Tacket C O, Sztein M B, Losonsky G A, Wasserman S S, Nataro J P, Edelman R, Pickard D, Dougan G, Chatfield S N, Levine M M
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
Infect Immun. 1997 Feb;65(2):452-6. doi: 10.1128/iai.65.2.452-456.1997.
A single-dose, oral Salmonella typhi vaccine strain has been sought as a carrier or vector of cloned genes encoding protective antigens of other pathogens. Such a hybrid vaccine, administered orally, would stimulate immune responses both at the mucosal surface and in the systemic compartment and would potentially provide protection against multiple pathogens. S. typhi CVD 908 and CVD 906, which harbor deletions in aroC and aroD, were further engineered by deletion in htrA to produce strains CVD 908-htrA and CVD 906-htrA, which are unable to sustain growth and are severely impaired in their ability to survive in host tissues. These strains were fed to humans at doses of 5 x 10(7) to 5 x 10(9) CFU with buffer, and safety and immune responses were assessed. CVD 908-htrA and CVD 906-htrA were well tolerated in volunteers; mild diarrhea in 3 of 36 volunteers and mild fever in 1 volunteer were the only notable adverse responses. The vaccine strains were not detected in blood cultures and only transiently detected in stool. Serum immune responses to S. typhi lipopolysaccharide and H antigens were observed in 75 to 100% of volunteers who received 5 x 10(8) to 5 x 10(9) CFU, and cells secreting S. typhi-specific antibodies were found in all volunteers after ingestion of either strain. Sixty-three percent to 83% of volunteers developed lymphoproliferative responses to S. typhi flagellar and particulate antigens after the higher doses. These studies demonstrate the potential of CVD 908-htrA as a live vector for the delivery of heterologous genes, and a clinical trial of such a construct is planned.
人们一直在寻找一种单剂量口服伤寒沙门氏菌疫苗株，作为编码其他病原体保护性抗原的克隆基因的载体。这种口服的混合疫苗将刺激粘膜表面和全身系统的免疫反应，并有可能提供针对多种病原体的保护。携带aroC和aroD基因缺失的伤寒沙门氏菌CVD 908和CVD 906，通过缺失htrA基因进一步改造，产生CVD 908-htrA和CVD 906-htrA菌株，这些菌株无法维持生长，在宿主组织中的生存能力严重受损。将这些菌株以5×10⁷至5×10⁹CFU的剂量与缓冲液一起喂给人类，并评估安全性和免疫反应。CVD 908-htrA和CVD 906-htrA在志愿者中耐受性良好；36名志愿者中有3人出现轻度腹泻，1名志愿者出现轻度发热，这是唯一值得注意的不良反应。在血培养中未检测到疫苗菌株，仅在粪便中短暂检测到。在接受5×10⁸至5×10⁹CFU的志愿者中，75%至100%观察到对伤寒沙门氏菌脂多糖和H抗原的血清免疫反应，摄入任一菌株后，在所有志愿者中均发现分泌伤寒沙门氏菌特异性抗体的细胞。较高剂量后，63%至83%的志愿者对伤寒沙门氏菌鞭毛和颗粒抗原产生了淋巴细胞增殖反应。这些研究证明了CVD 908-htrA作为递送异源基因的活载体的潜力，并计划对此类构建体进行临床试验。
