Barry Eileen M, Wang Jin, Wu Tao, Davis Tamar, Levine Myron M
Center for Vaccine Development, University of Maryland, Baltimore, 685 West Baltimore Street, MD 21201, USA.
Vaccine. 2006 May 1;24(18):3727-34. doi: 10.1016/j.vaccine.2005.07.013. Epub 2005 Jul 22.
Shigella and enterotoxigenic Escherichia coli continue to be significant causes of diarrheal disease in infants and young children in developing countries as well as prevalent agents of traveler's diarrhea. A vaccine which provides protection against disease caused by both pathogens would serve common at-risk populations. Such a vaccine would require inclusion of multiple Shigella strains as well as multiple ETEC antigens. The use of attenuated strains of Shigella as live vectors for the expression of ETEC antigens is one strategy for the development of such a multivalent vaccine. Live attenuated strains of S. flexneri 2a, S. sonnei and S. dysenteriae 1 containing deletions in guaBA biosynthetic pathway genes as well as in genes encoding enterotoxins, were constructed. Each strain was subsequently used as a live vector for the expression of one or two critical ETEC antigens. The resulting three Shigella derivative strains were tested for immunogenicty and protective capacity alone or as mixtures in the guinea pig model. S. flexneri strain CVD 1208(pCFA/I-CS3), S. sonnei strain CVD 1233(pCS4-LThK63) and S. dysenteriae 1 strain CVD 1252(pCS2) were able to elicit serum and mucosal antibody responses against the live vector as well as the guest ETEC antigens. Vaccination with combinations of two or three of these strains was able to elicit specific immune responses against each live vector as well as each ETEC antigen represented in the mixture. These studies demonstrate the potential of the use of mixtures of live Shigella derivatives expressing ETEC antigens to serve as an immunogenic multivalent vaccine.
志贺氏菌和产肠毒素大肠杆菌仍然是发展中国家婴幼儿腹泻病的重要病因，也是旅行者腹泻的常见病原体。一种能预防这两种病原体所致疾病的疫苗将造福于共同的高危人群。这样一种疫苗需要包含多种志贺氏菌菌株以及多种产肠毒素大肠杆菌抗原。使用减毒志贺氏菌菌株作为表达产肠毒素大肠杆菌抗原的活载体是开发这种多价疫苗的一种策略。构建了福氏志贺氏菌2a、宋内志贺氏菌和痢疾志贺氏菌1的减毒株，这些菌株在guaBA生物合成途径基因以及编码肠毒素的基因中存在缺失。随后，每种菌株都被用作活载体来表达一种或两种关键的产肠毒素大肠杆菌抗原。在豚鼠模型中，单独或混合测试了所得的三种志贺氏菌衍生菌株的免疫原性和保护能力。福氏志贺氏菌菌株CVD 1208(pCFA/I-CS3)、宋内志贺氏菌菌株CVD 1233(pCS4-LThK63)和痢疾志贺氏菌1菌株CVD 1252(pCS2)能够引发针对活载体以及外来产肠毒素大肠杆菌抗原的血清和粘膜抗体反应。用这些菌株中的两种或三种组合进行疫苗接种能够引发针对每种活载体以及混合物中每种产肠毒素大肠杆菌抗原的特异性免疫反应。这些研究证明了使用表达产肠毒素大肠杆菌抗原的活志贺氏菌衍生物混合物作为免疫原性多价疫苗的潜力。
