Molecular modeling of Streptococcus pneumoniae serogroup 23 capsular polysaccharide conformations provides insight into antibody binding and cross-reactivity

The bacterial pathogen Streptococcus pneumoniae is a common cause of disease in humans. The S. pneumoniae capsular polysaccharide (CPS), a key virulence factor, is the target of pneumococcal conjugate vaccines (PCVs) recently developed. However, although PCVs have greatly reduced disease, increasing prevalence of non-vaccine serotypes necessitates the development of higher valency vaccines. For pneumococcal serogroup 23, although serotype 23F CPS is present in all anti-pneumococcal pediatric vaccines, serotypes 23A and 23B show increasing clinical prevalence, despite the expectation of cross-protection from their structural similarity. We employ molecular modeling to compare the CPS of serogroup 23 and so provide structural insight into the limited and asymmetrical cross-reactivity reported within serogroup 23. This work attributes the absence of significant cross-protection within serogroup 23 not to a conformational epitope, but rather to the relative accessibility of the common epitopes for antibody binding. The limited, asymmetric cross-reactivity within this serogroup can be rationalized by the presence of two distinct common epitopes: the functional Abs produced by Pn23B against Pn23F can be attributed to a common backbone epitope, while the functional Abs produced by Pn23A can be attributed to the common, and more accessible, Gro2P and α-Rha epitope in Pn23F. There is no indication of potential common epitopes for Pn23A and Pn23B. These findings therefore support the exclusion of serotype Pn23F in current vaccines containing both Pn23A and Pn23B and illustrate how clarifying the structural basis for asymmetric immunological behavior may inform future vaccine design.