Experimental infection of healthy volunteers with enterotoxigenic Escherichia coli wild-type strain TW10598 in a hospital ward
Steinar Skrede, Hans Steinsland, Halvor Sommerfelt, Audun Aase, Per Brandtzaeg, Nina Langeland, Rebecca J Cox, Marianne Saevik, Marita Wallevik, Dag Harald Skutlaberg, Marit Gjerde Tellevik, David A Sack, James P Nataro, Anne Berit Guttormsen, Steinar Skrede, Hans Steinsland, Halvor Sommerfelt, Audun Aase, Per Brandtzaeg, Nina Langeland, Rebecca J Cox, Marianne Saevik, Marita Wallevik, Dag Harald Skutlaberg, Marit Gjerde Tellevik, David A Sack, James P Nataro, Anne Berit Guttormsen
Abstract
Background: Enterotoxigenic Escherichia coli (ETEC) is an important cause of childhood diarrhea in resource-limited regions. It is also an important cause of diarrhea in travellers to these areas.To evaluate the protective efficacy of new ETEC vaccines that are under development, there is a need to increase the capacity to undertake Phase IIB (human challenge) clinical trials and to develop suitable challenge models.
Methods: An in-hospital study was performed where fasting adult volunteers were experimentally infected with 1 × 106 to 1 × 109 colony forming units (CFUs) of the wild-type ETEC strain TW10598, which had been isolated from a child with diarrhea in West Africa in 1997. We recorded symptoms and physical signs and measured serum immune response to the TW10598 bacterium.
Results: We included 30 volunteers with mean age 22.8 (range 19.8, 27.4) years. The most common symptoms were diarrhea (77%), abdominal pain (67%), nausea (63%), and abdominal cramping (53%). Seven subjects (23%) experienced fever, none were hypotensive. Most of the volunteers responded with a substantial rise in the level of serum IgA antibodies against the challenge strain.
Conclusions: We established the capacity and methods for safely undertaking challenge studies to measure the efficacy of ETEC vaccine candidates in a hospital ward. Strain TW10598 elicited both clinical symptoms and an immune response across the doses given.
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References
- Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, Wu Y, Sow SO, Sur D, Breiman RF, Faruque AS, Zaidi AK, Saha D, Alonso PL, Tamboura B, Sanogo D, Onwuchekwa U, Manna B, Ramamurthy T, Kanungo S, Ochieng JB, Omore R, Oundo JO, Hossain A, Das SK, Ahmed S, Qureshi S, Quadri F, Adegbola RA, Antonio M, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case–control study. Lancet. 2013;382:209–222. doi: 10.1016/S0140-6736(13)60844-2.
- DuPont HL, Formal SB, Hornick RB, Snyder MJ, Libonati JP, Sheahan DG, LaBrec EH, Kalas JP. Pathogenesis of Escherichia coli diarrhea. N Engl J Med. 1971;285:1–9. doi: 10.1056/NEJM197107012850101.
- Zhang W, Sack DA. Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans. Expert Rev Vaccines. 2012;11:677–694. doi: 10.1586/erv.12.37.
- Steinsland H, Valentiner-Branth P, Gjessing HK, Aaby P, Mølbak K, Sommerfelt H. Protection from natural infections with enterotoxigenic Escherichia coli: longitudinal study. Lancet. 2003;362:286–291. doi: 10.1016/S0140-6736(03)13971-2.
- Qadri F, Saha A, Ahmed T, Al Tarique A, Begum YA, Svennerholm AM. Disease burden due to enterotoxigenic Escherichia coli in the first 2 years of life in an urban community in Bangladesh. Infect Immun. 2007;75:3961–3968. doi: 10.1128/IAI.00459-07.
- Porter CK, Riddle MS, Tribble DR, Burgeois AL, McKenzie R, Isidean SD, Sebeny P, Savarino SJ. A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC) Vaccine. 2011;29:5869–5885. doi: 10.1016/j.vaccine.2011.05.021.
- Walker RI, Steele D, Aguado T, Ad Hoc Technical Expert Committtee Analysis of strategies to successfully vaccinate infants in developing countries against enterotoxigenic E. coli (ETEC) disease. Vaccine. 2007;25:2545–2566. doi: 10.1016/j.vaccine.2006.12.028.
- Steinsland H, Lacher DW, Sommerfelt H, Whittam TS. Ancestral lineages of human enterotoxigenic Escherichia coli. J Clin Microbiol. 2010;48:2916–2924. doi: 10.1128/JCM.02432-09.
- Sahl JW, Steinsland H, Redman JC, Angiuoli SV, Nataro JP, Sommerfelt H, Rasko DA. A comparative genomic analysis of diverse clonal types of enterotoxigenic Escherichia coli reveals pathovar-specific conservation. Infect Immun. 2011;79:950–960. doi: 10.1128/IAI.00932-10.
- Steinsland H, Valentiner-Branth P, Perch M, Dias F, Fischer TK, Aaby P, Mølbak K, Sommerfelt H. Enterotoxigenic Escherichia coli infections and diarrhea in a cohort of young children in Guinea-Bissau. J Infect Dis. 2002;186:1740–1747. doi: 10.1086/345817.
- Stacy-Phipps S, Mecca JJ, Weiss JB. Multiplex PCR assay and simple preparation method for stool specimens detect enterotoxigenic Escherichia coli DNA during course of infection. J Clin Microbiol. 1995;33:1054–1059.
- Harro C, Chakraboty S, Feller A, DeNearing B, Cage A, Ram M, Lundgren A, Svennerholm A-M, Burgeois AL, Walker RI, Sack DA. Refinement of a human challenge model for evaluation of Enterotoxigenic Escherichia coli vaccines. Clin Vaccine Immunol. 2011;18:1719–1727. doi: 10.1128/CVI.05194-11.
- Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, Hennessy T, Griffin PM, DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, Reller LB, Osterholm MT, Bennish ML, Pickering LK. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32:331–351. doi: 10.1086/318514.
- Aase A, Herstad TK, Merino S, Bolstad M, Sandbu S, Bakke H, Aaberge IS. Immunization of Teenagers with a Fifth Dose of Reduced DTaP-IPV Induces High Levels of Pertussis Antibodies with a Significant Increase in Opsonophagocytic Activity. Clin Vaccine Immunol. 2011;18:1269–1274. doi: 10.1128/CVI.05067-11.
- The pre-publication history for this paper can be accessed here:
Source: PubMed