AsianScientist (Jul. 24, 2015) – Researchers have isolated an antibody that effectively neutralizes all group 2 and some group 1 influenza viruses, publishing their results in Nature Communications. The crystal structure of the antibody, revealing its epitope binding pattern, could lead to the design of better influenza vaccines.
Although yearly vaccination is able to reduce mortality from seasonal influenza, there remains the risk of mutations giving rise to pandemic influenza outbreaks. In such cases, antiviral drugs such as Tamiflu are often the first line of defence. However, the effectiveness of antivirals has been reduced due to the emergence of resistance. Alternative treatments such as therapeutic antibodies are being developed, but have been hampered by the high variability of influenza epitopes and are difficult to scale-up quickly.
In the present study, led by Professor George Gao from Chinese Center for Disease Control and Prevention, researchers studied the serum of patients who had recovered from an influenza A infection, searching for antibodies that could neutralize many different strains.
“Ideally, we’d like to isolate a natural antibody from the human host, which would the advantage of being readily used in humans,” Gao told Asian Scientist Magazine.
“You can usually isolate a lot of antibodies from a single patient but they often do not cross-react with different strains or different subtypes of flu viruses. This is because immune dominance that means the antibodies produced would dominantly recognize certain ‘fixed’ epitopes and usually would not cross-react with different viruses.”
Working together with the biopharmaceutical company Celltrion, Gao and colleagues isolated an antibody named CT149 from the B cells of patients who had been infected with the 2009 H1N1 pandemic strain. They found that it was cross-reactive with many different influenza subtypes, including H3, H5 and H7, working especially well against H7N9 viruses from China.
The team then went on to solve the crystal structure of CT149, in complex with both H3 and H7 influenza viruses. The crystal structures revealed that CT149 recognized residues in the stem region of hemagglutinin, with both the heavy and light chain of the antibody binding to different regions of the molecule.
“CT149 works through binding to two monomers of hemagglutinin, which is embedded on the surface of virus as a trimer. This cross-linking of the two monomers prevents the hemagglutinin from changing its conformations, an important step for virus fusion and entry,” Gao explained.
“This is the novelty of our paper—we have made the mechanism crystal-clear,” he added.
Mice treated with CT149 either before or after infection with influenza viruses were protected against lethal doses of the virus, showing the protective ability of the antibody in vivo.
“Celltrion has already started their clinical trials with CT149. I believe this is a very good candidate antibody for cross-protection against many different viruses,” Gao said.
The article can be found at: Wu et al. (2015) A Potent Broad-Spectrum Protective Human Monoclonal Antibody Crosslinking Two Haemagglutinin Monomers of Influenza A Virus.
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Copyright: Asian Scientist Magazine; Photo: George Gao.
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