We’re on the brink of wiping out polio, but the virus used in vaccines keeps evolving to become harmful again. The discovery of how the virus mutates to do this could lead to a safer vaccine.
Polio once killed hundreds of thousands of children every year. The disease has largely been brought under control by the oral polio vaccine, which contains a weakened form of the live poliovirus. We do have a vaccine that uses dead virus instead, but this is less effective at spreading immunity. When the weakened live vaccine reaches the intestine, the virus replicates and can be passed on to others in close contact, transmitting immunity to people who haven’t been vaccinated.
It’s an effective way of wiping out polio, but it carries a risk. From time to time, the weakened virus re-evolves the ability to cause disease, and spreads rapidly through unvaccinated populations. In the 10 years leading up to 2015, there were around 750 reported cases of paralysis caused by vaccine-derived poliovirus (VDPV) worldwide.
A new vaccine in development may put a stop to this. Raul Andino and colleagues at the University of California, San Francisco, have analysed the genes of 424 samples of VDPV from 30 different outbreaks, and compared them with the genetic makeup of the vaccine. They found that in every case, the weakened vaccine virus had undergone the same three evolutionary steps to become virulent again.
The first step was to acquire mutations that enabled the virus to make proteins more easily, opening up the possibility for further evolution. Next, the poliovirus swapped genes with other viruses in the human gut that are better adapted to replicating there. “The virus doesn’t bother to create its own solutions, it steals them from other viruses,” says Andino.
Finally, the virus undergoes a few more mutations before becoming virulent. These mutations don’t alter the amino acids in the protein they encode. How exactly these “silent” mutations increase the virus’s fitness is unclear, but they seem to be more important than we realised, says Andino.
The whole process involves only around seven or eight mutations. Once they had identified these key steps, the researchers recreated the same mutations in the lab, and found that they made the vaccine virus replicate much more efficiently, and it was more deadly when tested on mice.
Using this knowledge, Andino’s team have designed a live virus vaccine that should have a lower risk of re-evolving virulence. By increasing the accuracy of how the virus replicates, they have reduced the likelihood of it acquiring the necessary mutations to become harmful again, and have also made it less able to swap genes with other viruses. “What we’re trying to do is put the virus in an evolutionary cage so it can’t evolve further,” says Andino.
Close to eradication
The team is hoping to begin a small clinical trial of this new vaccine in May. “This is exciting science,” says Roland Sutter, who works on polio eradication at the World Health Organization.
However, with worldwide eradication already in sight, a safer live vaccine may not actually be necessary. Once polio has stopped spreading, the WHO plans to switch completely to the dead virus vaccine to protect children.
Andino hopes the live vaccine already in use will be enough for the WHO to reach this stage, but he thinks we should be prepared in case the disease makes a comeback. Many times in the last 20 years, we have come close to wiping out polio, but the last step has proved to be a challenge, in part because political issues in its remaining footholds in Afghanistan, Pakistan and Nigeria have made it difficult for vaccination campaigns to operate.
The approach his team have used to understand the virus’s evolutionary pathway could also be applied to develop safer vaccines for other diseases, says Andino. “Live attenuated vaccines are the best, but nobody’s been thinking about them from an evolutionary perspective.”
Journal reference: Cell, DOI: 10.1016/j.cell.2017.03.013