A paper about pandemic vaccines: shaped by a pandemic.
We first started writing the grant application that
supported this work in 2017. The work was funded by the Coalition for Epidemic
Preparedness Innovations (or CEPI). CEPI is a global
partnership that was set up to accelerate the development and delivery of vaccines.
The original plan was to look at three viruses – the one I was leading was
influenza. We had a remit to develop a vaccine that could provide protection
against infection within 6 weeks of the first immunisation.
The approach we used was an RNA vaccine, which unless you
have been living under a rock for the last 3 years I am assuming you have heard
of. But just in case, what these vaccines do is to take the genetic material that
encodes a tiny bit of the virus and inject it into the muscle. Once injected
your muscle cells make the viral protein training your immune system to
recognise them. This means that when you are exposed to the real virus, you can
fight it off better. Specifically we were using a self-amplifying RNA vaccine,
this is subtly different; you can in theory get bigger responses for smaller amounts
of material. I have described them before here.
One of the first questions we looked at was how best to
formulate the vaccine; the work is described in our recently published paper Formulation,
inflammation and RNA sensing impact the immunogenicity of self-amplifying RNA
vaccines. RNA is quite unstable and needs to be mixed with other compounds
in order to get it into cells. We tried three approaches a cationic polymer
(pABOL), a lipid emulsion (nano-structured lipid carrier, NLC) and three lipid
nanoparticles (LNP). In simple terms to get RNA into a cell, you either need to
add positive molecules (the cationic polymer) or some fat bubbles (the LNP and
the NLC). We noticed that responses to the LNP were very much better than the other
approaches and wanted to understand why.
One of the questions we asked was about the role of
inflammation. Inflammation is a cascade of signalling by which the immune
system recruits cells to a site of infection or danger. In conventional vaccines
it is important because it alerts the cells that there is something foreign to
be recognised and trains up the vaccine response. However, there was a question
about its role in RNA vaccines, because RNA vaccines need to be made into proteins
in the body to work some aspects of the immune system might inhibit this.
Surprisingly (which is up there in the go to words of academic writing,
alongside interestingly), we saw that vaccine induced inflammation was
associated with better, not worse responses. The next step is to further dissect
how this inflammation is beneficial.
Coming back to the timing of this project. We started the
labwork in 2019, when the idea of a world changing pandemic virus was somewhere
in the future. Then of course the events of 2020 caught up with us. The work
definitely slowed down – though aspects of it were incorporated into the
Imperial College vaccine trial. The formulation that we had showed to work best
in the saRNA system was the one used in the clinical trial. As part of the
ongoing vaccine research, I was able to come into the lab occasionally, providing
a sanity lifeline and also the very odd experience of commuting through an
empty London. Where this exciting vaccine technology goes next is still an important
research question and one I look forward to continuing to investigate.
