Passive protection of mice againstStreptococcus pneumoniaechallenge 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.

A bivalent pneumococcal histidine triad protein D-choline-binding protein A vaccine elicits functional antibodies that passively protect mice from Streptococcus pneumoniae challenge

“…This study confirms our previous findings that vaccine-induced anti-PhtD antibodies are functional 20 . Similarly, Verhoeven et al.…”

“…Also, naturally acquired anti-PhtD antibodies protect mice against pneumococcal colonization 14 . A monovalent PhtD vaccine was shown to be well tolerated and immunogenic in a phase I trial, 19 and we have confirmed that the antibodies induced by the vaccine are functional in a mouse passive protection sepsis model 20 . Likewise, immunization with PcpA, another highly conserved surface protein, 21,22 has been shown to be protective in active immunization murine models of both sepsis and pneumonia 22 .…”

“…We previously used the same passive protection model to show that human antibodies induced by a monovalent PhtD candidate vaccine are functional 20 . A trivalent vaccine containing PhtD, PcpA, and detoxified pneumolysin has also been shown to protect infant mice against nasal challenge with a lethal dose of S. pneumoniae serotype 6A and 3 25 …”

“…Mouse passive protection assays were performed as described previously 20 . Briefly, sera were diluted in phosphate-buffered saline and passively transferred by intraperitoneal injection to 6- to 8-week-old female CBA/CaHN-Btk xid /J (CBA/N) mice, a model of human X-linked immunodeficiency (Sanofi, Montpellier, France or Jackson Laboratories, Bar Harbor, ME, USA).…”

“…Here, we tested sera from these subjects for the presence of functional antibodies using the same passive protection mouse model that we previously used to examine antibodies induced by a monovalent PhtD candidate vaccine 20 . We also investigated the relationship between activity in this passive protection model, serum anti-PhtD and anti-PcpA antibody concentrations, and activity in a bacterial surface binding assay.…”