Passive protection of mice against Streptococcus pneumoniae challenge by naturally occurring and vaccine-induced human anti-PhtD antibodies.
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.
a Sanofi Pasteur ; Toronto , Ontario , Canada.
Roger H
RH
Brookes
Marin
M
Ming
Kimberley
K
Williams
Robert
R
Hopfer
Sanjay
S
Gurunathan
Scott
S
Gallichan
Mei
M
Tang
Martina M
MM
Ochs
D000328:Adult; D000368:Aged; D000818:Animals; D000907:Antibodies, Bacterial / Q000032:analysis / Q000096:biosynthesis / Q000627:therapeutic use; D000918:Antibody Specificity; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D017321:Clinical Trials, Phase I as Topic; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008875:Middle Aged; D011008:Pneumococcal Infections / Q000276:immunology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D016019:Survival Analysis
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; D022242:Pneumococcal Vaccines
CI, confidence interval; ED50, dose providing 50% survival; ELISA, enzyme-linked immunosorbent assay; EU, ELISA units; PhtD, pneumococcal histidine triad protein D; Streptococcus pneumoniae; antibody; cfu, colony forming units; passive protection; pneumococcal histidine triad protein D; vaccine