cholera-toxin--b-subunit-(50-64) and Escherichia-coli-Infections

The concept of a common mucosal immune system, through which specific antigen-activated lymphocytes from the gut can disseminate immunity both along the intestinal tract and to various other mucosal and glandular tissues, has generated much current interest in the possibility of developing oral vaccines, not only for enteric infections but also for infections in the respiratory and urogenital tracts. However, to date it has proven difficult in practice to stimulate strong mucosal IgA immune responses by either parenteral or oral-mucosal administration of most antigens, and experience with soluble protein antigens has, on the whole, been disappointing. A notable exception in this regard is cholera toxin (CT) and in humans more than in other species, its nontoxic B subunit pentamer moiety (CTB). Based on this, CTB has become an important component in recently developed oral vaccines against cholera as well as against diarrhea caused by enterotoxigenic Escherichia coli producing CT-like heat-labile enterotoxin(s). Since the strong immunogenicity of CT and CTB can, to a large extent, be explained by their ability to bind to receptors on the intestinal mucosal surface, there has recently been much interest in approaches using CTB as an oral delivery carrier system for other vaccine-relevant antigens, and much progress has been made in preparing immunogenic hybrid proteins by coupling various protein or peptide antigens chemically or genetically to CTB. Indeed, in several systems, oral administration of such hybrid antigens has been found to markedly potentiate both intestinal and extraintestinal IgA immune responses against the CTB-coupled antigens and also to elicit substantial circulating antibody responses. Besides the mucosal immunopotentiating effect of either CT or CTB owing to their similar capacity as oral antigen-delivery vehicles, CT, but in most systems tested not CTB, also has strong adjuvant properties for stimulating mucosal IgA immune responses to admixed (not coupled) unrelated antigens after oral immunization. This adjuvant activity appears to be closely linked to the ADP-ribosylating action of CT (and specifically of its A subunit) leading to enhanced cyclic AMP formation in the affected cell, and efforts to eliminate the enterotoxic activity without losing adjuvanticity have so far not met with success.

Topics: Adjuvants, Immunologic; Animals; Bacterial Vaccines; Cholera; Cholera Toxin; Cholera Vaccines; Diarrhea; Escherichia coli; Escherichia coli Infections; Humans; Immunoglobulin A, Secretory; Intestinal Mucosa; Mucous Membrane; Peptide Fragments

The B subunit (BS) of cholera toxin and that of the heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli (ETEC) are antigenically similar. We therefore assessed whether a combined cholera toxin BS/whole-cell (BS-WC) oral vaccine against cholera conferred cross-protection against LT-producing ETEC (LT-ETEC) diarrhea in a randomized, double-blind field trial among rural Bangladeshi children and women. The 24,770 persons who ingested two or more doses of BS-WC vaccine were compared with 24,842 controls who took two or more doses of killed whole-cell (WC) oral cholera vaccine. Sixty-seven percent fewer episodes of LT-ETEC diarrhea were noted in the BS-WC group than in the WC group during short-term (three-month) follow-up (P less than .01), but no reduction was evident during the ensuing nine months. Short-term protection was particularly notable against LT-ETEC diarrhea causing life-threatening dehydration (protective efficacy, 86%; P less than .05).

Topics: Adolescent; Bacterial Toxins; Child; Child, Preschool; Cholera Toxin; Cholera Vaccines; Clinical Trials as Topic; Cross Reactions; Diarrhea; Double-Blind Method; Enterotoxins; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Female; Humans; Immunity; Peptide Fragments; Random Allocation; Vaccination

We examined whether infection with enterotoxigenic Escherichia coli (ETEC) producing the heat-labile enterotoxin (LT) can prime the gut immune system to respond more efficiently to the immunologically related cholera B subunit component of a recently developed oral B subunit-whole-cell cholera vaccine (B-WCV). Nine Bangladeshi adults who had been hospitalized for watery diarrhea caused by LT-producing ETEC were given a single oral immunization with B-WCV on day 28 after hospital admission. The vaccine preparation used was adjusted to contain a lower-than-usual dose of B subunit, which had been found in previous studies to elicit a significant gut mucosal immunoglobulin A antitoxin response mainly in individuals with previous toxin-specific priming of their gut immune system. For comparison, nine patients convalescing from severe cholera disease and eight healthy subjects with no recent history of either cholera or ETEC infection were given the same oral vaccination with B-WCV. Vaccination in the ETEC convalescents induced an immunoglobulin A antitoxin response in intestinal lavage fluid which was comparable with that in the vaccinated cholera convalescents and superior to that in the vaccinated, previously uninfected controls. By contrast, only the cholera patients responded with anamnestic-type anti-cholera lipopolysaccharide antibody titer rises in the intestine after vaccination. These data support the specificity of the anamnestic anti-cholera toxin response in the ETEC patients after vaccination with cholera B-WCV.

Topics: Bacterial Toxins; Cholera Toxin; Convalescence; Diarrhea; Enterotoxins; Escherichia coli Infections; Escherichia coli Proteins; Female; Humans; Immunoglobulin A; Immunologic Memory; Intestinal Mucosa; Middle Aged; Peptide Fragments