Effectiveness and safety of mutant Escherichia coli heat-labile enterotoxin (LT H44A) as an adjuvant for nasal influenza vaccine

被引:22
作者
Hagiwar, Y
Tsuji, T
Iwasaki, T
Kadowaki, S
Asanuma, H
Chen, Z
Komase, K
Suzuki, Y
Aizawa, C
Kurata, T
Tamura, S
机构
[1] Natl Inst Infect Dis, Dept Pathol, Shinjuku Ku, Tokyo 1628640, Japan
[2] Kitasato Inst, Biol Res Ctr, Kitamoto, Saitama 3640026, Japan
[3] Fujita Hlth Univ, Sch Med, Dept Microbiol, Aichi 4701192, Japan
关键词
adjuvant; mucosal immunity; mutant heat-labile enterotoxin; nasal influenza vaccine;
D O I
10.1016/S0264-410X(00)00414-X
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 effectiveness and safety of mutant Escherichia coli heat-labile enterotoxin, LT H44A (His to Arg substitution at position 44 from the N-terminus of the Al fragment of the A subunit) as an adjuvant for nasal influenza vaccine were examined. (1) When 0.2 mug of LT H44A, together with 0.2 mug of influenza A/PR/8/34 virus (PR8, H1N1) vaccine, was administered intranasally into BALB/c mice (twice, 4 weeks apart), anti-PR8 hemagglutinin (HA) IgA and IgG antibody (Ab) responses were induced at levels that were sufficient to provide either complete protection against infection with a small volume of PR8 virus suspension or partial protection against infection with a lethal dose of the suspension. The dose of the mutant LT and vaccine used here (0.2 mug/20 g doses mouse) corresponded to the estimated dose per person. i.e. 0.1 mg/10 kg body weight. (2) Using these vaccination conditions, no additional total IgE Ab responses were induced. (3) The mutant was confirmed to be less toxic than the native LT when the toxicity was analyzed either using Y1 adrenal cells in vitro (1/483 EC50) or by an ileal loop test. (4) One hundred micrograms of the mutant, administered intranasally or intraperitoneally into guinea-pigs (Heartley strain, 0.3-0.4 kg), caused no body-weight changes 7 days after administration, although 100 mug of the native LT administered intraperitoneally caused death in all guinea-pigs due to diarrhea within 2 days. The intranasal administration of 100 mug of the mutant resulted in almost no pathological changes in the nasal mucosa 3 days after administration. These results suggest that LT H44A, which can be produced in high yields in an E. coli culture (about 5 mg/l), could be used as one of the effective and safe adjuvants for nasal influenza vaccine in humans. (C) 2001 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:2071 / 2079
页数:9
相关论文
共 47 条
[1]   Immunogenicity and efficacy of DNA vaccines encoding influenza A proteins in aged mice [J].
Bender, BS ;
Ulmer, JB ;
DeWitt, CM ;
Cottey, R ;
Taylor, SF ;
Ward, AM ;
Friedman, A ;
Liu, MA ;
Donnelly, JJ .
VACCINE, 1998, 16 (18) :1748-1755
[2]   RECOGNITION OF CLONED INFLUENZA-VIRUS HEMAGGLUTININ GENE-PRODUCTS BY CYTOTOXIC LYMPHOCYTES-T [J].
BENNINK, JR ;
YEWDELL, JW ;
SMITH, GL ;
MOSS, B .
JOURNAL OF VIROLOGY, 1986, 57 (03) :786-791
[3]   SITE-SPECIFIC MUTAGENESIS OF THE CATALYTIC SUBUNIT OF CHOLERA-TOXIN - SUBSTITUTING LYSINE FOR ARGININE-7 CAUSES LOSS OF ACTIVITY [J].
BURNETTE, WN ;
MAR, VL ;
PLATLER, BW ;
SCHLOTTERBECK, JD ;
MCGINLEY, MD ;
STONEY, KS ;
ROHDE, MF ;
KASLOW, HR .
INFECTION AND IMMUNITY, 1991, 59 (11) :4266-4270
[4]   ADJUVANT ACTIVITY OF ESCHERICHIA-COLI HEAT-LABILE ENTERO-TOXIN AND EFFECT ON THE INDUCTION OF ORAL TOLERANCE IN MICE TO UNRELATED PROTEIN ANTIGENS [J].
CLEMENTS, JD ;
HARTZOG, NM ;
LYON, FL .
VACCINE, 1988, 6 (03) :269-277
[5]   AMINO-ACID-SEQUENCE HOMOLOGY BETWEEN CHOLERA-TOXIN AND ESCHERICHIA-COLI HEAT-LABILE TOXIN [J].
DALLAS, WS ;
FALKOW, S .
NATURE, 1980, 288 (5790) :499-501
[6]  
DAVENPORT FM, 1964, J LAB CLIN MED, V63, P5
[7]   CHOLERA-TOXIN B-SUBUNIT GENE FUSION - STRUCTURAL AND FUNCTIONAL-ANALYSIS OF THE CHIMERIC PROTEIN [J].
DERTZBAUGH, MT ;
PETERSON, DL ;
MACRINA, FL .
INFECTION AND IMMUNITY, 1990, 58 (01) :70-79
[8]   DISSOCIATION OF ESCHERICHIA-COLI HEAT-LABILE ENTEROTOXIN ADJUVANTICITY FROM ADP-RIBOSYLTRANSFERASE ACTIVITY [J].
DICKINSON, BL ;
CLEMENTS, JD .
INFECTION AND IMMUNITY, 1995, 63 (05) :1617-1623
[9]   DETECTION OF HEAT-LABILE ESCHERICHIA-COLI ENTEROTOXIN WITH USE OF ADRENAL-CELLS IN TISSUE-CULTURE [J].
DONTA, ST ;
MOON, HW ;
WHIPP, SC .
SCIENCE, 1974, 183 (4122) :334-336
[10]   Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin [J].
Douce, G ;
Fontana, M ;
Pizza, M ;
Rappuoli, R ;
Dougan, G .
INFECTION AND IMMUNITY, 1997, 65 (07) :2821-2828