VACCINE EFFICACY AND SAFETY: IMMUNOGENICITY AND IMMUNOPATHOGENICITY OF MEASLES VI

疫苗功效和安全性：麻疹的免疫原性和免疫致病性 VI

• 批准号: 6293745
• 负责人: JUDY BEELER
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6293745
• 关键词: active immunization; age difference; antiviral antibody; child (0-11); clinical research; drug administration rate /duration; drug quality /standard; drug screening /evaluation; human subject; human therapy evaluation; immunity; measles vaccine; microorganism immunology; neutralizing antibody; thrombocytopenia

One of the major goals of the USPHS is the regional elimination of measles by the year 2000, a goal that is achievable due to an increase in immunization rates and implementation of a two dose schedule for measles vaccine. However, there are still some unanswered questions regarding optimal use of measles vaccines . For example, research is needed in order to understand the safest method for immunization of immunocompomised children, such as those with HIV infection, who could suffer serious disease as the result of measles infection or serve as a focus of persistent shedding and spread of measles virus that could impede eradication efforts. In addition, increasing numbers of infants are born to mothers with vaccine induced immunity. These mothers have lower levels of measles antibody than mothers with immunity induced by wild type measles infection. As a result, infants born to vaccinated mothers have lower levels of passively acquired antibody at birth and these infants become susceptible to measles infection early, with loss of antibody by 6-9 months of age. Previously, vaccine failure in infants less than 12 months of age was thought to result from neutralization of vaccine virus with passively acquired antibody. It is not known if immunization of young infants with or without passive antibody would prime for measles specific cell mediated immune responses, or if immaturity of the infant immune system contributes to vaccine failure. Dr. Hayley Gans, along with Drs. Maldonado, DeHovitz and Arvin at Stanford Unversity Medical Center, evaluated IL-12, IFN-gamma and T-cell lymphoproliferative responses in infants immunized with measles vaccine at 6, 9 and 12 months of age. Our laboratory provided support, and determined levels of measles antibody in 162 infants prior to and following immunization with measles vaccine. T cell lymphoproliferative responses were induced in 71, 69 and 62% of infants immunized at 6, 9 or 12 months, respectively, and occurred in the presence or absence of passive antibody. Likewise, passively acquired measles antibody had no effect on the ability of measles to induce IL-12 or IFN-gamma from PBMCs of immunized infants. Interestingly, there were no differences between T- cell or cytokine responses among infants at 6, 9 or 12 months of age, however, responses of infants were diminished when compared to the responses of immunized adults, suggesting that the lower responses were age related. In order to investigate this further, infant PBMCs were stimulated with measles antigen in the presence and absence of recombinant IL12. Infant cells stimulated with virus and rIL12 produced higher levels of IFNgamma (747 pg/ml)than when stimulated with measles antigen alone, however,the levels of IFNgamma produced were significantly less than levels produced from adult PBMCs,(1634 pg/ml),stimulated under similar conditions. These results suggest that the immune response to measles vaccine in early life may be characterized by T cell priming and diminished TH1 type cytokine responses may be age related.

美国公共卫生署的主要目标之一是到2000年在该地区消灭麻疹，由于免疫接种率的提高和麻疹疫苗两剂接种计划的实施，这一目标是可以实现的。 然而，在麻疹疫苗的最佳使用方面仍有一些未回答的问题。 例如，需要进行研究，以了解免疫缺陷儿童（如感染艾滋病毒的儿童）免疫接种的最安全方法，这些儿童可能因麻疹感染而患上严重疾病，或成为麻疹病毒持续脱落和传播的焦点，这可能会阻碍根除工作。 此外，越来越多的婴儿是由具有疫苗诱导免疫力的母亲所生。 这些母亲的麻疹抗体水平低于野生型麻疹感染诱导免疫的母亲。因此，接种疫苗的母亲所生的婴儿在出生时被动获得的抗体水平较低，这些婴儿很容易感染麻疹，在6-9个月大时失去抗体。以前，12个月以下婴儿的疫苗失败被认为是由于疫苗病毒被被动获得的抗体中和。目前尚不清楚是否有被动抗体的幼儿免疫接种将引发麻疹特异性细胞介导的免疫应答，或者婴儿免疫系统的不成熟是否导致疫苗失败。 Hayley Gans博士与斯坦福大学医学中心的马尔多纳多，DeHovitz和阿尔文博士一起评估了6，9和12个月大的麻疹疫苗免疫婴儿的IL-12，IFN-γ和T细胞淋巴增殖反应。 我们的实验室提供了支持，并确定了162名婴儿在接种麻疹疫苗前后的麻疹抗体水平。分别在6、9或12个月时免疫的婴儿中，71%、69%和62%诱导了T细胞淋巴增殖反应，并且在存在或不存在被动抗体的情况下发生。同样，被动获得的麻疹抗体对麻疹从免疫婴儿的PBMC中诱导IL-12或IFN-γ的能力没有影响。 有趣的是，在6、9或12月龄的婴儿中，T细胞或细胞因子应答之间没有差异，然而，与免疫的成人的应答相比，婴儿的应答减少，表明较低的应答与年龄相关。 为了进一步研究这一点，在存在和不存在重组IL 12的情况下用麻疹抗原刺激婴儿PBMC。 用病毒和rIL 12刺激的婴儿细胞产生比单独用麻疹抗原刺激时更高水平的IFN γ（747 pg/ml），然而，产生的IFN γ水平显著低于在类似条件下刺激的成人PBMC产生的水平（1634 pg/ml）。 这些结果表明，麻疹疫苗在生命早期的免疫反应的特点可能是T细胞启动和减少的TH 1型细胞因子反应可能与年龄有关。