Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism

• Main Authors: Lucian Visan (Author), Nicolas Rouleau (Author), Emilie Proust (Author), Loïc Peyrot (Author), Arnaud Donadieu (Author), Martina Ochs (Author)
• Format: Book
• Published: Taylor & Francis Group, 2018-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2164-5515; 2164-554X; 10.1080/21645515.2017.1403698
• Keywords: antibody; complement; macrophage; neutrophil; opsonophagocytosis; phagocytosis; streptococcus pneumoniae; vaccination; Immunologic diseases. Allergy; RC581-607; Therapeutics. Pharmacology; RM1-950
• Source: Human Vaccines & Immunotherapeutics, Vol 14, Iss 2, Pp 489-494 (2018)

Currently marketed Streptococcus pneumoniae (Spn) vaccines, which contain polysaccharide capsular antigens from the most common Spn serotypes, have substantially reduced pneumococcal disease rates but have limited coverage. A trivalent pneumococcal protein vaccine containing pneumococcal choline-binding protein A (PcpA), pneumococcal histidine triad protein D (PhtD), and detoxified pneumolysin is being developed to provide broader, cross-serotype protection. Antibodies against detoxified pneumolysin protect against bacterial pneumonia by neutralizing Spn-produced pneumolysin, but how anti-PhtD and anti-PcpA antibodies protect against Spn has not been established. Here, we used a murine passive protection sepsis model to investigate the mechanism of protection by anti-PhtD and anti-PcpA antibodies. Depleting complement using cobra venom factor eliminated protection by anti-PhtD and anti-PcpA monoclonal antibodies (mAbs). Consistent with a requirement for complement, complement C3 deposition on Spn in vitro was enhanced by anti-PhtD and anti-PcpA mAbs and by sera from PhtD- and PcpA-immunized rabbits and humans. Moreover, in the presence of complement, anti-PhtD and anti-PcpA mAbs increased uptake of Spn by human granulocytes. Depleting neutrophils using anti-Ly6G mAbs, splenectomy, or a combination of both did not affect passive protection against Spn, whereas depleting macrophages using clodronate liposomes eliminated protection. These results suggest anti-PhtD and anti-PcpA antibodies induced by pneumococcal protein vaccines protect against Spn by a complement- and macrophage-dependent opsonophagocytosis.