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Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines.

Artikel i vetenskaplig tidskrift
Författare Clayton Harro
Subhra Chakraborty
Andrea Feller
Barbara DeNearing
Alicia Cage
Malathi Ram
Anna Lundgren
Ann-Mari Svennerholm
August L Bourgeois
Richard I Walker
David A Sack
Publicerad i Clinical and vaccine immunology : CVI
Volym 18
Nummer/häfte 10
Sidor 1719-27
ISSN 1556-679X
Publiceringsår 2011
Publicerad vid Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi
Sidor 1719-27
Språk en
Länkar dx.doi.org/10.1128/CVI.05194-11
Ämnesord Antibodies, Bacterial, blood, Biomedical Research, methods, Diarrhea, immunology, microbiology, prevention & control, Drug Evaluation, methods, Enterotoxigenic Escherichia coli, immunology, pathogenicity, Escherichia coli Infections, immunology, microbiology, prevention & control, Escherichia coli Vaccines, administration & dosage, immunology, Human Experimentation, Humans, Immunoglobulin A, blood, Immunoglobulin G, blood
Ämneskategorier Mikrobiologi inom det medicinska området

Sammanfattning

Enterotoxigenic Escherichia coli (ETEC) strain H10407 (serotype O78:H11 producing heat-labile toxin [LT], heat-stable toxin [ST], and colonization factor I [CFA/I]) induces reliably high diarrheal attack rates (ARs) in a human challenge model at doses of ≥10(9) CFU. A descending-dose challenge study was conducted with changes to the standard fasting time and buffer formulation, seeking conditions that permit lower inocula while maintaining reproducibly high ARs. In cohort 1, 20 subjects were fasted overnight and randomized 1:1:1:1 to receive H10407 at doses of 10(8) CFU with bicarbonate, 10(8) CFU with CeraVacx, 10(7) CFU with bicarbonate, or 10(7) CFU with CeraVacx. Subsequent cohorts received H10407 (10(7) CFU with bicarbonate) with similar fasting conditions. Cohort 2 included 15 ETEC-naïve volunteers. Cohort 3 included 10 ETEC-naïve volunteers and 10 rechallenged volunteers. In all, 25/35 (71%) ETEC-naïve recipients of 10(7) CFU of H10407 developed moderate or severe diarrhea (average maximum stool output/24 h = 1,042 g), and most (97%) shed H10407 (maximum geometric mean titer = 7.5 × 10(7) CFU/gram of stool). Only one of 10 rechallenged volunteers developed diarrhea. These rechallenged subjects had reduced intestinal colonization, reflected by quantitative microbiology of fecal samples. Among the 35 ETEC-naïve subjects, anti-lipopolysaccharide (LPS) O78 serum antibody responses were striking, with positive IgA and IgG antibody responses in 33/35 (94%) and 25/35 (71%), respectively. Anti-heat-labile enterotoxin (LTB) serum IgA and IgG responses developed in 19/35 (54%) and 14/35 (40%) subjects, respectively. Anti-CFA/I serum IgA and IgG responses were detected in 15/35 (43%) and 8/35 (23%) subjects. After the second challenge, participants exhibited blunted anti-LPS and -LTB responses but a booster response to CFA/I. This ETEC model should prove useful in the future evaluation of ETEC vaccine candidates.

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