title: Comparative safety and immunogenicity of two attenuated enterotoxigenic Escherichia coli vaccine strains in healthy adults.
abstract: A vaccine against enterotoxigenic Escherichia coli (ETEC) is needed to prevent diarrheal illness among children in developing countries and at-risk travelers. Two live attenuated ETEC strains, PTL002 and PTL003, which express the ETEC colonization factor CFA/II, were evaluated for safety and immunogenicity. In a randomized, double-blind, placebo-controlled trial, 19 subjects ingested one dose, and 21 subjects ingested two doses (days 0 and 10) of PTL-002 or PTL-003 at 2 x 10(9) CFU/dose. Anti-CFA/II mucosal immune responses were determined from the number of antibody-secreting cells (ASC) in blood measured by enzyme-linked immunospot assay, the antibody in lymphocyte supernatants (ALS) measured by enzyme-linked immunosorbent assay (ELISA), and fecal immunoglobulin A (IgA) levels determined by ELISA. Time-resolved fluorescence (TRF) ELISA was more sensitive than standard colorimetric ELISA for measuring serum antibody responses to CFA/II and its components, CS1 and CS3. Both constructs were well tolerated. Mild diarrhea occurred after 2 of 31 doses (6%) of PTL-003. PTL-003 produced more sustained intestinal colonization than PTL-002 and better IgA response rates: 90% versus 55% (P = 0.01) for anti-CFA/II IgA-ASCs, 55% versus 30% (P = 0.11) for serum anti-CS1 IgA by TRF, and 65% versus 25% (P = 0.03) for serum anti-CS3 IgA by TRF. Serum IgG response rates to CS1 or CS3 were 55% in PTL-003 recipients and 15% in PTL-002 recipients (P = 0.02). Two doses of either strain were not significantly more immunogenic than one. Based on its superior immunogenicity, which was comparable to that of a virulent ETEC strain and other ETEC vaccine candidates, PTL-003 will be developed further as a component of a live, oral attenuated ETEC vaccine.
authors.affiliation: Center for Immunization Research, Department of International Health, Johns Hopkins University, Bloomberg School of Public Health, 624 N. Broadway, HH, Rm. 203, Baltimore, MD 21205, USA. rmckenz@jhmi.edu
authors.forename: Robin
authors.initials: R
authors.lastname: McKenzie
authors.forename: A Louis
authors.initials: AL
authors.lastname: Bourgeois
authors.forename: Fayette
authors.initials: F
authors.lastname: Engstrom
authors.forename: Eric
authors.initials: E
authors.lastname: Hall
authors.forename: H Sunny
authors.initials: HS
authors.lastname: Chang
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gomes
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kyle
authors.forename: Fred
authors.initials: F
authors.lastname: Cassels
authors.forename: Arthur K
authors.initials: AK
authors.lastname: Turner
authors.forename: Roger
authors.initials: R
authors.lastname: Randall
authors.forename: Michael
authors.initials: M
authors.lastname: Darsley
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lee
authors.forename: Philip
authors.initials: P
authors.lastname: Bedford
authors.forename: Janet
authors.initials: J
authors.lastname: Shimko
authors.forename: David A
authors.initials: DA
authors.lastname: Sack
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000032:analysis / Q000097:blood; D000921:Antibody-Producing Cells; D004311:Double-Blind Method; D004768:Enterotoxins / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000517:prevention & control; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D005243:Feces / Q000382:microbiology; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008875:Middle Aged; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D004768:Enterotoxins; D022361:Escherichia coli Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D014613:Vaccines, Attenuated