Immune Responses to Biodefense Vaccines Early in Life

生命早期对生物防御疫苗的免疫反应

• 批准号: 8127368
• 负责人: Marcela F Pasetti
• 金额: $ 4.78万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-23 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127368
• 关键词: Achyrocline; Adjuvant; Adult; Aerosols; Age; Anthrax Attack; Anthrax Vaccines; Antibodies; Antigens; Area; Attenuated; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Bioterrorism; Biothrax; Cell Maturation; Cell Separation; Cell physiology; Cellular Immunity; Child; Childhood; Color; Data; Dendritic Cells; Development; Diphtheria; Disease; Distress; Dose; Elderly; Emergency Situation; Equilibrium; Event; Flagella; Flow Cytometry; Generations; Goals; Hepatitis B; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunocompromised Host; In Vitro; Individual; Infant; Infection; Knowledge; Life; Link; Lipopolysaccharides; Mails; Maternal antibody; Mediating; Military Personnel; Modeling; Mothers; Mus; Natural Immunity; Neonatal; Newborn Infant; Organism; Pertussis; Plague; Plasmids; Population; Production; Property; Public Health; Readiness; Regimen; Relative (related person); Research; Research Personnel; Risk; Safety; Salmonella; Salmonella Vaccines; Salmonella typhi; Subunit Vaccines; System; T memory cell; T-Cell Activation; Tern; Testing; Tetanus; Time; Tissues; United States; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Virulent; Vulnerable Populations; Yersinia pestis; abstracting; adaptive immunity; age group; base; biodefense; capsule; cell mediated immune response; cytokine; high risk; immune function; immunogenic; immunogenicity; improved; in vivo; mouse model; neonate; oral vaccine; pathogen; physical conditioning; preclinical study; prevent; programs; protective efficacy; pup; response; tool; vaccine candidate; vaccine delivery; vaccine development; vector; vector vaccine; weapons

Bioterrorism is no longer a threat in the United States, but a reality. In 2001, the spread of anthrax spores through the U.S. mail illustrated that deadly agents can be acquired and spread using relatively unsophisticated means. It also highlighted our vulnerability to such attacks and the urgency for preparedness. Vaccine-induced protective immunity to potential bioterror weapons could be one of the most effective biodefense strategies. Most of the biodefense vaccines available have been tailored for military personnel (healthy adults). The civilian population in need of protection, however, includes people of all ages and physical conditions (newborns, infants, immunocompromised and the elderly), who are at greater risk and could become the enemy's sinister targets to inflict more casualties. Clearly, there is an urgent need for safe and effective vaccines for these highly vulnerable groups. We propose to evaluate protective efficacy of a new generation of biodefense vaccines based on attenuated Salmonella as a live vector to mucosally deliver protective antigens from Yersinia pestis and Bacillus anthracis. Our first goal is to determine whether these Salmonella biodefense vaccines are well tolerated and induce long-lasting protective immunity using a neonatal mouse model of immunogenicity that closely resembles the responses in humans. Based on preliminary data, we hypothesize that 1) Salmonella live vectors will be highly immunogenic in newborn mice; and 2) antibody and cell-mediated immunity will be induced despite the presence of maternal antibodies. We also aim to explore the mechanisms involved in the induction of neonatal adaptive immunity to Salmonella and encoded foreign antigens. Although neonatal responses to vaccines are usually feeble and Th2 biased, our preliminary data suggest that Salmonella-based biodefense vaccines can induce potent (adult-like) and balanced Th1/Th2- type responses in newborns despite the presence of maternal antibodies. We hypothesize that this is linked to the the capacity of the bacteria to induce neonatal dendritic cell maturation and T cell activation. This research will be highly relevent to public health as it will enable us to identify biodefense vaccines that can be safe and protect children and infants against bioterror weapons. It will also provide knowledge to better understand the mechanisms mediating neonatal-infant immunity to develop more effectivevaccines to prevent diseases early in life.

生物恐怖主义在美国不再是威胁，而是现实。 2001年，炭疽孢子传播 通过美国邮件表明，可以使用相对相对的方法来获取和传播致命制剂 手段简单。它还强调了我们对此类攻击的脆弱性以及采取行动的紧迫性 准备。疫苗引起的对潜在生物恐怖武器的保护性免疫力可能是最有效的之一 有效的生物防御策略。大多数可用的生物防御疫苗都是为军事量身定制的 人员（健康成年人）。然而，需要保护的平民包括各族人民 年龄和身体状况（新生儿、婴儿、免疫功能低下者和老年人），谁的影响更大 存在风险，可能成为敌人的险恶目标，造成更多伤亡。显然，迫切需要 为这些高度脆弱的群体提供安全有效的疫苗。我们建议评估保护性 以减毒沙门氏菌为活载体的新一代生物防御疫苗的功效 粘膜传递来自鼠疫耶尔森氏菌和炭疽杆菌的保护性抗原。我们的首要目标是 确定这些沙门氏菌生物防御疫苗是否具有良好的耐受性并诱导持久 使用与反应非常相似的新生小鼠免疫原性模型进行保护性免疫 在人类中。根据初步数据，我们假设 1) 沙门氏菌活载体将高度 新生小鼠具有免疫原性； 2）尽管存在，仍会诱导抗体和细胞介导的免疫 母体抗体的存在。我们还旨在探索诱导的机制 新生儿对沙门氏菌的适应性免疫和编码的外来抗原。尽管新生儿的反应 疫苗通常效果较弱且偏向 Th2，我们的初步数据表明基于沙门氏菌的生物防御 疫苗可以在新生儿中诱导有效的（类似成人的）和平衡的 Th1/Th2 型反应，尽管 母体抗体的存在。我们假设这与细菌的能力有关 诱导新生儿树突状细胞成熟和T细胞活化。这项研究与公众高度相关 健康，因为它将使我们能够识别安全并保护儿童和婴儿的生物防御疫苗 反对生物恐怖武器。它还将提供知识以更好地理解调解机制 新生儿-婴儿免疫力，以开发更有效的疫苗来预防生命早期的疾病。

项目成果

Neonatal mucosal immunization with a non-living, non-genetically modified Lactococcus lactis vaccine carrier induces systemic and local Th1-type immunity and protects against lethal bacterial infection.

使用非活体、非转基因乳酸乳球菌疫苗载体对新生儿进行粘膜免疫可诱导全身和局部 Th1 型免疫，并防止致命细菌感染。

• 发表时间: 2010-03
• 影响因子: 8
• 作者: Ramirez, K;Ditamo, Y;Rodriguez, L;Picking, W L;van Roosmalen, M L;Leenhouts, K;Pasetti, M F
• 通讯作者: Pasetti, M F

Mucosal priming of newborn mice with S. Typhi Ty21a expressing anthrax protective antigen (PA) followed by parenteral PA-boost induces B and T cell-mediated immunity that protects against infection bypassing maternal antibodies.

用表达炭疽保护性抗原 (PA) 的伤寒沙门氏菌 Ty21a 对新生小鼠进行粘膜启动，然后进行肠外 PA 增强，诱导 B 细胞和 T 细胞介导的免疫，从而绕过母体抗体防止感染。

• 发表时间: 2010-08-23
• 影响因子: 5.5
• 作者: Ramirez, Karina;Ditamo, Yanina;Galen, James E;Baillie, Les W J;Pasetti, Marcela F
• 通讯作者: Pasetti, Marcela F