Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis.

Paola De Benedictis,Emma Bentley,Ilaria Capua,Anthony Lepelletier,Rachel Lavenir,Gloria Agatic,Federica Sallusto,Barbara Zecchin,Antonio Lanzavecchia,Davide Corti,Edward Wright,Giovanni Cattoli,Fabrizia Vanzetta,Hervé Bourhy,Mathilde Foglierini,Roberta Aiello,Andrea Minola,Angela Salomoni,Robin A Weiss ,E Rota Nodari

doi:10.15252/emmm.201505986

Abstract

Currently available rabies post‐exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad‐spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non‐RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20–RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post‐vaccination antibody response.

Highlights

Available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG)
The 29 with the highest binding titers (ED50 > 50) were tested for their ability to neutralize a panel of 12 pseudotyped lyssaviruses representing rabies virus (RABV) and non-RABV lyssaviruses isolates of phylogroup I, II, and III viruses (Fig 1B and Appendix Table S1)
Memory B cells from four vaccinees selected for the presence of serum antibodies capable of broadly neutralizing multiple lyssavirus species were immortalized with Epstein–Barr virus (EBV) and CpG, as previously described (Traggiai et al, 2004)

Summary

Introduction

Available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). We identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58. RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. The RVC20–RVC58 cocktail protected Syrian hamsters from a lethal

Methods

Results

Conclusion