The burden of rabies in Africa is estimated at 24 000 human deaths year⁻¹, almost all of which result from infection with dog rabies viruses (RABV). To investigate the evolutionary dynamics of RABV in western and central Africa, 92 isolates sampled from 27 African countries over 29 years were collected and sequenced. This revealed that RABV currently circulating in dogs in this region fell into a single lineage designated ‘Africa 2’. A detailed analysis of the phylogeographical structure of this Africa 2 lineage revealed strong population subdivision at the country level, with only limited movement of virus among localities, including a possible east-to-west spread across Africa. In addition, Bayesian coalescent analysis suggested that the Africa 2 lineage was introduced into this region of Africa only recently (probably <200 years ago), in accordance with the timescale of expanding European colonial influence and urbanization, and then spread relatively slowly, perhaps occupying the entire region in a 100 year period.

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.