Effects of aging on vaccine efficacy in non human primate models

描述(申请人提供)：人类发动有效免疫反应的能力随着年龄的增长而下降，使老年人容易感染传染病和癌症。此外，在年轻人身上测试的疫苗对老年人往往无效。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。虽然年轻的非人灵长类动物在测试普通人类群体的疫苗效力方面起到了关键作用，但使用老年非人灵长类动物来评估老年人疫苗保护的模型尚未建立。我们已经开始解决这个问题，在最近的一项研究中，令我们惊讶的是，在生物医学研究中广泛使用的一种非人类灵长类物种狒狒并没有随着年龄的增长而表现出免疫衰老。事实上，用鼠疫细菌的保护性抗原LcrV免疫19-24岁的老年狒狒时，它们的反应甚至比年轻的动物(2岁半)更好。因此，尽管在人类、啮齿动物和一些非人类灵长类物种中观察到了与年龄相关的免疫功能丧失，但狒狒似乎是不寻常的；它们在衰老时不会失去免疫能力。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、黑猩猩和绒猴)免疫功能的影响。这一点很重要，原因有两个。首先，在选择合适的非人类灵长类动物来测试老年人的疫苗效力时，关键的一点是要知道，所选的模型像人类一样，会随着年龄的增长而免疫受损。其次，如果狒狒是例外的，因为它们的免疫系统会以不同的方式老化，它们将提供一个新的模型系统，用于与衰老确实对免疫产生深远影响的人类进行比较。为了解决这些关键问题，将实现两个目标。目的研究年龄对非人类灵长类动物对鼠疫耶尔森氏菌和破伤风三种不同蛋白抗原产生有效免疫应答能力的影响。将评估B细胞参数[抗体效价、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、良好的特异性、体外增殖和细胞因子产生]。此外，AIM II将研究这些非人类灵长类物种的胸腺退化，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类灵长类动物的免疫反应调控提供新的见解，并将对选择NHP动物模型用于测试老年人使用的疫苗至关重要。此外，通过将产生保护性免疫的能力与免疫参数相关联，将识别与免疫能力相关的生物标记物。与公共卫生的相关性：有充分的证据表明，老年人的免疫反应往往不那么有效，从而增加了对传染病的易感性，并降低了对免疫的反应。这笔赠款的目标是识别最准确地反映老年人免疫衰老的非人类灵长类动物模型，并作为开发用于老年人的疫苗的合适测试对象。

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.