鸡球虫病疫苗研发新思考

Rethinking novel anticoccidial vaccine design

虽然球虫激发宿主产生的保护性免疫应答机制已有很多相关研究,但是保护记忆性免疫应答机制这一关键点常常被忽视。高效保护记忆性免疫应答是球虫感染宿主和球虫病疫苗设计的基础。本研究对该领域50年的相关研究进行系统性回顾和分析,提出开发高效球虫疫苗的设想和评估候选球虫病疫苗产生高效免疫保护的新策略,该设想和新策略基于产生高效保护性记忆免疫应答的三大关键点,即产生免疫水平的阈值、效应部位以及时间。结果表明:1)球虫病活卵囊疫苗与球虫重组蛋白疫苗、DNA疫苗、以病毒或细菌为载体的球虫病活载体疫苗免疫鸡群激发宿主产生的免疫应答存在本质区别,活卵囊疫苗免疫过的鸡对球虫的感染处于“Primed”免疫状态(即免疫系统可快速高效地识别球虫百余个抗原,抵抗球虫再次感染的能力更高。),而非活卵囊疫苗对球虫的感染仍处于“Naive”状态(即免疫系统仅能识别特定的1个或几个球虫抗原,抵抗球虫再次感染的能力较弱。)。这也是目前研发的基于一个或几个抗原的球虫“死”疫苗效果不佳的根本原因。2)高效的保护性记忆免疫应答的主要机制是多种效应机制协同发挥作用,如肠道微环境中的组织常驻记忆细胞(Tissue resident memory cells,T_(RM))、循环的效应记忆细胞(Effector memory T cells,TEM)、中心记忆性T细胞(Central memory T cell,T_(CM)),尤其是T_(RM)的量和质起关键作用。在疫苗设计中可以将抗原靶向可激发宿主产生针对鸡球虫高效保护性记忆免疫应答的重要部位—肠道。3)抑制球虫早期裂殖生殖是记忆性免疫应答抵抗球虫感染最重要的特征,为评估高效球虫疫苗提供了新思路。综上,对鸡球虫感染过程中产生高效免疫保护的机制有清晰的认识和理解,是实现基于免疫学理论的球虫病科学防控的基础。

Understanding how effective protective memory responses are produced in coccidiosis and how to design a successful anticoccidial vaccine are long goals in the coccidiosis research area.This study summarizes research progresses in the last 50 years and pinpoints possible directions to guide novel anticoccidial vaccine design.The assumption and new strategy are based on the three key points of generating efficient protective memory immune response,namly,threshold,effect site and time of generating protective immune level.The results show that:1)Differences should be noted between the immune responses induced by infections and antigens delivered either as recombinant proteins,DNA or live vectors.Live oocysts vaccine can induce protective memory immune responses,rendering the infected hosts to a‘Primed'immune state(that is,the immune system can quickly and efficiently recognize hundreds of coccidian antigen and have higher resistance to reinfection by coccidia);Non-live oocyst vaccine may fail to develop protective memory responses,and the vaccinated hosts are in immune‘Naive'state(that is,the immune system can only recognize one or several specific coccidian antigens,and its ability ro resist reinfection by coccidia is not effective to resist pathogen infection).This also explains the limited success achieved in developing new anticoccidial vaccines.2)The primed immune state originated from multiple players,including tissue resident memory cells(T_(RM)),circulating effector memory T cells(T_(EM)),central memory T cells(T_(CM)),etc.,which can inhibit the infection at an early stage.How to develop vaccines inducing effective memory cells,especially T_(RM)cells which populate the front line of coccidia infection,is key to achieve primed immune states for vaccinated hosts.Targeting antigen-experienced DCs to the gut offers a tremendous potential.3)Inhibiting early schizogenesis of coccidian is an important feature of a‘primed'host to resist coccidiosis,which provides a new idea for evaluating high-efficient coccidian vaccine.In summary,only when we fully understand how to achieve the‘primed'immune state after infection or vaccination,can the scientific prevention and control of coccidiosis be realized.