The first successful vaccines, like Jenner's smallpox vaccine and the first Salk vaccine against polio, were based on viruses that do not cause illness or severe symptoms. Vaccine development has since shifted largely to the use of proteins that are used by the disease-causing agents, but there are still some cases where a dead or attenuated virus is the most effective method of generating immunity.

The use of viruses for vaccines, however, has always come with a bit of a concern. When it comes to viruses, one-in-a-million events happen all the time, and evolution gives any viruses used in vaccines a lot to work with: many related viruses in the wild, and animal genomes that are littered with pieces of former viruses. Now, researchers have discovered a case where two different agricultural vaccines have recombined to create a new, virulent strain of the disease they were intended to prevent.

In poultry, a form of herpesvirus (gallid herpesvirus 1) causes a respiratory disease that is sometimes fatal; even if it doesn't kill the animals, it causes a reduced egg production. As a result, several vaccines have been developed against the virus responsible, based on attenuated forms that do not cause serious illness. Three of these vaccines are approved for use in Australia: two based on viral strains that are present in Australia, and a third developed against a strain common in Europe.

As these vaccines were introduced to the Australian poultry population, two previously unidentified viral strains (class 8 and 9) emerged. The timing of their appearance and some initial genetic characterization suggested they were relatives of the attenuated European virus used in the vaccine. A group of researchers isolated samples of the virus and subjected them to whole-genome sequencing in order to determine their origin.

As expected, large portions of the genome were closely related to the attenuated European virus used as a vaccine. But for the class 8 virus, a small portion of the European DNA had been replaced by recombination with another virus. That other virus appeared to be most closely related to the Australian strains used in the other vaccine. A similar thing was found in the genome of the class 9 virus, where an even larger portion of Australian viruses had recombined into the European backbone. The viruses had picked up additional base changes throughout the genomes, but the majority of the sequence appears to be derived from strains used in vaccines.

To confirm that these viruses had really changed sufficiently to cause disease, the authors cultured them in disease-free chickens. Both recombined viruses (class 8 and 9) had either significantly increased virulence or replicated much more efficiently than the parental strains used in vaccines.

The risks created by the use of related attenuated viruses are well understood both on the level of molecular biology and in terms of evolutionary principles. But the clear demonstration that the risk has become a reality makes this finding an important caution. "The findings from this study raise concerns about the use of multiple distinct attenuated herpesvirus vaccines under conditions that favor recombination," the authors conclude. "These findings have implications for the use of herpesviruses, and possibly other DNA viruses, as attenuated vaccines or vaccine vectors."

Science, 2012. DOI: 10.1126/science.1217134 (About DOIs).