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. 2019 Aug;104(8):e340-e344.
doi: 10.3324/haematol.2018.209692. Epub 2019 Jan 31.

Differential effects of therapeutic complement inhibitors on serum bactericidal activity against non-groupable meningococcal isolates recovered from patients treated with eculizumab

Dan M Granoff  1 , Howard Kim  2 , Nadav Topaz  3 , Jessica MacNeil  3 , Xin Wang  3 , Lucy A McNamara  3
Affiliations
Free PMC article

Differential effects of therapeutic complement inhibitors on serum bactericidal activity against non-groupable meningococcal isolates recovered from patients treated with eculizumab

Dan M Granoff et al. Haematologica. 2019 Aug.
Free PMC article
No abstract available

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Figures

Figure 1.
Figure 1.
Effect of complement inhibitors on serum bactericidal activity measured against a control encapsulated serogroup B strain (H44/76) and two non-groupable isolates with disrupted or phase variable “off” B capsular loci. All sera were diluted 1:5 and assayed with internal (endogenous) complement. The horizontal line indicates 50% survival of bacteria after incubation for 60 min. Sera with <50% bacterial survival have serum bactericidal activity (SBA) titers ≥1:5. Blue bars, test sera with no added inhibitor; orange bars, test sera with 50 μg/mL eculizumab; gray bars, test sera with 1 μM ACH-4471. (A-C) Adults not vaccinated with a serogroup B vaccine (subject 9010 represents a pre-immunization serum). (D-F) Adults vaccinated with MenB-4C (subject 9010 is a post-vaccination serum). (G-I) Adults vaccinated with MenB-FHbp. The encapsulated H44/76 strain [hypervirulent clonal complex (CC) 32] expressed FHbp sub-family B (present in both MenB vaccines). The non-groupable CH891 and CH892 isolates were both from CC41/44 and both expressed NHba (present in MenB-4C) and FHbp subfamily A (present in MenB-FHbp). Data for each isolate are from two to four replicates. NG: non-groupable; SEM: standard error of mean.
Figure 2.
Figure 2.
Effect of complement inhibitors on serum bactericidal activity measured against non-groupable isolate CH886 with CC60 and a disrupted E capsular locus. (A-E) Without added inhibitor, two of eight unvaccinated subjects (subjects C and E) had titers <1:5 (bacterial survival >50% after 1 h incubation) (blue bars in panel A) compared to none of eight vaccinated subjects (blue bars in panels B and C). (D,E) Among the six unvaccinated subjects with titers ≥1:5 without inhibitor, serum bactericidal activity (SBA) at 1:5 dilution was inhibited (bacterial survival >50%) by 1 μM ACH-4471 (gray bars in panels A and D) or at a 1:2.5 serum dilution by 2 μM ACH-4471 (teal bars in panel D). Among the eight vaccinated subjects, the addition of 1 μM ACH-4471 inhibited SBA at a dilution of 1:5 for three of eight vaccinated subjects (black bars in panels B and C; gray bars in panel E) but all three sera had SBA when retested at a 1:2.5 dilution in the presence of 2 μM ACH-4471 (bacterial surival <50%; teal bars in panel E). With eculizumab, SBA titers were <1:5 or <1:2.5 for all unvaccinated or vaccinated sera tested at both dilutions (bacterial survival >50%, orange bars). (A-C) Data from two to four replicate assays using 50 μg/mL of eculizumab and 1 μM ACH-4471. (D, E) Data are representative of two assays, each performed in duplicate with 1 μM ACH-4471 for sera tested at 1:5, 2 μM ACH-4471 for sera tested at 1:2.5 (see text), and 50 μg/mL of eculizumab for sera assayed at 1:2.5. NG: non-groupable; SEM: standard error of mean.
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References

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