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

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.

mRNA mediates passive vaccination against infectious agents, toxins, and tumors

“…Thus, the use of a previously approved design for the various constructs instead of having individually optimized mRNA formats is most likely responsible for the different outcomes. Fourthly, the effective dose of an antibody is strongly dependent on its characteristics, that is, potential limitations may be overcome with the right protein (De Benedictis et al , ). Overall, with regard to antibody titers, mRNA appears to be applicable to a broad range of indications.…”

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies

“…Neutralizing mAbs are now considered as a potential therapeutic approach for the prevention and treatment of chronic and acute viral infections, including newly emerging viral infections (1). In recent years, there has been a dramatic increase in the development of new mAbs with improved neutralizing activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Notably, in addition to antirespiratory syncytial virus (RSV) mAb used to treat infant respiratory disease, several mAbs directed against human cytomegalovirus, HIV, influenza, Ebola, and rabies virus are currently engaged in promising clinical trials (1,3,9,14).…”

Vaccinations for Neuroinfectious Disease: A Global Health Priority

“…Recently, De Benedictis et al [44] identified two broadly neutralizing human monoclonal antibodies from vaccinated donors, and demonstrated that the antibodies were able to neutralize all 35 rabies viruses and 25 nonrabies lyssaviruses, showing higher potency and breadth than other antibodies under clinical development and the currently available RIG [44]. It is thought that infection with all lyssaviruses culminates in viral encephalitides clinically indistinguishable from rabies; therefore, it is significant to identify broadly neutralizing antibodies capable of binding RABV and non-RABV lyssaviruses [44].…”

“…The rabies virus is found in the saliva of many domestic and wild mammals and transmission to humans occurs directly, usually through the bite of an infected animal. Rabies infection results in an acute encephalomyelitis, which is almost always fatal following symptom onset [44]. A less common presentation is paralytic rabies, which closely simulates Guillain-Barré syndrome or ascending myelitis [45].…”

“…It is thought that infection with all lyssaviruses culminates in viral encephalitides clinically indistinguishable from rabies; therefore, it is significant to identify broadly neutralizing antibodies capable of binding RABV and non-RABV lyssaviruses [44].…”