Recombinant vaccine displaying the loop-neutralizing determinant from protective antigen completely protects rabbits from experimental inhalation anthrax.
Recombinant vaccine displaying the loop-neutralizing determinant from protective antigen completely protects rabbits from experimental inhalation anthrax.
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显示来自保护性抗原的环中和决定簇的重组疫苗完全保护兔子免受实验性吸入炭疽的侵害。
DOI：
10.1128/cvi.00612-12
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Cease,KempB
中科院分区：
文献类型：
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作者：
Oscherwitz,Jon;Yu,Fen;Jacobs,JanaL;Cease,KempB
我们以前证明，显示来自保护性抗原2β2-2β3环的氨基酸（aa）304至319的多抗原肽（MAP）疫苗能够保护兔免受炭疽杆菌艾姆斯菌株的雾化孢子攻击。该序列的抗体，称为环中和决定簇（LND），在中和致死毒素方面非常有效，但在兔和人保护性抗原（PA）抗血清中几乎不存在。虽然MAP疫苗对炭疽具有保护性，但它含有单个异源辅助T细胞表位，这对于刺激远交人群可能是次优的。因此，我们设计了一种重组疫苗（Rec-LND），含有两个串联重复拷贝的LND融合到麦芽糖结合蛋白，具有增强的免疫原性，来自曼氏血吸虫的p38/P4辅助T细胞表位。Rec-LND被发现是高度免疫原性的四个主要组织相容性复合体（MHC）不同品系的小鼠。用Rec-LND免疫的7只家兔均产生高滴度抗体，6只产生中和抗体，所有家兔均能抵抗B 193 50%致死剂量（LD_（50））的孢子攻击。炭疽艾姆斯菌株。从Rec-LND免疫兔的存活血清显示显着增加的中和滴度和比活性相比，prechallenge水平，但缺乏PA或致死因子（LF）抗原血症。对照兔免疫PA，这也是完全保护，出现无菌免疫，表现出显着下降，中和滴度和比活性相比，prechallenge水平。我们的结论是，Rec-LND可能代表了单独使用或可能与含PA疫苗联合使用的炭疽疫苗原型。
We previously showed that a multiple antigenic peptide (MAP) vaccine displaying amino acids (aa) 304 to 319 from the 2β2-2β3 loop of protective antigen was capable of protecting rabbits from an aerosolized spore challenge with Bacillus anthracis Ames strain. Antibodies to this sequence, referred to as the loop-neutralizing determinant (LND), are highly potent at neutralizing lethal toxin yet are virtually absent in rabbit and human protective antigen (PA) antiserum. While the MAP vaccine was protective against anthrax, it contains a single heterologous helper T cell epitope which may be suboptimal for stimulating an outbred human population. We therefore engineered a recombinant vaccine (Rec-LND) containing two tandemly repeated copies of the LND fused to maltose binding protein, with enhanced immunogenicity resulting from the p38/P4 helper T cell epitope from Schistosoma mansoni. Rec-LND was found to be highly immunogenic in four major histocompatibility complex (MHC)-diverse strains of mice. All (7/7) rabbits immunized with Rec-LND developed high-titer antibody, 6 out of 7 developed neutralizing antibody, and all rabbits were protected from an aerosolized spore challenge of 193 50% lethal doses (LD50) of the B. anthracis Ames strain. Survivor serum from Rec-LND-immunized rabbits revealed significantly increased neutralization titers and specific activity compared to prechallenge levels yet lacked PA or lethal factor (LF) antigenemia. Control rabbits immunized with PA, which were also completely protected, appeared sterilely immune, exhibiting significant declines in neutralization titer and specific activity compared to prechallenge levels. We conclude that Rec-LND may represent a prototype anthrax vaccine for use alone or potentially combined with PA-containing vaccines.