Current progress in developing subunit vaccines against enterotoxigenic Escherichia coli-associated Diarrhea

Clinical and Vaccine Immunology

Volumn 22, Issue 9, 2015, Pages 983-991

  Zhang, Weiping ^a   Sack, David A ^b  

^a KANSAS STATE UNIVERSITY   (United States)

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

Author keywords

[No Author keywords available]

Indexed keywords

ADHESIN; ADHESIN ANTIBODY; ADHESIN TIP ANTIGEN; ANTIGEN; COLONIZATION FACTOR ANTIGEN; ESCHERICHIA COLI ENTEROTOXIN; ESCHERICHIA COLI VACCINE; FREUND ADJUVANT; MONTANIDE ISA 51; MUCIN; MULTIEPITOPE FUSION ANTIGEN; PEPTIDE VACCINE; PROTEIN ANTIBODY; PROTEINASE; SUBUNIT VACCINE; TOXOID; UNCLASSIFIED DRUG; ANTITOXIN; BACTERIAL ANTIGEN; BACTERIAL TOXIN; BACTERIUM ANTIBODY; COLONIZATION FACTOR ANTIGENS; ENTEROTOXIN; ESCHERICHIA COLI PROTEIN; FIMBRIA PROTEIN; HEAT-LABILE ENTEROTOXIN, E COLI;

BACTERIAL STRAIN; BACTERIAL VIRULENCE; BACTERIUM ADHERENCE; CAUSE OF DEATH; CHILD DEATH; DIARRHEA; DRUG DEVELOPMENT; ENTEROTOXIGENIC ESCHERICHIA COLI; GENE FUSION; HUMAN; NONHUMAN; PRIORITY JOURNAL; REVIEW; BIOSYNTHESIS; CHILD; ESCHERICHIA COLI INFECTIONS; GENETICS; IMMUNOLOGY; PATHOGENICITY; PRESCHOOL CHILD; STANDARDS;

ADHESINS, BACTERIAL; ANTIBODIES, BACTERIAL; ANTIGENS, BACTERIAL; ANTITOXINS; BACTERIAL TOXINS; CHILD; CHILD, PRESCHOOL; DIARRHEA; ENTEROTOXIGENIC ESCHERICHIA COLI; ENTEROTOXINS; ESCHERICHIA COLI INFECTIONS; ESCHERICHIA COLI PROTEINS; ESCHERICHIA COLI VACCINES; FIMBRIAE PROTEINS; HUMANS; VACCINES, SUBUNIT;

EID: 84941561651     PISSN: 15566811     EISSN: 1556679X     Source Type: Journal    
DOI: 10.1128/CVI.00224-15     Document Type: Review

References (94)

1. Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, Jha P, Campbell H, Walker CF, Cibulskis R, Eisele T, Liu L, Mathers C, Child Health Epidemiology Reference Group of WHO and UNICEF. 2010. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 375:1969-1987. http://dx.doi.org/10.1016/S0140-6736 (10) 60549-1.
2. Fischer Walker CL, Sack D, Black RE. 2010. Etiology of diarrhea in older children, adolescents and adults: a systematic review. PLoS Negl Trop Dis 4:e768. http://dx.doi.org/10.1371/journal.pntd.0000768.
3. Lamberti LM, Fischer Walker CL, Black RE. 2012. Systematic review of diarrhea duration and severity in children and adults in low- and middleincome countries. BMC Public Health 12:276. http://dx.doi.org/10.1186/1471-2458-12-276.
4. Levine MM, Kotloff KL, Nataro JP, Muhsen K. 2012. The Global Enteric Multicenter Study (GEMS): impetus, rationale, and genesis. Clin Infect Dis 55(Suppl 4):S215-S224. http://dx.doi.org/10.1093/cid/cis761.
5. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, Rudan I, Campbell H, Cibulskis R, Li M, Mathers C, Black RE, Child Health Epidemiology Reference Group of WHO and UNICEF. 2012. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379:2151-2161. http://dx.doi.org/10.1016/S0140-6736 (12) 60560-1.
6. Fischer Walker CL, Perin J, Aryee MJ, Boschi-Pinto C, Black RE. 2012. Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. BMC Public Health 12:220. http://dx.doi.org/10.1186/1471-2458-12-220.
7. World Health Organization (WHO). Global health observatory data repository 2012. http://apps.who.int/gho/data/?theme=main.
8. United Nations Children's Fund (UNICEF). 2013. Level and trends in child mortality, report 2013. http://www.childinfo.org/files/Child-Mortality-Report-2013.pdf.
9. United Nations Children's Fund (UNICEF). 2013. Committing to child survival: promise renewed progress report 2013. http://www.unicef.org/publications/files/APR-Progress-Report-2013-9-Sept-2013.pdf.
10. Anonymous. 2006. Future directions for research on enterotoxigenic Escherichia coli vaccines for developing countries. Wkly Epidemiol Rec 81:97-107.
11. Kotloff KL, Blackwelder WC, Nasrin D, Nataro JP, Farag TH, van Eijk A, Adegbola RA, Alonso PL, Breiman RF, Faruque AS, Saha D, Sow SO, Sur D, Zaidi AK, Biswas K, Panchalingam S, Clemens JD, Cohen D, Glass RI, Mintz ED, Sommerfelt H, Levine MM. 2012. The Global Enteric Multicenter Study (GEMS) of diarrheal disease in infants and young children in developing countries: epidemiologic and clinical methods of the case/control study. Clin Infect Dis 55(Suppl 4):S232-S245. http://dx.doi.org/10.1093/cid/cis753.
12. Nataro JP, Kaper JB. 1998. Diarrheagenic Escherichia coli. Clin Microbiol Rev 11:142-201.
13. Snyder JD, Merson MH. 1982. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bull World Health Organ 60:605-613.
14. Black RE, Morris SS, Bryce J. 2003. Where and why are 10 million children dying every year? Lancet 361:2226-2234. http://dx.doi.org/10.1016/S0140-6736 (03) 13779-8.
15. Liu L, Li Q, Lee RA, Friberg IK, Perin J, Walker N, Black RE. 2011. Trends in causes of death among children under 5 in Bangladesh, 1993-2004: an exercise applying a standardized computer algorithm to assign causes of death using verbal autopsy data. Population Health Metrics 9:43. http://dx.doi.org/10.1186/1478-7954-9-43.
16. Lanata CF, Fischer-Walker CL, Olascoaga AC, Torres CX, Aryee MJ, Black RE, Child Health Epidemiology Reference Group of the WHO and UNICEF. 2013. Global causes of diarrheal disease mortality in children < 5 years of age: a systematic review. PLoS One 8:e72788. http://dx.doi.org/10.1371/journal.pone.0072788.
17. Zhang W, Sack DA. 2012. Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans. Expert Rev Vaccines 11:677-694. http://dx.doi.org/10.1586/erv. 12.37.
18. Svennerholm AM. 2011. From cholera to enterotoxigenic Escherichia coli (ETEC) vaccine development. Indian J Med Res 133:188-196.
19. MacLennan CA, Saul A. 2014. Vaccines against poverty. Proc Natl Acad Sci U S A 111:12307-12312. http://dx.doi.org/10.1073/pnas.1400473111.
20. PATH. 2011 The case for investment in enterotoxigenic Escherichia coli vaccines. PATH, Seattle, WA. http://www.path.org/publications/files/VAC-etec-investment-rpt.pdf.
21. Gaastra W, Svennerholm AM. 1996. Colonization factors of human enterotoxigenic Escherichia coli (ETEC). Trends Microbiol 4:444-452. http://dx.doi.org/10.1016/0966-842X (96) 10068-8.
22. Wolf MK. 1997. Occurrence, distribution, and associations of O and H serogroups, colonization factor antigens, and toxins of enterotoxigenic Escherichia coli. Clin Microbiol Rev 10:569-584.
23. Qadri F, Svennerholm AM, Faruque A S G, Sack RB. 2005. Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clin Microbiol Rev 18:465-483. http://dx.doi.org/10.1128/CMR.18.3.465-483.2005.
24. Zhang W. 2014. Perspective of use of vaccines for preventing enterotoxigenic Escherichia coli diarrhea in humans, p 273-302. In Morabito S (ed), Pathogenic Escherichia coli: molecular and cellular microbiology. Caister Academic Press, Norfolk, United Kingdom.
25. Clements JD. 1990. Construction of a nontoxic fusion peptide for immunization against Escherichia coli strains that produce heat-labile and heatstable enterotoxins. Infect Immun 58:1159-1166.
26. Svennerholm AM, Ahrén C, Wenneras C, Holmgren J. 1991. Development of an oral vaccine against enterotoxigenic Escherichia coli diarrhea, p 287-294. In Wadström T, Mäkelä PH, Svennerholm AM, Wolf-Watz H (ed), Molecular pathogenesis of gastrointestinal infections. Plenum Press, London, United Kingdom.
27. Evans DJ, Jr, Evans DG, Opekun AR, Graham DY. 1988. 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 1:9-18.
28. Evans DG, Evans DJ, Jr, Opekun AR, Graham DY. 1988. Nonreplicating oral whole cell vaccine protective against enterotoxigenic Escherichia coli (ETEC) diarrhea: stimulation of anti-CFA (CFA/I) and antienterotoxin (anti-LT) intestinal IgA and protection against challenge with ETEC belonging to heterologous serotypes. FEMS Microbiol Immunol 1:117-125.
29. Levine MM. 1990. Modern vaccines. Enteric infections. Lancet 335:958-961.
30. Svennerholm AM, Wenneras C, Holmgren J, McConnell MM, Rowe B. 1990. 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 58:341-346.
31. Sommerfelt H, Svennerholm AM, Kalland KH, Haukanes BI, Bjorvatn B. 1988. Comparative study of colony hybridization with synthetic oligonucleotide probes and enzyme-linked immunosorbent assay for identification of enterotoxigenic Escherichia coli. J Clin Microbiol 26:530-534.
32. Svennerholm AM, Holmgren J, Sack DA. 1989. Development of oral vaccines against enterotoxinogenic Escherichia coli diarrhoea. Vaccine 7:196-198. http://dx.doi.org/10.1016/0264-410X (89) 90228-4.
33. Walker RI. 2015. An assessment of enterotoxigenic Escherichia coli and Shigella vaccine candidates for infants and children. Vaccine 33:954-965. http://dx.doi.org/10.1016/j.vaccine.2014.11.049.
34. Jertborn M, Ahrén C, Holmgren J, Svennerholm AM. 1998. Safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli vaccine. Vaccine 16:255-260. http://dx.doi.org/10.1016/S0264-410X (97) 00169-2.
35. Ahrén C, Jertborn M, Svennerholm AM. 1998. Intestinal immune responses to an inactivated oral enterotoxigenic Escherichia coli vaccine and associated immunoglobulinAresponses in blood. Infect Immun 66:3311-3316.
36. Harro C, Sack D, Bourgeois AL, Walker R, Denearing B, Feller A, Chakraborty S, Buchwaldt C, Darsley MJ. 2011. 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 18:2118-2127. http://dx.doi.org/10.1128/CVI.05342-11.
37. Turner AK, Terry TD, Sack DA, Londono-Arcila P, Darsley MJ. 2001. Construction and characterization of genetically defined aro omp mutants of enterotoxigenic Escherichia coli and preliminary studies of safety and immunogenicity in humans. Infect Immun 69:4969-4979. http://dx.doi.org/10.1128/IAI.69.8.4969-4979.2001.
38. Sack DA, Shimko J, Torres O, Bourgeois AL, Francia DS, Gustafsson B, Karnell A, Nyquist I, Svennerholm AM. 2007. Randomised, doubleblind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. coli diarrhoea of travellers to Guatemala and Mexico. Vaccine 25:4392-4400.
39. Savarino SJ, Hall ER, Bassily S, Wierzba TF, Youssef FG, Peruski LF, Jr, Abu-Elyazeed R, Rao M, Francis WM, El Mohamady H, Safwat M, Naficy AB, Svennerholm AM, Jertborn M, Lee YJ, Clemens JD. 2002. Introductory evaluation of an oral, killed whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Egyptian infants. Pediatr Infect Dis J 21:322-330. http://dx.doi.org/10.1097/00006454-20020 4000-00012.
40. Svennerholm AM, Tobias J. 2008. Vaccines against enterotoxigenic Escherichia coli. Expert Rev Vaccines 7:795-804. http://dx.doi.org/10.1586/14760584.7.6.795.
41. Harro C, Chakraborty S, Feller A, DeNearing B, Cage A, Ram M, Lundgren A, Svennerholm AM, Bourgeois AL, Valker RI, Sack DA. 2011. Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines. Clin Vaccine Immunol 18:1719-1727. http://dx.doi.org/10.1128/CVI.05194-11.
42. Darsley MJ, Chakraborty S, DeNearing B, Sack DA, Feller A, Buchwaldt C, Bourgeois AL, Walker RI, Harro CD. 2012. The oral, live attenuated enterotoxigenic Escherichia coli vaccine ACE527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease. Clin Vaccine Immunol 19:1921-1931. http://dx.doi.org/10.1128/CVI.00364-12.
43. Holmgren J, Bourgeois L, Carlin N, Clements J, Gustafsson B, Lundgren A, Nygren E, Tobias J, Walker RI, Svennerholm AM. 2013. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant. Vaccine 31:2457-2464. http://dx.doi.org/10.1016/j.vaccine.2013.03.027.
44. Lundgren A, Leach S, Tobias J, Carlin N, Gustafsson B, Jertborn M, Bourgeois L, Walker RI, Holmgren J, Svennerholm AM. 2013. Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein. Vaccine 31:1163-1170. http://dx.doi.org/10.1016/j.vaccine.2012.12.063.
45. Frantz JC, Robertson DC. 1981. Immunological properties of Escherichia coli heat-stable enterotoxins: development of a radioimmunoassay specific for heat-stable enterotoxins with suckling mouse activity. Infect Immun 33:193-198.
46. Frantz JC, Mellencamp MW. 1983. Production and testing of Escherichia coli (LTb) toxoid, p 500-517. In Acres S (ed), Proceedings, 4th International Symposium on Neonatal Diarrhea. Saskatoon, Saskatchewan, Canada.
47. Qadri F, Ahmed T, Ahmed F, Begum YA, Sack DA, Svennerholm AM. 2006. 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 24:1726-1733. http://dx.doi.org/10.1016/j.vaccine.2005.08.110.
48. Qadri F, Bhuiyan TR, Sack DA, Svennerholm AM. 2013. Immune responses and protection in children in developing countries induced by oral vaccines. Vaccine 31:452-460. http://dx.doi.org/10.1016/j.vaccine.2012.11.012.
49. Yu J, Cassels F, Scharton-Kersten T, Hammond SA, Hartman A, Angov E, Corthesy B, Alving C, Glenn GM. 2002. Transcutaneous immunization using colonization factor and heat-labile enterotoxin induces correlates of protective immunity for enterotoxigenic Escherichia coli. Infect Immun 70:1056-1068. http://dx.doi.org/10.1128/IAI.70.3.1056-1068.2002.
50. Güereńa-Burgueńo F, Hall ER, Taylor DN, Cassels FJ, Scott DA, Wolf MK, Roberts ZJ, Nesterova GV, Alving CR, Glenn GM. 2002. Safety and immunogenicity of a prototype enterotoxigenic Escherichia coli vaccine administered transcutaneously. Infect Immun 70:1874-1880. http://dx.doi.org/10.1128/IAI.70.4.1874-1880.2002.
51. Glenn GM, Villar CP, Flyer DC, Bourgeois AL, McKenzie R, Lavker RM, Frech SA. 2007. 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 75:2163-2170. http://dx.doi.org/10.1128/IAI.01740-06.
52. McKenzie R, Bourgeois AL, Frech SA, Flyer DC, Bloom A, Kazempour K, Glenn GM. 2007. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Vaccine 25:3684-3691. http://dx.doi.org/10.1016/j.vaccine.2007.01.043.
53. Frech SA, Dupont HL, Bourgeois AL, McKenzie R, Belkind-Gerson J, Figueroa JF, Okhuysen PC, Guerrero NH, Matinez-Sandoval FG, Melendez-Romero JH, Jiang ZD, Asturias EJ, Halpern J, Torres OR, Hoffman AS, Villar CP, Kassem RN, Flyer DC, Andersen BH, Kazempour K, Breisch SA, Glenn GM. 2008. Use of a patch containing heatlabile toxin from Escherichia coli against travellers' diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 371:2019-2025. http://dx.doi.org/10.1016/S0140-6736 (08) 60839-9.
54. Behrens RH, Cramer JP, Jelinek T, Shaw H, von Sonnenburg F, Wilbraham D, Weinke T, Bell DJ, Astuias E, Pauwells HL, Maxwell R, Paredes-Paredes M, Glenn GM, Dewasthaly S, Stablein DM, Jiang ZD, Dupont HL. 2014. Efficacy and safety of a patch vaccine containing heatlabile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 14:197-204. http://dx.doi.org/10.1016/S1473-3099 (13) 70297-4.
55. Ellingsworth LR. 2011. Transcutaneous immunization and the travelers' diarrhea vaccine system: a phase III pivotal efficacy study. 6th International Conference on Vaccines for Enteric Diseases, VED 2011, Cannes, France.
56. Steffen R, Cramer JP, Burchard G, Jelinek T, Schwarz U, Ramdas P, Chatterjee C, Jiang ZD, DuPont HL, Dewasthaly S, Westrischnig K, Behrens RH. 2013. Efficacy of a travelers' diarrhea vaccine system in travelers to India. J Travel Med 20:374-379. http://dx.doi.org/10.1111/jtm.12064.
57. Riddle MS, Savarino SJ. 2014. Moving beyond a heat-labile enterotoxinbased vaccine against enterotoxigenic Escherichia coli. Lancet Infect Dis 14:174-175. http://dx.doi.org/10.1016/S1473-3099 (13) 70355-4.
58. Norton EB, Lawson LB, Freytag LC, Clements JD. 2011. Characterization of a mutant Escherichia coli heat-labile toxin, LT (R192G/L211A), as a safe and effective oral adjuvant. Clin Vaccine Immunol 18:546-551. http://dx.doi.org/10.1128/CVI.00538-10.
59. Lundgren A, Bourgeois L, Carlin N, Clements J, Gustafsson B, Hartford M, Holmgren J, Petzold M, Walker RI, Svennerholm AM. 2014. Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebocontrolled phase I study. Vaccine 32:7077-7084. http://dx.doi.org/10.1016/j.vaccine.2014.10.069.
60. Savarino SJ, O'Dowd A, Poole S, Maciel M, Rollenhagen J, McVeigh A, Porter C, Ellingsworth L, Glenn GM, Gourgeois AL, Riddle M. 2011. Advancement of an adhesin-based ETEC vaccine into clinical evaluation. 6th International Conference on Vaccines for Enteric Diseases, VED 2011, Cannes, France.
61. Zhang W, Zhang C, Francis DH, Fang Y, Knudsen D, Nataro JP, Rotertson DC. 2010. 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 78:316-325. http://dx.doi.org/10.1128/IAI.00497-09.
62. Taxt A, Aasland R, Sommerfelt H, Nataro J, Puntervoll P. 2010. Heat-stable enterotoxin of enterotoxigenic Escherichia coli as a vaccine target. Infect Immun 78:1824-1831. http://dx.doi.org/10.1128/IAI.01397-09.
63. Sanchez J, Hirst TR, Uhlin BE. 1988. Hybrid enterotoxin LTA::STa proteins and their protection from degradation by in vivo association with B-subunits of Escherichia coli heat-labile enterotoxin. Gene 64:265-275. http://dx.doi.org/10.1016/0378-1119 (88) 90341-1.
64. Svennerholm AM, Holmgren J. 1992. Immunity to enterotoxinproducing bacteria, p 227-246. In MacDonald TT (ed), Immunology of gastrointestinal diseases. Kluwer Academic Publishers, Dordrecht, The Netherlands.
65. Svennerholm AM, Lindvlad M, Svennerholm B, Holmgren J. 1988. Synthesis of nontoxic, antibody-binding Escherichia coli heat-stable enterotoxin (STa) peptides. FEMS Microbiol Lett 55:23-28. http://dx.doi.org/10.1111/j.1574-6968.1988.tb02792.x.
66. Yamasaki S I H, Hirayama T, Takeda Y, Shimonishi Y. 1988. Effects on the activity of amino acids replacement at positions 12, 13, and 14 heatstable enterotoxin (STh) by chemical synthesis, p 42. 24th Joint Conference of the US-Japan Cooperative Medical Sciences Program on Cholera and Related Diarrheal Disease Panel, Tokyo, Japan.
67. Liu M, Ruan X, Zhang C, Lawson SR, Knudsen DE, Nataro JP, Robertson DC, Zhang W. 2011. Heat-labile- and heat-stable-toxoid fusions (LTR192G-STaP13F) of human enterotoxigenic Escherichia coli elicit neutralizing antitoxin antibodies. Infect Immun 79:4002-4009. http://dx.doi.org/10.1128/IAI.00165-11.
68. Liu M, Zhang C, Mateo K, Nataro JP, Robertson DC, Zhang W. 2011. Modified heat-stable toxins (hSTa) of enterotoxigenic Escherichia coli lose toxicity but display antigenicity after being genetically fused to heatlabile toxoid LT (R192G). Toxins (Basel) 3:1146-1162. http://dx.doi.org/10.3390/toxins3091146.
69. Zhang W, Francis DH. 2010. 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 17:1223-1231. http://dx.doi.org/10.1128/CVI.00095-10.
70. Zhang C, Knudsen DE, Liu M, Robertson DC, Zhang W, STa Toxoid Vaccine Consortium Group. 2013. Toxicity and immunogenicity of enterotoxigenic Escherichia coli heat-labile and heat-stable toxoid fusion 3xSTa (A14Q)-LT (S63K/R192G/L211A) in a murine model. PLoS One 8:e77386. http://dx.doi.org/10.1371/journal.pone.0077386.
71. Ruan X, Robertson DC, Nataro JP, Clements JD, Zhang W, STa Toxoid Vaccine Consortium Group. 2014. Characterization of heat-stable (STa) toxoids of enterotoxigenic Escherichia coli fused to double mutant heatlabile toxin peptide in inducing neutralizing anti-STa antibodies. Infect Immun 82:1823-1832. http://dx.doi.org/10.1128/IAI.01394-13.
72. Gaastra W, Sommerfelt H, van Dijk L, Kusters JG, Svennerholm AM, Grewal HM. 2002. 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 292:43-50. http://dx.doi.org/10.1078/1438-4221-00189.
73. Anantha RP, McVeigh AL, Lee LH, Agnew MK, Cassels FJ, Scott DA, Whittam TS, Savarino SJ. 2004. Evolutionary and functional relationships of colonization factor antigen i and other class 5 adhesive fimbriae of enterotoxigenic Escherichia coli. Infect Immun 72:7190-7201. http://dx.doi.org/10.1128/IAI.72.12.7190-7201.2004.
74. McConnell MM, Chart H, Rowe B. 1989. 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 52:105-108.
75. Rudin A, McConnell MM, Svennerholm AM. 1994. Monoclonal antibodies against enterotoxigenic Escherichia coli colonization factor antigen I (CFA/I) that cross-react immunologically with heterologous CFAs. Infect Immun 62:4339-4346.
76. Svennerholm AM, Steele D. 2004. Microbial-gut interactions in health and disease. Progress in enteric vaccine development. Best Pract Res Clin Gastroenterol 18:421-445. http://dx.doi.org/10.1016/j.bpg.2003.11.004.
77. Savarino SJ, Poole S, Sincock SA, McVeigh A, Lee LH, Akay Y. 2005. One step beyond: a new approach for vaccines against enterotoxigenic Escherichia coli. 40th Joint Conference of the US-Japan Cooperative Medical Sciences Program on Cholera and Related Diarrheal Disease Panel, Boston, MA.
78. Purcell AW, McCluskey J, Rossjohn J. 2007. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov 6:404-414. http://dx.doi.org/10.1038/nrd2224.
79. Oyarzun P, Ellis JJ, Gonzalez-Galarza FF, Jones AR, Middleton D, Boden M, Kobe B. 2015. A bioinformatics tool for epitope-based vaccine design that accounts for human ethnic diversity: application to emerging infectious diseases. Vaccine 33:1267-1273. http://dx.doi.org/10.1016/j.vaccine.2015.01.040.
80. Ruan X, Knudsen DE, Wollenberg KM, Sack DA, Zhang W. 2014. Multiepitope fusion antigen induces broadly protective antibodies that prevent adherence of Escherichia coli strains expressing colonization factor antigen I (CFA/I), CFA/II, and CFA/IV. Clin Vaccine Immunol 21:243-249. http://dx.doi.org/10.1128/CVI.00652-13.
81. Isidean SD, Riddle MS, Savarino SJ, Porter CK. 2011. A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression. Vaccine 29:6167-6178. http://dx.doi.org/10.1016/j.vaccine.2011.06.084.
82. Ofek I, Zafriri D, Goldhar J, Eisenstein BI. 1990. Inability of toxin inhibitors to neutralize enhanced toxicity caused by bacteria adherent to tissue culture cells. Infect Immun 58:3737-3742.
83. Zhang C, Zhang W. 2010. Escherichia coli K88ac fimbriae expressing heat-labile and heat-stable (STa) toxin epitopes elicit antibodies that neutralize cholera toxin and STa toxin and inhibit adherence of K88ac fimbrial E. coli. Clin Vaccine Immunol 17:1859-1867. http://dx.doi.org/10.1128/CVI.00251-10.
84. Ruan X, Liu M, Casey TA, Zhang W. 2011. A tripartite fusion, FaeGFedF-LT (192) A2:B, of enterotoxigenic Escherichia coli (ETEC) elicits antibodies that neutralize cholera toxin, inhibit adherence of K88 (F4) and F18 fimbriae, and protect pigs against K88ac/heat-labile toxin infection. Clin Vaccine Immunol 18:1593-1599. http://dx.doi.org/10.1128/CVI.05120-11.
85. Ruan X, Zhang W. 2013. Oral immunization of a live attenuated Escherichia coli strain expressing a holotoxin-structured adhesin-toxoid fusion (1FaeG-FedF-LTA2:5LTB) protected young pigs against enterotoxigenic E. coli (ETEC) infection. Vaccine 31:1458-1463. http://dx.doi.org/10.1016/j.vaccine.2013.01.030.
86. Ruan X, Sack DA, Zhang W. 2015. Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity. PLoS One 10:e0121623. http://dx.doi.org/10.1371/journal.pone.0121623.
87. Fleckenstein JM, Roy K, Fischer JF, Burkitt M. 2006. Identification of a two-partner secretion locus of enterotoxigenic Escherichia coli. Infect Immun 74:2245-2258. http://dx.doi.org/10.1128/IAI.74.4.2245-2258.2006.
88. Sheikh A, Luo Q, Roy K, Shabaan S, Kumar P, Qadri F, Fleckenstein JM. 2014. Contribution of the highly conserved EaeH surface protein to enterotoxigenic Escherichia coli pathogenesis. Infect Immun 82:3657-3666. http://dx.doi.org/10.1128/IAI.01890-14.
89. Kumar P, Luo Q, Vickers TJ, Sheikh A, Lewis WG, Fleckenstein JM. 2014. EatA, an immunogenic protective antigen of enterotoxigenic Escherichia coli, degrades intestinal mucin. Infect Immun 82:500-508. http://dx.doi.org/10.1128/IAI.01078-13.
90. Luo Q, Kumar P, Vickers TJ, Sheikh A, Lewis WG, Rasko DA, Fleckenstein JM. 2014. Enterotoxigenic Escherichia coli secretes a highly conserved mucin-degrading metalloprotease to effectively engage intestinal epithelial cells. Infect Immun 82:509-521. http://dx.doi.org/10.1128/IAI.01106-13.
91. Roy K, Hilliard GM, Hamilton DJ, Luo J, Ostmann MM, Fleckenstein JM. 2009. Enterotoxigenic Escherichia coli EtpA mediates adhesion between flagella and host cells. Nature 457:594-598. http://dx.doi.org/10.1038/nature07568.
92. Roy K, Hamilton D, Allen KP, Randolph MP, Fleckenstein JM. 2008. The EtpA exoprotein of enterotoxigenic Escherichia coli promotes intestinal colonization and is a protective antigen in an experimental model of murine infection. Infect Immun 76:2106-2112. http://dx.doi.org/10.1128/IAI.01304-07.
93. Moriel DG, Bertoldi I, Spagnuolo A, Marchi S, Rosini R, Nesta B, Pastorello I, Corea VA, Torricelli G, Cartocci E, Savino S, Scaselli M, Dobrindt U, Hacker J, Tettelin H, Tallon LJ, Sulivan S, Wieler LH, Ewers C, Pickard D, Dougan G, Fontana MR, Pizza M, Serino L. 2010. Identification of protective and broadly conserved vaccine antigens from the genome of extraintestinal pathogenic Escherichia coli. Proc Natl Acad Sci U S A 107:9072-9077. http://dx.doi.org/10.1073/pnas.0915077107.
94. Fleckenstein J, Sheikh A, Qadri F. 2014. Novel antigens for enterotoxigenic Escherichia coli vaccines. Expert Rev Vaccines 13:631-639. http://dx.doi.org/10.1586/14760584.2014.905745.