RNA technology has reshaped the vaccine landscape. The biggest advantage is the flexibility. Every single virus, bacteria, fungus or parasite that has ever infected a human uses the same code set to make its proteins. It’s basically universal science Lego. This means we can build vaccines against any pathogen using the same tool kit.
In theory.
The first generation of RNA vaccines were highly effective during the pandemic, they significantly reduced the burden of disease and helped protect many people from hospitalisation and death. But more can be done to improve them for future pandemics or more routine use. One area that requires attention is how the RNA is delivered to cells.
RNA is a large, charged and fragile molecule. If injected into the body on its own, it gets chewed up; this is a natural defence system from the body to protect it against viruses, bacteria, fungi and parasites (which as mentioned above, all use RNA too, and would like nothing more than our cells to make their proteins). We therefore need to package it up to deliver the vaccine payload.
As part of a collaboration with Professor Cameron Alexander (University of Nottingham) and a Cambridge biotech company called Aqdot, we explored a new approach to package RNA. This was recently published in the journal Advanced Materials. The licensed RNA vaccines (from Pfizer and Moderna) use a delivery technology called LNPs. These are Lipid NanoParticles – they use fat particles to encapsulate the RNA, a bit like salad dressing (but not really). There is an alternative approach, that exploits the charge of the RNA molecule. It is long and negatively charged, this means it can then be combined with long positively charged molecules. However, long positive molecules can be toxic to cells – because they bind other stuff, disrupting normal function. The breakthrough in our published study: ‘Modular Supramolecular Polycations Enable Efficient Delivery of Diverse RNA Therapeutics and Vaccines’ was a novel way of packaging RNA, developed by the chemistry team at Nottingham.
Instead of using long molecules, they used much shorter ones, but used a linker to join it all together. The linker was developed by Aqdot – it is from a family of molecules named cucurbiturils (so called because they vaguely look like cucumbers). The cucurbituril molecules are barrel shaped and the hole in the middle is able to accommodate other polymers. This can then link everything together in a web – including the RNA. Using the new platform, we were able to show that you can deliver RNA vaccines and protect against infection with influenza.
There are three major challenges with RNA vaccines – the reactogenicity (side effects after immunisation), the longevity (how long the response lasts) and the stability (the need to keep them in -80). Much of this relates to how the RNA is packaged, the ability to deliver RNA with different formulations opens up opportunities for the further development of the RNA vaccine platform.