Synthetic antigen constructs against Campylobacter jejuni

Inventors

Guerry, PatriciaMonteiro, Mario ArturJiao, Yuening

Assignees

University of GuelphUS Department of Navy

Publication Number

US-10500262-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 Campylobacter jejuni (C. jejuni) in a subject comprising one or more MeOPN→6 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 construct, to the subject.

Core Innovation

The invention is directed to immunogenic synthetic constructs capable of inducing an immune response against Campylobacter jejuni (C. jejuni) in a subject, wherein said constructs comprise one or more monosaccharides containing one or more O-methyl phosphoramidate (MeOPN) moieties, including specifically one or more MeOPN→6 Gal monosaccharides. The invention also relates to compositions comprising these synthetic constructs, pharmaceutical compositions including vaccine formulations, and methods of inducing an immune response against C. jejuni by administering these constructs or compositions to a subject. These constructs can be conjugated to carrier proteins, such as CRM197, and methods of synthesizing these constructs are also provided.

The problem being solved addresses the lack of licensed, commercially available vaccines against C. jejuni despite its significance as a major cause of diarrheal disease worldwide. Traditional vaccines using purified capsule polysaccharides (CPS) extracted from C. jejuni suffer from variability in the levels of important epitopes such as MeOPN, which are phase variable, leading to inconsistencies in immunogenicity. Furthermore, conventional vaccines face concerns of inducing autoimmunity due to structural mimicry of lipooligosaccharides with human gangliosides. The synthesized immunogenic constructs overcome these limitations by providing defined, synthetic MeOPN monosaccharides that are immunogenic, can be controlled for epitope content, and circumvent concerns related to purification of CPS containing potentially autoimmune-inducing LOS.

Compared to previous anti-C. jejuni vaccine approaches that rely on native CPS conjugates, the synthetic constructs of this invention offer advantages including consistent and controlled levels of MeOPN epitopes, broader immunogenic coverage potentially reducing vaccine valency, and improved cost-effectiveness by eliminating the need to cultivate and purify fastidious C. jejuni strains. The approach also minimizes risks of autoimmunity by excluding LOS components, thus improving safety profiles.

Claims Coverage

The patent includes multiple inventive features centered on synthetic immunogenic constructs against C. jejuni and their formulations and methods of use, as delineated in the independent claims.

Synthetic immunogenic construct comprising MeOPN-6-Gal and MeOPN-2-Gal monosaccharides

An immunogenic synthetic construct capable of inducing an immune response against Campylobacter jejuni comprising one or more MeOPN-6-Gal monosaccharides and one or more MeOPN-2-Gal monosaccharides.

Conjugation of the synthetic construct to carrier proteins

The synthetic immunogenic construct can be conjugated to a carrier protein that contains at least one T-cell epitope. Suitable carrier proteins include ETEC proteins and CRM197.

Inclusion of additional saccharides in the synthetic construct

The immunogenic construct may further comprise one or more additional saccharides selected from monosaccharides containing one or more MeOPN moieties (e.g., MeOPN-1-Fru), galactose, fructose, glucose, heptose, N-acetyl galactosamine, N-acetyl glucosamine, glucitol, glucose, and modified derivatives thereof, including CPS repeating blocks, heptose units, and MeOPN linkages of C. jejuni serotype complexes HS1, HS3, HS4, and HS23/36.

Pharmaceutical compositions comprising the synthetic construct

Compositions comprising the immunogenic synthetic construct as an active ingredient, which can be pharmaceutical compositions in the form of vaccines. These vaccines may be monovalent or polyvalent, the latter formulated against one or more strains of C. jejuni (including serotypes HS 23/36, HS 1, HS2, HS3, HS4, HS5/31) and optionally against enterotoxigenic Escherichia coli (ETEC) or Shigella.

Inclusion of immunoregulatory agents and adjuvants in vaccine compositions

The vaccine compositions may further comprise one or more additional immunoregulatory agents such as antigens of C. jejuni strains, ETEC antigens, Shigella lipopolysaccharide structures, and unconjugated carrier proteins. Adjuvants can be included, selected from toll-like receptor ligands, aluminum phosphate, aluminum hydroxide, monophosphoryl lipid A, liposomes, saponins, QS-21, and combinations thereof.

Methods of inducing an immune response by administering the synthetic construct and compositions

Methods directed to inducing an immune response against C. jejuni in a subject by administering an effective amount (e.g., about 0.1 μg to about 10 mg) of the immunogenic synthetic construct and/or compositions containing the construct, with or without adjuvants and optionally comprising boosting doses. The subject can be human.

The claims collectively cover synthetic immunogenic constructs comprising specific MeOPN-modified galactose monosaccharides singly or in combination with other saccharides, their conjugation to carrier proteins, formulations into pharmaceutical and vaccine compositions including adjuvants, and methods of administration to induce immunity against C. jejuni in humans or animals.

Stated Advantages

Consistent and controlled vaccine immunogenicity by use of synthetic constructs with defined levels of MeOPN epitopes.

Broader immunogenic coverage potentially reducing valency needed in vaccines against multiple C. jejuni serotypes.

Cost-effective vaccine production avoiding cultivation and capsule purification of fastidious C. jejuni.

Avoidance of autoimmunity risks by excluding lipooligosaccharide contaminants that mimic human gangliosides.

Documented Applications

Inducing an immune response against Campylobacter jejuni for the prevention and/or amelioration of campylobacteriosis and related pathological conditions such as gastroenteritis, Reiter's Syndrome, inflammatory bowel syndrome, and Guillain-Barré Syndrome.

Use as monovalent or polyvalent vaccine formulations against one or more serotypes of C. jejuni prevalent in human disease.

Inclusion in vaccine compositions targeting multiple pathogens such as C. jejuni, enterotoxigenic Escherichia coli (ETEC), and Shigella.

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