Researchers at Liverna Therapeutics have developed a new vaccine candidate for the deadly rabies virus using mRNA-based technology. With no treatments available for the disease, the use of preventative measures is vital. The work, published in Virology Journal, sees the creation of an effective vaccine and shows the potential of mRNA-based interventions.
Lethal exposure
Infection with the rabies virus is primarily spread to humans via bites from animals such as bats and dogs. The virus is found worldwide, and despite effective control measures to prevent its spread in some countries, is still responsible for around 59,000 deaths each year.
The disease is almost 100% lethal after the onset of symptoms and no effective therapy is available to treat this stage of infection. However, a successful form of early intervention exists in the use of vaccines, which can be administered before or soon after exposure to prevent the spread of the virus through the body.
The use of vaccines in rabies prevention is long documented and there are currently multiple options on the market. These consist primarily of inactivated vaccines and live attenuated vaccines, both of which have their drawbacks. Exposure to inactivated viruses can require up to five doses to stimulate an effective immune response, and the use of live attenuated vaccines is plagued with safety concerns. These issues are at the forefront of the mission to develop safe and efficient pre- and post-exposure prophylactic treatments.
The future of vaccine research
The scientists from Liverna Therapeutics set about creating a new vaccine candidate using mRNA technology. Famously used in the past two years to combat the SARS-CoV-2 virus, mRNA vaccines are known to be safe and cost-efficient, changing the landscape of preventive medicine as we know it.
This technology works by injecting viral mRNA into a host’s body, providing their cells with the blueprints to create relevant viral proteins and trigger an immune response. The resulting antibodies protect the host from future illness.
The most effective target proteins are those found in the viral envelope and are known to trigger antibody responses upon detection by the host immune system. In the case of the rabies virus, only one of its five proteins fits these criteria – the glycoprotein RABV-G. The team created three different glycoprotein-expressing vaccine constructs to determine the efficacy of different open reading frames and the inclusion of structural components such as histone loops. They used flow cytometry to analyse the levels of protein expression resulting from each. A construct containing a poly(A) tail, termed “RABV-G C”, was seen to produce high levels of the protein and was taken forward for in vivo testing.
Figure 1: Image showing the three potential vaccine constructs. Sequences were optimised with regards to GC% and different structural components were tested. Adapted from Li et al., 2022.
100% survival
The researchers packaged the RABV-G C construct into a lipid nanoparticle vector and delivered it into mice and dogs to determine optimum dosage and intervals.
The vaccine was seen to produce strong immune responses in the animals. In pre-exposure tests, mice who were infected with rabies virus 14 days post-immunisation had a 100% survival rate after two doses. Likewise, dogs who had been injected with two or three doses of the construct showed 100% survival post-infection.
To analyse the efficacy of the vaccine as a post-exposure prophylactic, dogs were immunised six hours following infection. Once again, survival at three months post-exposure was 100% in those vaccinated two or three times. In all cases, these results were an improvement on traditional rabies vaccines.
A candidate for human use
The results showed the safety and effectiveness of the model in animals, but of course further research must be carried out to analyse the human response to the vaccine.
The authors believe this “could be a good vaccine candidate for future rabies control”. mRNA vaccines are easier, quicker and cheaper to produce than current competitors, and – as described here – require fewer doses to activate the required immune response, further decreasing the potential price. Deaths from rabies are disproportionately seen in countries with limited access to medical resources, highlighting the potential for the use of these more cost-effective and less intrusive options.
