Vaccination is one of the major success stories of modern medicine, greatly reducing the incidence of infectious diseases such as measles, and eradicating others, such as smallpox. Conventional vaccine approaches have not been as effective against rapidly evolving pathogens like influenza or emerging disease threats such as the Ebola or Zika viruses. RNA based vaccines could have an impact in these areas due to their shorter manufacturing times and greater effectiveness. Beyond infectious diseases, RNA vaccines have potential as novel therapeutic options for major diseases such as cancer.
Conventional vaccines usually contain inactivated disease-causing organisms or proteins made by the pathogen (antigens), which work by mimicking the infectious agent. They stimulate the body’s immune response, so it is primed to respond more rapidly and effectively if exposed to the infectious agent in the future.
RNA vaccines use a different approach that takes advantage of the process that cells use to make proteins: cells use DNA as the template to make messenger RNA (mRNA) molecules, which are then translated to build proteins. An RNA vaccine consists of an mRNA strand that codes for a disease-specific antigen. Once the mRNA strand in the vaccine is inside the body’s cells, the cells use the genetic information to produce the antigen. This antigen is then displayed on the cell surface, where it is recognised by the immune system.
A major advantage of RNA vaccines is that RNA can be produced in the laboratory from a DNA template using readily available materials, less expensively and faster than conventional vaccine production, which can require the use of chicken eggs or other mammalian cells.
RNA vaccines can be delivered using a number of methods: via needle-syringe injections or needle-free into the skin; via injection into the blood, muscle, lymph node or directly into organs; or via a nasal spray. The optimal route for vaccine delivery is not yet known. The exact manufacturing and delivery process of RNA vaccines can vary depending on the type.
The simplest type of RNA vaccine, an mRNA strand is packaged and delivered to the body, where it is taken up by the body’s cells to make the antigen.
In vivo self-replicating mRNA
The pathogen-mRNA strand is packaged with additional RNA strands that ensure it will be copied once the vaccine is inside a cell. This means that greater quantities of the antigen are made from a smaller amount of vaccine, helping to ensure a more robust immune response.
In vitro dendritic cell non-replicating mRNA vaccine
Dendritic cells are immune cells that can present antigens on their cell surface to other types of immune cells to help stimulate an immune response. These cells are extracted from the patient’s blood, transfected with the RNA vaccine, then given back to the patient to stimulate an immune reaction.
Benefits of mRNA vaccines over conventional approaches are1:
The methods to make mRNA vaccines can be very effective. However, there are technical challenges to overcome to ensure these vaccines work appropriately:
The most active areas of research into RNA vaccines are infectious diseases and cancer where there is research ongoing as well as early-stage clinical trials. Work into the use of RNA vaccines to treat allergy is still at the early research stage2.
Researchers using conventional approaches have struggled to develop effective vaccines against a number of pathogens, particularly viruses, that cause both acute (Influenza, Ebola, Zika) and chronic (HIV-1, herpes simplex virus) infection. RNA vaccines are being explored as a way to more rapidly and cheaply produce vaccines for these diseases, particularly in response to emerging outbreaks. Clinical trials have been carried out or are ongoing on mRNA vaccines for influenza, cytomegalovirus, HIV-1, rabies and Zika virus.
Case study: A recent study3 explored the use of programmable self-replicating RNA vaccines, delivered in a nanoparticle, for a range of infectious diseases including Ebola virus, H1N1 Influenza and Toxoplasma gondii, which were effective in mice. These vaccines can be manufactured in approximately one week and made against a range of diseases, demonstrating potential terms of swift response to disease outbreaks.
Cancer vaccines are a form of immunotherapy, where the vaccine triggers the immune system into targeting the cancer. Both dendritic cell vaccines and personalised cancer vaccines, where the RNA sequence in the vaccine is designed to code for cancer-specific antigens, are being explored. Over 50 clinical trials are listed on clinicaltrials.gov for RNA vaccines in a number of cancers, including blood cancers, melanoma, glioblastoma (brain cancer) and prostate cancer.
Case study: Researchers sequenced the genomes of tumours from patients with melanoma. They made RNAs coding for mutant proteins, specific to the patients’ cancers, that could generate an immune response and made these into patient-specific vaccines. Eight out of thirteen people vaccinated stayed tumour free up to two years later4
There are a number of companies and initiatives with an interest in RNA vaccines including the Merit Consortium, which is a European initiative to develop cancer vaccines, while UniVax is a research collaboration to develop a universal influenza vaccine. Companies such as Moderna Therapeutics, CureVac and BioNTech, are involved in phase I trials of RNA vaccines in cancer and infectious disease. These companies are also exploring the broader use of RNA therapeutics for diseases where important proteins are missing or defective and mRNA treatments could be used to express a functional copy of the protein.