A murine model of intranasal immunization to assess the immunogenicity of attenuated Salmonella typhi live vector vaccines in stimulating serum antibody responses to expressed foreign antigens

被引:91
作者
Galen, JE
GomezDuarte, OG
Losonsky, GA
Halpern, JL
Lauderbaugh, CS
Kaintuck, S
Reymann, MK
Levine, MM
机构
[1] UNIV MARYLAND, SCH MED, DEPT PEDIAT, DIV INFECT DIS & TROP PEDIAT, BALTIMORE, MD 21201 USA
[2] US FDA, CTR BIOL EVALUAT & RES, DIV BACTERIAL PROD, BETHESDA, MD 20892 USA
关键词
D O I
10.1016/S0264-410X(96)00227-7
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The lack of a practical small animal model to study the immunogenicity of Salmonella typhi-based five vector vaccines expressing foreign antigens has seriously impeded the vaccine development process. For some foreign antigens, stimulation of serum IgG antibody is the desired protective immune response. We administered to mice, by orogastric or intranasal (i.n.) routes, attenuated Delta aroC Delta aroD S. typhi CVD 908 carrying a plasmid encoding fragment C (fragC) of tetanus toxin fused to the eukaryotic cell receptor binding domain of diphtheria toxin (fragC-bDt), and monitored serum antibody. White orogastric inoculation of three doses was not immunogenic, in. immunization elicited high titers of serum IgG tetanus antitoxin, generating peak ELISA geometric mean titers (GMT) of 27024 and 35658 with 10(8) and 10(9) c.f.u. dosages, respectively; 10(9) c.f.u. i.n. of an Delta aroA S. typhimurium live vector stimulated apeak antitoxin GMT of 376 405. Mice immunized with the S. typhi live vector were 100% protected against challenge with 100 50% lethal doses of tetanus toxin that rapidly killed all control mice. Intranasal immunization with two doses of S. typhi expressing unfused fragment C under control of art anaerobically-activated promoter derived from nirB stimulated significantly higher titers of serum neutralizing antitoxin than fused fragC-bDt controlled by the same promoter (GMT 0.10 AU ml(-1) vs 0.01 AU ml(-1), P=0.0095). Two i.n. doses of S typhi encoding fragC under control of powerful constitutive promoter Ipp led to significantly higher peak serum neutralizing antitoxin titers than the otherwise identical construct utilizing the nirB promoter (peak GMT 0.72 AU ml(-1) vs 0.10 AU ml(-1), P=0.022). The in. route of inoculation of mice may constitute a practical breakthrough that could expedite the development of some S. typhi-based live vector vaccines by allowing, for the first time, quantitative measurement of serum antibody responses to candidate constructs following Ln, mucosal immunization. (C) 1997 Elsevier Science Ltd.
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页码:700 / 708
页数:9
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