Choi Jin Huk, Schafer Stephen C, Zhang Lihong, Juelich Terry, Freiberg Alexander N, Croyle Maria A
Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin , Austin, Texas 78712, United States.
Mol Pharm. 2013 Sep 3;10(9):3342-55. doi: 10.1021/mp4001316. Epub 2013 Aug 19.
Pre-existing immunity (PEI) to human adenovirus serotype 5 (Ad5) worldwide is the primary limitation to routine clinical use of Ad5-based vectors in immunization platforms. Using systemic and mucosal PEI induction models in rodents (mice and guinea pigs), we assessed the influence of PEI on the type of adaptive immune response elicited by an Ad5-based vaccine for Ebola with respect to immunization route. Splenocytes isolated from vaccinated animals revealed that immunization by the same route in which PEI was induced significantly compromised Ebola Zaire glycoprotein (ZGP)-specific IFN-γ+ CD8+ T cells and ZGP-specific multifunctional CD8+ T cell populations. ZGP-specific IgG1 antibody levels were also significantly reduced and a sharp increase in serum anti-Ad5 neutralizing antibody (NAB) titers were noted following immunization. These immune parameters correlated with poor survival after lethal challenge with rodent-adapted Ebola Zaire virus (ZEBOV). Although the number of IFN-γ+ CD8+ T cells was reduced in animals given the vaccine by a different route from that used for PEI induction, the multifunctional CD8+ T cell response was not compromised. Survival rates in these groups were higher than when PEI was induced by the same route as immunization. These results suggest that antigen-specific multifunctional CD8(+) T cell and Th2 type antibody responses compromised by PEI to Ad5 are required for protection from Ebola. They also illustrate that methods for induction of PEI used in preclinical studies must be carefully evaluated for successful development of novel Ad5-based vaccines.
全球范围内对人腺病毒5型（Ad5）的既有免疫力（PEI）是基于Ad5的载体在免疫平台上常规临床应用的主要限制因素。我们利用啮齿动物（小鼠和豚鼠）的全身和黏膜PEI诱导模型，评估了PEI对基于Ad5的埃博拉疫苗针对免疫途径所引发的适应性免疫反应类型的影响。从接种疫苗的动物中分离出的脾细胞显示，在诱导PEI的相同途径进行免疫，会显著损害埃博拉扎伊尔糖蛋白（ZGP）特异性IFN-γ+ CD8+ T细胞和ZGP特异性多功能CD8+ T细胞群体。ZGP特异性IgG1抗体水平也显著降低，并且在免疫后血清抗Ad5中和抗体（NAB）滴度急剧升高。这些免疫参数与用啮齿动物适应的埃博拉扎伊尔病毒（ZEBOV）进行致死性攻击后的低存活率相关。尽管通过与诱导PEI不同的途径给动物接种疫苗时，IFN-γ+ CD8+ T细胞数量减少，但多功能CD8+ T细胞反应并未受损。这些组的存活率高于通过与免疫相同的途径诱导PEI时的存活率。这些结果表明，PEI对Ad5所损害的抗原特异性多功能CD8(+) T细胞和Th2型抗体反应是预防埃博拉所必需的。它们还表明，在临床前研究中用于诱导PEI的方法必须经过仔细评估，以便成功开发新型基于Ad5的疫苗。
