Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody
Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang
Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang
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Research Article Immunology Infectious disease

Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody

Abstract

Disrupting transmission of Borrelia burgdorferi sensu lato complex (B. burgdorferi) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human mAb, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human mAb for tick season presents a significant challenge for a preexposure prophylaxis strategy. Here, we describe the optimization of mAb 2217 by amino acid substitutions (2217LS: M428L and N434S) in the Fc domain. The LS mutation led to a 2-fold increase in half-life in cynomolgus monkeys. In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA revealed that 2217 bound an epitope that was highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective preexposure prophylaxis in Lyme-endemic regions, with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk.

Authors

Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang

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Figure 1

Efficacy characterization of 2217LS.

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Efficacy characterization of 2217LS. (A) The binding activity of 2217 (r...
(A) The binding activity of 2217 (red circles) and 2217LS (blue squares) was determined by ELISA against B. burgdorferi outer surface protein A (OspA) using ELISA. The EC50 values were calculated and represent the concentration of mAb required for a 50% reduction in absorbance measured at 405 nm. Binding data are plotted as n = 3 independent studies. (B) The borreliacidal activity of 2217 and 2217LS was determined by incubating 2217 and 2217LS (0.4 nM to 50 nM) with B. burgdorferi spirochetes. The viability of spirochetes was quantified by luciferase detection and normalized against an irrelevant IgG control. The percentages of live spirochetes were plotted as n = 4 independent studies. The EC50 for B. burgdorferi increased from 0.48 ± 0.32 nM for 2217 to 3.71 ± 2.81 nM for 2217LS. Whiskers represent minimum and maximum. Boxes represent IQR. Line represents the median, and dots represent data points (n = 4 for each group). (C) The in vivo efficacy was determined by challenging mice that were administered 5 mg/kg of either 2217 or 2217LS. The results indicated that 90% of mice (n = 10) treated with 2217LS were protected, which is comparable to the 93% of mice (n = 15) that were protected by 2217. Protection comparisons were conducted using 2-sided Fisher’s exact test.