Measles needs only a two-dose vaccine during childhood for lifelong immunity while the influenza virus mutates constantly and requires a yearly shot to get even a certain percentage of protection.

What explains that? Surface proteins that the measles virus uses to enter cells are ineffective if they suffer any mutation, meaning that any changes to the virus come at a major cost, according to a new paper.

The researchers used a high-throughput approach to mutate all of the genes in a virus in one experiment -- a useful way to understand the future of viral evolution. They inserted mutations across the measles genome and looked to see whether the viruses were still capable of infection. They found that measles could not tolerate any mutations to the proteins that are recognized by the human immune system, making it very unlike influenza.

"We didn't know what we were going to see when we started," says senior study author Nicholas Heaton, a microbiologist at the Icahn School of Medicine at Mount Sinai, New York. "The almost complete lack of tolerance to insertional mutation of the measles proteins was surprising. We thought that they may be less tolerant than the influenza proteins, but we were surprised by the magnitude of the difference."

It's only possible to speculate why the measles virus would find an evolutionary advantage to being so rigid, but one hypothesis is that measles uses a more complex strategy to get into human cells than influenza. Influenza, for instance, simply requires the binding of one of the sugars that decorate the outside of cells as a means of getting inside. In contrast, measles requires binding to specific cellular protein receptors as its doorway.

"There are many potential explanations for why measles virus proteins can't tolerate insertional mutations, from changing protein stability to changing the structure or function of the proteins," Heaton says. "If we can better understand why flexibility or rigidity is imposed at a molecular level, we may be able to understand more about why we see different dynamics of viral evolution."

Citation: Fulton et al. "Mutational analysis of measles virus suggests constraints on antigenic variation of the glycoproteins" Cell Reports DOI:10.1016​j.celrep.2015.04.054. Funded by the National Institutes of Health.