Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a
Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a
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DOI：
10.1128/iai.71.2.726-732.2003
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发表时间：
2003-02-01
影响因子：
3.1
通讯作者：
Lewis, DJM
中科院分区：
文献类型：
--
作者：
Mills, KHG;Cosgrove, C;Lewis, DJM
亚单位鼻内疫苗提供了诱导针对粘膜传播感染（例如人类免疫缺陷病毒）的联合系统-粘膜免疫的前景。然而，尽管人体研究已经证明了主动免疫的诱导，分泌型免疫球蛋白A（sIgA）的反应是可变的，没有研究表明通过直接毒素中和活性测量的公认疫苗许可标准的保护作用。在生物粘附性聚阳离子多糖壳聚糖递送系统中使用遗传失活的突变白喉类毒素CRM 197，我们发现单次鼻免疫耐受性良好，并增强了健康志愿者的抗毒素中和活性，这可以通过第二次免疫进一步增强。中和活性远远超过了可接受的保护水平，相当于标准肌内疫苗诱导的中和活性，并且显著高于在不存在壳聚糖的情况下用CRM 197进行的鼻内免疫。一个引人注目但出乎意料的观察结果是，虽然单侧鼻内免疫诱导循环抗毒素抗体分泌细胞，但鼻内抗毒素sIgA应答仅在第二次免疫后且仅在接种疫苗的小鼠中观察到。如果这些数据在更大规模的研究中重现，基于CRM 197-壳聚糖的鼻内白喉疫苗可以迅速获得许可用于人类使用。然而，限制性sIgA反应表明，在评估此类疫苗诱导局部粘膜免疫时，必须注意初免-加强策略和临床采样技术。
Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM197 in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM197 in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM197-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.