title: Epitopic overload at the site of injection may result in suppression of the immune response to combined capsular polysaccharide conjugate vaccines.
abstract: Capsular polysaccharide (CP) conjugate vaccines targeting a variety of bacterial infections are currently under development and clinical evaluation. The inclusion of multiple CP serotypes combined in a single injection is an important maneuver being evaluated. The combination of CP conjugate vaccines into a single multivalent injection may result in competition among the different components and adversely affect the immunogenicity of any individual conjugate. We observed a reduction of 30-90% in antibody responses to several serotypes in mice when immunogenicity of a 12-valent Escherichia coli (E. coli) lipopolysaccharide (LPS) conjugate vaccine was compared to the immunogenicity of each monovalent vaccine evaluated separately. A reduction of 30% was observed in the Staphylococcus aureus (S. aureus) type 8 CP antibodies when a type 8-rEPA conjugate was combined with a type 5-rEPA conjugate. S. aureus types 5 and 8-rEPA conjugates were combined with 100 micrograms of either rEPA (homologous) or diphtheria toxoid (DT) (heterologous) carrier proteins, and evaluated in rEPA or DT primed mice. The addition of the homologous protein resulted in a 64% reduction in type 5 CP antibodies. The heterologous protein did not affect the immunogenicity of the type 5. We postulate that the free protein competed with the conjugate and recruited most of the rEPA primed T cells. In the case of the DT conjugates, the DT targeted different populations of the T cells, thus interference was not observed. These data suggested that the epitopic load rather than the antigenic load at the site of injection caused reduced immunogenicity of the conjugates. We theorize that individual components of multivalent CP vaccines conjugated to the same carrier proteins would compete for a limited number of specific carrier protein primed T cells. This would result in one or more components being unavailable in eliciting a sufficient immune response. The use of multiple carrier proteins should be considered as an approach to reduce interference when multivalent conjugate vaccines are to be formulated into a single injection.
authors.affiliation: Walter Karakawa Microbial Pathogenesis Laboratory, NABI, Rockville, MD 20852, USA. afatom@nabi.com
authors.forename: A
authors.initials: A
authors.lastname: Fattom
authors.forename: Y H
authors.initials: YH
authors.lastname: Cho
authors.forename: C
authors.initials: C
authors.lastname: Chu
authors.forename: S
authors.initials: S
authors.lastname: Fuller
authors.forename: L
authors.initials: L
authors.lastname: Fries
authors.forename: R
authors.initials: R
authors.lastname: Naso
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D000939:Epitopes / Q000008:administration & dosage; D005260:Female; D007108:Immune Tolerance; D007279:Injections, Subcutaneous; D051379:Mice; D008813:Mice, Inbred ICR; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage* / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000276:immunology; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology