Induction of protective immunity to anthrax lethal toxin with a nonhuman primate adenovirus-based vaccine in the presence of preexisting anti-human adenovirus immunity
Induction of protective immunity to anthrax lethal toxin with a nonhuman primate adenovirus-based vaccine in the presence of preexisting anti-human adenovirus immunity
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DOI：
10.1128/iai.73.10.6885-6891.2005
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发表时间：
2005-10-01
影响因子：
3.1
通讯作者：
Crystal, RG
中科院分区：
文献类型：
--
作者：
Hashimoto, M;Boyer, JL;Crystal, RG
预防或治疗与生物恐怖主义有关的炭疽感染需要迅速有效的疫苗。最近，我们发现（Y。谭，N. R.哈克特，J.L. Boyer和R. G.克里斯托，Gene Ther. 14：1673-1682，2003），单次施用表达炭疽保护性抗原（PA）的重组血清型5腺病毒（Ad）载体提供了针对炭疽致死毒素攻击的快速保护。然而，大约35%至50%的人具有针对Ad 5的预先存在的中和抗体。本研究评估的假设，即重组腺病毒疫苗的基础上的非人灵长类动物来源的血清型AdC 7，对人类没有免疫力，表达PA（AdC 7 PA）将保护炭疽致死毒素，即使在存在预先存在的抗Ad 5免疫。幼稚和Ad 5免疫的BALB/c小鼠接受（肌内）10（8）至10（11）颗粒单位（PU）的AdC 7 PA、Ad 5 PA（基于人血清型Ad 5的载体，表达分泌形式的PA）或Ad 5（无转基因的Ad 5载体）。稳健的抗PA免疫球蛋白G和中和抗体检测到2至4周后，首次或Ad 5预免疫小鼠的AdC 7 PA管理，而低抗PA滴度检测到Ad 5预免疫小鼠后，管理的Ad 5 PA。为了评估体内保护，用AdC 7 PA或Ad 5 PA免疫先前针对Ad 5免疫的幼稚或小鼠，然后用致死静脉内剂量的炭疽芽孢杆菌致死毒素攻击。而Ad 5 PA保护幼稚小鼠免受B攻击。炭疽致死毒素，Ad 5 PA是无效的，在小鼠中，先前免疫针对Ad 5。相反，AdC 7 PA不仅有效地保护幼稚小鼠，而且还保护Ad 5预免疫的小鼠，在致死毒素攻击后100%存活。这些数据表明，非人基载体AdC 7 PA是一种有效的疫苗，用于开发针对B的保护性免疫。炭疽杆菌，并且重要的是作为腺病毒疫苗的“血清转换”基础，以在预先存在的抗Ad免疫的情况下发挥作用。
Prevention or therapy for bioterrorism-associated anthrax infections requires rapidly acting effective vaccines. We recently demonstrated (Y. Tan, N. R. Hackett, J. L. Boyer, and R. G. Crystal, Hum. Gene Ther. 14:1673-1682, 2003) that a single administration of a recombinant serotype 5 adenovirus (Ad) vector expressing anthrax protective antigen (PA) provides rapid protection against anthrax lethal toxin challenge. However, approximately 35 to 50% of humans have preexisting neutralizing antibodies against Ad5. This study assesses the hypothesis that a recombinant adenovirus vaccine based on the nonhuman primate-derived serotype AdC7, against which humans do not have immunity, expressing PA (AdC7PA) will protect against anthrax lethal toxin even in the presence of preexisting anti-Ad5 immunity. Naive and Ad5-immunized BALB/c mice received (intramuscularly) 10(8) to 10(11) particle units (PU) of AdC7PA, Ad5PA (a human serotype Ad5-based vector expressing a secreted form of PA), or AdNull (an Ad5 vector with no transgene). Robust anti-PA immunoglobulin G and neutralizing antibodies were detected by 2 to 4 weeks following administration of AdC7PA to naive or Ad5 preimmunized mice, whereas low anti-PA titers were detected in Ad5-preimmunized mice following administration of Ad5PA. To assess protection in vivo, naive or mice previously immunized against Ad5 were immunized with AdC7PA or Ad5PA and then challenged with a lethal intravenous dose of Bacillus anthracis lethal toxin. Whereas Ad5PA protected naive mice against challenge with B. anthracis lethal toxin, Ad5PA was ineffective in mice that were previously immunized against Ad5. In contrast, AdC7PA functioned effectively not only to protect naive mice but also to protect Ad5-preimmunized mice, with 100% survival after lethal toxin challenge. These data suggest the nonhuman-based vector AdC7PA is an effective vaccine for the development of protective immunity against B. anthracis and importantly functions as a "sero-switch" base for an adenovirus vaccine to function in the context of preexisting anti-Ad immunity.