By targeting the flu-facilitating protein, the antibody can protect against large strains

A national team of researchers has discovered an antibody that protects mice against a wide range of life-threatening influenza viruses, advancing efforts to design a universal vaccine that could either treat or protect people from all strains of the virus.

A national team of researchers has discovered an antibody that protects mice against a wide range of life-threatening influenza viruses, advancing efforts to design a universal vaccine that could either treat or protect people from all strains of the virus.

The study, which Scripps Research carried out jointly with the faculty of medicine of the University of Washington in Saint-Louis and the faculty of medicine Icahn of the mount Sinai in New York, indicates a new approach to fight against the serious cases of influenza , including pandemics. The research is published in the October 25 issue of Science.

Ian Wilson, DPhil, of Scripps Research, one of the three main co-authors, says that the antibody at the center of the study binds to a protein called neuraminidase, which is essential for the flu virus to replicate. in the body.

The protein, located on the surface of the virus, allows infected host cells to release the virus so that it can spread to other cells. Tamiflu, the most widely used drug for severe influenza infections, works by inactivating neuraminidase. However, there are many forms of neuraminidase, depending on the strain of the flu, and these drugs are not always effective - especially when drug resistance develops.

"There are many strains of the flu virus circulating so every year we have to design and produce a new vaccine to match the most common strains this year," says lead co-author Ali Ellebedy, PhD, assistant professor of Pathology and Immunology at the University of Washington. "Now imagine if we could have a vaccine that protects against all strains of the flu, including human, swine and other deadly avian influenza viruses. This antibody could be the key to designing a truly universal vaccine. "

Ellebedy discovered the antibody - an immune molecule that recognizes and attaches to a foreign molecule - in the blood taken from a patient hospitalized for influenza at the Barnes-Jewish Hospital in Saint-Louis in winter 2017.

Ellebedy was working on a study analyzing the immune response to influenza infection in humans in collaboration with the Washington University Emergency Care and Research Core, which sent him blood samples from willing influenza patients. He quickly noticed that a particular blood sample was unusual: in addition to containing antibodies to hemagglutinin, the main protein on the surface of the virus, it contained other antibodies that were clearly targeting something else.

"By the time we were just starting out, and I was setting up my lab so that we didn't have the tools to see what other antibodies could target," said Ellebedy, assistant professor of medicine and molecular microbiology.

He sent three of the antibodies to lead co-author Florian Krammer, PhD, professor of microbiology at the Icahn School of Medicine in Mount Sinai. An expert in neuraminidase, Krammer tested antibodies against his extensive library of neuraminidase proteins. At least one of the three antibodies has blocked neuraminidase activity in all known types of neuraminidase in influenza viruses, representing a variety of human and non-human strains.

"The scale of the antibodies really surprised us," says Krammer. "Generally, anti-neuraminidase antibodies may be broad within a subtype, such as H1N1, but an antibody with potent activity across the subtypes was unknown. At first we did not believe our results "In particular, the ability of antibodies to pass through influenza A and the influenza B virus is simply breathtaking. It is incredible what the human immune system is capable of if presented with the right antigens."

To find out if the antibodies could be used to treat severe cases of influenza, Krammer and colleagues tested them on mice given a lethal dose of influenza virus. The three antibodies were effective against many strains, and one antibody, called "1G01", protected against the 12 strains tested, which included the three groups of human influenza viruses as well as avian and other non-human strains.

"All the mice survived, even though they received the antibody 72 hours after infection," says Ellebedy. "They definitely got sick and lost weight, but we still saved them. It was remarkable. This made us think that you may be able to use this antibody in an intensive care scenario when you have someone with the flu and it is too late to use it. Tamiflu. "

Tamiflu must be administered within 24 hours of symptoms. A drug that could be used later would help many people diagnosed after the Tamiflu window was closed. But before the researchers could even think of designing such an antibody-based drug, they had to understand how it interfered with neuraminidase.

They turned to Wilson of Scripps Research, known worldwide for his work as a structural biologist. Wilson is chair of the Institute's structural and computational biology department and has made many defining discoveries that have shaped efforts to develop universal vaccines for influenza and other complex viruses such as HIV.

Wilson and Xueyong Zhu, PhD, a scientist from the Wilson laboratory, mapped the structures of antibodies while they were linked to neuraminidase. They discovered that the antibodies each had a loop that slid inside the active site of neuraminidase like a stick between the gears. The loops prevented neuraminidase from releasing new viral particles from the cell surface, thus disrupting the cycle of viral production in the host cells.

"We were surprised to see how these antibodies succeeded in inserting a single loop in the conserved active site without coming into contact with the surrounding hypervariable regions, thus reaching a greater extent against the neuraminidase of various influenza viruses that we have seen before, "said Wilson.

The structures have shown that the antibodies offer such protection because they target the residues conserved in the active site of the protein neuraminidase. This site remains much the same for distant flu strains, because even minor changes could abolish the protein's ability to do its job, preventing the virus from replicating.

Researchers are working on the development of new and improved 1G01 antibodies and flu treatments and vaccines.

"Neuraminidase has long been overlooked as a vaccine candidate," says Ellebedy. "These antibodies tell us that it shouldn't have been overlooked. Now that we know what a broadly protective antibody to neuraminidase looks like, we have an alternative approach to start designing new vaccines that induce antibodies like this one. And that could be really important if we are to find out how to design a truly universal vaccine. "

The study was funded by grants from the National Institute of Allergies and Infectious Diseases (R01 AI117287, R21 AI139813, U01 AI141990) and the National Institutes of Health (R56 AI117675).

Journal Reference:

Daniel Stadlbauer, Xueyong Zhu, Meagan McMahon, Jackson S. Turner, Teddy J. Wohlbold, Aaron J. Schmitz, Shirin Strohmeier, Wenli Yu, Raffael Nachbagauer, Philip A. Mudd, Ian A. Wilson, Ali H. Ellebedy, Florian Krammer. Broadly protective human antibodies that target the active site of influenza virus neuraminidase. Science, 2019; 366 (6464): 499 DOI: 10.1126/science.aay0678

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