The scientists used leading-edge genomics to identify and eliminate the virus' defense mechanisms, enabling them to develop a vaccine "candidate" -- meaning that it must still undergo evaluation and approval by the FDA -- that in animals has been proven to be safe and highly effective against influenza.

Mice vaccinated with the newly designed influenza virus, called hyper-interferon-sensitive (HIS) virus, survived exposure to lethal doses of several different influenza A strains. But the majority of those exposed but not vaccinated with HIS died, researchers report in the journal Science.

"Because the variations of seasonal influenza viruses can be unpredictable, current vaccines may not provide effective protection against them," said the study's senior author. "Previous pandemics and recent outbreaks of avian influenza highlight the need to develop vaccines that offer broader, more effective protection."

The key to the new vaccine is an understanding of the interactions between the virus and interferons, which are proteins that are critical to the body's immune response. Interferons have two main functions: one is a first line of defense to kill invading viruses very quickly; a second is to coordinate the adaptive immune responses, which provide long-lasting protection against the virus. The latter is the basis of vaccination.

"If viruses do not induce interferons, they will not be killed in the first-line defense; and without interferons, the adaptive immune response is limited," said the senior author. "For these reasons, viruses have evolved strategies to evade detection and limit the production of interferons by host organisms."

Researchers have spent the past four years searching the influenza virus's entire genome for its anti-interferon properties. After defining the function of every amino acid in the genome, they deactivated the sequences that prevent interferon induction, which meant that interferon production would be highly stimulated in organisms infected with the virus.

"By disabling these interferon-evasion functions, the engineered virus is weakened in typical hosts," said the study's first author. "At the same time, however, due to interferon stimulation, the engineered virus generates very strong immune responses."

Senior author added: "With this approach, the safety and efficacy requirement of vaccines can potentially be achieved simultaneously. In traditional vaccine development, one is usually sacrificed for the other."

Although researchers have disabled genetic sequences that block interferon before, the UCLA scientists were the first to systematically identify and eliminate multiple interferon-evasion sites at single amino acid resolution on the virus.

"Other researchers have knocked out one anti-interferon sequence, but we knocked out eight locations by changing one amino acid at a time," first author said.

Researchers  vaccinated 40 mice with the HIS virus vaccine. After 28 days, they exposed those mice and another 40 not vaccinated with HIS to lethal doses of one of four different influenza A strains — three from the H1N1 subtype and one from the H3N2 subtype (H3N2 viruses are causing much of the misery this flu season). All of the vaccinated mice survived, while most of the other mice died, depending on which flu strain caused their infection.

Researchers now plan to test the vaccine in animals with two strains of influenza before moving to clinical trials with humans. The approach could also be applied to developing vaccines against a wide range of other viruses.

https://www.uclahealth.org/the-flu-vaccine-could-get-a-muchneeded-boost

http://science.sciencemag.org/content/359/6373/290