April 2017

In the 1940s and 50s, the polio virus, which mainly affects young children, crippled 35,000 Americans each year. Today, thanks to vaccinations, the disease has been completely eradicated from the United States — and from most of the world’s countries. In 2015, there were just 74 confirmed cases of polio on the entire planet. The virus lives on due to incomplete vaccination, particularly in countries where vaccination efforts have been hindered by poverty and strife. Now new research provides clues about how to prevent some of these rare outbreaks, getting us ever closer to a polio-free world.

Where's the evolution?

Modern polio outbreaks stem either from a wild polio strain that has been circulating from victim to victim, or from a polio strain that evolved from one of our vaccines. “Why would we use a vaccine that could evolve into a dangerous form?” one might wonder. The answer is that the vaccine saves vastly more lives than it threatens. Before a vaccine was developed, polio infected half a million children every year. Today, we are down to a handful of cases. That reduction is entirely due to the vaccine — and to the organizations, doctors, and parents who saw to it that kids were vaccinated. Now researchers are working on preventing those last few cases of polio, and that means studying the vaccine virus and how it evolves.

Two types of polio vaccine are used today: a dead virus (which can’t ever evolve into a dangerous form and is given as a series of shots) and a weakened live virus (which, on very rare occasions, can evolve into a virulent strain and is given as oral droplets). Beyond being easier to administer, the live vaccine has several advantages over the dead vaccine: it is cheaper, requires only one dose for lifetime immunity, and if spread to others (for example, through poor sanitation, the same route of transmission used by the dangerous wild virus), can provide immunity to other people in the community who didn’t receive the vaccine themselves. In the United States, where the chance of being exposed to polio is extremely low, children receive a vaccine containing the non-evolving, dead virus. However, because of the oral vaccine’s advantages, it is generally used in poorer countries where polio is more common, more people are unvaccinated, and vaccinations are administered through large campaigns. In these areas, using the live virus saves many more lives than it threatens.

Of course, with a live virus, as with any living thing, evolution is always a possibility. And in the case of the oral polio vaccine, this evolution threatens human health. In the last 17 years, this has led to at least 24 outbreaks of polio. (That might sound like a lot, but remember that before the vaccine was available, polio affected hundreds of thousands of kids each year.) So what has to happen for a life-saving vaccine to evolve into a dangerous pathogen? When someone receives the live, oral polio vaccine, the virus copies itself within his or her gut, just as a wild polio virus would. However, instead of making the person sick, the weakened virus merely causes an immune response, making the host immune to future infection by the crippling wild virus. The vaccine strain is now present in the person’s feces. If others in the community are not vaccinated, they may pick up this strain and pass it on to others. Usually, this transmission causes no problems — and in fact, has the benefit of immunizing anyone infected against wild polio strains. The vaccine strain is designed to be a poor reproducer (i.e., have low evolutionary fitness) in human hosts; that’s why the vaccine is as safe as it is. However, over time, if the virus is transmitted, the processes of random mutation and natural selection act, favoring viral strains that are better able to reproduce and, hence, more likely to cause disease. In some cases, through these processes, the life-saving vaccine strain evolves into a viral strain that can once again cause illness, paralysis, and even death.

Last month, a team of researchers from the U.S., U.K., and Israel announced a surprising result after decoding and analyzing the genomes of virus samples from different vaccine-derived polio outbreaks: the evolution of the virus nearly always occurred in the same way. First, natural selection favored three specific “gatekeeper” mutations that allowed the virus to copy itself more easily. Viral strains carrying these mutations quickly outcompeted others. Then those viral strains swapped genetic material with other non-polio viruses naturally living in the human gut. Then came other, less important genetic changes that seemed to have the effect of “fine tuning” the virus for human infection. Sorting through the data, the researchers saw these same three steps happen over and over again: three gatekeeper mutations, genetic swapping, then fine tuning. In fact, the gatekeeper mutations were so predictable that they were even observed occurring in viral strains in the lab!

This might make it sound like the virus is trying to evolve or like mutation isn’t random: after all, how else could evolution repeat itself so precisely in so many different outbreaks?  But of course, a virus can’t try to evolve and mutation is random. The key to understanding how all these identical evolutionary trajectories came about is to remember that viruses (and particularly the polio virus) have a high mutation rate and pick up genetic material easily. This provides a treasure trove of genetic variation for natural selection to act upon. Amidst all that genetic variation, natural selection for higher replication and transmission rates merely picked out the same winning genetic combination again and again.

This predictability could be the key to preventing vaccine-derived polio outbreaks, as we work to fully eradicate the disease. To get rid of polio once and for all, we need more complete immunization in a few regions of the world, and that is most likely to happen using the live virus vaccine. But the live virus carries the risk of evolving into a dangerous form. Identifying the three gatekeeper mutations that consistently represent the first steps of this evolutionary path to virulence prompted the researchers to design a vaccine virus in which these mutations were much less likely to occur. The new “evolution-resistant” vaccine strain is now approaching clinical trials to check its safety and efficacy. Researchers hope that the new virus will be just as effective at preventing polio as the current live vaccine, but with a much lower risk of evolving virulence.  Check back here for updates on the progress of this exciting research!