Synthetic antigen constructs against campylobacter jejuni
Inventors
Guerry, Patricia • Monteiro, Mario Artur • Jiao, Yuening • Pequegnat, Brittany Michele
Assignees
University of Guelph • US Department of Navy
Publication Number
US-10500261-B2
Publication Date
2019-12-10
Expiration Date
2035-11-05
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Abstract
The invention relates to immunogenic synthetic constructs capable of inducing an immune response against Campylobacter jejuni (C. jejuni) in a subject comprising one or more monosaccharides comprising one or more MeOPN moieties. Specifically, the invention relates to immunogenic synthetic constructs capable of inducing an immune response against C. jejuni in a subject comprising one or more MeOPN-6-Gal monosaccharides, one or more MeOPN-4-Gal monosaccharides, and/or one or more MeOPN-2-Gal monosaccharides. The invention also relates to compositions comprising the immunogenic synthetic constructs, and methods of inducing an immune response against C. jejuni in a subject comprising administering the immunogenic synthetic constructs, and/or compositions comprising the immunogenic synthetic constructs, to the subject. Methods of treating, preventing, or ameliorating a C. jejuni bacterial infection in a subject comprising administering to the subject one or more doses of immunoglobulins directed to one or more of the MeOPN moieties are also contemplated.
Core Innovation
The invention relates to immunogenic synthetic constructs capable of inducing an immune response against Campylobacter jejuni in a subject, comprising one or more monosaccharides containing one or more O-methyl phosphoramidate (MeOPN) moieties, specifically MeOPN-2-Gal, MeOPN-4-Gal, and/or MeOPN-6-Gal. It includes compositions of these constructs and methods of inducing an immune response by administering these constructs or compositions to subjects. Additionally, methods of treating, preventing, or ameliorating C. jejuni bacterial infection by administering immunoglobulins directed to MeOPN moieties are contemplated.
The problem being solved addresses the significant morbidity and mortality caused by C. jejuni gastroenteritis worldwide, for which currently no licensed vaccines exist. Prior capsule polysaccharide conjugate vaccines have limitations, such as variability in MeOPN levels due to phase variation in bacterial capsules influencing immunogenicity, and difficulties in growing and purifying C. jejuni capsules. Furthermore, purified capsules may co-purify lipooligosaccharides mimicking human gangliosides that can induce undesirable autoimmune responses like Guillain-Barré Syndrome.
The invention overcomes these issues by providing chemically synthesized monosaccharide constructs with controlled MeOPN epitopes that enable standardized immunogenicity, potentially broader immunological coverage across serotypes, and cost-effective production without the need to grow C. jejuni or purify capsules. The synthetic approach also reduces risks related to autoimmunity by avoiding lipooligosaccharide contamination. Moreover, constructs conjugated to carrier proteins enhance T-cell dependent immune responses.
Claims Coverage
The patent claims encompass one independent claim directed to synthetic constructs comprising MeOPN-4-Gal moieties, their compositions, methods of use, and immunoglobulin-based therapies. Main inventive features focus on the inclusion of MeOPN-4-Gal and optionally other MeOPN moieties for immunogenicity, conjugation to carrier proteins including CRM197, and methods for immune induction and treatment of infection.
Synthetic constructs comprising MeOPN-4-Gal moieties
An immunogenic synthetic construct capable of inducing an immune response against C. jejuni in a subject comprising one or more monosaccharides comprising MeOPN moieties specifically at the 4-position of galactose (MeOPN-4-Gal).
Combination with other MeOPN moieties
The immunogenic synthetic construct can further comprise one or more MeOPN moieties selected from MeOPN-2-Gal and MeOPN-6-Gal in addition to MeOPN-4-Gal.
Conjugation to carrier proteins containing T-cell epitopes
The constructs may be conjugated to carrier proteins which contain at least one T-cell epitope, with a preferred carrier protein being the inactivated bacterial toxin CRM197.
Compositions including pharmaceutical and vaccine formulations
Pharmaceutical compositions and vaccine formulations comprising the synthetic constructs, optionally with immune-effective adjuvants such as toll-like receptor ligands, aluminum phosphate, aluminum hydroxide, monophosphoryl lipid A, liposomes, and derivatives or combinations thereof.
Use of additional immunoregulatory agents
Compositions may include additional immunoregulatory agents such as antigens from C. jejuni strains, ETEC, Shigella lipopolysaccharides, and unconjugated carrier proteins.
Methods of inducing immune responses
Methods to induce immune responses by administering effective amounts of the synthetic constructs or compositions to subjects, including human subjects, optionally with boosting doses and immune-effective adjuvants.
Therapeutic use of immunoglobulins recognizing MeOPN moieties
Methods of treating, preventing, or ameliorating C. jejuni infection in subjects by administering immunoglobulins recognizing MeOPN-4-Gal and optionally other MeOPN moieties in C. jejuni capsules.
In summary, the independent claims cover immunogenic synthetic constructs comprising MeOPN-4-Gal monosaccharides, optionally combined with MeOPN-2-Gal and MeOPN-6-Gal, their conjugation to carrier proteins (preferably CRM197), compositions including pharmaceutical and vaccine formulations comprising these constructs with adjuvants and immunoregulatory agents, methods of administering these constructs or compositions to induce immune responses in subjects, particularly humans, and immunoglobulin-based therapies targeting these MeOPN epitopes to treat or prevent infections.
Stated Advantages
The synthetic constructs enable controlled and consistent immunogenicity by standardizing MeOPN epitope levels, overcoming natural variability in purified capsule vaccines.
Potential for broader immunological coverage across multiple C. jejuni serotypes, reducing vaccine valency requirements.
Cost-effective production without the need to cultivate fastidious C. jejuni bacteria or purify capsules, increasing commercial viability.
Reduced risk of autoimmune responses such as Guillain-Barré Syndrome by avoiding lipooligosaccharide contamination found in purified capsules.
Enhanced immune response due to conjugation with carrier proteins converting the response from T-cell independent to T-cell dependent.
Documented Applications
Inducing an immune response against Campylobacter jejuni infections in subjects, including vaccination of humans and animals.
Use in prophylactic and therapeutic vaccine formulations comprising synthetic MeOPN-containing constructs conjugated to carrier proteins such as CRM197.
Treatment, prevention, or amelioration of C. jejuni bacterial infections through administration of immunoglobulins recognizing MeOPN moieties including MeOPN-4-Gal.
Creation of multivalent vaccines targeting multiple C. jejuni serotypes by inclusion of synthetic constructs comprising MeOPN-2-Gal, MeOPN-4-Gal, and MeOPN-6-Gal.
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