The battle with flu is a seasonal struggle, and one we don’t always win.
The effectiveness of flu vaccines vary tremendously from year to year, and the reason is simple. There are three major types of the influenza virus (A, B and C) that, depending on the sprinkling of proteins decorating their surface, can be further subdivided into many different strains and lineages.
Conventional flu vaccines target the head of a lollipop-shaped molecule called haemagglutinin (HA) that sticks out from the surface of flu viruses. HA heads are unique to each flu strain, which means that each vaccine has to be individually made to target a particular strain of virus.
Right now, the uncomfortable truth is that every year, months before flu season actually strikes, scientists are forced to make educated guesses on which three to four strains of influenza virus to include in our vaccines. The decision — made by the World Health Organization in conjunction with the CDC and other health organizations — heavily relies on epidemiological data from previous flu outbreaks, such as when and where they occurred, whom they infected and what the outcome was.
It’s a dicey proposition, but most of the time the WHO gets lucky and the public breezes through a mild flu season. But sometimes even the best guesses fail, not because the scientists are inept, but because they were outmaneuvered by rapid and unpredictable HA mutations that happen after the vaccines have already been made.
Then there are the terrifying, Contagion-like nightmare scenarios.
In rare cases, such as the bird and swine flu, influenza that can previously only infect other animals suddenly “jump” to humans. Without a universal flu vaccine on hand — one that can target any influenza virus regardless of whether or not scientists have previously seen it before — such epidemics may happen again.
Now, in a pair of studies in Science and Nature Medicine, two teams separately reported a new way to create new vaccines by targeting a relatively stable part of the HA molecule — the stem.
“This is a leap forward compared to anything done recently,” said Dr. John Oxford, a flu expert at the University of London to BBC News.
Back in the early 2000s, scientists had already realized that people develop “broad spectrum” antibodies that can neutralize multiple types of flu virus by latching on to the stem of the HA molecule, suggesting that this mechanism may be used to engineer vaccines that also swipe out entire lineages of flu, even new emerging strains.
Yet this initial excitement was dampened by further observation that the human immune system struggles to create antibodies against the stem, most likely due to simple topography — the stem is buried under bulbous HA heads. Unfortunately, when scientists tried to simply chop off the head, the whole stem ended up disintegrating, making it unrecognizable as a vaccine target.
In the new studies, the two groups took slightly different technical approaches to realize the same concept: both starting with the H1N1 virus, the teams used rational design to slowly “evolve” the heads away, thus creating stem-only antigens for the immune system to rage against.
One team, led by Dr. Barney Graham and based at the National Institute of Health, slowly built a headless HA molecule that they attached to self-assembled nanoparticles to boost the mutated HA’s ability to trigger an immune response.
When given to mice and ferrets infected with several non-targeted flu strains, the vaccine prevented weight loss that often occurs after infection in the animals. The modified HA molecule also protected four out of six ferrets that were infected with a highly lethal dose of the H5 bird virus, whereas all of the untreated ones died. It’s a nasty strain, even for humans. Since 2004, the H5 has killed more than 400 people who mostly caught the virus from infected poultry.
The other team, led by Dr. Antonietta Impagliazzo at the Crucell Vaccine Institute, tinkered with the amino acids that made up the HA stem until they made a stable mini-HA (lacking a head) that retained the 3D structure of the original stem. The mini-HA elicited immune responses that protected mice from lethal doses of multiple strains of influenza, and guarded five out of six cynomolgus monkeys against swine flu-induced fever.
We now have very nice proof of concept that this strategy works, Hanneke Schuitemaker, Head of Viral Vaccines Discovery at Janssen Infectious Diseases & Vaccines, told Singularity Hub.
To be clear, these are not truly universal vaccines. The raw material that both teams used came from the H1N1 virus, which means that their stem-only HAs are limited to stimulating immunity against other group 1 type A strains, such as the swine or avian flu.
The vaccine, however large a step forward, would not protect against infection from two other major groups of epidemic-causing strains.
For a true universal vaccine, we really need also to demonstrate proof of concept for those two groups, said Schuitemaker.
Nevertheless, it’s a huge step up.
The biggest test now is whether vaccines engineered in this way will work in humans. It may still take several years, but Graham is optimistic.
This is a first proof-of-concept step, he said, but certain genetic differences between people and animals could mean that humans might elicit an even stronger response to the vaccine than the mice, ferrets and monkeys did.
“The results highlighted today show there is potential in the development of a single ‘universal’ vaccine to protect against all seasonal and pandemic influenza strains,” said Schuitemaker. “We are now working on components that will bring us a truly universal vaccine.”
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