Adhesin as immunogen against enterotoxigenic Escherichia coli
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Publication Number
US-9079945-B2
Publication Date
2015-07-14
Expiration Date
2026-01-10
Abstract
The inventive subject matter relates to the methods for the induction of immunity and prevention of diarrhea resulting from Escherichia coli. The inventive subject matter also relates to the use Escherichia coli adhesins as immunogens and to the construction of conformationally stability and protease resistant Escherichia coli adhesin constructs useful for inducing immunity to Escherichia coli pathogenic bacteria. The methods provide for the induction of B-cell mediated immunity and for the induction of antibody capable of inhibiting the adherence and colonization of Escherichia coli including enterotoxigenic Escherichia coli, to human cells.
Core Innovation
The invention relates to methods for inducing immunity and preventing diarrhea caused by Escherichia coli, particularly enterotoxigenic Escherichia coli (ETEC), by using Escherichia coli adhesins as immunogens. It provides for the construction of conformationally stable and protease resistant Escherichia coli adhesin constructs useful in inducing immunity. The method induces B-cell mediated immunity and the production of antibodies capable of inhibiting adherence and colonization of Escherichia coli to human cells.
The problem addressed is the inadequate efficacy of currently available vaccines against diarrheagenic bacteria such as ETEC, which are a principal cause of diarrhea especially in young children in resource-limited countries. The invention targets the critical bacterial components responsible for host cell adhesion, specifically the minor subunits (adhesins) of Class 5 fimbriae and CS3 fibrillae, because these adhesins mediate bacterial attachment and colonization. Existing vaccines using whole fimbriae or whole bacteria require improvement in antigen use and efficacy.
The invention includes the identification of the minor subunits of Class 5 fimbriae as the critical adhesins responsible for binding to host cells, thereby making them the most important targets for vaccine-induced immunity. It describes designing protease resistant, conformationally-stable adhesin polypeptide constructs by in cis donor strand complementation, linking adhesin sequences at the C-terminal end to a linker and a donor β-strand from the major fimbrial subunit to confer stability and immunogenicity. The invention provides methods for immunization with these conformationally stable adhesin constructs through various administration routes to induce specific antibody responses that block bacterial colonization.
Claims Coverage
The claims feature one independent claim describing an immunogenic composition composed of linked Escherichia coli adhesin and fimbrial subunit polypeptides. Two main inventive features are present.
Immunogenic composition comprising adhesion and fimbrial subunit linked polypeptides
An immunogenic composition comprising CfaE or a fragment thereof linked at its C-terminal end to a polypeptide linker, which is linked at the C-terminal end of the linker to CfaB or a fragment thereof.
Use of specific linker and donor β-strand sequences for conformational stability
The linker comprises the amino acid sequence of SEQ ID No. 1, SEQ ID No. 2, or SEQ ID No. 3 or fragments thereof; the CfaB or fragment thereof includes a donor β-strand comprising at least the first 12 amino acids of the major CfaB, such as SEQ ID No. 7 or fragments between 12 and 19 amino acids long, to confer conformational stability.
The claims cover an immunogenic composition consisting of adhesin polypeptides linked via specific polypeptide linkers to donor β-strands derived from the major fimbrial subunit to provide stable immunogens inducing immunity to Escherichia coli.
Stated Advantages
The use of adhesin subunits as immunogens requires significantly less antigen to elicit immunity with improved efficacy compared to whole fimbriae or whole bacteria.
Construction of conformationally stable and protease resistant adhesin polypeptides enhances immunogenicity and vaccine efficacy.
Induction of B-cell mediated immunity and production of antibodies that inhibit bacterial adherence and colonization.
Documented Applications
Induction of immunity and prevention of diarrhea caused by enterotoxigenic Escherichia coli and related diarrheagenic bacteria.
Use of conformationally stable fimbrial adhesin polypeptide constructs as vaccine components administered via oral, nasal, subcutaneous, intradermal, transdermal, intramuscular, or rectal routes.
Whole cell vaccines comprising recombinant bacteria expressing adhesin constructs from Escherichia coli, Shigella, Campylobacter, Salmonella, Vibrio, or Vibrio cholerae for induction of immunity.
Generation of anti-adhesive immune responses to inhibit bacterial colonization by steric hindrance of fimbrial adhesin attachment.
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