Science Spotlight

mRNA: the future of vaccines?

The Gottardo Laboratory, Vaccine and Infectious Disease Division
Electron micrograph of rabies virus (bullet shaped) in a cell. wiki commons

    Historically, vaccine development has had great success with live and attenuated virus vaccines. However, novel approaches are still being investigated, working to decrease cost and increase vaccine accessibility. When developing a new vaccine, efficacy is not the only thing that should be considered. Production, storage, cost, and safety are all factors that need to be taken into account. One novel idea currently being tested is the use of genetic material such as DNA or RNA for vaccine administration. The idea of using RNA as a vaccine platform has been looked at in preclinical studies and found to provide protection in animals. The notion is that mRNA would be delivered into target cells where it would be translated into the encoded antigen thus allowing for immune recognition and hopefully protection. By using genetic material to encode antigens, new vaccines could be created or modified quickly with very little cost. Production cost of the vaccine would be much lower than a protein or viral based vaccine that have to be produced biologically rather than synthesized. Another advantage of RNA vaccines is that they can be stable for long periods of time at room temperature, allowing for use in rural locations where cold storage is costly or non-existent.  A collaboration between researchers in Germany and with Drs. Gottardo and Finak at Fred Hutch  (Vaccine and Infectious Disease Division) published in The Lancet was the first to evaluate the safety and immunogenicity of a candidate prophylactic mRNA vaccine in humans.

    In this study the group used rabies as a model antigen to test the effects of mRNA vaccination. Rabies was selected for multiple reasons, including the fact that the population at large is naive to the virus.  This eliminates added complexity of identifying the immune response to mRNA encoding a common antigen, and because there is a known immunological correlate of protection. A neutralizing titer of 0.5 IU (International units)/mL of induced antibodies or higher is known to protect against rabies, therefore if the new vaccine could achieve this titer level in vaccinated people, protection should be achieved upon infection. Specifically, the researchers tested CV7201, a temperature stable lyophilized mRNA vaccine candidate that has been shown to induce long lived B and T cell immunity in animal models when administered by intramuscular (i.m.) or intradermal (i.d.) injection. This study looked at the safety and efficacy of various doses, routes, and injection methods over time. Various conditions were tested in groups of 6-7 people all of similar demographics.

    Overall, the safety of the vaccine was similar to the expected safety profile of other vaccines and stimulated immune responses. When comparing virus neutralizing antibody titer after vaccination, groups that received the vaccine by needle-syringe showed no response in all cases but 1. In contrast, groups administered vaccine by needle-free injectors showed over 75% neutralizing antibody titer. Intradermal compared to intramuscular administration had slightly higher (89% versus 77%) antibody titers. Since a neutralizing titer over 0.5IU/mL is known to protect, this parameter was also analyzed revealing that 50% i.m. and 71% i.d. (non-needle injections) produced this level of titer. In order to test long-lived immunity 14 participants were boosted 1 year later and sera was measured for antibody titer. Just prior to boost, 2 of the 14 participants had measurable rabies titers and after boost, 13 of the 14 had measurable titers. This suggests that there is a memory response to the vaccine and that boosting engages this population. Unfortunately only 8 of the 14 had neutralizing titers over the cutoff for protection. In addition to looking at antibodies the group looked at intracellular cytokine staining assays to identify antigen specific T cell responses. Results were analyzed using COMPASS, a computational tool to analyze cellular cytokine staining for antigen specific T cell responses, which found an induction of rabies-specific T cell responses post vaccination.

    Results from this study showed that a mRNA vaccine can induce humoral and cellular immune responses in humans. However, these responses don’t appear to be long-lived under the current conditions. Modifications to the vaccine are needed to increase immunogenicity and longevity. Nevertheless, Dr. Fink said, “The study was a phase I trial that showed low immunogenicity and very short-lived Ab titers when vaccine was injected by needle-free device. It is essentially a proof of principle, but it is important, because mRNA vaccines can be produced rapidly and when stored properly are more stable than inactivated virus vaccines, making them suitable for use in areas where refrigeration is not available.”

Funding for this study was provided by CureVac AG.

Alberer M, Gnad-Vogt U, Hong HS,Mehr KT, Backert L, Finak G, Gottardo R, Bica MA, Garofano A, Koch SD, Fotin-Mleczek M, Hoerr I, Clemens R, von Sonnenburg F. 2017. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet.