A Llama Antibody Could Be the Key to a Universal Flu Vaccine
Published November 2, 2018 by Alex Keown

Less than a week ago,  Roche snagged regulatory approval for Xofluza, a single-dose oral medication, the first new flu treatment approved in 20 years. Now, new research indicates that llamas, the doe-eyed South American pack animal, may hold the key to flu vaccines.

The Los Angeles Times reports that a team from the Scripps Institute in Southern California has been able to take antibodies made by llamas and used them as the basis for a flu vaccine. The llama antibodies are effective enough to work on a wide number of flu viruses, according to the report. The Times reported that the Scripps researchers reported their findings in the latest issue of Science.

According to the article abstract, diverse camelid single-domain antibodies to influenza virus hemagglutinin were used to generate multidomain antibodies with impressive breadth and potency. In the study, the researchers used the multidomain antibody MD3606 in mice. They found that the antibody protected the mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector.

“Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus–mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens,” the researchers said in the article abstract.

The researchers noted that flu vaccines are essential to prevent the spread of the virus, but the efficacy in them is “substantially reduced in the elderly, who are at increased risk of influenza-related complications.” The researchers added that annual selection of vaccine strains presents many challenges and if the strains selected don’t match up against circulating viruses, the vaccines are not as effective. Most current flu vaccine-induced antibodies are directed against the highly variable head region of hemagglutinin (HA) and are strain specific, the researchers said.

However, the Scripps researchers were able to develop a single protein from the llama antibodies that are capable of getting into the smallest of spaces on the surface of a virus – spaces that are too small for most proteins, the Times said. The multidomain antibody MD3606 is the result and it could provide protection against most strains of the flu, the researchers said. That would be true even if a strain of flu were to change. The llama-based vaccine would be effective, the researchers noted.

If the vaccine were to pan out in human trials, that would be a significant factor in preventing people from coming down with the flu, which represents a serious health threat each year. Globally, there are about 650,000 deaths from the flu worldwide and millions of people are hospitalized due to the illness. According to the U.S. Centers for Disease Control and Prevention, those people who are considered at high risk of serious flu complications include people over the age of 65, as well as people who have pre-existing conditions such as asthma, diabetes, heart disease or chronic lung disease.

However, it will be years before the llama-based antivirus could potentially find its way into use. There are numerous hurdles to overcome, but the researchers are moving forward, the Times reported.


Scientists May Have Found the Key Ingredient For a Universal
Flu Vaccine, And It Comes From Llamas

by Melissa Healey   Nov 2, 2018    Los Angeles Times

Along with soulful eyes, endearingly long necks and warm fuzzy coats, llamas have a far less appreciated feature: They make an array of immune system antibodies so tiny they can fit into crevices on the surface of an invading virus.

That feat could one day protect humans from entire families of flu viruses that bedevil scientists with their unpredictable and shape-shifting ways.

All, potentially, with a once-a-year puff up the nose.

In a study in Friday’s edition of the journal Science, a team from the Scripps Research Institute in La Jolla and their international colleagues have taken a major step toward the long-sought goal of developing a universal vaccine against influenza.

When they tested their intranasal formulation in mice, it quickly conferred complete protection against a raft of human flu strains adapted to mice. Those include A viruses, such as the H1N1 “swine flu” that touched off a global pandemic in 2009, and B viruses, which occur only in humans.

Against H1N1, a dose of the experimental vaccine was shown to protect for at least 35 days — a span of time equivalent to more than a single flu season for humans.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, offered a full-throated appreciation for the new study, which received funding from the National Institutes of Health.“From a scientific and technical standpoint, this is really a very elegant study — the highest quality of science,” Fauci said. He praised it for demonstrating that in order to protect people from pathogens that can change or emerge unpredictably, scientists must construct vaccines that can knock down an array of viruses, even in people whose immune systems are fragile or compromised.

A dose of flu vaccine is drawn into a syringe. By developing a universal flu vaccine, scientists hope to eliminate
the need to design a new shot every year. (Brent Lewis/Denver Post via Getty Images)

Influenza is a viral scourge that kills as many as 650,000 people each year, according to the World Health Organization. To fight it, the research team borrowed new techniques from immunology, microbiology, nanotechnology and genetic engineering labs around the world.

First, they vaccinated llamas against a number of A and B strains of influenza. Then they took blood samples to collect the antibodies the llamas produced in response.

Among them were four uniquely small antibodies that showed an ability to destroy many different strains of influenza. In a nod to their size and function, they called their creations “nanobodies.”

From those multitasking little powerhouses, the researchers engineered a single protein capable of squeezing into spaces on a virus’ surface that are too small for most proteins. The resulting “multidomain antibody MD3606,” with its “impressive breadth and potency,” could confer protection against pretty much any strain of flu that nature could throw in humankind’s way, the study authors said.

If the dominant strain in a given season were to suddenly change, these antibodies would be ready for the unwelcome guest. If a flu strain came out of nowhere and threatened a population with no immunity to it — the nightmare scenario of pandemic flu — this supercharged defender would recognize that flu and counter it. If health officials guessed wrong about what flu strain was coming and ordered up a vaccine that would be largely ineffective — a scenario that played out last flu season — this package of antibodies could save the day.

But the researchers still faced a key hurdle: getting the human immune system to make such a super-protein even when it’s weighed down by age, stress and disease.

Their solution: Don’t even try.

Instead, they devised a way to work around humans’ unreliable response to vaccines, building a gene that encoded the production plans for their powerhouse protein. To ferry that gene into a host organism, they enlisted a harmless virus used by labs working on gene therapy.

By splicing their designer gene into this viral delivery device, the scientists not only found a way to get their antibody package into a host, they were delivering the manufacturing machinery to produce it. This “passive transfer” of antibodies gives this vaccine candidate the potential to be equally effective in everyone, Fauci said.

A group of llamas look around on a farm in New Jersey.. (AP Photo/Mel Evans)

The next step is to conduct further tests in animals and clinical trials in humans, and that “will take years,” he said. “But if fully successful — a majestic leap right now — it could essentially eliminate the need from season to season” to divine which of countless possible flu viruses will rear up, and to then build a yearly flu vaccine that neatly fits the bill.

Scripps immunologist Ian Wilson, the study’s senior author, said that as the cells “infected” by the delivery virus turn over, repeated doses might be needed to sustain the production of antibodies. “We don’t really know how long this treatment would survive in humans yet,” he said.

But even less-than-permanent immunity against a broad range of flu threats would help buffer people from the emergence of unexpected flu strains, Wilson said. And the rapid response of mice to the vaccine suggests it could be used to inoculate a population after a new viral threat has emerged, he added.

That the experimental vaccine might need to be administered each year makes it an interesting hybrid, said Ted M. Ross, who directs the University of Georgia’s Center for Vaccines and Immunology.

“This approach is similar to antivenom,” said Ross. “The therapeutic is an antibody that was made in another species to neutralize the toxin. It’s short-term, but it gets you through the period of time where bad things could happen.”

Over time, patients who got the same antibodies repeatedly might start to build resistance to them, he said. Vaccine makers could counter that by finding and including new antibodies in their formulation every few years, he suggested.

Ross and other scientists also cautioned that the human immune system might see the llama-derived proteins as foreign and attack them.

This is not the only universal flu vaccine under development. In May, Fauci’s NIAID launched the first clinical trial to test the safety of a universal flu vaccine in 120 healthy humans. The candidate vaccine, called M-001, targets portions of the flu virus that tend not to change even as other proteins do. This should prime the human immune system to recognize and fight many different strains of influenza viruses.

Janssen Vaccines and Prevention, a Dutch company that employs some of the study authors, has applied for a patent that would cover some of the molecules described in the new report.


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