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Programmable RNA Vaccines Are Effective in Mice Against Ebola and Flu

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The insertion of a rapid response force requires the right vehicle, however small the deployment. At the nanoscale, the right vehicle might be a dendrimer platform, one that can encapsulate messenger RNA (mRNA) vaccines and transport them across cell membranes as readily as viral particles. MIT engineers have developed a new type of easily customizable vaccine that can be manufactured in one week, allowing it to be rapidly deployed in response to disease outbreaks. So far, they have designed vaccines against Ebola, H1N1 influenza, and Toxoplasma gondii (a relative of the parasite that causes malaria), which were 100% effective in tests in mice.

In addition to targeting infectious diseases, the MIT researchers are using their dendrimer-RNA approach to create cancer vaccines that would teach the immune system to recognize and destroy tumors.

“This nanoformulation approach allows us to make vaccines against new diseases in only 7 days,” asserts Daniel Anderson, Ph.D. one of the MIT researchers. “[It has] the potential to deal with sudden outbreaks or make rapid modifications and improvements.”

Dr. Anderson is the senior author of a new study (“Dendrimer-RNA Nanoparticles Generate Protective Immunity against Lethal Ebola, H1N1 Influenza, andToxoplasma gondiiChallenges with a Single Dose”) that appeared July 4 in the Proceedings of the National Academy of Sciences. The study describes how the MIT researchers created a “fully synthetic, single-dose, adjuvant-free nanoparticle vaccine platform wherein modified dendrimer molecules nanoencapsulate antigen-expressing replicon mRNAs.”

Most traditional vaccines consist of an inactivated form of a virus or other pathogen. These vaccines usually take a long time to manufacture, and for some diseases they are too risky. Other vaccines consist of proteins normally produced by the microbe, but these don’t always induce a strong immune response, requiring researchers to seek an adjuvant (a chemical that enhances the response).

RNA vaccines are appealing because they induce host cells to produce many copies of the proteins they encode, which provokes a stronger immune reaction than if the proteins were given on their own. The idea of using mRNA molecules as vaccines has been around for about 30 years, but one of the major obstacles has been finding a safe and effective way to deliver them.

The MIT team decided to package RNA vaccines into a nanoparticle made from a branched molecule known as a dendrimer. One key advantage of this material is that the researchers can give it a temporary positive charge, which allows it to form close associations with RNA, which is negatively charged.

The nanoparticle approach also makes it possible to control the size and pattern of the final structure. In the current study, the dendrimer-RNA structure was induced to fold over itself many times, which resulted in spherical vaccine particles with a diameter of about 150 nanometers. That makes them of similar size as many viruses, enabling the particles to enter cells by exploiting the same surface proteins that viruses use for this purpose.

By customizing the RNA sequences, the researchers can design vaccines that produce nearly any protein they want. The RNA molecules also include instructions for amplification of the RNA, so that the cell will produce even more of the protein.

The vaccine is designed to be delivered by intramuscular injection, making it easy to administer. Once the particles get into cells, the RNA is translated into proteins that are released and stimulate the immune system.

“The vaccine can be formed with multiple antigen-expressing replicons, and is capable of eliciting both CD8+T-cell and antibody responses,” wrote the study’s authors. “The ability to generate viable, contaminant-free vaccines within days, to single or multiple antigens, may have broad utility for a range of diseases.”

The ability to design and manufacture these vaccines rapidly could be especially beneficial for fighting influenza, because the most common flu vaccine manufacturing method, which requires the viruses to be grown inside chicken eggs, takes months. This means that when an unexpected flu strain appears, such as the 2009 pandemic-causing H1N1 virus, there is no way toproduce a vaccine against it rapidly.

The researchers also believe that their vaccines would be safer than DNA vaccines, another alternative that scientists are pursuing, because unlike DNA, RNA cannot be integrated into the host genome and cause mutations.

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