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。

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在世界范围内，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，Ct 引起的眼部感染可导致沙眼，这是最常见的疾病。全世界可预防性失明的常见原因。基于小鼠的保护和血清学研究 Ct 是分为 15 种主要血清型，其中 8 种占大多数性传播感染 (STI)。在无论男性还是女性，大多数生殖器 Ct 感染都是无症状的，因此无需治疗。即使在有症状的病例，除非及时正确地实施治疗，否则会出现长期后遗症，包括可能会发生盆腔炎（PID）、慢性腹痛、宫外孕和不孕症。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，我们想要检验假设用 Ct 抗原配制的亚单位疫苗可引发强烈的免疫反应并诱导交叉血清型保护雌性小鼠免受生殖器挑战。为了实现这个目标，我们将在 C3H/HeN 中进行测试雌性小鼠，用 Ct 主要外膜蛋白 (MOMP) 和多态性疫苗配制的疫苗膜蛋白（ppm）。来自 Ct 高级血清型的 MOMP、MOMP 肽、MOMP DNA 和 RNA 将被使用基于纳米支架的纳米脂蛋白颗粒 (NLP) 配制和递送。免疫接种天然 MOMP 将有助于指导这些疫苗构建体的生产。加强对生殖器的保护在小鼠道中，将使用佐剂通过粘膜和全身途径进行疫苗接种。接种疫苗后，粘膜系统细胞和体液免疫反应将被确定并与保护相关。接种疫苗的动物将接受八种临床最相关的 Ct 血清型的经宫颈攻击。通过确定阴道培养物呈阳性的小鼠数量来评估对感染的保护，阴道培养物阳性总数、小鼠排毒时间长短以及阴道排毒的严重程度。为了确定对接种疫苗和受到攻击的雌性小鼠的长期后遗症的保护作用，随后将与经过验证的雄性种鼠一起关在笼子里，并具有生育能力和上生殖器病理学特征，包括输卵管积水形成，将被评估。如果我们仅通过疫苗接种无法获得强大、广泛的跨血清型保护借助 MOMP，我们将使用 NLP 测试 MOMP 与 Ppm C、G 或 H 组合的多价疫苗。到疫苗接种后确定每种抗原的中性、相加、协同或拮抗作用，对每种抗原的免疫反应将被表征，并且数据将与保护相关联。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挑战感染人类生殖道的 Ct 血清型。该项目结束时构建了保护性疫苗将为扩大生产和人工实施做好准备。有效的 Ct 疫苗将具有广泛的全球健康和社会经济影响。