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February 18, 2011

Synthetic Universal Flu Nasal Spray Vaccine shows success in Mice

University of Adelaide researcher Dr Darren Miller and colleagues have successfully trialled a synthetic universal flu vaccine in mice.

Dr Miller and colleagues used specific peptides delivered to the noses of mice. The peptides trigger an immune response to a tiny region of the flu virus that is present in all influenza A and B viruses, which effectively neutralises the virus.

The test vaccine provided mice with 100% protection against a laboratory strain of virus (H3N2) and 20% protection against a highly pathogenic virus (H5N1, known as "bird flu"), which is consistent with the protection levels achieved with commercially available anti-influenza drugs.

Journal of General Virology - Preclinical efficacy studies of influenza A haemagglutinin precursor loop peptides as a potential vaccine.



He says that while the universal vaccine could be given as an injection, using a nasal spray has a number of advantages: "It is non-invasive and would be a preferred option for people afraid of needles. Importantly, a nasal spray stimulates local immune responses at the natural site of virus entry.

"This vaccine would also reduce the allergy risk for many patients - because current flu vaccines are grown in eggs, those who are hypersensitive to eggs can't be vaccinated. Such a universal vaccine may also, of course, do away with the need for annual re-vaccinations, which is the situation many patients face today."

A universal influenza vaccine that does not require annual reformulation would have clear advantages over the currently approved seasonal vaccine. In this study, we combined the mucosal adjuvant alpha-galactosylceramide ({alpha}GalCer) and peptides designed across the highly conserved influenza precursor haemagglutinin (HA0) cleavage loop as a vaccine. Peptides designed across the HA0 of influenza A/H3N2 viruses, delivered to mice via the intranasal route with {alpha}GalCer as adjuvant, provided 100% protection following H3N2 virus challenge. Similarly, intranasal inoculation of peptides across the HA0 of Influenza A/H5N1 with {alpha}GalCer completely protected mice against heterotypic challenge with H3N2 virus. Our data suggest that these peptide vaccines effectively inhibited subsequent Influenza A/H3N2 virus replication. In contrast, only 20% of mice vaccinated with {alpha}GalCer-adjuvanted peptides spanning the HA0 of H5N1 survived homologous viral challenge, possibly because the HA0 of this virus subtype is cleaved by intracellular furin-like enzymes. Results of these studies demonstrated that HA0 peptides adjuvanted with {alpha}GalCer have the potential to form the basis of a synthetic, intranasal, influenza vaccine.

Previously reported T-Cell Universal Vaccine human trials

Oxford University had the results of a trial of a vaccine to activate t-cells in humans from 2008-2010. The results showed that the vaccine worked as planned. "Fewer of the people who were vaccinated got flu than the people who weren't vaccinated," said Gilbert. "We did get an indication that the vaccine was protecting people, not only from the numbers of people who got flu but also from looking at their T-cells before we gave them flu. The people we vaccinated had T-cells that were more activated. The people we hadn't vaccinated had T-cells as well but they were in a resting state so they would probably have taken longer to do anything.

Hill said the trial proved two important things about the vaccine. "It showed that it was safe; and giving people flu virus in the presence of lots of T-cells induced by the vaccine was absolutely fine.

"The [traditional flu] vaccine efficacy is 70-80% of young people, but only 30-40% in old people," said Hill. "What we'll do is an efficacy trial in the elderly and try to improve that 30-40% to hopefully double that."

Other Flu Research - predicting flu evolution

Sergey Kryazhimskiy, University of Pennsylvania, thinks it might be possible to predict the evolution of flu viruses by looking for gateway mutations.

Kryazshimsky reasoned that certain combinations of mutations would crop up far more often than others. Maybe one of them compensates for the other, just like H274Y and its gateway mutations. Maybe one mutation boosts the beneficial effect of the other. Either way, the whole is much greater than the sum of the parts. This phenomenon is known as epistasis.

Kryazhimskiy looked at over 40 years of flu genomes and measured how quickly mutations appear at one place in the flu genome given another mutation at a second site. If the first mutation acts as a gateway for the second, the latter would turn up quickly after the former, and it would do so independently on many branches of the flu family tree. Kryazhimskiy found hundreds of such pairs.

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