US scientists have produced a number of monoclonal antibodies that seem to fight the influenza A virus strains. By attaching itself to a virus molecule, the antibodies prevent the virus from performing the necessary shape change that it needs to infect a cell.
Read on the explanation from NIH:
Key to their research, Dr. Marasco [Wayne Marasco, M.D., Ph.D., associate professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School] and his colleagues discovered and described the atomic structure of an obscure but genetically stable region of the influenza virus to which their monoclonal antibodies bind. The hidden part of the influenza virus is in the neck below the peanut-shaped head of the hemagglutinin (HA) protein. HA and neuraminidase are the two main surface proteins on the influenza virus.
The scientists also identified a new mechanism of antibody action against influenza: Once the antibody binds, the virus cannot change its shape, a step required before it can fuse with and enter the cell it is attempting to infect.
Dr. Marasco, Jianhua Sui, M.D., Ph.D., and other Dana-Farber colleagues began their study with avian flu viruses. They scanned tens of billions of monoclonal antibodies produced in bacterial viruses, or bacteriophages, and found 10 antibodies active against the four major strains of H5N1 avian influenza viruses. Encouraged by these findings, they collaborated with Ruben O. Donis, Ph.D., of the CDC Influenza Division, and found that three of these monoclonal antibodies had broader neutralization capabilities when tested in cell cultures and in mice against representative strains of other known influenza A viruses.
Influenza A viruses can include any one of the 16 known subtypes of HA proteins, which fall into two groups, Group 1 and Group 2. Their monoclonal antibodies neutralized all testable viruses containing the 10 Group 1 HAs—which include the seasonal H1 viruses, the H1 virus that caused the 1918 pandemic and the highly pathogenic avian H5 subtypes—but none of the viruses containing the six Group 2 HAs.
Simultaneously, Dr. Marasco’s group teamed up with Robert C. Liddington, Ph.D., professor and chair of the Infectious and Inflammatory Disease Center at Burnham, to determine the atomic structure of one of their monoclonal antibodies bound to the H5N1 HA. Their detailed picture shows one arm of the antibody inserted into a genetically stable pocket in the neck of the HA protein, an interaction that blocks the shape change required for membrane fusion and virus entry into the cell.
When they surveyed more than 6,000 available HA genetic sequences of the 16 HA subtypes, they found the pockets to be very similar within each Group but to be significantly different between the two Groups. The genetically stable pockets, they note, may be a result of evolutionary constraints that enable virus-cell fusion. This could also explain why they did not detect so-called escape mutants, viruses that elude the monoclonal antibodies through genetic mutation.
“One of the most remarkable findings of our work is that we identified a highly conserved region in the neck of the influenza hemagglutinin protein to which humans rarely make antibodies,” says Dr. Marasco. “We believe this is because the head of the hemagglutinin protein acts as a decoy by constantly undergoing mutation and thereby attracting the immune system to produce antibodies against it rather than against the pocket in the neck of the protein.”
Their findings could also assist vaccine developers. Current influenza vaccines target the constantly mutating head of the HA protein and do not readily generate antibodies against the conserved region in the neck.
The monoclonal antibodies identified in their paper are very well-characterized, Dr. Marasco notes, and he is optimistic about their further clinical development. “These are fully human monoclonal antibodies that are ready for advanced preclinical testing,” he says. He currently is arranging to use NIAID research resources to take the next steps: first, testing the antibodies in ferrets, the gold standard animal model for influenza, and then developing a clinical grade version of one antibody that could enter human clinical trials as soon as 18 months from when the development program begins. Should the antibodies prove safe and effective in humans, it could take several years to develop a licensed product.
NIH press release: Scientists Identify Lab-Made Proteins That Neutralize Multiple Strains of Seasonal and Pandemic Flu Viruses …
Image: Ribbon diagram of the influenza virus H5 hemagglutinin (HA) surface protein bound by the F10 monoclonal antibody (red). The two chains of H5 are HA1 (yellow) and HA2 (blue). (Credit: William Hwang and Jianhu Su, Dana-Farber Cancer Institute)
