Effects of aging on vaccine efficacy in non human primate models

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，使老年人易患传染病和癌症。此外，在年轻人身上测试的疫苗往往对老年人无效。因此，随着新疫苗的开发，测试这些配方对老年人和年轻人的有效性将是极其重要的。虽然年轻的非人类灵长类动物在测试疫苗对一般人群的效力方面至关重要，但尚未建立使用老年非人类灵长类动物评估老年人疫苗保护的模型。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，并没有随着年龄的增长而出现免疫衰老。事实上，当老年狒狒（19-24岁）接种鼠疫细菌的保护性抗原LcrV免疫时，它们的反应甚至比幼年狒狒（2岁半）更好。因此，尽管在人类、啮齿动物和少数非人类灵长类动物中观察到与年龄相关的免疫功能丧失，但狒狒似乎是不寻常的；它们衰老却不会失去免疫能力。因此，我们建议在四种非人灵长类动物（狒狒、恒河猴、黑猩猩和狨猴）中评估衰老对免疫的影响。这一点之所以重要，有两个原因。首先，在选择合适的非人类灵长类动物来测试疫苗在老年人中的功效时，关键是要知道，所选择的模型与人类一样，会随着年龄的增长而免疫受损。其次，如果狒狒的免疫系统老化不同，那么它们将提供一个新的模型系统来与人类进行比较，在人类中，衰老确实对免疫系统有深远的影响。为了解决这些关键问题，将实现两个目标。目的：我将测试年龄对非人类灵长类动物产生有效免疫反应能力的影响，这些免疫反应来自鼠疫杆菌和破伤风的三种不同的蛋白抗原，LcrV和F1，这是一种广泛用于人类的免疫原。将评估B细胞参数（抗体滴度、保护指数、同型、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将检查这些相同的非人类灵长类动物的胸腺退化，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。完成这些目标将为老年非人类灵长类动物的免疫反应调节提供新的见解，并将对选择用于老年人疫苗试验的NHP动物模型至关重要。此外，通过将产生保护性免疫的能力与免疫参数相关联，将确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，免疫反应在老年人中往往不太有效，导致对传染病的易感性增加，对免疫接种的反应减少。这项拨款的目的是确定最准确反映老年人免疫衰老的非人类灵长类动物模型，并作为开发用于老年人的疫苗的适当试验对象。

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.