Antigen Persistence and Protective Immunity After Protein Vaccination

描述（由申请方提供）：基于使用减毒活感染因子（即牛痘病毒，MMR）的疫苗接种可产生持续数十年的免疫记忆，无需任何加强。这些减毒活疫苗产生体液和细胞免疫记忆，占保护性免疫记忆持续时间增加的大部分。此外，有充分证据表明，在感染从宿主清除后，源自感染原的抗原持续延长的时间段。已经假定，并且在某些情况下显示，抗原的这种持久性有助于维持抗原特异性记忆细胞的不同功能库，所述抗原特异性记忆细胞在二次感染性攻击的清除中显示不同的效率。然而，目前尚不清楚1）亚单位疫苗接种中所含的蛋白质抗原是否也在宿主中持续延长的时间段，2）如果是这样，通过什么基础建立和维持这种持续性，以及3）这种持续性抗原是否有助于或减损宿主中保护性免疫记忆的维持。在我们考虑未来疫苗设计和开发时，这些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引发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，我们的基于亚基的疫苗方法也可以导致抗原在宿主中的长期持久性。基于这些初步的数据，我们假设，来自非感染性，亚单位疫苗接种的结果，从DC和LEC之间的相互作用和通信的抗原的持久性。我们的数据预测，这种通信是依赖于先天受体激活的DC或LEC或两者。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，消除持久性抗原将对维持能够介导病毒或细菌因子快速清除的效应细胞和效应记忆细胞产生有害影响。我们将检验这些假设的机制，蛋白质抗原坚持在主机后亚单位接种，并确定抗原持久性的免疫学影响的发展和维护的保护性免疫对传染性病原体。 公共卫生相关性：基于使用减毒活感染因子（即，牛痘病毒（MMR）可以产生持续数十年的免疫记忆，而无需任何加强。这些减毒活疫苗产生体液和细胞免疫记忆，占保护性免疫记忆持续时间增加的大部分。此外，有充分证据表明，在感染从宿主清除后，源自感染原的抗原持续延长的时间段。已经假定，并且在某些情况下显示，抗原的这种持久性有助于维持抗原特异性记忆细胞的不同功能库，所述抗原特异性记忆细胞在二次感染性攻击的清除中显示不同的效率。我们已经发表了大量关于疫苗佐剂的性质及其引发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，我们的基于亚基的疫苗方法也可以导致抗原在宿主中的长期持久性。本项目将阐明亚单位疫苗接种后蛋白质抗原在宿主中持续存在的机制，并确定该抗原持续存在对保护性免疫力的发展和维持的免疫学影响。

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.