A vaccine to prevent diarrhea by administering an immunogenic capsulated polysaccharide based on repeating units of an O-methyl phosphoramidated heptose disaccharide without concomitantly inducing Barre-Guillain Syndrome; bioconjugating with a carrier to effect enhanced T-cell dependent immunity
Inventors
Guerry, Patricia • Monteiro, Mario Artur
Assignees
NAVY United States, AS REPRESENTED BY SECTRETARY OF • United States, AS REPRESENTED BY SEC OF NAVY • University of Guelph • US Department of Navy
Publication Number
US-7700578-B2
Publication Date
2010-04-20
Expiration Date
2026-09-20
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Abstract
An immunogenic composition, and method of using the composition to elicit an immune response to Campylobacter jejuni. The composition is an isolated polysaccharide polymer composed of one or more forms of disaccharide polymers.
Core Innovation
The invention relates to an immunogenic composition capable of conferring protection against diarrhea caused by Campylobacter jejuni and a method of inducing an immune response to said composition. The composition comprises isolated capsular polysaccharide polymers composed of repeating disaccharide units with specific structural formulas containing O-methyl phosphoramidate modifications. The invention includes formulations wherein these polysaccharides are conjugated to carrier proteins to enhance T-cell dependent immunity, thereby improving immunogenic effectiveness, particularly in populations such as infants where pure polysaccharide antigens elicit weak immune responses.
The invention addresses the problem that Campylobacter jejuni is a leading cause of diarrheal disease worldwide and particularly threatens certain populations such as US military personnel. No licensed vaccines currently exist because most strategies targeting lipooligosaccharides (LOS) induce antibodies that cross-react with human gangliosides, leading to Guillain Barre Syndrome (GBS), a serious autoimmune neuropathy. Molecular mimicry between C. jejuni LOS cores and human neural gangliosides causes autoimmune responses that have prevented effective vaccine development. This invention seeks to provide a vaccine formulation that does not induce GBS by focusing on capsule polysaccharides, which are highly immunogenic, structurally distinct from LOS, and less likely to cause autoimmune reactions.
The disclosed invention includes the identification, characterization, and utilization of specific capsular polysaccharides from C. jejuni strains, such as strain BH0142 and CG8486, which contain unique disaccharide repeating units with O-methyl phosphoramidate groups. These capsules can be purified and conjugated to carrier proteins like CRM197 by reductive amination to enhance immune responses. Immunization studies demonstrate that conjugated vaccines elicit strong antibody responses and protect mice against homologous bacterial challenge. Furthermore, the invention provides methods for human vaccination using these polysaccharide compositions with or without adjuvants administered via various routes to produce protective immunity without GBS induction.
Claims Coverage
The patent contains multiple independent claims focusing on immunogenic compositions comprising specific capsular polysaccharide polymers and methods of producing anti-Campylobacter jejuni immunity.
Immunogenic compositions comprising isolated polysaccharide polymers with defined disaccharide repeats
An immunogenic composition composed of isolated carbohydrate polymers containing repeating disaccharide units with specified structural formulas involving alpha-D-Galactose and modified 6-deoxy or L-glycero alpha-D-ido-Heptose residues carrying O-methyl phosphoramidate groups in non-stoichiometric amounts.
Conjugation of capsular polysaccharides to carrier molecules to enhance immunogenicity
The immunogenic compositions wherein the polysaccharide polymers are conjugated to carrier proteins, such as CRM197, by reductive amination to improve T-cell dependent immune responses.
Methods of inducing anti-Campylobacter jejuni immunity via administration of said immunogenic compositions
Methods comprising administration of the immunogenic polysaccharide compositions, optionally conjugated to carrier molecules, at doses ranging from 0.1 μg to 10 mg with or without adjuvants, followed by booster doses, using various routes including oral, nasal, subcutaneous, intradermal, transdermal, transcutaneous, intramuscular, or rectal.
Immunogenic compositions comprising capsular polysaccharides with alternative disaccharide structures
Compositions comprising isolated Campylobacter jejuni capsule polysaccharides comprising a repeating disaccharide structure composed of →3)-6-d-β-D-ido-Heptose-(1→4)-β-D-GlcNAc-(1→, also optionally conjugated to carrier proteins.
These independent claims cover the core innovation of immunogenic capsular polysaccharide polymers with specific disaccharide repeats and O-methyl phosphoramidate modifications, their conjugation to carrier molecules to enhance immunity, and methods of administration to elicit protective anti-Campylobacter jejuni immune responses without inducing Guillain Barre Syndrome.
Stated Advantages
The vaccine compositions avoid causing Guillain Barre Syndrome by excluding lipooligosaccharide components that mimic human gangliosides, thereby reducing autoimmune risk.
Conjugation of capsular polysaccharides to carrier proteins enhances T-cell dependent immune responses, enabling stronger and longer-lasting immunity especially in infants and populations with weaker responses to polysaccharides alone.
The vaccines elicit protective immunity against important pathogenic strains of Campylobacter jejuni, demonstrated by significant antibody titers and protection in murine challenge models.
Documented Applications
Prevention of diarrhea caused by Campylobacter jejuni infection by inducing an immune response in humans via vaccination using purified capsular polysaccharide compositions, conjugated or unconjugated, with or without adjuvants.
Immunization of populations at risk such as military personnel or infants through various administration routes including oral, nasal, subcutaneous, intradermal, transdermal, transcutaneous, intramuscular, or rectal to confer protective immunity.
Use of conjugated capsule vaccines to enhance T-cell dependent immunity against Campylobacter jejuni in vaccinated subjects.
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