O'Hagan D T
Chiron Corporation, Emeryville, CA, USA.
J Pharm Pharmacol. 1998 Jan;50(1):1-10. doi: 10.1111/j.2042-7158.1998.tb03298.x.
Although vaccines produced by recombinant DNA technology are safer than traditional vaccines, which are based on attenuated or inactivated bacteria or viruses, they are often poorly immunogenic. Therefore, adjuvants are often required to enhance the immunogenicity of these vaccines. A number of adjuvants which are particulates of defined dimensions (<5 microm) have been shown to be effective in enhancing the immunogenicity of weak antigens in animal models. Two novel adjuvants which possess significant potential for the development of new vaccines include an oil-in-water microemulsion (MF59) and polymeric microparticles. MF59 has been shown to be a potent and safe adjuvant in human subjects with several vaccines (for example HSV-2, HIV-1 and influenza virus). An MF59 adjuvanted influenza has been recommended for approval in Italy. Microparticles prepared from the biodegradable polymers the poly(lactide-co-glycolides) (PLG) are currently undergoing extensive pre-clinical evaluation as vaccine adjuvants. Because of their controlled release characteristics, microparticles also possess considerable potential for the development of single dose vaccines. The development of single dose vaccines would offer significant advantages and would improve vaccination uptake rates in at risk populations, particularly in the developing world. In addition to systemic administration, microparticles have also also been shown to enhance the immunogenicity of vaccines when administered by mucosal routes. Therefore microparticles may allow the development of novel vaccines which can be administered by non-parenteral routes. Mucosal administration of vaccines would significantly improve patient compliance by allowing immunization to be achieved without the use of needles. An alternative approach to the development of mucosally administered vaccines involves the production of genetically detoxified toxins. Heat labile enterotoxin (LT) from Escherichia coli and cholera toxin from Vibrio cholerae are two closely related bacterially produced toxins, which are the most potent adjuvants available. However, these molecules are too toxic to be used in the development of human vaccines. Nevertheless, these toxins have been modified by site-directed mutagenesis to produce molecules which are adjuvant active, but non-toxic. The most advanced of these molecules (LTK63), which has a single amino acid substitution in the enzymatically active subunit of LT, is active as an adjuvant, but non-toxic in pre-clinical models. The approach of genetically detoxifying bacterial toxins to produce novel adjuvants offers significant potential for the future development of mucosally administered vaccines.
尽管通过重组DNA技术生产的疫苗比基于减毒或灭活细菌或病毒的传统疫苗更安全，但它们的免疫原性往往较差。因此，通常需要佐剂来增强这些疫苗的免疫原性。已证明一些尺寸确定（<5微米）的颗粒状佐剂在增强动物模型中弱抗原的免疫原性方面是有效的。两种具有开发新疫苗巨大潜力的新型佐剂包括水包油微乳剂（MF59）和聚合物微粒。MF59已被证明在多种疫苗（例如单纯疱疹病毒2型、人类免疫缺陷病毒1型和流感病毒）的人体试验中是一种有效的安全佐剂。一种含MF59佐剂的流感疫苗已在意大利被推荐批准使用。由可生物降解聚合物聚（丙交酯-共-乙交酯）（PLG）制备的微粒目前正在作为疫苗佐剂进行广泛的临床前评估。由于其控释特性，微粒在单剂量疫苗的开发中也具有相当大的潜力。单剂量疫苗的开发将带来显著优势，并将提高高危人群，特别是发展中世界人群的疫苗接种率。除了全身给药外，微粒在通过粘膜途径给药时也已被证明能增强疫苗的免疫原性。因此，微粒可能有助于开发可通过非肠道外途径给药的新型疫苗。通过粘膜途径给药疫苗将通过无需使用针头即可实现免疫接种，从而显著提高患者的依从性。开发粘膜给药疫苗的另一种方法涉及生产基因解毒毒素。大肠杆菌的热不稳定肠毒素（LT）和霍乱弧菌的霍乱毒素是两种密切相关的细菌产生的毒素，它们是现有的最有效的佐剂。然而，这些分子毒性太大，无法用于人类疫苗的开发。尽管如此，这些毒素已通过定点诱变进行修饰，以产生具有佐剂活性但无毒的分子。其中最先进的分子（LTK63）在LT的酶活性亚基中有一个氨基酸取代，在临床前模型中作为佐剂具有活性但无毒。对细菌毒素进行基因解毒以生产新型佐剂的方法为粘膜给药疫苗的未来发展提供了巨大潜力。
