Researchers Uncover How Human Immunity Evades Influenza Virus

A new study that looked at how the influenza (flu) virus escapes antibodies found the site of the escape mutation varies among most individuals’ sera. As part of the study, Juhye Lee, a former PhD student of Jesse Bloom, PhD, a biochemist at the Fred Hutchinson Cancer Research Center in Seattle, Wash., designed a means of examining which mutations help the viruses overcome immunity and infect cells. Dr. Lee used polymerase chain reaction to make approximately 10,000 different mutations to the amino acid building blocks of the HA protein in a strain of the H3N2 virus that was isolated from a human in 2009. The mutant viruses were exposed to different concentrations of antibody-rich blood serum of four individuals ranging in age from 21 years to 65 years. They then infected canine kidney cells with the viruses-antibody mixtures and used high-throughput sequencing to determine which mutant viruses were able to replicate in the presence of serum antibodies.

Findings showed that in the serum of subjects aged 21 years and 65 years, viruses with a mutation at site F193D on the HA protein could replicate. In the serum of the 64-year-old, viruses with a mutation at site F159G were able to replicate. In all three sera, the single mutations reduced immunity by 10-fold, meaning 10 times more antibodies were needed to stop the viruses from infecting cells compared to that required by the original nonmutated virus. In a subject aged 53 years, a single mutation at site L157D reduced immunity by five times.

According to the researchers, these findings show human immunity is focused and may come from just one or a few antibodies that target a specific region of the virus protein. It also demonstrates one mutation is capable of helping the virus evade antibodies in one person but not in another, said Dr. Bloom, co-author of the study’s paper. “Despite the fact that our immune system can potentially make antibodies that target all over the viral protein, the results show that human immunity is instead very focused on just one part of the protein,” he says. “Mutations that are strongly selected by one person’s serum often aren’t selected by another person’s serum.”

This variation in the ability of mutations to escape immunity could boil down to people’s histories of flu strain infection. To see if the variations persist, the team is now repeating its experiments with the blood serum of young children who have had a single influenza infection with hopes the findings from both studies can help researchers develop better targeted vaccines against influenza.