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.

抽象的 全世界沙眼衣原体（CT）是最常见的性传播细菌 病原。在卫生条件较差的国家中，眼部感染CT可能会导致沙丘瘤，这是最多的 在全球范围内经常引起可预防失明的原因。根据小鼠的保护和血清学研究，CT是 分类为15个主要血清，其中8个占性传播感染（STI）的大多数。在 男性和女人，大多数生殖器CT感染无症状，因此没有治疗。甚至在 有症状的病例，除非及时，正确的方式实施治疗，包括 可能发生骨盆炎症性疾病（PID），慢性腹痛，异位妊娠和不育。因此， 疫苗接种是控制衣原体感染的最佳方法。在这个项目中，我们想检验假设 用CT抗原配制的亚基疫苗会引起稳健的免疫反应并诱导交叉旋转 雌性小鼠免受生殖器挑战的保护。为了实现这一目标，我们将在C3H/HEN中进行测试 雌性小鼠，用CT主要外膜蛋白（MOMP）配制的疫苗和多态性 膜蛋白（PPM）。来自CT高级血清的MOMP，MOMP肽，MOMP DNA和RNA将是 使用基于纳米折线的纳米脂蛋白颗粒（NLP）制定并传递。免疫 本地MOMP将有助于指导这些疫苗构建体的生产。增强生殖器的保护 小鼠将通过粘膜和全身途径接种小鼠。疫苗接种后，粘膜 和全身性细胞和体液免疫反应将被确定并与保护相关。 疫苗接种的动物将通过八个最临床相关的CT血清可接种挑战。 保护感染的保护将通过确定具有阳性阴道培养的小鼠数量来评估， 阴道阳性培养的总数，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接种疫苗和挑战的雌性小鼠的保护，随后将 用经过验证的雄性育种小鼠和生殖力和上生殖器病理笼 编队将进行评估。如果我们不能仅通过接种疫苗来获得坚固的，广泛的跨层保护 使用MOMP，我们将使用NLP测试与PPM C，G或H结合使用MOMP的多价疫苗。到 确定每种抗原的中性，加性，协同或拮抗作用，疫苗接种后， 对每种抗原的免疫反应将被表征，并且数据将与保护相关。我们的 目标是设计一种安全的基于纳米折线的亚基疫苗，可保护小鼠免受生殖器挑战 带有感染人类生殖道的CT血清。在该项目结束时，保护性疫苗结构 将准备好进行扩大生产和人类实施。针对CT的有效疫苗将有一个 广泛的全球健康和社会经济影响。