫生条件差的国家，沙眼衣原体的眼部感染可导致沙眼， 全球常见的可预防性失明原因。基于小鼠的保护和血清学研究， 分为15个主要血清型，其中8个占性传播感染的大多数。在 在男性和女性中，大多数生殖器Ct感染是无症状的，因此没有得到治疗。即使在 症状性病例，除非及时和正确地实施治疗，否则会产生长期后遗症，包括 盆腔炎（PID）、慢性腹痛、宫外孕和不孕都可能发生。因此，在本发明中， 接种疫苗是控制衣原体感染的最佳方法。在这个项目中，我们想测试假设 用Ct抗原配制的亚单位疫苗激发了强烈的免疫应答并诱导交叉血清型免疫应答。 保护雌性小鼠免受生殖器攻击。为了实现这一目标，我们将在C3 H/HeN中进行测试， 雌性小鼠，用Ct主要外膜蛋白（MOMP）和多态性配制的疫苗 膜蛋白（Ppms）。来自Ct高级血清型的MOMP、MOMP肽、MOMP DNA和RNA，将 使用基于纳米支架的纳米脂蛋白颗粒（NLP）配制和递送。免疫 天然MOMP将有助于指导这些疫苗构建体的生产。加强生殖器保护 道，将使用佐剂通过粘膜和全身途径对小鼠进行疫苗接种。接种后，粘膜 并测定全身细胞和体液免疫应答并将其与保护相关联。 将使用8种最具临床相关性的Ct血清型对接种动物进行经颈攻毒。 通过确定阴道培养阳性的小鼠数量来评估抗感染保护， 阳性阴道培养物的总数、小鼠脱落的时间长度和阴道脱落的严重程度。 为了确定对长期后遗症的保护作用，随后将接种疫苗和激发的雌性小鼠 与经证实的雄性育种小鼠和生育力和上生殖器病理（包括输卵管积水）一起笼养 将进行评估。如果我们不能仅仅通过疫苗接种获得强大的、广泛的交叉血清型保护， 对于MOMP，我们将使用NLP测试MOMP与Ppm C、G或H组合的多价疫苗。到 确定接种后每种抗原的中性、相加、协同或拮抗作用， 将表征对每种抗原的免疫应答，并将数据与保护相关联。我们 我们的目标是设计一种安全的基于纳米支架的亚单位疫苗，保护小鼠免受生殖器攻击 感染人类生殖道的Ct血清型在该项目结束时， 将准备好进行大规模生产和人工实施。针对Ct的有效疫苗将具有 广泛的全球健康和社会经济影响。