The very vaccines used to prevent a respiratory disease in chickens caused several recent outbreaks of the same disease at farms across Australia, according to a report published today (July 12) in Science. Different weakened versions of a live herpes virus used in the vaccines exchanged portions of their genomes, resulting in virulent, disease-causing strains. This suggests that such in-the-field genetic recombination is more common than previously thought, and has implications for both animal and human health.
“I think that we completely underestimate the role of recombination in [vaccine] viruses,” said veterinary virologist Etienne Thiry of the University of Liège in Belgium, who was not involved in the work. “All RNA and DNA viruses do recombine to different extents,” he said. In fact, recombination, also known as reassortment, was part of the method used by one of the two groups that recently succeeded in making the H5N1 bird flu virus transmissible between ferrets in a laboratory setting.
But while researchers were well aware that viruses could recombine, “we didn’t really think that recombination could be a problem in the field,” said Joanne Devlin, a veterinary scientist at the University of Melbourne who led the study. “We should probably reassess that risk.”
Prior to 2006, two closely related vaccines had been used to prevent infectious laryngotracheitis virus (ILTV) from spreading among chickens in Australia. This herpes virus causes mild or severe respiratory disease that can lead to reduced egg production in poultry, and sometimes death, resulting in substantial economic losses for farmers. In 2006, a third European ILTV vaccine, less similar to the other two, was introduced and, within a few years, outbreaks of the disease started to occur, in some instances killing nearly 18 percent of the birds.
Devlin and her team isolated viruses from infected chickens and found that they were similar to the European vaccine strain. They presumed that the weakened virus had somehow mutated into virulent forms. However, whole genome sequencing of the three vaccines and the disease-associated strains revealed that the European vaccine virus had recombined with one or both of the Australian vaccine viruses, generating new, more dangerous strains.
Although recombination of herpes virus strains can occur readily in the laboratory, for it to occur in the field, Devlin said, two separate strains would have to infect one cell in the same animal at the same time. “It was thought that just wouldn’t occur or would be so unlikely as to be not worth worrying about,” she said.
Other herpes experts were less surprised. “The idea of creating virulent viruses by mutation or recombination of genes from avirulent ancestors is certainly not a new one,” said Jim MacLachlan, professor of veterinary medicine at the University of California, Davis. “Concerns have previously been raised about the genetic roulette associated with live attenuated virus vaccines. In particular, extensive use of such vaccines in intensively housed livestock creates an environment where novel virus strains rapidly can emerge.”
It is thought that the two Australian vaccine viruses had not given rise to virulent strains before because they are genetically almost identical—one was derived from the other, explained Devlin. The European vaccine virus, on the other hand, had been weakened by a different method meaning it could gain functional copies of the genes it lacked, or that were mutated, from the Australian versions and revert to a virulent form.
Although the findings highlight precautions that need to be considered for human and animal vaccination strategies—particularly, that the use of a single version of weakened virus might be safest—they do not suggest that live attenuated virus vaccines are inherently unsafe, said Nick Davis-Poynter a medical virologist at the University of Queensland in Australia who was not involved in the study. “Live attenuated vaccines for humans have resulted in tremendous public health benefits combating devastating diseases such as smallpox, yellow fever, measles and polio,” he said.
Indeed, many of the flocks that succumbed to disease outbreaks were not vaccinated due to vaccine shortages, said Devlin. Others were insufficiently vaccinated—given low doses—or may have contained unvaccinated animals due to the nature of the vaccination method: the vaccine is provided in the drinking water and thus may not reach every animal.
Although vaccinated animals can get infected with such virulent recombinant strains, Devlin explained, the disease symptoms are generally much less severe. “[It is] similar to when you get the flu vaccine,” she said. “You can still get the flu but you generally don’t get as sick.”
MacLachlan added, “I personally worry that any negative press might be used to justify not vaccinating children, which is precisely the wrong thing to do.”
S-W. Lee et al., “Attenuated Vaccines Can Recombine to Form Virulent Field Viruses,” Science, doi: 10.1126/science.1217134, 2012.