Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans

Expert Review of Vaccines

Volumn 11, Issue 6, 2012, Pages 677-694

  Zhang, Weiping ^a   Sack, David A ^b  

^a SOUTH DAKOTA STATE UNIVERSITY   (United States)

^b JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

Diarrhea; Enterotoxigenic Escherichia coli; ETEC; Subunit vaccine; Whole cell vaccine

Indexed keywords

ADHESIN; BACTERIAL ANTIGEN; CHOLERA VACCINE; ESCHERICHIA COLI ENTEROTOXIN; ESCHERICHIA COLI VACCINE; SHANCHOL; UNCLASSIFIED DRUG;

BACTERIAL COLONIZATION; BACTERIAL STRAIN; BACTERIAL VIRULENCE; BACTERIUM ADHERENCE; CAUSE OF DEATH; CHILDHOOD DISEASE; DEVELOPING COUNTRY; DIARRHEA; DRUG COST; DRUG SAFETY; ENDEMIC DISEASE; ENTEROTOXIGENIC ESCHERICHIA COLI; ESCHERICHIA COLI INFECTION; HOST PATHOGEN INTERACTION; HUMAN; IMMUNOGENICITY; INTESTINE EPITHELIUM; PATHOGENESIS; PRIORITY JOURNAL; REVIEW;

ADHESINS, BACTERIAL; BACTERIAL TOXINS; BIOMEDICAL RESEARCH; DIARRHEA; ENTERITIS; ENTEROTOXIGENIC ESCHERICHIA COLI; ESCHERICHIA COLI INFECTIONS; ESCHERICHIA COLI VACCINES; HUMANS; VIRULENCE FACTORS;

EID: 84864949289     PISSN: 14760584     EISSN: 17448395     Source Type: Journal    
DOI: 10.1586/erv.12.37     Document Type: Review

References (155)

1. Black RE, Cousens S, Johnson HL et al.; Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 375(9730), 1969-1987 (2010).
2. WHO. Future directions for research on enterotoxigenic Escherichia coli vaccines for developing countries. Epidemiosl. Rec. 81, 97-104 (2006).
3. Sack DA, Merson MH, Wells JG, Sack RB, Morris GK. Diarrhoea associated with heat-stable enterotoxin-producing strains of Escherichia coli. Lancet 2(7928), 239-241 (1975).
4. Sack DA, Kaminsky DC, Sack RB et al. Prophylactic doxycycline for travelers' diarrhea. Results of a prospective double-blind study of Peace Corps volunteers in Kenya. N. Engl. J. Med. 298(14), 758-763 (1978).
5. Sanders JW, Putnam SD, Riddle MS, Tribble DR. Military importance of diarrhea: lessons from the Middle East. Curr. Opin. Gastroenterol. 21(1), 9-14 (2005).
6. Jiang ZD, Lowe B, Verenkar MP et al. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay). J. Infect. Dis. 185(4), 497-502 (2002).
7. Steffen R, Connor BA. Vaccines in travel health: from risk assessment to priorities. J. Travel Med. 12(1), 26-35 (2005).
8. Sack DA, Shimko J, Torres O et al. Randomised, double-blind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. coli diarrhoea of travellers to Guatemala and Mexico. Vaccine 25(22), 4392-4400 (2007).
9. Wenneras C, Erling V. Prevalence of enterotoxigenic Escherichia coli-associated diarrhoea and carrier state in the developing world. J. Health. Popul. Nutr. 22(4), 370-382 (2004).
10. Qadri F, Svennerholm AM, Faruque AS, Sack RB. Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clin. Microbiol. Rev. 18(3), 465-483 (2005).
11. Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin. Microbiol. Rev. 11(1), 142-201 (1998).
12. Chapman TA, Wu XY, Barchia I et al. Comparison of virulence gene profiles of Escherichia coli strains isolated from healthy and diarrheic swine. Appl. Environ. Microbiol. 72(7), 4782-4795 (2006).
13. Gaastra W, Svennerholm AM. Colonization factors of human enterotoxigenic Escherichia coli (ETEC). Trends Microbiol. 4(11), 444-452 (1996).
14. Spangler BD. Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiol. Rev. 56(4), 622-647 (1992).
15. Cieplak W Jr, Mead DJ, Messer RJ, Grant CC. Site-directed mutagenic alteration of potential active-site residues of the A subunit of Escherichia coli heat-labile enterotoxin. Evidence for a catalytic role for glutamic acid 112. J. Biol. Chem. 270(51), 30545-30550 (1995).
16. Crane JK, Wehner MS, Bolen EJ et al. Regulation of intestinal guanylate cyclase by the heat-stable enterotoxin of Escherichia coli (STa) and protein kinase C. Infect. Immun. 60(12), 5004-5012 (1992).
17. Mezoff AG, Giannella RA, Eade MN, Cohen MB. Escherichia coli enterotoxin (STa) binds to receptors, stimulates guanyl cyclase, and impairs absorption in rat colon. Gastroenterology 102(3), 816-822 (1992).
18. Nair GB, Takeda Y. The heat-stable enterotoxins. Microb. Pathog. 24(2), 123-131 (1998).
19. Sack RB, Gorbach SL, Banwell JG, Jacobs B, Chatterjee BD, Mitra RC. Enterotoxigenic Escherichia coli isolated from patients with severe cholera-like disease. J. Infect. Dis. 123(4), 378-385 (1971).
20. Gorbach SL, Banwell JG, Chatterjee BD, Jacobs B, Sack RB. Acute undifferentiated human diarrhea in the tropics. I. Alterations in intestinal micrflora. J. Clin. Invest. 50(4), 881-889 (1971).
21. Sack RB. Enterotoxigenic Escherichia coli: identification and characterization. J. Infect. Dis. 142(2), 279-286 (1980).
22. Merson MH, Sack RB, Islam S et al. Disease due to enterotoxigenic Escherichia coli in Bangladeshi adults: clinical aspects and a controlled trial of tetracycline. J. Infect. Dis. 141(6), 702-711 (1980).
23. Qadri F, Das SK, Faruque AS et al. Prevalence of toxin types and colonization factors in enterotoxigenic Escherichia coli isolated during a 2-year period from diarrheal patients in Bangladesh. J. Clin. Microbiol. 38(1), 27-31 (2000).
24. Levine MM, Svennerholm AM. Immunoprophylaxis and immunologic control. In:Travelers' Diarrhea (2nd Edition) . Ericsson C, DuPont H, Steffen R (Eds). BC Decker Inc., Hamilton, Canada, 215-232 (2008).
25. Harro C, Chakraborty S, Feller A et al. Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines. Clin. Vaccine Immunol. 18(10), 1719-1727 (2011).
26. Clemens JD, Sack DA, Harris JR et al. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. J. Infect. Dis. 158(2), 372-377 (1988).
27. Peltola H, Siitonen A, Kyrönseppa H et al. Prevention of travellers' diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 338(8778), 1285-1289 (1991).
28. Scerpella EG, Sanchez JL, Mathewson III JJ et al. Safety, immunogenicity, and protective efficacy of the whole-cell/recombinant B subunit (wc/rbs) oral cholera vaccine against travelers' diarrhea. J. Travel Med. 2(1), 22-27 (1995).
29. Evans DJ Jr, Evans DG, Opekun AR, Graham DY. Immunoprotective oral whole cell vaccine for enterotoxigenic Escherichia coli diarrhea prepared by in situ destruction of chromosomal and plasmid DNA with colicin E2. FEMS Microbiol. Immunol. 1(1), 9-18 (1988).
30. Evans DJ, Evans DG, Opekun AR, Graham DY. Non-replicating oral whole cell vaccine protective against enterotoxigenic Escherichia coli (ETEC) diarrhea: Stimulation of anti-CFA (CFA/I) and anti-enterotoxin (anti-LT) intestinal IgA and protection against challenge with ETEC belonging to heterologous serotypes. FEMS Microbiol. Immunol. 47(1), 117-126 (1988).
31. Anantha RP, McVeigh AL, Lee LH et al. Evolutionary and functional relationships of colonization factor antigen I and other class 5 adhesive fimbriae of enterotoxigenic Escherichia coli. Infect. Immun. 72(12), 7190-7201 (2004).
32. Svennerholm AM, Holmgren J, Sack DA. Development of oral vaccines against enterotoxinogenic Escherichia coli diarrhoea. Vaccine 7(3), 196-198 (1989).
33. Svennerholm AM, Ahren C, Wenneras C, Holmgren J. Development of an oral vaccine against enterotoxigenic Escherichia coli diarrhea. In:Molecular Pathogenesis of Gastrointestinal Infections. Wadstrom T, Makela PH, Svernnerholm AM, Wolf-Watz H (Eds). Plenum Press, London, UK, 287-294 (1991).
34. Wenneras C, Svennerholm AM, Ahrén C, Czerkinsky C. Antibody-secreting cells in human peripheral blood after oral immunization with an inactivated enterotoxigenic Escherichia coli vaccine. Infect. Immun. 60(7), 2605-2611 (1992).
35. Ahrén C, Wenneras C, Holmgren J, Svennerholm AM. Intestinal antibody response after oral immunization with a prototype cholera B subunit-colonization factor antigen enterotoxigenic Escherichia coli vaccine. Vaccine 11(9), 929-934 (1993).
36. Jertborn M, Ahrén C, Holmgren J, Svennerholm AM. Safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli vaccine. Vaccine 16(2-3), 255-260 (1998).
37. Ahrén C, Jertborn M, Svennerholm AM. Intestinal immune responses to an inactivated oral enterotoxigenic Escherichia coli vaccine and associated immunoglobulin A responses in blood. Infect. Immun. 66(7), 3311-3316 (1998).
38. Savarino SJ, Brown FM, Hall E et al. Safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli-cholera toxin B subunit vaccine in Egyptian adults. J. Infect. Dis. 177(3), 796-799 (1998).
39. Cohen D, Orr N, Haim M et al. Safety and immunogenicity of two different lots of the oral, killed enterotoxigenic Escherichia coli-cholera toxin B subunit vaccine in Israeli young adults. Infect. Immun. 68(8), 4492-4497 (2000).
40. Savarino SJ, Hall ER, Bassily S et al. Oral, inactivated, whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine: results of the initial evaluation in children. PRIDE Study Group. J. Infect. Dis. 179(1), 107-114 (1999).
41. Savarino SJ, Hall ER, Bassily S et al.; Pride Study Group. Introductory evaluation of an oral, killed whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Egyptian infants. Pediatr. Infect. Dis. J. 21(4), 322-330 (2002).
42. Hall ER, Wierzba TF, Ahrén C et al. Induction of systemic antifimbria and antitoxin antibody responses in Egyptian children and adults by an oral, killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine. Infect. Immun. 69(5), 2853-2857 (2001).
43. Qadri F, Wennerâs C, Ahmed F et al. Safety and immunogenicity of an oral, inactivated enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Bangladeshi adults and children. Vaccine 18(24), 2704-2712 (2000).
44. Qadri F, Wennerâs C, Ahmed F et al. Safety and immunogenicity of an oral, inactivated enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Bangladeshi children 18-36 months of age. Vaccine 21(19-20), 2394-2403 (2003).
45. Qadri F, Ahmed T, Ahmed F, Begum YA, Sack DA, Svennerholm AM; PTE Study Group. Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is safe and immunogenic in Bangladeshi infants 6-17 months of age: dosing studies in different age groups. Vaccine 24(10), 1726-1733 (2006).
46. Savarino SJ, Abu-Elyazeed R, Rao M et al. Efficacy of an oral, inactivated whole-cell enterotoxigenic E. coli/cholera toxin B subunit vaccine in Egyptian infants. as a safe and effective oral adjuvant. Presented at: The 6th Annual Conference on Vaccine Research, National Foundation for Infectious Diseases. Arlington, VA, USA, 5-7 May 2003.
47. Norton EB, Lawson LB, Freytag LC, Clements JD. Characterization of a mutant Escherichia coli heat-labile toxin, LT(R192G/L211A), as a safe and effective oral adjuvant. Clin. Vaccine Immunol. 18(4), 546-551 (2011).
48. Holmgren J, Blomquist M, Bourgeois L et al. Preclinical evaluation of an oral inactivated ETEC vaccine, based on E. coli overexpressing CFA/I, CS3, CS5 and CS6 together with LTB/CTB subunit, and of the adjuvant effect of co-administration with dmLT. Presented at: The 6th International Conference on Vaccines for Enteric Diseases (VED) 2011. Cannes, France, 14-16 September 2011.
49. Lundgren A, Leach S, Jertborn M et al. Clinical trial of an inactivated whole cell ETEC prototype vaccine. Presented at: The 6th International Conference on Vaccines for Enteric Diseases (VED) 2011. Cannes, France, 14-16 September 2011.
50. Tobias J, Svennerholm AM, Carlin NI, Lebens M, Holmgren J. Construction of a non-toxigenic Escherichia coli oral vaccine strain expressing large amounts of CS6 and inducing strong intestinal and serum anti-CS6 antibody responses in mice. Vaccine 29(48), 8863-8869 (2011).
51. Tobias J, Svennerholm AM, Holmgren J, Lebens M. Construction and expression of immunogenic hybrid enterotoxigenic Escherichia coli CFA/I and CS2 colonization fimbriae for use in vaccines. Appl. Microbiol. Biotechnol. 87(4), 1355-1365 (2010).
52. Sack RB, Kline RL, Spira WM. Oral immunization of rabbits with enterotoxigenic Escherichia coli protects against intraintestinal challenge. Infect. Immun. 56(2), 387-394 (1988).
53. Levine MM. Vaccines against enterotoxigenic Escherichia coli infections. In:New Generation Vaccines. Woodrow GC, Levine MM (Eds). Marcel Dekker, New York, NY, USA, 649-660 (1990).
54. Turner AK, Terry TD, Sack DA, Londoño-Arcila P, Darsley MJ. Construction and characterization of genetically defined aro omp mutants of enterotoxigenic Escherichia coli and preliminary studies of safety and immunogenicity in humans. Infect. Immun. 69(8), 4969-4979 (2001).
55. Tacket CO, Levine MM. Vaccines against enterotoxigenic Escherichia coli infection. In:New Generation Vaccines (2nd Edition). Levine MM, Woodrow GC, Kaper JB, Cobon GS (Eds). Marcel Dekker, New York, NY, USA 875-883 (1997).
56. McKenzie R, Bourgeois AL, Engstrom F et al. Comparative safety and immunogenicity of two attenuated enterotoxigenic Escherichia coli vaccine strains in healthy adults. Infect. Immun. 74(2), 994-1000 (2006).
57. McKenzie R, Darsley M, Thomas N et al. A double-blind, placebo-controlled trial to evaluate the efficacy of PTL-003, an attenuated enterotoxigenic E. coli (ETEC) vaccine strain, in protecting against challenge with virulent ETEC. Vaccine 26(36), 4731-4739 (2008).
58. Harro C, Sack D, Bourgeois AL et al. A combination vaccine consisting of three live attenuated enterotoxigenic Escherichia coli strains expressing a range of colonization factors and heat-labile toxin subunit B is well tolerated and immunogenic in a placebo-controlled double-blind Phase I trial in healthy adults. Clin. Vaccine Immunol. 18(12), 2118-2127 (2011).
59. Turner AK, Stephens JC, Beavis JC et al. Generation and characterization of a live attenuated enterotoxigenic Escherichia coli combination vaccine expressing six colonization factors and heat-labile toxin subunit B. Clin. Vaccine Immunol. 18(12), 2128-2135 (2011).
60. Turner AK, Beavis JC, Stephens JC et al. Construction and Phase I clinical evaluation of the safety and immunogenicity of a candidate enterotoxigenic Escherichia coli vaccine strain expressing colonization factor antigen CFA/I. Infect. Immun. 74(2), 1062-1071 (2006).
61. Harro C, Sack DA, Darsley M et al. Volunteers receiving live attenuated ETEC vaccine (ACE527) have reduced severity of illness following H10407 challenge. Presented at: The 6th International Conference on Vaccines for Enteric Diseases (VED) 2011. Cannes, France, 14-16 September 2011.
62. Guillobel HC, Carinhanha JI, Cárdenas L, Clements JD, de Almeida DF, Ferreira LC. Adjuvant activity of a nontoxic mutant of Escherichia coli heat-labile enterotoxin on systemic and mucosal immune responses elicited against a heterologous antigen carried by a live Salmonella enterica serovar Typhimurium vaccine strain. Infect. Immun. 68(7), 4349-4353 (2000).
63. Lásaro MO, Luiz WB, Sbrogio-Almeida ME, Nishimura LS, Guth BE, Ferreira LC. Combined vaccine regimen based on parenteral priming with a DNA vaccine and administration of an oral booster consisting of a recombinant Salmonella enterica serovar Typhimurium vaccine strain for immunization against infection with human-derived enterotoxigenic Escherichia coli strains. Infect. Immun. 72(11), 6480-6491 (2004).
64. Yang X, Thornburg T, Holderness K et al. Serum antibodies protect against intraperitoneal challenge with enterotoxigenic Escherichia coli. J. Biomed. Biotechnol. 2011, 632396 (2011). 65 Khan S, Chatfield S, Stratford R et al. Ability of SPI2 mutant of S. typhi to effectively induce antibody responses to the mucosal antigen enterotoxigenic E. coli heat labile toxin B subunit after oral delivery to humans. Vaccine 25(21), 4175-4182 (2007).
65. Koprowski H 2nd, Levine MM, Anderson RJ, Losonsky G, Pizza M, Barry EM. Attenuated Shigella flexneri 2a vaccine strain CVD 1204 expressing colonization factor antigen I and mutant heat-labile enterotoxin of enterotoxigenic Escherichia coli. Infect. Immun. 68(9), 4884-4892 (2000).
66. Altboum Z, Barry EM, Losonsky G, Galen JE, Levine MM. Attenuated Shigella flexneri 2a Delta guaBA strain CVD 1204 expressing enterotoxigenic Escherichia coli (ETEC) CS2 and CS3 fimbriae as a live mucosal vaccine against Shigella and ETEC infection. Infect. Immun. 69(5), 3150-3158 (2001).
67. Barry EM, Altboum Z, Losonsky G, Levine MM. Immune responses elicited against multiple enterotoxigenic Escherichia coli fimbriae and mutant LT expressed in attenuated Shigella vaccine strains. Vaccine 21(5-6), 333-340 (2003).
68. Altboum Z, Levine MM, Galen JE, Barry EM. Genetic characterization and immunogenicity of coli surface antigen 4 from enterotoxigenic Escherichia coli when it is expressed in a Shigella live-vector strain. Infect. Immun. 71(3), 1352-1360 (2003).
69. Barry EM, Wang J, Wu T, Davis T, Levine MM. Immunogenicity of multivalent Shigella-ETEC candidate vaccine strains in a guinea pig model. Vaccine 24(18), 3727-3734 (2006).
70. Walker RI, Steele D, Aguado T; Ad Hoc ETEC Technical Expert Committee. Analysis of strategies to successfully vaccinate infants in developing countries against enterotoxigenic E. coli (ETEC) disease. Vaccine 25(14), 2545-2566 (2007).
71. Roland KL, Cloninger C, Kochi SK et al. Construction and preclinical evaluation of recombinant Peru-15 expressing high levels of the cholera toxin B subunit as a vaccine against enterotoxigenic Escherichia coli. Vaccine 25(51), 8574-8584 (2007).
72. Tobias J, Lebens M, Bölin I, Wiklund G, Svennerholm AM. Construction of non-toxic Escherichia coli and Vibrio cholerae strains expressing high and immunogenic levels of enterotoxigenic E. coli colonization factor I fimbriae. Vaccine 26(6), 743-752 (2008).
73. Glenn GM, Scharton-Kersten T, Vassell R, Mallett CP, Hale TL, Alving CR. Transcutaneous immunization with cholera toxin protects mice against lethal mucosal toxin challenge. J. Immunol. 161(7), 3211-3214 (1998).
74. Glenn GM, Taylor DN, Li X, Frankel S, Montemarano A, Alving CR. Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nat. Med. 6(12), 1403-1406 (2000).
75. Scharton-Kersten T, Glenn GM, Vassell R, Yu J, Walwender D, Alving CR. Principles of transcutaneous immunization using cholera toxin as an adjuvant. Vaccine 17(Suppl. 2), S37-S43 (1999).
76. Yu J, Cassels F, Scharton-Kersten T et al. Transcutaneous immunization using colonization factor and heat-labile enterotoxin induces correlates of protective immunity for enterotoxigenic Escherichia coli. Infect. Immun. 70(3), 1056-1068 (2002).
77. Gudie;ereña-Burgueño F, Hall ER, Taylor DN et al. Safety and immunogenicity of a prototype enterotoxigenic Escherichia coli vaccine administered transcutaneously. Infect. Immun. 70(4), 1874-1880 (2002).
78. Glenn GM, Villar CP, Flyer DC et al. Safety and immunogenicity of an enterotoxigenic Escherichia coli vaccine patch containing heat-labile toxin: use of skin pretreatment to disrupt the stratum corneum. Infect. Immun. 75(5), 2163-2170 (2007).
79. McKenzie R, Bourgeois AL, Frech SA et al. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Vaccine 25(18), 3684-3691 (2007).
80. Frech SA, Dupont HL, Bourgeois AL et al. Use of a patch containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 371(9629), 2019-2025 (2008).
81. Ellingsworth L. Transcutaneous immunization and the travelers' diarrhea vaccine system: a Phase III pivotal efficacy study. Presented at: The 6th International Conference on Vaccines for Enteric Diseases (VED) 2011. Cannes, France, 14-16 September 2011.
82. Frantz JC, Robertson DC. Immunological properties of Escherichia coli heat-stable enterotoxins: development of a radioimmunoassay specific for heat-stable enterotoxins with suckling mouse activity. Infect. Immun. 33(1), 193-198 (1981).
83. Frantz JC, Mellencamp MW. Production and testing of Escherichia coli (LTb) toxoid. In:Fourth International Symposium on Neonatal Diarrhea. Acres S (Ed.). Saskatoon, SK, Canada, 500-517 (1983).
84. Wolf MK. Occurrence, distribution, and associations of O and H serogroups, colonization factor antigens, and toxins of enterotoxigenic Escherichia coli. Clin. Microbiol. Rev. 10(4), 569-584 (1997).
85. Sanchez J, Svennerholm AM, Holmgren J. Genetic fusion of a non-toxic heat-stable enterotoxin-related decapeptide antigen to cholera toxin B-subunit. FEBS Lett. 241(1-2), 110-114 (1988).
86. Svennerholm AM, Holmgrem J. Immunity to enterotoxin-producing bacteria. In:Immunology of Gastrointestinal Diseases. MacDonald TT (Ed.). Kluwer Academic Publishers, Dordrecht, The Netherlands, 227-246 (1992).
87. Zhang W, Zhang C, Francis DH et al. Genetic fusions of heat-labile (LT) and heat-stable (ST) toxoids of porcine enterotoxigenic Escherichia coli elicit neutralizing anti-LT and anti-STa antibodies. Infect. Immun. 78(1), 316-325 (2010).
88. Taxt A, Aasland R, Sommerfelt H, Nataro J, Puntervoll P. Heat-stable enterotoxin of enterotoxigenic Escherichia coli as a vaccine target. Infect. Immun. 78(5), 1824-1831 (2010).
89. Svennerholm AM, Lindblad M, Svennerholm B, Holmgren J. Synthesis of nontoxic, antibody-binding Escherichia coli heat-stable enterotoxin (STa) peptides. FEMS Microbiol. Lett. 55(1), 23-28 (1988).
90. Yamasaki S, Ito H, Hirayama T, Takeda Y, Shimonishi Y. Effects on the activity of amino acids replacement at positions 12, 13, and 14 heat-stable enterotoxin (STh) by chemical synthesis. Presented at: The 24th Joint Conference US Japan Cooperative Medical Sciences Program on Cholera and Related Diarrheal Disease Panel. Tokyo, Japan, 13-16 November 1988.
91. Liu M, Ruan X, Zhang C et al. Heat-labileand heat-stable-toxoid fusions (LTR192G-STaP13F) of human enterotoxigenic Escherichia coli elicit neutralizing antitoxin antibodies. Infect. Immun. 79(10), 4002-4009 (2011).
92. Liu M, Zhang C, Mateo K, Nataro JP, Robertson DC, Zhang W. Modified heat-stable toxins (hSTa) of Enterotoxigenic Escherichia coli lose toxicity but display antigenicity after being genetically fused to heat-labile toxoid LT(R192G). Toxins (Basel) 3(9), 1146-1162 (2011).
93. Clements JD. Construction of a nontoxic fusion peptide for immunization against Escherichia coli strains that produce heat-labile and heat-stable enterotoxins. Infect. Immun. 58(5), 1159-1166 (1990).
94. Sanchez J, Hirst TR, Uhlin BE. Hybrid enterotoxin LTA:STa proteins and their protection from degradation by in vivo association with B-subunits of Escherichia coli heat-labile enterotoxin. Gene 64(2), 265-275 (1988).
95. Sanchez J, Uhlin BE, Grundström T, Holmgren J, Hirst TR. Immunoactive chimeric ST-LT enterotoxins of Escherichia coli generated by in vitro gene fusion. FEBS Lett. 208(2), 194-198 (1986).
96. Batisson I, Der Vartanian M. Contribution of defined amino acid residues to the immunogenicity of recombinant Escherichia coli heat-stable enterotoxin fusion proteins. FEMS Microbiol. Lett. 192(2), 223-229 (2000).
97. Batisson I, Der Vartanian M, Gaillard-Martinie B, Contrepois M. Full capacity of recombinant Escherichia coli heat-stable enterotoxin fusion proteins for extracellular secretion, antigenicity, disulfide bond formation, and activity. Infect. Immun. 68(7), 4064-4074 (2000).
98. Boedeker EC. Vaccines for enterotoxigenic Escherichia coli: current status. Curr. Opin. Gastroenterol. 21(1), 15-19 (2005).
99. Norton EB, Lawson LB, Mahdi Z, Freytag LC, Clements JD. Revelations in secretion, antibody neutralization and mucosal adjuvanticity of the A-subunit of Escherichia coli heat-labile toxin. Presented at: The 6th International Conference on Vaccines for Enteric Diseases (VED) 2011. Cannes, France, 14-16 September 2011.
100. Zhang W, Francis DH. Genetic fusions of heat-labile toxoid (LT) and heat-stable toxin b (STb) of porcine enterotoxigenic Escherichia coli elicit protective anti-LT and anti-STb antibodies. Clin. Vaccine Immunol. 17(8), 1223-1231 (2010).
101. Gaastra W, Sommerfelt H, van Dijk L, Kusters JG, Svennerholm AM, Grewal HM. Antigenic variation within the subunit protein of members of the colonization factor antigen I group of fimbrial proteins in human enterotoxigenic Escherichia coli. Int. J. Med. Microbiol. 292(1), 43-50 (2002).
102. McConnell MM, Chart H, Rowe B. Antigenic homology within human enterotoxigenic Escherichia coli fimbrial colonization factor antigens: CFA/I, coli-surface-associated antigens (CS)1, CS2, CS4 and CS17. FEMS Microbiol. Lett. 52(1-2), 105-108 (1989).
103. Rudin A, McConnell MM, Svennerholm AM. Monoclonal antibodies against enterotoxigenic Escherichia coli colonization factor antigen I (CFA/I) that cross-react immunologically with heterologous CFAs. Infect. Immun. 62(10), 4339-4346 (1994).
104. Svennerholm AM, Steele D. Microbial-gut interactions in health and disease. Progress in enteric vaccine development. Best Pract. Res. Clin. Gastroenterol. 18(2), 421-445 (2004).
105. Savarino SJ, Poole S, Sincock SA et al. One step beyond: A new approach for vaccines against enterotoxigenic Escherichia coli. Presented at: The 40th Joint Conference on Cholera and Other Bacteria Enteric Infection and Bill and Melinda Gates Foundation Symposium on Vaccine Development. MA, USA, 30 November-2 December 2005.
106. Savarino SJ, O'Dowd A, Poole S et al. Advancement of an adhesin-based ETEC vaccine into clinical evaluation. Presented at: The 6th International Conference on Vaccines for Enteric Diseases (VED) 2011. Cannes, France, 14-16 September 2011.
107. Roy K, Hamilton D, Allen KP, Randolph MP, Fleckenstein JM. The EtpA exoprotein of enterotoxigenic Escherichia coli promotes intestinal colonization and is a protective antigen in an experimental model of murine infection. Infect. Immun. 76(5), 2106-2112 (2008).
108. Roy K, Hamilton D, Ostmann MM, Fleckenstein JM. Vaccination with EtpA glycoprotein or flagellin protects against colonization with enterotoxigenic Escherichia coli in a murine model. Vaccine 27(34), 4601-4608 (2009).
109. Roy K, Hamilton DJ, Munson GP, Fleckenstein JM. Outer membrane vesicles induce immune responses to virulence proteins and protect against colonization by enterotoxigenic Escherichia coli. Clin. Vaccine Immunol. 18(11), 1803-1808 (2011).
110. Reid RH, Boedeker EC, McQueen CE et al. Preclinical evaluation of microencapsulated CFA/II oral vaccine against enterotoxigenic E. coli. Vaccine 11(2), 159-167 (1993).
111. Edelman R, Russell RG, Losonsky G et al. Immunization of rabbits with enterotoxigenic E. coli colonization factor antigen (CFA/I) encapsulated in biodegradable microspheres of poly (lactide-co-glycolide). Vaccine 11(2), 155-158 (1993).
112. Tacket CO, Reid RH, Boedeker EC et al. Enteral immunization and challenge of volunteers given enterotoxigenic E. coli CFA/II encapsulated in biodegradable microspheres. Vaccine 12(14), 1270-1274 (1994).
113. Katz DE, DeLorimier AJ, Wolf MK et al. Oral immunization of adult volunteers with microencapsulated enterotoxigenic Escherichia coli (ETEC) CS6 antigen. Vaccine 21(5-6), 341-346 (2003).
114. Byrd W, Cassels FJ. Intranasal immunization of BALB/c mice with enterotoxigenic Escherichia coli colonization factor CS6 encapsulated in biodegradable poly(DL-lactide-co-glycolide) microspheres. Vaccine 24(9), 1359-1366 (2006).
115. Byrd W, Cassels FJ. The encapsulation of enterotoxigenic Escherichia coli colonization factor CS3 in biodegradable microspheres enhances the murine antibody response following intranasal administration. Microbiology 152(Pt 3), 779-786 (2006).
116. Lapa JA, Sincock SA, Ananthakrishnan M et al. Randomized clinical trial assessing the safety and immunogenicity of oral microencapsulated enterotoxigenic Escherichia coli surface antigen 6 with or without heat-labile enterotoxin with mutation R192G. Clin. Vaccine Immunol. 15(8), 1222-1228 (2008).
117. Haq TA, Mason HS, Clements JD, Arntzen CJ. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science 268(5211), 714-716 (1995).
118. Mason HS, Warzecha H, Mor T, Arntzen CJ. Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends Mol. Med. 8(7), 324-329 (2002).
119. Tacket CO, Pasetti MF, Edelman R, Howard JA, Streatfield S. Immunogenicity of recombinant LT-B delivered orally to humans in transgenic corn. Vaccine 22(31-32), 4385-4389 (2004).
120. Karaman S, Cunnick J, Wang K. Expression of the cholera toxin B subunit (CT-B) in maize seeds and a combined mucosal treatment against cholera and traveler's diarrhea. Plant Cell Rep. 31(3), 527-537 (2012).
121. Kim TG, Kim BG, Kim MY, Choi JK, Jung ES, Yang MS. Expression and immunogenicity of enterotoxigenic Escherichia coli heat-labile toxin B subunit in transgenic rice callus. Mol. Biotechnol. 44(1), 14-21 (2010).
122. Mason HS, Haq TA, Clements JD, Arntzen CJ. Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine 16(13), 1336-1343 (1998).
123. Rosales-Mendoza S, Soria-Guerra RE, López-Revilla R, Moreno-Fierros L, Alpuche-Solis AG. Ingestion of transgenic carrots expressing the Escherichia coli heat-labile enterotoxin B subunit protects mice against cholera toxin challenge. Plant Cell Rep. 27(1), 79-84 (2008).
124. Rosales-Mendoza S, Alpuche-Solis AG, Soria-Guerra RE et al. Expression of an Escherichia coli antigenic fusion protein comprising the heat labile toxin B subunit and the heat stable toxin, and its assembly as a functional oligomer in transplastomic tobacco plants. Plant J. 57(1), 45-54 (2009).
125. Rosales-Mendoza S, Soria-Guerra RE, Moreno-Fierros L et al. Immunogenicity of nuclear-encoded LTB:ST fusion protein from Escherichia coli expressed in tobacco plants. Plant Cell Rep. 30(6), 1145-1152 (2011).
126. Tacket CO. Plant-based oral vaccines: results of human trials. Curr. Top. Microbiol. Immunol. 332, 103-117 (2009).
127. Granell A, Fernández del-Carmen A, Orzáez D. In planta production of plant-derived and non-plant-derived adjuvants. Expert Rev. Vaccines 9(8), 843-858 (2010).
128. Spira WM, Sack RB, Froehlich JL. Simple adult rabbit model for Vibrio cholerae and enterotoxigenic Escherichia coli diarrhea. Infect. Immun. 32(2), 739-747 (1981).
129. Spira WM, Sack RB. Kinetics of early cholera infection in the removable intestinal tie-adult rabbit diarrhea model. Infect. Immun. 35(3), 952-957 (1982).
130. Cray WC Jr, Tokunaga E, Pierce NF. Successful colonization and immunization of adult rabbits by oral inoculation with Vibrio cholerae O1. Infect. Immun. 41(2), 735-741 (1983).
131. Ahrén CM, Svennerholm AM. Experimental enterotoxin-induced Escherichia coli diarrhea and protection induced by previous infection with bacteria of the same adhesin or enterotoxin type. Infect. Immun. 50(1), 255-261 (1985).
132. Svennerholm AM, Wenneras C, Holmgren J, McConnell MM, Rowe B. Roles of different coli surface antigens of colonization factor antigen II in colonization by and protective immunogenicity of enterotoxigenic Escherichia coli in rabbits. Infect. Immun. 58(2), 341-346 (1990).
133. Zhang W, Berberov EM, Freeling J, He D, Moxley RA, Francis DH. Significance of heat-stable and heat-labile enterotoxins in porcine colibacillosis in an additive model for pathogenicity studies. Infect. Immun. 74(6), 3107-3114 (2006).
134. Berberov EM, Zhou Y, Francis DH, Scott MA, Kachman SD, Moxley RA. Relative importance of heat-labile enterotoxin in the causation of severe diarrheal disease in the gnotobiotic piglet model by a strain of enterotoxigenic Escherichia coli that produces multiple enterotoxins. Infect. Immun. 72(7), 3914-3924 (2004).
135. Smith HW, Linggood MA. Observations on the pathogenic properties of the K88, Hly and Ent plasmids of Escherichia coli with particular reference to porcine diarrhoea. J. Med. Microbiol. 4(4), 467-485 (1971).
136. Zhang W, Robertson DC, Zhang C, Bai W, Zhao M, Francis DH. Escherichia coli constructs expressing human or porcine enterotoxins induce identical diarrheal diseases in a piglet infection model. Appl. Environ. Microbiol. 74(18), 5832-5837 (2008).
137. Erickson AK, Willgohs JA, McFarland SY, Benfield DA, Francis DH. Identification of two porcine brush border glycoproteins that bind the K88ac adhesin of Escherichia coli and correlation of these glycoproteins with the adhesive phenotype. Infect. Immun. 60(3), 983-988 (1992).
138. Erickson AK, Baker DR, Bosworth BT, Casey TA, Benfield DA, Francis DH. Characterization of porcine intestinal receptors for the K88ac fimbrial adhesin of Escherichia coli as mucin-type sialoglycoproteins. Infect. Immun. 62(12), 5404-5410 (1994).
139. Francis DH, Grange PA, Zeman DH, Baker DR, Sun R, Erickson AK. Expression of mucin-type glycoprotein K88 receptors strongly correlates with piglet susceptibility to K88(+) enterotoxigenic Escherichia coli, but adhesion of this bacterium to brush borders does not. Infect. Immun. 66(9), 4050-4055 (1998).
140. Roberts JA, Kaack MB, Baskin G, Svenson SB. Vaccination with a formalin-killed P-fimbriated E. coli whole-cell vaccine prevents renal scarring from pyelonephritis in the non-human primate. Vaccine 13(1), 11-16 (1995).
141. Jones FR, Hall ER, Tribble D et al. The New World primate, Aotus nancymae, as a model for examining the immunogenicity of a prototype enterotoxigenic Escherichia coli subunit vaccine. Vaccine 24(18), 3786-3792 (2006).
142. Porter CK, Riddle MS, Tribble DR et al. A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC). Vaccine 29(35), 5869-5885 (2011).
143. Gaastra W, de Graaf FK. Host-specific fimbrial adhesins of noninvasive enterotoxigenic Escherichia coli strains. Microbiol. Rev. 46(2), 129-161 (1982).
144. Zhang C, Rausch D, Zhang W. Little heterogeneity among genes encoding heat-labile and heat-stable toxins of enterotoxigenic Escherichia coli strains isolated from diarrheal pigs. Appl. Environ. Microbiol. 75(19), 6402-6405 (2009).
145. Lasaro MA, Rodrigues JF, Mathias-Santos C et al. Genetic diversity of heat-labile toxin expressed by enterotoxigenic Escherichia coli strains isolated from humans. J. Bacteriol. 190(7), 2400-2410 (2008).
146. Isidean SD, Riddle MS, Savarino SJ, Porter CK. A systematic review of ETEC epidemiology focusing on coloniz r and toxin expression. Vaccine 29(37), 6167-6178 (2011).
147. Sack DA, Qadri F, Svennerholm AM. Determinants of responses to oral vaccines in developing countries. Ann. Nestlé 66, 71-79 (2008).
148. Hallander HO, Paniagua M, Espinoza F et al. Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children. Vaccine 21(1-2), 138-145 (2002).
149. Levine MM. Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. BMC Biol. 8, 129 (2010). 151 Steffen R, Castelli F, Dieter Nothdurft H, Rombo L, Jane Zuckerman N. Vaccination against enterotoxigenic Escherichia coli, a cause of travelers' diarrhea. J. Travel Med. 12(2), 102-107 (2005).
150. Rao MR, Wierzba TF, Savarino SJ et al. Serologic correlates of protection against enterotoxigenic Escherichia coli diarrhea. J. Infect. Dis. 191(4), 562-570 (2005).
151. Tobias J, Andersson K, Bialik A, Cohen D. Preexisting antibodies to homologous colonization factors and heat-labile toxin in serum, and the risk to develop enterotoxigenic Escherichia coli-associated diarrhea. Diagn. Microbiol. Infect. Dis. 60(2), 229-231 (2008).
152. Zaman K, Dang DA, Victor JC et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebocontrolled trial. Lancet 376(9741), 615-623 (2010).
153. Madhi SA, Cunliffe NA, Steele D et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N. Engl. J. Med. 362(4), 289-298 (2010).
154. Phase I study to determine the safety and immunogenicity of an oral ETEC candidate vaccine, attenuated, recombinant double mutant heat-labile toxin (dmLT) from enterotoxigenic Escherichia coli. http://clinicaltrials.gov/ct2/ show/NCT01147445?term=dmLT&rank=1 (Accessed 17 May 2012)
155. A Phase 1 dose-escalating study of dscCfaE, co-administered with and without LTR192G, by transcutaneous immunization (TCI) in healthy adult US volunteers. http://clinicaltrials.gov/ct2/show/NCT01382095?term= adhesin&rank=1 (Accessed 19 August 2011)