cholera-toxin--b-subunit-(50-64) and Cholera

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 capacity of peroral immunization with either two or three doses of B subunit-whole cell (B-WC) cholera vaccine to induce immunological memory was examined in Swedish volunteers by testing the immune responses to a single dose of B-WC vaccine given 10 months after the initial immunization. Antibody responses in serum and antibody-secreting cell (ASC) responses in peripheral blood were studied, since these responses seem to reflect the gut mucosal IgA immune responses after oral immunization with B-WC vaccine. Previously immunized volunteers responded to a single dose of B-WC vaccine more frequently and with higher levels of IgA and IgG antitoxin antibodies as well as vibriocidal antibodies in serum than did previously unvaccinated controls. The IgA-ASC responses to cholera toxin B subunit were also higher in primed volunteers than in controls. Two doses of B-WC vaccine were as effective as three doses in inducing immunological memory for cholera immunity. A new B-WC cholera vaccine based on recombinant B subunit had the same capacity as the first generation of B-WC vaccine to induce immunological memory for cholera antitoxin immunity.

Topics: Administration, Oral; Adolescent; Adult; Antibodies, Bacterial; Antibody-Producing Cells; Cholera; Cholera Toxin; Cholera Vaccines; Female; Humans; Immunization, Secondary; Immunoglobulin A; Immunoglobulin G; Immunologic Memory; Male; Middle Aged; Peptide Fragments; Sweden; Vaccination; Vaccines, Synthetic; Vibrio cholerae

New-generation, orally administered cholera vaccines offer the promise of improved control of cholera in sub-Saharan Africa. However, the high prevalence of human immunodeficiency virus (HIV) infection in many cholera-affected African populations has raised doubts about the level of protection possible with vaccination. We evaluated a mass immunization program with recombinant cholera-toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in Beira, Mozambique, a city where the seroprevalence of HIV is 20 to 30 percent.. From December 2003 to January 2004, we undertook mass immunization of nonpregnant persons at least two years of age, using a two-dose regimen of rBS-WC vaccine in Esturro, Beira (population 21,818). We then assessed vaccine protection in a case-control study during an outbreak of El Tor Ogawa cholera in Beira between January and May 2004. To estimate the level of vaccine protection, antecedent rates of vaccination were compared between persons with culture-confirmed cholera severe enough to have prompted them to seek treatment and age- and sex-matched neighborhood controls without treated diarrhea.. We assessed the effectiveness of the vaccine in 43 persons with cholera and 172 controls. Receipt of one or more doses of rBS-WC vaccine was associated with 78 percent protection (95 percent confidence interval, 39 to 92 percent; P=0.004). The vaccine was equally effective in children younger than five years of age and in older persons. A concurrently conducted case-control study designed to detect bias compared persons with treated, noncholeraic diarrhea and controls without diarrhea in the same population and found no protection associated with receipt of the rBS-WC vaccine.. The rBS-WC vaccine was highly effective against clinically significant cholera in an urban sub-Saharan African population with a high prevalence of HIV infection.

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Cholera; Cholera Toxin; Cholera Vaccines; Diarrhea; Feasibility Studies; Female; HIV Infections; Humans; Immunization Programs; Logistic Models; Male; Middle Aged; Mozambique; Peptide Fragments; Population Surveillance; Treatment Outcome; Vaccines, Inactivated; Vibrio cholerae

An engineered E. coli strain containing high expression level of CT-B subunits has been obtained by the application of recombinant DNA techniques. The B subunit can be secreted into the medium and reaches 20-40 micrograms/ml when this strain is incubated in a 50 l fermentation tank. The CT-B subunit purified with affinity chromatography in E. coli has the same characters as the natural CT-B subunit in molecular weight, N terminal amino acid analysis and antigenicity. The CT-B subunit has good immunogenicity and can be used as a preparation for protecting against diarrhea caused by V. cholera and enterotoxigenic E. coli. It can also be used as a vector for hepatins.

Topics: Animals; Cholera; Cholera Toxin; DNA, Recombinant; Escherichia coli; Genetic Engineering; Immunodiffusion; Immunoelectrophoresis; Male; Peptide Fragments; Rabbits; Vaccination