27 February 2019
New paradigm in universal flu vaccine research?
The flu virus is a master of disguise, but Melbourne researchers have found a way to alert the human immune system to the infection no matter how much the virus shape-shifts.
While vaccines that protect against a broader range of flu viruses are under development, no vaccine has been able to protect against A, B and C viruses simultaneously.
According to a paper published in Nature Immunology this month, all that could be about to change.
A team of 37 researchers, headed up by Professor Katherine Kedzierska and PhD candidate Marios Koutsakos at the Peter Doherty Institute for Infection and Immunity, has discovered a number of conserved regions of the flu virus that are exactly the same across type A, B and C flu viruses – and could form the building blocks for a truly universal flu vaccine.
These regions of the flu virus haven’t changed for a hundred years and aren’t likely to change any time soon. Crucially, the research team found that the human immune system responds to these conserved flu peptides by mounting an effective killer T cell response.
Around 54% of people can react to these specific flu antigens, however, so any vaccine emerging from this research would only protect around half of the world’s population.
When the researchers vaccinated transgenic mice using the novel epitopes (regions of the virus that interact with the immune system), they found the mice were protected against type B flu.
The T cell branch of the immune system takes a few days to kickstart, so people who have been vaccinated and then infected with the flu might get a sniffle before they start fighting off the virus, Professor Anthony Purcell, an author on the paper and a scientist at the Monash Biomedicine Discovery Institute, said.
One big advantage of the cytotoxic T cell approach was that the flu peptides were relatively cheap and easy to manufacture on a large scale, he said. Unlike traditional flu vaccines, they didn’t depend on chicken eggs in the manufacturing process.
However, it was wickedly difficult to get these flu particles to stimulate a lasting cellular immune response in humans, Professor Rajiv Khanna, a scientist at QIMR Berghofer Medical Research Institute, said. “This is where we struggle,” he said.
Even if you could identify the right part of the flu virus to stimulate a T-cell response and package that up into a vaccine formulation, there weren’t any adjuvants available on the market to boost cellular immunity, Professor Khanna said.
Cytotoxic T cells only become aware of a flu infection when other human cells engulf the flu virus, break it into pieces and attach those fragments to the outside of the cell.
Because these fragments come from the centre of the flu virus – which is conserved over time and across flu strains – this immune pathway has proved popular among universal flu vaccine researchers.
A few companies are currently using this approach. A spin-out company from the University of Oxford called Vaccitech is testing its MVA+NP+M1 vaccine in two large clinical trials in the UK and Australia. This vaccine targets at all A strains. An Israeli company called BiondVax is running phase 3 clinical trials on a universal flu vaccine candidate called Multimeric-001.
The Medical Republic contacted both of these companies to ask what they thought of the Melbourne researchers’ work.
Dr Tamar Ben-Yedidia, the CSO at BiondVax Pharmaceuticals, said the discovery of common epitopes in influenza A and B was important, particularly as type B was understudied.
“The coverage of influenza C is nice to see, but since this virus does not cause disease in [adults] it is academically interesting but not so important for real life,” she said.
The approach for vaccine design that led to the development of BiondVax’s M-001 vaccine was similar to the one described in the paper, she said. “Although ours was developed in the 1990s when current advanced techniques were not yet available,” she said.
The M-001 vaccine contains nine epitopes from the HA, NP and M1 protein derived from influenza A and B viruses. “Actually, one of the peptides described in the paper (NP338) is included within M-001,” Dr Ben-Yedidia said.
“The most important difference is that the paper describes in-vitro assays and pre-clinical studies in mice, whereas the M-001 was already shown to be safe and immunogenic to a broad range of flu strains in six human clinical trials.”
Sarah Gilbert, a professor of vaccinology at the University of Oxford who helped develop Vaccitech’s flu vaccine, said the finding of an epitope present in three influenza types (A, B and C) was “novel and of scientific interest”.
“The challenge is then how to use this information to produce a vaccine that will be effective in protecting humans against influenza infections,” she said.