If you become infected with the flu after getting vaccinated, your body activates an immune response that stops you from becoming ill. Although, this can trigger the virus to change into a slightly different form - one that may be more infectious.

A novel investigation from MIT reveals the mechanism responsible for this phenomenon, known as antigenic drift. The study was funded by the National Institutes of Health and the Singapore-MIT Alliance for Research and Technology and appears in the December 19 online edition of Scientific Reports, an open-access journal published by Nature.

The chain of amino acids that create viral protein hemagglutinin was examined by the researchers, led by Ram Sasisekharan. The team identified which amino acids are most likely to encounter mutations that enhance the virus' ability to infect novel hosts.

"This knowledge could help flu-vaccine designers produce vaccines that don't induce the evolution of fitter viruses", explained Sasisekharan, The Edward Hood Taplin Professor of Health Sciences and Technology and Biological Engineering at MIT, director of the Harvard-MIT Division of Health Sciences and Technology and senior author of the report.

As novel strains of influenza arise constantly throughout the world, the World Health Organization finds novel strains that should be included in the seasonal influenza vaccine, which is reformulated each year.

Influenza vaccines provoke creation of antibodies that target a part of the hemagglutinin (HA) protein known as the antigenic site. In 2009, Sasisekharan and investigators at the National Institute of Allergy and Infectious Diseases (NIAID) revealed that viruses can evolve into a slightly changed strain when it comes across such antibodies. This novel strain can then spread to non-vaccinated individuals.

Some novel strains are more infectious because they attach stronger to receptors found on the surfaces of cells in the respiratory tract of potential flu victims. This discovery baffled investigators as the antigenic site, where the mutations took place, is a long way from the HA site where the receptor attachment occurs.

The team decided to solve the mystery by examining the interactions between the amino acids that create viral hemagglutinin.

Like all proteins, HA is constructed by a long network of amino acids. These networks mutate into complex structures determined by the interactions between amino acids. The researchers used a method called network analysis in order to analyze how each amino acid interacts with every other amino acid in the protein, which is determined by electric charges as well we additional properties of atoms within the amino acids.

The resulting model provided data on how powerfully each amino acid is connected to other amino acids in the protein. Focusing on amino acids in the antigenic site, the team discovered that the more strongly they were connected to amino acids in the receptor-binding region, the more likely the amino acids were to change receptor-binding affinity upon mutating. In addition they found that amino acids that were weakly connected in the antigen region did not change receptor-binding upon mutation. These findings offer new insight into the mechanism of how selection pressure as a result of vaccination could contribute to the virus evolving into a more infectious strain by generating better-binding HA proteins.

According to the previous MIT/NIAID investigation the more individuals that get vaccinated, the less chance these novel mutations have to spread through the population. Sasisekharan explains:

"Incomplete vaccination could be causing a lot of these problems and therefore effective vaccinations are key to limiting drift.

Now that there is a way to predict which amino acids are most likely to mutate into a more infectious form, vaccine designers could create vaccines that don't provoke such mutations. This understanding of the relationship between the antigenic site and the receptor-binding site could be added to the current methods of vaccine selection and vaccine designs to limit drift."

Further examinations of circulating influenza HA sequences can possibly speed up and assist in the design of ideal vaccines for each flu season.

Written by Grace Rattue