Protective Meningococcal Capsular Polysaccharide Epitopes and the Role of O Acetylation

Abstract

Previous studies with group C meningococcal polysaccharide-tetanus toxoid (GCMP-TT) conjugates had suggested that the GCMP O-acetyl group masked the protective epitope for group C meningococci through steric hindrance or altered conformations. For this report, we confirmed this phenomenon and performed comparative studies with group Y meningococcal polysaccharide (GYMP)-TT to determine whether it might extend to other serogroups. The de-O-acetylated (dOA) polysaccharides (PSs) resulted in higher serum bactericidal activities (SBA) towards the O-acetylated (OA) meningococcal strains from the respective serogroups. High-resolution H-nuclear magnetic resonance spectroscopy at 500 MHz and competitive inhibition serum bactericidal assays were used to characterize the nature of the protective epitope. In head-to-head comparisons with OA PSs as SBA inhibitors, the dOA PSs provided 10 to 1,000 times better inhibition for GCMP in human and mouse antisera and 6 to 13 times better inhibition for GYMP in mouse antisera, using OA strains in all assays. In addition, the SBA for OA strains was highly correlated with dOA PS-specific immunoglobulin G (r ‫؍‬ 0.72 to 0.98) for both GCMP and GYMP. The results suggest that there may be a generalized role for the O-acetyl group to provide an epitope of misdirected immunogenicity for meningococcal PS capsules, enabling escape from immune surveillance. In addition to greater chemical consistency, the dOA forms of GCMP and GYMP conjugate vaccines endow greater immunologic competence to the PSs, rendering them capable of eliciting higher levels of functional antibodies toward the protective epitopes.

Antibodies to Staphylococcus aureus Serotype 8 Capsular Polysaccharide React with and Protect against Serotype 5 and 8 Isolates

“…O-acetylation of CPs has been identified among many pathogenic bacteria, such as Neisseria meningitidis, Salmonella enterica serovar Typhi Vi, and S. pneumoniae, and O-acetyl groups are important immunogenic determinants (34)(35)(36)(37). The S. aureus ⌬cap5H mutant was more susceptible to complement-mediated OPK and less virulent for mice than the isogenic parental strain (24).…”

The Pneumococcal Serotype 15C Capsule Is Partially O-Acetylated and Allows for Limited Evasion of 23-Valent Pneumococcal Polysaccharide Vaccine-Elicited Anti-Serotype 15B Antibodies

“…In many bacteria, O-acetylation alters the physicochemical properties of capsule by changing the conformation of capsular repeat units (13) or increasing viscosity (14). O-acetylation also alters the host-pathogen interaction by creating immunogenic epitopes (11,13,15), by neutralizing reactive chlorine species (16,17), and/or by mediating resistance to lysozyme and complement deposition (18)(19)(20)(21). Many bacteria have membrane-bound O-acetyltransferases (MOATs) that are thought to attach O-acetyl groups to the capsular repeat unit at the end of the capsular biosynthetic process (22)(23)(24).…”

Functional Antibodies to the O-Acetylated Pneumococcal Serotype 15B Capsular Polysaccharide Have Low Cross-Reactivities with Serotype 15C

“…O acetylation has been shown to be an important parameter when measuring functional antibody activity in meningococcus (2,10). With meningococcus groups C and Y, the O acetylation masks the epitopes on the Ps backbone to which functional antibody is directed (8). Although some investigators (21) have suggested that conjugation of Ps to different carriers can potentially result in the generation of crossreactive antibodies, in the case of unconjugated Ps there is no aid in the presentation of the antigen to the host.…”