Freytag L C, Clements J D
Department of Microbiology and Immunology, Tulane University Medical Center, New Orleans, LA 70112, USA.
Curr Top Microbiol Immunol. 1999;236:215-36. doi: 10.1007/978-3-642-59951-4_11.
The use of mucosally administered killed bacteria or viruses as vaccines has a number of attractive features over the use of viable attenuated organisms, including safety, cost, storage and ease of delivery. Unfortunately, mucosally administered killed organisms are not usually effective as vaccines. The use of LT(R192G), a genetically detoxified derivative of LT, as a mucosal adjuvant enables the use of killed bacteria or viruses as vaccines by enhancing the overall humoral and cellular host immune response to these organisms, especially the Th1 arm of the immune response. With this adjuvant, protective responses equivalent to those elicited by live attenuated organisms can be achieved with killed organisms without the potential side effects. These findings have significant implications for vaccine development and further support the potential of LT(R192G) to function as a safe, effective adjuvant for mucosally administered vaccines. There are a number of unresolved issues regarding the use of LT and CT mutants as mucosal adjuvants. Both active-site and protease-site mutants of LT and CT have been constructed and adjuvanticity reported for these molecules in various animal models and with different antigens. There needs to be a side-by-side comparison of CT, LT, active-site mutants, protease-site mutants and recombinant B subunits regarding the ability to induce specific, targeted immunological outcomes as a function of route of immunization and nature of the co-administered antigen. Those side-by-side comparisons have not been carried out and there is a substantial body of evidence indicating that the outcomes may very well be different. With that information, vaccine strategies could be designed employing the optimum adjuvant/antigen formulation and route of administration for a variety of bacterial and viral pathogens. Also lacking is an understanding of the underlying cellular and intracellular signaling pathways activated by these different molecules and an understanding of the mechanisms of adjuvanticity at the cellular level. These are important issues because they take us beyond the phenomenological observations of "enhanced immunity" to a more clear understanding of the mechanisms of adjuvant activity.
与使用减毒活生物体相比，使用经粘膜给药的灭活细菌或病毒作为疫苗具有许多吸引人的特性，包括安全性、成本、储存和给药便利性。不幸的是，经粘膜给药的灭活生物体通常作为疫苗效果不佳。使用LT（R192G），一种LT的基因解毒衍生物，作为粘膜佐剂，通过增强宿主对这些生物体的整体体液和细胞免疫反应，特别是免疫反应的Th1分支，使得灭活细菌或病毒能够用作疫苗。有了这种佐剂，灭活生物体可以实现与减毒活生物体引发的保护性反应相当的效果，而没有潜在的副作用。这些发现对疫苗开发具有重要意义，并进一步支持了LT（R192G）作为经粘膜给药疫苗的安全、有效佐剂的潜力。关于使用LT和CT突变体作为粘膜佐剂存在一些未解决的问题。LT和CT的活性位点和蛋白酶位点突变体均已构建，并在各种动物模型中针对不同抗原报道了这些分子的佐剂活性。需要对CT、LT、活性位点突变体、蛋白酶位点突变体和重组B亚基在诱导特异性、靶向免疫结果的能力方面进行并排比较，该能力是免疫途径和共同给药抗原性质的函数。尚未进行那些并排比较，并且有大量证据表明结果很可能不同。有了这些信息，就可以设计疫苗策略，采用针对各种细菌和病毒病原体的最佳佐剂/抗原配方和给药途径。同样缺乏的是对这些不同分子激活的潜在细胞和细胞内信号通路的理解以及对细胞水平上佐剂活性机制的理解。这些都是重要问题，因为它们使我们超越了“增强免疫力”的现象学观察，从而更清楚地理解佐剂活性的机制。
