Passive protection of mice against Streptococcus pneumoniae challenge by naturally occurring and vaccine-induced human anti-PhtD antibodies

Abstract

Currently marketed Streptococcus pneumoniae vaccines are based on polysaccharide capsular antigens from the most common strains. Pneumococcal histidine triad protein D (PhtD) is a conserved surface protein that is being evaluated as a candidate for a vaccine with improved serotype coverage. Here, we measured the functional activity of human anti-PhtD antibodies in a passive protection model wherein mice were challenged with a lethal dose of S. pneumoniae by intravenous injection. This functional activity was compared with anti-PhtD antibody concentrations measured by enzyme-linked immunosorbent assay (ELISA) to estimate the 50% protective dose (ED50). Anti-PhtD antibodies affinity purified from pooled normal human sera passively protected mice with an ED50 of 1679 ELISA units/ml (95% confidence interval, 1420–1946). Sera from subjects injected with aluminum-adjuvanted PhtD in a phase I trial had similar activity per unit of antibody (ED50 = 1331 ELISA units/ml [95% confidence interval, 762–2038]). Vaccine-induced activity in the passive protection model was blocked by pre-incubation with recombinant PhtD but not by a control S. pneumoniae antigen (LytB). These results show that human anti-PhtD antibodies, whether naturally acquired or induced by the PhtD candidate vaccine, are functional. This supports the development of the PhtD candidate as part of a broadly protective pneumococcal vaccine.

Keywords:

• antibody
• passive protection
• pneumococcal histidine triad protein D
• Streptococcus pneumoniae
• vaccine

Abbreviations:

• cfu, colony forming units
• CI, confidence interval
• ED50, dose providing 50% survival
• ELISA, enzyme-linked immunosorbent assay
• EU, ELISA units
• PhtD, pneumococcal histidine triad protein D

Disclosure of Potential Conflicts of Interest

All authors are employees of Sanofi Pasteur.

Acknowledgments

Medical writing was provided by Dr. Phillip Leventhal (4Clinics, Paris, France). The authors thank Elena Newman for purification of antibody from human serum.

Funding

Medical writing was funded by Sanofi Pasteur.