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Looking to Llamas for New Ways to Fight the Flu

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Lllama nanobodiesResearchers are making tremendous strides toward developing better ways to reduce our risk of getting the flu. And one of the latest ideas for foiling the flu—a “gene mist” that could be sprayed into the nose—comes from a most surprising source: llamas.

Like humans and many other creatures, these fuzzy South American relatives of the camel produce immune molecules, called antibodies, in their blood when exposed to viruses and other foreign substances. Researchers speculated that because the llama’s antibodies are so much smaller than human antibodies, they might be easier to use therapeutically in fending off a wide range of flu viruses. This idea is now being leveraged to design a new type of gene therapy that may someday provide humans with broader protection against the flu [1].

Scientists have had an interest in antibodies made by llamas and their camel cousins ever since their small size first was discovered about 25 years ago [2]. In fact, there are companies in Europe focused entirely on developing new treatments and technologies inspired by llama antibodies.

Recently, an international team, funded in part by NIH, has begun applying some of this fundamental knowledge about llama antibodies to our ongoing battle against the flu. In a study published in the journal Science, Joost Kolkman of Janssen Infectious Diseases, Belgium; Ian Wilson, Scripps Research Institute, La Jolla, CA; and their colleagues describe a series of experiments that have opened the door to the possibility of a new flu-fighting “gene mist.”

The work began with researchers giving llamas a fairly traditional flu shot that contained three different influenza viruses and a viral surface protein called hemagglutinin from two other viruses, representing influenza type A and B strains. Analysis of the antibodies produced by the immunized animals led to the identification of four distinct antibody types that protected against a wide range of flu viruses.

To understand better how those antibodies worked and why they could be protective against multiple strains, researchers used X-ray crystallography and cryo-electron microscopy (cryo-EM) to determine their precise molecular structures. Those studies revealed the most essential portions of the four types of antibodies for recognizing influenza viruses, each targeting a different, highly conserved location on the surface hemagglutinin of flu viruses. A conserved location is one that has been maintained through evolution, meaning the antibody’s target will be present in most viral strains, rather than changing from year to year.

Next, those antibodies were further pared down by bioengineering and the resulting “nanobodies” strung together to create a broadly protective, four-in-one antibody. Test tube studies showed that this quadruple threat effectively targets and neutralizes dozens of influenza A and B viruses, including several types of avian influenza, or bird flu.

But could this llama-derived tetravalent antibody neutralize the flu virus in living creatures? To explore that question, researchers infused the antibody directly into the bloodstreams of mice. The antibody treatment completely protected the mice against many influenza viruses that otherwise would have been deadly.

Then, with collaborators at the University of Pennsylvania, Philadelphia, the team tried a different delivery method. They designed a bioengineered gene containing the instructions for the four-in-one antibody, inserted that gene into a harmless adeno-associated virus, and sprayed that as a “gene mist” into the noses of mice. The viral vectors then inserted the genes into respiratory tract cells, which in turn produced the desired four-in-one antibody. A week later, the mice were exposed in aerosol form to various, potentially lethal influenza viruses—but they were protected.

The researchers are hopeful that a similar “gene mist” approach might provide humans with broad protection against multiple influenza strains. However, they acknowledge that such protection would gradually wear off as the cells lining the nasal passages turn over. So, depending on how long that takes, it’s possible that people would still need to get an annual flu shot.

Many questions remain to be answered before this “gene mist” approach to fending off the flu might be ready for human studies to evaluate its safety and effectiveness. Nevertheless, the strategy holds considerable promise, especially for people with fragile or compromised immune systems who may have difficulty producing their own antibodies in response to traditional flu vaccines.

And there are other intriguing possible advantages. For example, the rapid protection this approach might afford, along with its potential to neutralize many forms of avian influenza, suggest it might be called into action to help quell an emerging flu pandemic far more swiftly than is possible with traditional vaccines.

Of course, none of this is reality yet. As we look to the flu season already underway, the best way to protect yourself and your loved ones is to get your annual flu shot. So, if you’ve been procrastinating, don’t wait any longer!

 References:

 [1] Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin. Laursen NS, Friesen RHE, Zhu X, Jongeneelen M, Blokland S, Vermond J, van Eijgen A, Tang C, van Diepen H, Obmolova G, van der Neut Kolfschoten M, Zuijdgeest D, Straetemans R, Hoffman RMB, Nieusma T, Pallesen J, Turner HL, Bernard SM, Ward AB, Luo J, Poon LLM, Tretiakova AP, Wilson JM, Limberis MP, Vogels R, Brandenburg B, Kolkman JA, Wilson IA. Science. 2018 Nov 2;362(6414):598-602.

[2] Naturally occurring antibodies devoid of light chains. Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R. Nature. 1993 Jun 3;363(6428):446-448.

Links:

Wilson Lab (The Scripps Research Institute, La Jolla, CA)

Frequently Asked Flu Questions 2018-2019 Influenza Season (Centers for Disease Control and Prevention)

Influenza (National Institute of Allergy and Infectious Diseases/NIH)

Universal Influenza Vaccine Research (National Institute of Allergy and Infectious Diseases/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of General Medical Sciences