Monoclonal Antibodies to Meningococcal Factor H Binding Protein with Overlapping Epitopes and Discordant Functional Activity

Background: Meningococcal factor H binding protein (fHbp) is a promising vaccine candidate. Anti-fHbp antibodies can bind to meningococci and elicit complement-mediated bactericidal activity directly. The antibodies also can block binding of the human complement down-regulator, factor H (fH). Without bound fH, the organism would be expected to have increased susceptibility to bacteriolysis. Here we describe bactericidal activity of two anti-fHbp mAbs with overlapping epitopes in relation to their different effects on fH binding and bactericidal activity. Methods and Principal Findings: Both mAbs recognized prevalent fHbp sequence variants in variant group 1. Using yeast display and site-specific mutagenesis, binding of one of the mAbs (JAR 1, IgG3) to fHbp was eliminated by a single amino acid substitution, R204A, and was decreased by K143A but not by R204H or D142A. The JAR 1 epitope overlapped that of previously described mAb (mAb502, IgG2a) whose binding to fHbp was eliminated by R204A or R204H substitutions, and was decreased by D142A but not by K143A. Although JAR 1 and mAb502 appeared to have overlapping epitopes, only JAR 1 inhibited binding of fH to fHbp and had human complement-mediated bactericidal activity. mAb502 enhanced fH binding and lacked human complement-mediated bactericidal activity. To control for confounding effects of different mouse IgG subclasses on complement activation, we created chimeric mAbs in which the mouse mAb502 or JAR 1 paratopes were paired with human IgG1 constant regions. While both chimeric mAbs showed similar binding to fHbp, only JAR 1, whic

Expanding the Paradigms of Plant Pathogen Life History and Evolution of Parasitic Fitness beyond Agricultural Boundaries

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Local and global subaxial cervical spine biomechanics after single-level fusion or cervical arthroplasty

An experimental in vitro biomechanical study was conducted on human cadaveric spines to evaluate the motion segment (C4–C5) and global subaxial cervical spine motion after placement of a cervical arthroplasty device (Altia TDI™,Amedica, Salt Lake City, UT) as compared to both the intact spine and a single-level fusion. Six specimens (C2–C7) were tested in flexion/extension, lateral bending, and axial rotation under a ± 1.5 Nm moment with a 100 N axial follower load. Following the intact spine was tested; the cervical arthroplasty device was implanted at C4–C5 and tested. Then, a fusion using lateral mass fixation and an anterior plate was simulated and tested. Stiffness and range of motion (ROM) data were calculated. The ROM of the C4–C5 motion segment with the arthroplasty device was similar to that of the intact spine in flexion/extension and slightly less in lateral bending and rotation, while the fusion construct allowed significantly less motion in all directions. The fusion construct caused broader effects of increasing motion in the remaining segments of the subaxial cervical spine, whereas the TDI did not alter the adjacent and remote motion segments. The fusion construct was also far stiffer in all motion planes than the intact motion segment and the TDI, while the artificial disc treated level was slightly stiffer than the intact segment. The Altia TDI allows for a magnitude of motion similar to that of the intact spine at the treated and adjacent levels in the in vitro setting