Biological safety concepts of genetically modified live bacterial vaccines
Biological safety concepts of genetically modified live bacterial vaccines
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DOI：
10.1016/j.vaccine.2006.11.058
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发表时间：
2007-07-26
期刊：
影响因子：
5.5
通讯作者：
Frey, Joachim
中科院分区：
文献类型：
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作者：
Frey, Joachim
活疫苗具有能够诱导细胞和抗体介导的免疫的优势；因此，在某些情况下，它们能够预防感染，而不仅仅是疾病。此外，活疫苗，特别是细菌活疫苗，生产成本相对较低，易于应用。因此，它们适合为大型社区或牛群接种疫苗。细胞免疫和抗体免疫的诱导都是通过疫苗株在宿主中定居和繁殖而不引起疾病的能力获得的，这在诱导粘膜免疫反应方面特别有益。出于这个原因，活疫苗需要减弱必须诱导免疫的细菌的毒力。传统上，衰减只是通过微生物在生长介质上的多次传代，在动物、鸡蛋或细胞培养中，或者通过化学或物理诱变来实现的，这会导致随机突变，从而导致衰减。相比之下，新的分子方法能够开发出针对特定基因的转基因生物(GMO)，这些基因特别适合在疫苗菌株繁殖和存活的组织中诱导衰减或减少不良影响。由于活疫苗毒株(经自然选择或基因工程减毒)可能由受种者释放到环境中，因此必须考虑与医疗和环境方面有关的安全问题。这涉及(I)细胞、组织和寄主嗜性的改变，(Ii)载体通过加入外源基因而产生的毒力，(Iii)通过获得互补基因而恢复毒力，(Iv)与其他疫苗或载体生物体的野生型菌株交换遗传信息，以及(V)传播不希望看到的基因，例如抗生素抗性基因。在应用活疫苗之前，必须逐一彻底评估安全问题。安全性评估包括要突变的基因的确切功能和遗传位置、其遗传稳定性、潜在的逆转机制、可能与休眠基因的重组事件、向其他生物的基因转移以及通过噬菌体转导、转座或质粒转移和顺式或反式互补从其他生物获得基因。在这一点上，用现代基因工程技术构建的转基因生物显示出明显的优势，而不是随机诱变衍生的活生物体。利用对相应细菌致病分子机制的基本知识，可以在体外条件下选择合适的转基因候选菌株，而不是通过在体内测试大量随机突变。这导致了对志愿者进行更有针对性的安全测试，并减少了动物实验的使用。(C)2006爱思唯尔有限公司。保留所有权利。
Live vaccines possess the advantage of having access to induce cell-mediated and antibody-mediated immunity; thus in certain cases they are able to prevent infection, and not only disease. Furthermore, live vaccines, particularly bacterial live vaccines, are relatively cheap to produce and easy to apply. Hence they are suitable to immunize large communities or herds. The induction of both cell-mediated immunity as well as antibody-mediated immunity, which is particularly beneficial in inducing mucosal immune responses, is obtained by the vaccine-strain's ability to colonize and multiply in the host without causing disease. For this reason, live vaccines require attenuation of virulence of the bacterium to which immunity must be induced. Traditionally attenuation was achieved simply by multiple passages of the microorganism on growth medium, in animals, eggs or cell cultures or by chemical or physical mutagenesis, which resulted in random mutations that lead to attenuation. In contrast, novel molecular methods enable the development of genetically modified organisms (GMOs) targeted to specific genes that are particularly suited to induce attenuation or to reduce undesirable effects in the tissue in which the vaccine strains can multiply and survive. Since live vaccine strains (attenuated by natural selection or genetic engineering) are potentially released into the environment by the vaccinees, safety issues concerning the medical as well as environmental aspects must be considered. These involve (i) changes in cell, tissue and host tropism, (ii) virulence of the carrier through the incorporation of foreign genes, (iii) reversion to virulence by acquisition of complementation genes, (iv) exchange of genetic information with other vaccine or wild-type strains of the carrier organism and (v) spread of undesired genes such as antibiotic resistance genes. Before live vaccines are applied, the safety issues must be thoroughly evaluated case-by-case. Safety assessment includes knowledge of the precise function and genetic location of the genes to be mutated, their genetic stability, potential reversion mechanisms, possible recombination events with dormant genes, gene transfer to other organisms as well as gene acquisition from other organisms by phage transduction, transposition or plasmid transfer and cis- or trans-complementation. For this, GMOs that are constructed with modern techniques of genetic engineering display a significant advantage over random mutagenesis derived live organisms. The selection of suitable GMO candidate strains can be made under in vitro conditions using basic knowledge on molecular mechanisms of pathogenicity of the corresponding bacterial species rather than by in vivo testing of large numbers of random mutants. This leads to a more targeted safety testing on volunteers and to a reduction in the use of animal experimentation. (c) 2006 Elsevier Ltd. All rights reserved.