Alliterative vaccines for influenza: DNA NA

In our latest paper, we take a marginal gains approach to improve influenza DNA vaccines
Alliterative vaccines for influenza: DNA NA
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Despite SARS-CoV-2 taking the limelight for the last 4 years, Influenza virus continues to be a significant threat to human health. It poses a number of threats to our health and wellbeing. These fall into three categories: seasonal, pandemic and zoonoses.

  1. Seasonal influenza. Lockdown type interventions (sometimes called NPI or non-pharmaceutical interventions) were highly effective at reducing the spread of not just SAR-CoV-2 (the virus that caused COVID) but other respiratory viruses too. The number of influenza virus infections went right down during 2020 and 2021. So much so that in fact one of the strains of influenza has disappeared. However, you can’t keep a good (bad) virus down and in the following winter (2022) flu had bounced back up to its usual levels causing illness, hospitalisation and death. Influenza virus is at its most serious at different times of the year depending upon where you live, but flu loves the winter – if you are in the southern hemisphere this means it peaks around June/ July, if you are in the Northern Hemisphere December is peak flu. These viruses change slowly over time, which is why there is a need for annual boosters.
  2. Pandemic influenza. There is a grinding low level of influenza disease year on year which causes a catalogue of low to middle grade misery. However, every so often (about once every 20 years) a completely new strain of influenza virus emerges infecting everyone. Not dissimilar to COVID a flu pandemic would cause immense disruption and death.
  3. Zoonotic influenza. We think of influenza as something that people get, but really it is an animal disease, particularly birds. The natural host of influenza is ducks, they spread it to chickens who spread it to pigs and people and the cycle continues. At the moment there is an unpleasant bird variant of influenza that has even made it to the icy shores of Antarctica causing penguins distress.

Vaccination takes the edge off some of these problems, and it is definitely worth getting vaccinated to protect yourself against the worst/ most severe disease. But the vaccines could be improved – giving you broader protection for longer. The huge breakthroughs with the RNA vaccines for COVID showed that other, newer platforms enable rapid responses to viral infections.

In our study Optimizing a linear ‘Doggybone’ DNA vaccine for influenza virus through the incorporation of DNA targeting sequences and neuraminidase antigen, we worked with a company called Touchlight Genetics who have a process for making DNA without all the bother of cells. Their Doggybone DNA (so called because of its shape) can be rapidly produced and in large amounts. This makes it a strong contender for future vaccine programs, especially against pandemic viruses. However, the Doggybone DNA vaccine platform needs a bit more work to be effective as a human vaccine, which is where our joint project came in.

We looked at two aspects to improve responses. The first was quite technical and involved tweaking the DNA sequence to allow more of it to get to the place it was needed (the nucleus). The second was looking at targeting a different part of the virus. Influenza makes two proteins on its surface, one that it uses to get into cells (Haemagglutinin or HA) and another that it uses to get out of them (Neuraminidase or NA). One thing to remember about the HA protein is that in spite of publishing papers about it for the last 15 years, I still cannot spell it – putting in too many or too few G’s, T’s or N’s. Most influenza vaccine research targets the HA protein, the idea being if you stop the virus before it ever gets into cells you can stop it in its tracks. However, targeting the NA protein has some advantages – it changes less than HA, so possibly you can increase the breadth of responses. This is helpful because the broader the anti-influenza response, the more protection you have when the virus changes its coat. We explored using the Doggybone DNA to make a vaccine that targeted influenza NA and showed that it could indeed protect against infection and disease.

Overall this work demonstrated that it is possible to further improve a DNA vaccine. By taking this marginal gains type of approach, it may be possible to develop influenza vaccines that cover all strains for all people.

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