A recombinant conjugated pneumococcal vaccine that protects against murine infections with a similar efficacy to Prevnar-13

Mark Reglinski,Jeremy S Brown,Giuseppe Ercoli,Fernanda C Petersen,Emily Kay,James C Paton,Brendan W Wren,Charlie Plumptre

doi:10.1038/s41541-018-0090-4

Abstract

The pneumococcal conjugate vaccine (PCV) strongly protects against vaccine serotypes, but the rapid expansion of non-vaccine serotype disease and the vaccine’s high expense has reduced its overall impact. We have developed Protein Glycan Coupling Technology (PGCT) as a flexible methodology for making low-cost polysaccharide/protein glycoconjugates recombinantly in Escherichia coli. We have used PGCT to make a recombinant PCV containing serotype 4 capsular polysaccharide linked to the Streptococcus pneumoniae proteins NanA, PiuA, and Sp0148. The introduction of the Campylobacter jejuni UDP-glucose 4-epimerase gene GalE (gne) into E. coli improved the yield of the resulting glycoprotein. PGCT glycoconjugate vaccination generated strong antibody responses in mice to both the capsule and the carrier protein antigens, with the PiuA/capsule glycoconjugate inducing similar anti-capsular antibody responses as the commercial PCV Prevnar-13. Antibody responses to PGCT glycoconjugates opsonised S. pneumoniae and Streptococcus mitis expressing the serotype 4 capsule and promoted neutrophil phagocytosis of S. pneumoniae to a similar level as antisera generated by vaccination with Prevnar-13. Vaccination with the PGCT glycoconjugates protected mice against meningitis and septicaemia with the same efficacy as vaccination with Prevnar-13. In addition, vaccination with the protein antigen components from PGCT glycoconjugates alone provided partial protection against septicaemia and colonisation. These data demonstrate that a vaccine made by PGCT is as effective as Prevnar-13, identifies PiuA as a carrier protein for glycoconjugate vaccines, and demonstrates that linking capsular antigen to S. pneumoniae protein antigens has additional protective benefits that could provide a degree of serotype-independent immunity.

Highlights

Streptococcus pneumoniae is a common cause of pneumonia, septicaemia, and meningitis, and is responsible for a considerable burden of morbidity and mortality worldwide.[1]
Using Protein Glycan Coupling Technology (PGCT) to produce recombinant glycoconjugates of S. pneumoniae ST4 capsule material linked to the S. pneumoniae protein antigens PiuA, Sp0148 and NanA initially resulted in relatively poor glycoconjugate yields (Fig. 1)
Together the enzyme-linked immunosorbent assay (ELISA), flow cytometry, and immunofluorescence data demonstrate that PGCT glycoconjugates induced anti-capsular IgG responses that varied in strength between carrier proteins, but were similar in strength for PiuA glycoconjugates to those induced by Prevnar-13

Summary

Introduction

Streptococcus pneumoniae (the pneumococcus) is a common cause of pneumonia, septicaemia, and meningitis, and is responsible for a considerable burden of morbidity and mortality worldwide.[1].

Results

Conclusion