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.
Highlights
Rabies virus causes an aggressive and lethal infection in the brain of humans and other mammals
Post-exposure prophylaxis (PEP) against rabies consists of a combination of passive and active immunisation directly after viral exposure
Combined treatment with anti-rabies VHH and vaccine gave significantly better protection than either compound alone in an intranasal rabies challenge model in mice, which validates the potential use of anti-rabies VHH as replacement of immune globulins in PEP
Summary
Rabies virus causes an aggressive and lethal infection in the brain of humans and other mammals. Passive antibody therapy with anti-rabies immune globulins (RIG) plays a major role in rabies post-exposure prophylaxis after high risk exposure [6]. Treatment with RIG and vaccine should be initiated as soon as possible after potential infection, with additional vaccine administrations in the following weeks to activate a fullblown and lasting immune response. Passive immunization with RIG serves to immediately neutralize the virus and close the gap between viral exposure and the vaccine-induced immune response [7]. In this regime, initial protection is offered by RIG, which is gradually replaced by vaccine-induced antibodies mounted between day 0 and 7–14, providing continued protection to patients [10]
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