First mRNA Vaccine Holds Great Promise

The first demonstration of an mRNA-based vaccine in humans opens the possibility that infectious disease outbreaks can be fought with faster production of vaccines that retain potency for longer periods and in wider temperature ranges.

Frank von Sonnenburg, MD, MPH (pictured), Department of Infectious Diseases and Tropical Medicine, University of Munich, Germany, and colleagues reported that an mRNA-based candidate vaccine induced functional antibodies against a viral antigen, and deemed it "generally safe with a reasonable tolerability profile."

"This technology platform offers many advantages over present cell-based, inactivated or purified antigen or toxoid vaccines," researchers wrote in a study. "mRNA vaccines are potentially quicker and more cost-efficient to produce, and more agile and flexible to allow rapid development of vaccines against newly emerging diseases in large quantities."

In an accompanying commentary, Mary Warrell, MB, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, welcomed the development, but pointed out that more work remains beyond this early open-label phase 1 trial.

"Before any predictions can be made, highly immunogenic viral mRNA vaccines must be devised,” Warrell said. “Let us hope that this innovation will not follow the path of DNA vaccines, which have not fulfilled the promise seen in animal experiments and have not been effective in human beings.”

The investigators noted that an mRNA vaccine acts in the cytoplasm rather than in the cell nucleus, and so does not share the potential of the DNA-based vaccine being integrated into the host genome. Instead, the mRNA enters target cells and is translated into the encoded antigen to promote the T-helper 2 immune response.

The researchers selected rabies as a model antigen for this first-in-human phase 1 clinical trial of an mRNA-based prophylactic vaccine. This choice facilitated identifying a virus-naїve population, and having an immunological surrogate of protection, in the available assessment of inactivated rabies vaccines. The investigational product (CV7201) was produced in a lyophilized form that maintained stability for 36 months at 5-25 degrees Celsius and for 6 months at 40 degrees Celsius.

The trial involved 101 participants receiving 1 of 3 different doses intradermally or intramuscularly by either needle/syringe or a needle-free injection device. The investigators reported that the needle-free injections, but not the injections by needle/syringe, induced virus neutralizing antibody titres of 0.5 IU/ml or more in 71% of those given 80 mcg or 160 mcg intradermally, and 46% of those given 200 mcg or 400 mcg intramuscularly. A booster dose of 80 mcg given by needle-free intradermal injection at 1 year also achieved titres of 0.5 IU/ml or more in 57% of 14 participants.

Von Sonnenburg and colleagues posit that the failure of response to the needle/syringe delivery reflects the broader dispersion patterns of the vaccine by needle-free administration which they wrote "could recruit more immunocompetent cells at the injection site or enable more efficient cellular uptake of nuleic acid-based vaccines, increasing antigen expression levels."

The investigators noted that few of the participants sustained virus neutralizing titres at 1 year, although a response was attained in over half of those receiving a booster dose. While acknowledging the need for further improvements to develop a viable vaccine, they noted that this trial provides “important guidance for improvements in this technology."

The study, "Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial," was published online in The Lancet last month.