Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody
Zachary A. Schiller, … , Mark S. Klempner, Yang Wang
Zachary A. Schiller, … , Mark S. Klempner, Yang Wang
Published April 29, 2021
Citation Information: J Clin Invest. 2021;131(11):e144843. https://doi.org/10.1172/JCI144843.
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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 4

2217LS blocks transmission of Borrelia burgdorferi in a nonhuman primate model.

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2217LS blocks transmission of Borrelia burgdorferi in a nonhuman primate...
Seroconversion for IgG antibodies against the B. burgdorferi antigen C6 were measured by ELISA to analyze transmissions as an indicator of efficacy (A). Only 1 animal, in the 2217LS 10 mg/kg group (red), showed evidence of transmission by an increase in anti-C6 IgGs by 21 days after tick exposure, which mirrored the seroconversion of irrelevant IgG–treated animals. All remaining animals in the 3 mg/kg (purple), 10 mg/kg (red), 30 mg/kg (yellow), and 90 mg/kg (blue) groups were protected, with no detectable IgG response against the C6 peptide, indicating protection levels of 100% with the exception of 83% for 10 mg/kg. Symbols represent the mean for each animal tested in n = 3 independent assays. ELISA results were confirmed by 5-antigen fluorescent bead–based assay using C6 (B), OspA (C), OspC (D), DbpA (E), and OppA2 (F) antigens. Data are plotted as the mean ± SD of n = 3 independent assays.