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Better understanding of pathogen evolution takes us closer to one-time vaccines

Flu presents a paradox: while strains adapt to increased host immunity, strain diversity during an epidemic is limited. UNIFLUVAC successfully developed an influenza antigenic thrift model in pursuit of a one-time vaccine – useful against other pathogens, including COVID-19.

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Key to our immune system is the production of protein antibodies which recognise and bind to antigens or molecules on the outside of pathogens, blocking or destroying them. In flu, caused by the influenza virus, these antigens constantly evolve. This process, known as ‘antigenic drift’, makes it harder for the immune system to recognise the antigens and so fight them. This means that widespread flu immunity is never established in populations. But ‘antigenic drift’ doesn’t explain why single or limited numbers of flu strains dominate each season, when an infinite number is theoretically possible. So the EU-supported DIVERSITY project developed a theory that specific antigenic parts recognised by the immune system, called epitopes, do not vary as widely as previously believed. The UNIFLUVAC project, supported by the European Research Council, has been successful in identifying such epitopes of limited variability in several influenza subtypes. “We have shown that these epitopes cycle between a limited number of variations as they evolve. So we can target them with a vaccine that protects against all past and present human influenza strains, as well as potentially against pandemic strains too,” says project coordinator, Craig Thompson from the University of Oxford, the project host. Crucially, the research, as well as the tools and techniques developed, could be applied to other pathogens, including COVID-19. Indeed, the Oxford group, alongside the Scottish National Blood Transfusion Service, have used project techniques to track the spread of COVID-19 in Scotland. The team are currently preparing for a phase I human trial of the influenza vaccine with adults aged 18-65 and have partnered with an American start-up Blue Water Vaccines to commercialise it, once ready.

Flu’s limited repertoire

UNIFLUVAC’s alternative ‘antigenic thrift’ model is based on the hypothesis that epitopes cycle through their repertoire of limited variants in response to population immunity changes. The project’s antigenic model was able to look for patterns in annual flu evolution to make predictions about its development which could be tested in the lab. The team identified epitopes of limited variability in avian-and-other-zoonotic (H1, H3 and influenza B), which typically only had between three and four variations. The location of these mutated epitopes also makes them highly likely to produce a protective immune response. The model was combined with structural bioinformatic analysis to design a vaccine which was trialled on mice for effectiveness against all influenza strains. These strains, with similar epitopes, were chronologically distinct – separated in time with one strain an ancestor of another but with multiple mutations in between. The mice were found to successfully produce antibodies against these strains, showing protection when infected with them. These results were also replicated by the team in human sera, taken from young children for a previous hepatitis B vaccine trial.

Towards a one-time vaccine

Vaccinating against all past and present epitope variations should mean not only higher levels of protection against flu but also the end of annual vaccinations. As the vaccines can be made using current manufacturing methods, using inactivated or attenuated influenza, this will help keep prices down. This could make the vaccines attractive to pharmaceutical companies, while the reduced number of doses required to confer immunity will also be appealing to healthcare providers. “Our flu vaccine is probably 5 to 10 years away from being commercially available. We also plan to use the technology to develop other vaccines, COVID-19 or a pan-coronavirus vaccine being an obvious candidate,” explains Thompson.

Keywords

UNIFLUVAC, vaccination, antigens, COVID-19, coronavirus, influenza, epitopes, antibodies, flu, pandemic, strain, pathogens

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