LONDON – Vaccines that use synthesized messenger RNA (mRNA) as their building blocks may be able to provide rapid protection against emerging infectious diseases in the future, a new study suggested.

The study, which used influenza virus to model the effectiveness of the novel type of vaccine, showed that after just one or two injections, it was possible to protect mice, ferrets and pigs against a normally lethal viral challenge.

As well as the effectiveness of the vaccination, one of the most encouraging features of the vaccine is that it does not require storage at low temperatures, so it has no need for the cold chain. Most, if not all, other vaccines currently in use need to be kept at 4 degrees centigrade, creating a logistical challenge for storage and delivery to those that need them.

"Once you have the sequence of your antigen, you can start to manufacture the RNA for your vaccine," Karl-Josef Kallen, chief scientific officer of CureVac GmbH, of Tübingen, Germany, told BioWorld International. "So if you received the sequence of a new virus today, for example, you could deliver a vaccine ready for use in the clinic within just six to eight weeks. With influenza, this would mean that you would have the vaccine before the epidemic peaks, rather than receiving it later."

Kallen, together with colleagues, reported the results of the study in a paper in the Nov. 25, 2012, issue of Nature Biotechnology, titled "Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection."

Lothar Stitz, head of the Institute of Immunology, Friedrich-Loeffler-Institut, in Tübingen, Germany, and one of the corresponding authors of the paper, said: "Our data highlight the potential and advantages of prophylactic mRNA-based vaccines and make immunization against a broad range of pathogens possible. These mRNA vaccines overcome the drawbacks of many other prophylactic vaccination methods including DNA-based approaches."

Previous work by CureVac scientists had established that, despite earlier concerns that mRNA was too unstable to use in vaccines, it was possible to develop modified mRNA molecules, using naturally occurring nucleotides, that could be injected into the skin in order to stimulate an immune response.

The company has already completed Phase I and Phase IIa trials of RNA vaccines designed to stimulate an immune response directed at cancer antigens.

Those studies, aimed at developing cancer immunotherapy for prostate cancer and non-small-cell lung cancer, had shown the vaccines were safe and that a program of several frequent immunizations could stimulate a strong T-cell response.

What the researchers then wanted to know was whether they could use the same technology to induce a protective antibody response to an infectious disease. They decided to focus on influenza.

CureVac's RNA vaccines have two components. The first is synthetic mRNA. That includes the region coding for the antigen of interest, topped and tailed by segments that are not translated but which help to determine the life span of the molecule and its expression level once it reaches the target cell. The second component comprises the first component, tightly bound in a complex to an approved drug called protamine. The second component essentially plays the role of an adjuvant; no further adjuvant is needed. Both components are mixed together but do not interact with each other.

Kallen explained what happens when the vaccine is injected into the skin, which is full of immunologically active cells: "The mRNA vaccine is internalized by these cells, and the first component – the mRNA – is transcribed into the viral protein. The second, protamine-complexed component ends up in the endosomes of the cells, where it activates the Toll-like receptor 7 system, which alerts the immune system to danger. The beauty of this twofold approach is that we deliver the antigen to the immunologically active cells at the same time as we tell them to look out for danger."

For the study reported in Nature Biotechnology, initial tests used vaccine containing the mRNA coding for the full-length hemagglutinin protein of the influenza strain A/PuertoRico/8/1934.

Investigations showed that the vaccine was immunogenic and that it induced balanced B-cell and T-cell responses in mice. The immunized mice were protected against death and disease following an infectious challenge, by a response involving protective antibodies.

Using further hemagglutinin-specific vaccines, the authors showed that all vaccines induced full protection against lethal infections, including H1N1pdm09 swine flu and H5N1 bird flu virus. Vaccination worked in both newborn and aged mice.

Further studies showed that a multicomponent hemagglutinin and neuraminidase mRNA vaccine provided full protection in mice against influenza A/PR8 with just a single-dose immunization. In addition, the mRNA vaccines were immunogenic in ferrets, and in pigs.

"These results are exciting and encouraging," said Ingmar Hoerr, CEO of CureVac. "We are now going to carry on with our cancer immunotherapy work, and will consider how best to take our work on vaccination against infectious diseases forward in order to obtain proof of concept in humans. We hope to announce these plans within a couple of months and to demonstrate that mRNA-based vaccination is a truly disruptive technology that can advance vaccinology."