Antigen Persistence and Protective Immunity After Protein Vaccination

描述（由申请人提供）：基于使用减毒活病原体（即牛痘病毒，MMR）的疫苗可以产生持续数十年的免疫记忆，而无需任何增强。这些减毒活疫苗产生体液和细胞免疫记忆，这在很大程度上增加了保护性免疫记忆的持续时间。此外，有充分的证据表明，在感染从宿主体内清除后，来自感染原的抗原会持续很长一段时间。这种抗原的持久性已经被假设，并在某些情况下被证明，有助于维持抗原特异性记忆细胞的不同功能池，这些细胞在清除继发性感染挑战时表现出不同的效率。然而，目前尚不清楚1)亚单位疫苗中所含的蛋白抗原是否也在宿主体内持续较长时间；2)如果是，这种持续存在是基于什么基础建立和维持的；3)这种持续存在的抗原是否有助于或损害宿主体内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基于亚单位的疫苗方法也可以导致抗原在宿主体内长期存在。基于这些初步数据，我们假设来自非传染性亚单位疫苗接种的抗原的持久性是dc和LECs之间相互作用和交流的结果。我们的数据预测，这种交流依赖于DCs或LECs或两者的先天受体激活。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，消除持久性抗原将对维持能够介导病毒或细菌病原体快速清除的效应细胞和效应记忆细胞产生有害影响。我们将通过检查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验证这些假设，并确定抗原持续存在对感染因子保护性免疫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.