Epidemics caused by RNA viruses cause millions of infections each year, and billions of euros in economic loss. In the last decade alone several human and animal viruses have swept through large geographical regions: MERS coronavirus, Ebola, dengue, chikungunya, Zika, West Nile, human enterovirus 71, Foot and Mouth Disease, Bovine viral diarrhea virus, avian influenza. For RNA viruses, vaccines are the only effective means of reducing morbidity and mortality; but exist for only a handful of diseases. The molecular determinants of attenuation of live virus vaccines are specific to a virus strain and cannot be applied across virus families, nor can they be predicted or rationally determined. Furthermore, while they are the most effective form, conventional attenuation readily reverts to pathogenic forms (e.g. oral poliovirus vaccines). The genetic diversity of RNA viruses result from the extreme error rates of viral replication machinery that copy their genomes (low replication fidelity), up to 1 million times higher than other life forms with DNA genomes. For this reason, and given their large population sizes (millions to billions per infection), every possible mutation is generated in just a few replication cycles. From this cloud of potentially beneficial mutations, emerges the resistance to antivirals and the antigenic drift that requires frequent update of vaccine strains. This is their strength. But it is also their Achiles’ heel. While some mutations help the virus, there is a tremendous cost of low replication fidelity.
We sought to develop a new way to attenuate RNA viruses, by increasing their chances of making fatal errors that would result in 'killing' their progeny viruses. Thus, we produced live attenuated vaccine strains of Coxsackie and influenza viruses that appear normal, but once they start to replicate, they lose infectivity. The benefit of this approach is that the immune system sees a normal virus, but it clears it more easily because the viruses falls prey to its own mutation rate. Our results show that most (or probably all) RNA viruses can be attenuated by using this method. The potential impact of this research is that new vaccines could be made for many viruses for which more conventional approaches have not been successful.
