Antigen Persistence and Protective Immunity After Protein Vaccination

描述(由申请人提供)：基于使用活的、减毒的感染剂(即痘苗病毒，MMR)的疫苗可以产生持续数十年的免疫记忆，而不需要任何增强。这些减毒活疫苗既能产生体液免疫记忆，又能产生细胞免疫记忆，这是保护性免疫记忆持续时间延长的主要原因。此外，有充分的证据表明，来自感染源的抗原在感染从宿主清除后会持续很长一段时间。这种抗原的持久性被假设并在某些情况下表明，有助于维持不同功能的抗原特异性记忆细胞池，这些细胞池在清除继发性感染挑战方面显示出不同的效率。然而，目前尚不清楚1)亚单位疫苗中包含的蛋白质抗原是否也在宿主中持续较长时间，2)如果是，这种持久性是基于什么建立和维持的，以及3)这种持久抗原是有助于还是损害宿主中保护性免疫记忆的维持。在我们考虑未来的疫苗设计和开发时，这些都是需要理解和控制的关键参数。我们已经发表了大量关于疫苗佐剂的性质及其诱导强大细胞免疫的能力的文章。在这个过程中，我们最近观察到，我们的基于亚单位的疫苗方法也可以导致抗原在宿主中长期存在。基于这些初步数据，我们推测，非感染性亚单位疫苗所产生的抗原的持久性是DC和LEC之间相互作用和沟通的结果。我们的数据预测，这种交流依赖于树突状细胞或晶状体上皮细胞或两者的固有受体激活。我们进一步假设，增强抗原持久性的疫苗接种方法将促进保护性免疫记忆，而消除持久性抗原将对维持能够迅速清除病毒或细菌的效应器和效应器记忆细胞产生有害影响。我们将通过检测在亚单位疫苗接种后蛋白质抗原在宿主体内持续存在的机制来检验这些假设，并确定抗原持续对发展和维持对感染性病原体的保护性免疫的免疫学影响。 公共卫生相关性：基于使用活的、减毒的感染剂(即痘苗病毒，MMR)可以产生持续数十年的免疫记忆，而不需要任何增强。这些减毒活疫苗既能产生体液免疫记忆，又能产生细胞免疫记忆，这是保护性免疫记忆持续时间延长的主要原因。此外，有充分的证据表明，来自感染源的抗原在感染从宿主清除后会持续很长一段时间。这种抗原的持久性被假设并在某些情况下表明，有助于维持不同功能的抗原特异性记忆细胞池，这些细胞池在清除继发性感染挑战方面显示出不同的效率。我们已经发表了大量关于疫苗佐剂的性质及其诱导强大细胞免疫的能力的文章。在这个过程中，我们最近观察到，我们的基于亚单位的疫苗方法也可以导致抗原在宿主中长期存在。该项目将阐明在亚单位疫苗接种后蛋白质抗原在宿主体内持续存在的机制，并确定该抗原持续存在对发展和维持对感染性病原体的保护性免疫的免疫学影响。

DESCRIPTION (provided by applicant): Vaccinations that are based on the use of live, attenuated infectious agents (i.e. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been postulated, and in some cases shown, to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of a secondary infectious challenge. However, it is currently unknown 1) whether the protein antigen contained within a subunit vaccination also persists in the host for extended periods of time, 2) if so, by what basis this persistence is established and maintained, and 3) whether this persisting antigen contributes to or detracts from the maintenance of protective immune memory in the host. These are critical parameters to comprehend and control as we consider future vaccine design and development. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. In the process, we recently observed that our subunit-based vaccine approach can also result in long term persistence of antigen in the host. Based on these preliminary data, we hypothesize that the persistence of antigen derived from non-infectious, subunit vaccination results from an interaction and communication between DCs and LECs. Our data predict that this communication is dependent upon innate receptor activation of either the DCs or the LECs or both. We further hypothesize that methods of vaccination that enhance antigen persistence will promote protective immune memory and that elimination of persisting antigen will have a deleterious effect on the maintenance of effector and effector memory cells capable of mediating rapid clearance of viral or bacterial agents. We will test these hypotheses by examining the mechanisms by which protein antigen persists in a host following a subunit vaccination, and determining the immunologic impact of antigen persistence on the development and maintenance of protective immunity against infectious agents. PUBLIC HEALTH RELEVANCE: Vaccinations that are based on the use of live, attenuated infectious agents (ie. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been postulated, and in some cases shown, to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of a secondary infectious challenge. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. In the process, we recently observed that our subunit-based vaccine approach can also result in long term persistence of antigen in the host. This project will elucidate the mechanisms by which protein antigen persists in a host following a subunit vaccination, and determine the immunologic impact of that antigen persistence on the development and maintenance of protective immunity against infectious agents.