Synthetic antigen constructs against Campylobacter jejuni
Inventors
Guerry, Patricia • Monteiro, Mario Artur • Jiao, Yuening
Assignees
Publication Number
US-9925254-B2
Publication Date
2018-03-27
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 relates to immunogenic synthetic constructs that are capable of inducing an immune response against Campylobacter jejuni in a subject. Specifically, the invention provides immunogenic synthetic constructs comprising one or more monosaccharides that include one or more O-methyl phosphoramidate (MeOPN) moieties, particularly MeOPN at the 6 position of galactose (MeOPN→6 Gal monosaccharides). These constructs may be conjugated to carrier proteins and are intended for use in compositions and methods to prevent or ameliorate diseases associated with C. jejuni infection.
The problem addressed by the invention is the lack of licensed, commercially available vaccines against C. jejuni despite its global significance as a cause of gastroenteritis and other post-infectious conditions. Challenges include the natural variability of capsular polysaccharide (CPS) epitopes such as MeOPN moieties, which are phase variable, resulting in variable immunogenicity in vaccines prepared from purified capsules. Additionally, previous vaccines purified from CPS risk inducing autoimmune responses due to contamination with lipooligosaccharides (LOS) that mimic human gangliosides. There is a need for immunogenic compositions that provide consistent and controlled immune responses while reducing risks associated with natural CPS purification.
The invention overcomes these issues by chemically synthesizing immunogenic constructs comprising defined MeOPN→6 Gal monosaccharides, thereby enabling control over the level and consistency of immunogenic epitopes in vaccine formulations. This synthetic approach avoids the need to cultivate and purify difficult C. jejuni strains and prevents LOS contamination, reducing the risk of undesirable autoimmune reactions. Furthermore, the synthetic constructs demonstrate broader coverage across multiple C. jejuni serotypes than native polysaccharides, potentially allowing cross-protection and reducing the complexity of vaccine valency required.
Claims Coverage
The patent claims cover several inventive features focused on synthetic immunogenic constructs and compositions for inducing immune responses against Campylobacter jejuni, methods of administration, and related formulations.
Immunogenic synthetic construct comprising MeOPN→6 Gal monosaccharides conjugated to a carrier protein
An immunogenic synthetic construct capable of inducing an immune response against C. jejuni, comprising one or more monosaccharides with O-methyl phosphoramidate (MeOPN) moieties specifically at the 6 position of galactose, where the construct is conjugated to a carrier protein containing at least one T-cell epitope.
Use of CRM197 as carrier protein in the synthetic construct
The carrier protein conjugated to the immunogenic synthetic construct can be CRM197, a nontoxic mutant of diphtheria toxin.
Pharmaceutical and vaccine compositions comprising the synthetic construct
Compositions containing the immunogenic synthetic construct, including pharmaceutical compositions and vaccine formulations, which may further comprise one or more adjuvants such as toll-like receptor ligands, aluminum phosphate, aluminum hydroxide, monophosphoryl lipid A, liposomes, and their derivatives or combinations.
Inclusion of additional immunoregulatory agents in compositions
Compositions may further include additional immunoregulatory agents selected from antigens of one or more strains of C. jejuni, antigens of enterotoxigenic Escherichia coli (ETEC), Shigella lipopolysaccharide structures, and unconjugated carrier proteins.
Methods of inducing immune responses by administering synthetic constructs or compositions
Methods for inducing an immune response against C. jejuni in a subject by administering an effective amount of the immunogenic synthetic construct or compositions thereof, optionally including one or more boosting doses and optionally administering with adjuvants. Effective doses range from about 0.1 micrograms to about 10 milligrams.
The claims collectively cover synthetic immunogenic constructs of MeOPN→6 Gal monosaccharides conjugated to carrier proteins, particularly CRM197, their inclusion in pharmaceutical and vaccine formulations with optional adjuvants and immunoregulatory agents, and methods of administering these constructs or compositions to induce immune responses against Campylobacter jejuni.
Stated Advantages
Control of MeOPN epitope levels in vaccine formulations leading to consistent immunogenicity.
Broader coverage potential across multiple C. jejuni serotypes, reducing required vaccine valency.
Elimination of the need to grow C. jejuni and purify CPS, increasing cost-effectiveness.
Reduced risk of autoimmune responses due to absence of LOS contamination.
Enhanced immune responses through conjugation to carrier proteins containing T-cell epitopes.
Documented Applications
Use in compositions and methods of inducing an immune response against Campylobacter jejuni in humans and animals.
Vaccine formulations to prevent or ameliorate campylobacteriosis and related pathological conditions such as gastroenteritis and Guillain-Barré Syndrome.
Use of synthetic constructs for cross-protective vaccine formulations covering multiple C. jejuni serotypes including HS23/36, HS1, and HS4.
Multivalent vaccine formulations that may include synthetic constructs from other bacterial pathogens such as ETEC and Shigella.
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