Post-exposure Treatment with Anti-rabies VHH and Vaccine Significantly Improves Protection of Mice from Lethal Rabies Infection

Abstract

Post-exposure prophylaxis (PEP) against rabies infection consists of a combination of passive immunisation with plasma-derived human or equine immune globulins and active immunisation with vaccine delivered shortly after exposure. Since anti-rabies immune globulins are expensive and scarce, there is a need for cheaper alternatives that can be produced more consistently. Previously, we generated potent virus-neutralising VHH, also called Nanobodies, against the rabies glycoprotein that are effectively preventing lethal disease in an in vivo mouse model. The VHH domain is the smallest antigen-binding functional fragment of camelid heavy chain-only antibodies that can be manufactured in microbial expression systems. In the current study we evaluated the efficacy of half-life extended anti-rabies VHH in combination with vaccine for PEP in an intranasal rabies infection model in mice. The PEP combination therapy of systemic anti-rabies VHH and intramuscular vaccine significantly delayed the onset of disease compared to treatment with anti-rabies VHH alone, prolonged median survival time (35 versus 14 days) and decreased mortality (60% versus 19% survival rate), when treated 24 hours after rabies virus challenge. Vaccine alone was unable to rescue mice from lethal disease. As reported also for immune globulins, some interference of anti-rabies VHH with the antigenicity of the vaccine was observed, but this did not impede the synergistic effect. Post exposure treatment with vaccine and human anti-rabies immune globulins was unable to protect mice from lethal challenge. Anti-rabies VHH and vaccine act synergistically to protect mice after rabies virus exposure, which further validates the possible use of anti-rabies VHH for rabies PEP.

A research agenda to reinforce rabies control: A qualitative and quantitative prioritization

“…Importantly, literature shows that these unmet needs are addressable. Recent developments regarding production systems for cheap and scalable alternatives for RIG include monoclonal antibodies [ 23 ] and nanobodies [ 24 ]. The identification of barriers hampering the efficacy of current mass vaccination programs would require such programs to include a qualitative causal component.…”

Single-Domain Antibodies As Therapeutics against Human Viral Diseases

“…Postexposure treatment with antirabies sdAbs can partly rescue mice from lethal disease and decrease the viral RNA load in the brain. In contrast, treatments with vaccines or human antirabies immune globulins could not meet this test, indicating that antirabies sdAbs can enter the brain and neutralize virus ( 49 , 50 ). Still, because of their short half-life, sdAbs may not have enough time to cross the endothelial barriers in sufficient amounts to clear out virus, thus limiting the effect of sdAb treatment at the more advanced stages of infection.…”

Use of camel single-domain antibodies for the diagnosis and treatment of zoonotic diseases

“…These VHHs were fused to an anti-albumin VHH to extend its serum half-life and were able to neutralize the virus at picomolar doses [76]. A combined treatment based on VHH and vaccine (Rabipur, Novartis) acted synergistically to protect mice in an intranasal rabies infection model [77]. However, the principal difficulty of an antiviral approach against rabies resides in the specific neurotropism of RABV, which makes it not readily accessible once it has accessed the CNS.…”