Effects of aging on vaccine efficacy in non human primate models

衰老对非人灵长类动物模型中疫苗功效的影响

• 批准号: 7907218
• 负责人: ELLEN KRAIG
• 金额: $ 27.06万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907218
• 关键词: 2 year old; Address; Affinity; Age; Aging; Animal Model; Animals; Antibodies; Antigens; B-Lymphocytes; Bacteria; Biological Markers; Biological Models; Biomedical Research; Callithrix; Characteristics; Communicable Diseases; Competence; DNA Vaccines; Drug Formulations; Elderly; Goals; Grant; Heterogeneity; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; In Vitro; Individual; Kinetics; Left; Longevity; Macaca; Macaca mulatta; Malignant Neoplasms; Maps; Measures; Modeling; Mus; Nature; Pan Genus; Papio; Plague; Population; Predisposition; Production; Proteins; Regulation; Reporting; Rodent; Specificity; Study models; Susceptibility Gene; T-Lymphocyte; Testing; Tetanus; Thymus Gland; Vaccines; Yersinia pestis; age effect; age related; base; cytokine; efficacy testing; human disease; immune function; immunosenescence; indexing; insight; juvenile animal; nonhuman primate; novel; novel vaccines; public health relevance; response; senescence; vaccine development; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): The ability of humans to mount an effective immune response declines with age, leaving the elderly susceptible to infectious diseases and cancer. Moreover, vaccines tested in younger individuals are often ineffective in older people. Thus, as new vaccines are developed, it will be extremely important to test these formulations for efficacy in the elderly as well as in the young. While young nonhuman primates have been critical in testing vaccine efficacy for the general human population, a model using old nonhuman primates to assess vaccine protection for the elderly has not been established. We have begun to address this issue and in a recent study, found to our surprise that baboons, a nonhuman primate species used extensively in biomedical research, did not show immune senescence with aging. In fact, when old baboons (19-24 years old) were immunized with LcrV, a protective antigen from the plague bacterium, they responded even better than young animals (2 1/2 years old). Thus, although age-related loss in immune function has been observed in humans, rodents and a few nonhuman primate species, baboons appear to be unusual; they age without losing immune competence. Therefore, we propose to assess the effects of aging on immunity in four nonhuman primate species (baboons, rhesus macaques, chimpanzees, and marmosets). This is important for two reasons. First, in choosing an appropriate nonhuman primate for testing efficacy of vaccines in the elderly, it is critical to know that the model selected, like humans, becomes immune compromised with age. Second, if baboons are exceptional in that their immune systems age differently, they would provide a new model system for comparison to humans where aging does have profound effects on immunity. To address these critical issues, two aims will be undertaken. Aim I will test the effects of age on the ability of nonhuman primates to generate an effective immune response to three different protein antigens, LcrV and F1, from Y. pestis and tetanus, an immunogen used extensively in humans. Both B cell parameters [antibody titer, protective index, isotype, heterogeneity, affinity] and T cell parameters [subsets, circulating cytokines, fine specificity, in vitro proliferation and cytokine production] will be assessed. Furthermore, Aim II will examine thymic involution in these same nonhuman primate species to determine whether they, like rodents and humans, lose the potential for generating naive T cells with age. Completion of these aims will provide novel insights into immune response regulation in elderly nonhuman primates and will be critically important in choosing a NHP animal model for testing vaccines for use in the elderly. In addition, by correlating the ability to generate protective immunity with immune parameters, biomarkers that correlate with immune competence will be identified. PUBLIC HEALTH RELEVANCE: It has been well documented that immune responses are often less effective in older individuals resulting in an increased susceptibility to infectious diseases and decreased responses to immunization. The goal of this grant is to identify nonhuman primate models that most accurately reflect the immunosenescence seen in older humans and would serve as appropriate test subjects for development of vaccines to be used in the elderly.

描述（由申请人提供）：人类产生有效免疫反应的能力随着年龄的增长而下降，使老年人容易患传染病和癌症。此外，在年轻人身上测试的疫苗通常对老年人无效。因此，随着新疫苗的开发，测试这些制剂对老年人和年轻人的功效将极其重要。虽然年轻的非人类灵长类动物对于测试普通人群的疫苗功效至关重要，但尚未建立使用老年非人类灵长类动物评估疫苗对老年人的保护作用的模型。我们已经开始解决这个问题，在最近的一项研究中，我们惊讶地发现狒狒（一种广泛用于生物医学研究的非人灵长类动物）并没有随着衰老而表现出免疫衰老。事实上，当年老狒狒（19-24 岁）接受鼠疫细菌保护性抗原 LcrV 免疫时，它们的反应甚至比年轻动物（2 1/2 岁）更好。因此，尽管在人类、啮齿动物和一些非人类灵长类动物中观察到与年龄相关的免疫功能丧失，但狒狒似乎不寻常。他们随着年龄的增长而不会丧失免疫能力。因此，我们建议评估衰老对四种非人类灵长类动物（狒狒、恒河猴、黑猩猩和狨猴）免疫力的影响。这很重要，原因有二。首先，在选择合适的非人类灵长类动物来测试老年人疫苗的功效时，至关重要的是要知道所选择的模型与人类一样，会随着年龄的增长而变得免疫受损。其次，如果狒狒的免疫系统衰老情况不同，那么它们将提供一个新的模型系统来与人类进行比较，而人类的衰老确实对免疫力产生了深远的影响。为了解决这些关键问题，我们将实现两个目标。目标 我将测试年龄对非人类灵长类动物对鼠疫耶尔森菌和破伤风菌（一种广泛用于人类的免疫原）的三种不同蛋白质抗原（LcrV 和 F1）产生有效免疫反应的能力的影响。将评估 B 细胞参数 [抗体滴度、保护指数、同种型、异质性、亲和力] 和 T 细胞参数 [亚群、循环细胞因子、精细特异性、体外增殖和细胞因子产生]。此外，Aim II 将检查这些非人类灵长类动物的胸腺退化情况，以确定它们是否像啮齿动物和人类一样，随着年龄的增长而失去产生幼稚 T 细胞的潜力。这些目标的完成将为老年非人灵长类动物的免疫反应调节提供新的见解，并且对于选择 NHP 动物模型来测试老年疫苗至关重要。此外，通过将产生保护性免疫的能力与免疫参数相关联，将鉴定与免疫能力相关的生物标志物。公共卫生相关性：有充分证据表明，老年人的免疫反应通常效果较差，导致对传染病的易感性增加和免疫反应下降。这笔赠款的目标是确定最准确地反映老年人免疫衰老的非人类灵长类动物模型，并将其作为开发老年人使用的疫苗的适当测试对象。