In the early 2000s, Andrew Read predicted that non-sterilizing vaccines would lead to more virulent disease. He was able to test his hypothesis with the real-world example of Marek’s disease, a disease of chickens. Read tells the story of his discovery, and talks about his work on myxoma virus.
Julie’s Biggest Takeaways:
Every chicken on the market is vaccinated against Marek’s disease. Infection with Marek’s disease causes tumors on the bird and can lead to direct death, or condemnation of a flock requiring their culling. Birds are vaccinated with a live, attenuated virus, and there have been 3 vaccine iterations. The first used a related herpesvirus isolated from turkeys, while the second vaccine added a second virus strain. Each of these vaccines conferred protection for about 10 years, after which the disease began popping up again. The 3rd generation vaccine added yet another serotype - this additional strain is a mutant strain of the chicken-infecting serotype - and has been effectively protecting chickens since the 1990s.
Chickens do not get sterilizing immunity from the Marek’s disease vaccine; they can be infected by the wild-type virus, but the vaccine prevents infected animals from having disease symptoms. These asymptomatically infected animals can still shed the virus. Contrast this to human immunity from many of our vaccines, such as measles or smallpox vaccines, in which our immune response stops the virus from entering our cells and therefore blocks virus replication.
Vaccination inhibits strains with lower virulence more than strains with higher virulence. This fact, combined with asymptomatic infection, means that although the infected birds don’t show disease symptoms, they are more likely to be shedding more virulent (or ‘hot’) strains. This generates selection for these hot strains that wouldn’t normally be successful. Without vaccination, host strains kill the host too quickly to allow viral replication and transmission to occur; Vaccines allow these hot strains to propagate.
Vaccine resistance is much more rare than antibiotic or antimicrobial resistance. This is due to a number of factors, including the diversity of microbial population being acted upon (small with initial infection, large when treated with antimicrobial drugs). Vaccines are much more evolution-proof for these reasons.
Purposeful release of myxoma virus during the 1950s in Australia killed between 10 and 100 million animals, or 99.9% of the rabbit population. Frank Fenner followed the virus and surviving rabbit populations and discovered that myxoma viruses that were too virulent were less likely to be transmitted, because they killed the host too quickly. He also showed that the small surviving number of rabbits were more resistant to viral infection. The arms race between the two has generated a virus so immunosuppressive that Read’s group has found the currently circulating myxoma virus has changed the way it kills its host: the virus disables the rabbit immune system and allows the rabbit’s own microbiome to cause invasive bacterial disease.
“The initial vaccine was actually quite a triumph, because there were huge losses going on in the industry. Some people have cited 4-10% of broiler chickens weren’t making it into the food chain, and so very large amounts of money were involved. Very quickly, these vaccines were found and rolled out across the U.S. and Europe, and the problem was solved for about a decade or so, until the disease started to come back.”
“The Marek’s disease vaccine is a very good anti-disease vaccine, but in terms of the virus, it’s a leaky vaccine; it lets the virus get through to the host.”
“Marek’s disease vaccination allowed super hot strains to spread in ways that would not be possible otherwise.”
“I don’t think this has relevance to classic childhood vaccines, because they’re all sterilizing. The issue is with non-sterilizing vaccines, and we’re now in an era of nonsterilizing vaccines: there are non-sterilizing malaria vaccines, non-sterilizing typhoid fever vaccines, changes in the whooping cough vaccine length of immunity. The question in my head is what can Marek’s disease vaccination tell us about vaccinating humans with vaccines that are nonsterilizing?”
“When pathogens jump species boundaries, what happens next? This is an important question in both agriculture and human disease.”
Links for This Episode:
- Andrew Read lab at Penn State University
- Nature article: Imperfect Vaccines and the Evolution of Pathogen Virulence
- Nature news item on imperfect vaccines
- FEMS Microbiology Reviews: Adventures with poxviruses of vertebrates
- MTM Listener Survey
History of Microbiology tidbit:
Isn’t it great when a guest naturally introduces the topic for a history of microbiology tidbit? This happens so often in our interviews, since microbiology has really been building on generations of discoveries and many of our guests are quick to acknowledge the contributions of previous scientists.
The story of the myxoma virus and rabbits in Australia that Andrew Read told during the interview rang a bell but I’ll admit the name Frank Fenner was not one I was familiar with. In today’s History of Microbiology tidbit, I want to highlight Frank Fenner’s place in microbiology.
Fenner was born in 1914 in Australia, where he was educated and lived most of his life. He trained as a medical doctor and surgeon and joined the Australian Army Medical Corps during the second war, fighting malaria in Papua New Guinea. After the war, he returned to Australia to work with Frank Burnet, himself no microbiology slouch - Burnet won the nobel prize in 1960 for work on acquired immune tolerance and developed the system for growing influenza in hen’s eggs which is still used today to produce most of the influenza vaccine strains.
Once establishing his own lab at Australian National University, Fenner studied a number of subjects, among them using the myxoma virus as a means to control the invasive rabbit population. Biological control of this invasive pest with infectious agents had been studied for decades, even by Louis Pasteur, who had suggested using the bacterium we now call Pasteurella multocida, though this had proved unsuccessful. Fenner collected myxoma virus strains from South America and studied their virulence in lab-raised rabbits before the virus was eventually released and Fenner followed virus and host evolution as Andrew described. But in addition to his work in on myxoma virus, Fenner played an important role in the Smallpox Eradication Campaign with the World Health Organization.
He worked with D.A. Anderson, the scientist overseeing the eradication campaign, evaluating mpox (formerly called monkeypox) and other poxlike diseases to determine if these would affect the success of the campaign. Fenner was the scientist who proclaimed to the World Health Assembly in Geneva that “The world and its peoples have won freedom from smallpox” in May 1980, signifying one of humanity’s greatest achievements in the fight against infectious disease. Fenner passed away in 2010, but wrote a summary of some of his work in FEMS Microbiology Reviews.