Rethinking vaccination with RNA vaccines

Laura Blackburn

13 November 2018

With winter approaching, thoughts are turning towards the annual flu season and ensuring that everyone who is eligible to receive a vaccine does. Predicting which vaccine to develop is always a challenge as the time it takes to grow the vaccine in hen’s eggs, means decisions about which strains of flu to develop a vaccine against are made six months before the start of the flu season. In addition the influenza virus is complicated and adaptable and can change before the vaccine is ready. This can mean that the vaccine is not fully effective against all the strains of flu circulating each winter. A partially effective vaccine is an improvement on no vaccine, but can we do better?

In a new policy briefing we outline a different approach to vaccine development – RNA vaccines. Not only could these have an impact on currently hard-to-vaccinate infectious diseases such as flu, but also on other diseases such as cancers.

Conventional vaccines contain inactivated pathogens or pathogen proteins (antigens). In contrast, RNA vaccines use the body’s own machinery to make pathogen antigens that prime the immune system to respond if it is exposed to the pathogen in the future. This approach sounds simple but is technically complex, however interest and funding in this area is rising as some of these challenges are overcome.

Tackling hard to reach infectious diseases

A universal flu vaccine would take some of the uncertainty out of deciding which strains to include in each year’s vaccine. For example, the German company BioNTech recently announced a partnership with Pfizer to develop a messenger RNA based flu vaccine, in a deal worth €374M. Their approach is to use flu mRNA in a vaccine to encourage patient’s cells to make viral proteins, which then elicit an immune response. One research study has shown that this type of approach works in mice. It is still too early to know if this will work in people, and other types of universal flu vaccine are in development and trials. However we should see progress in this priority area in the next few years.

Another disease of unmet need that has proved particularly difficult to vaccinate against is malaria. This is due to a number of factors: the malaria parasite Plasmodium has a complicated lifecycle, with stages occurring in the mosquito, and in the liver and bloodstream of infected humans; it is also a complex, genetically diverse organism that evolves resistance in response to treatments. A team from Yale University and Novartis developed a vaccine that targets a protein produced by the parasite called macrophage migration inhibitory factor (PMIF), which suppresses the host’s memory T cells and effectively allows the parasite to evade host immunity. In a recent paper on a mouse model of malaria, they used an RNA vaccine to protect animals from future infections, however this approach hasn’t yet been tested in humans.

A new approach to cancer treatment?

For patients with cancer, RNA vaccines are being developed that prime the immune system to target tumour cells with specific antigens. One of the big players in this area, Moderna Therapeutics, is working on cancer vaccines that are personalised to each patient’s tumour. Both a sample of the patient’s blood and their tumour are genotyped and then analysed with specific algorithms to detect mutations specific to the tumour, but not found in the blood, which represents healthy tissue. Further algorithms then produce a list of tumour-specific protein targets which are used to develop a personalised RNA vaccine against that person’s tumour. The vaccine development is a complex and delicate process, however, requiring stringent clean room conditions. The cost of these vaccines is currently unknown, however many novel cancer drugs have been priced at six-figure sums, out of reach of most patients.

Where is this going?

RNA vaccines is an area that is developing quickly and has the potential to target areas of unmet need, particularly some infectious diseases. There are a number of technical challenges to be overcome in terms of vaccine production and also in understanding the biology of the vaccines, such as how they enter cells effectively and any unintended effects including immune reactions against the vaccine itself.

The methods used to manufacture RNA vaccines could be easily adjusted to target a number of different pathogens raising the tantalising possibility of swift vaccine-development responses to emerging disease threats. However there is still a way to go in terms of testing and clinical trials, and more needs to be done to consider the costs of some of these vaccines, particularly in patients with cancer.



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