Some Vaccines Support Evolution of More-Virulent Viruses

Some Vaccines Support Evolution of More-Virulent Viruses

https://science.psu.edu/news/some-vaccines-support-evolution-more-virulent-viruses

26 July 2015

Scientific experiments with the herpesvirus that causes Marek's disease in poultry have confirmed, for the first time, the highly controversial theory that some vaccines could allow more-virulent versions of a virus to survive, putting unvaccinated individuals at greater risk of severe illness. The research has important implications for food-chain security and food-chain economics, as well as for other diseases that affect humans and agricultural animals.

"The challenge for the future is to identify other vaccines that also might allow more-virulent versions of a virus to survive and possibly to become even more harmful," said Andrew Read, a leader of the research team whose paper describing the research will be published in the July 27, 2015 issue of the scientific journal PLoS Biology. Read is the Evan Pugh Professor of Biology and Entomology and Eberly Professor in Biotechnology at Penn State University.

"When a vaccine works perfectly, as do the childhood vaccines for smallpox, polio, mumps, rubella, and measles, it prevents vaccinated individuals from being sickened by the disease, and it also prevents them from transmitting the virus to others," Read said. These vaccines are a type that is "perfect" because they are designed to mimic the perfect immunity that humans naturally develop after having survived one of these diseases. "Our research demonstrates that another vaccine type allows extremely virulent forms of a virus to survive -- like the one for Marek's disease in poultry, against which the poultry industry is heavily reliant on vaccination for disease control," said Venugopal Nair, who led the research team in the United Kingdom where the experimental work related to this study was carried out. Nair is the head of the Avian Viral Diseases program at the Pirbright Institute, which also hosts the OIE Reference Laboratory on Marek's disease. "These vaccines also allow the virulent virus to continue evolving precisely because they allow the vaccinated individuals, and therefore themselves, to survive, Nair said.

Less-than-perfect vaccines create a 'leaky' barrier against the virus, so vaccinated individuals sometimes do get sick, but typically with less-virulent symptoms. Because the vaccinated individuals survive long enough to transmit the virus to others, the virus also is able to survive and to spread throughout a population. "In our tests of the leaky Marek's-disease virus in groups of vaccinated and unvaccinated chickens, the unvaccinated died while those that were vaccinated survived and transmitted the virus to other birds left in contact with them," Nair said. "Our research demonstrates that the use of leaky vaccines can promote the evolution of nastier 'hot' viral strains that put unvaccinated individuals at greater risk."

The theory tested by the research team was highly controversial when it first was proposed over a decade ago. The team's experiments now show, for the first time, that the modern leaky vaccines, widely used in the agricultural production of poultry, can have precisely the effect on evolution of more-virulent strains of the virus that the controversial theory predicted.

Marek's disease used to be a minor disease that did not do much harm to chickens in the 1950s, but the virulence of the virus has evolved and today it even is capable of killing all the unvaccinated birds in poultry flocks, sometimes within 10 days. "Even though the Marek's disease virus is much nastier now than it was in the 1950s, it is becoming increasingly rare and now it causes relatively minor problems in the poultry industry because almost every chicken in agricultural production worldwide is vaccinated against the disease," Read said. If you can vaccinate all the individuals in a population against a virus, it does not matter if the virus has become super virulent so long as the vaccine continues to be effective."

The virus for Marek's disease is very virulent, but the virus causing avian influenza can be even worse. "The most-virulent strain of avian influenza now decimating poultry flocks worldwide can kill unvaccinated birds in just under three days," Read said. The vaccine against avian influenza is a leaky vaccine, according to Read. "In the United States and Europe, the birds that get avian influenza are culled, so no further evolution of the virus is possible," Read said. "But instead of controlling the disease by culling infected birds, farmers in Southeast Asia use vaccines that leak -- so evolution of the avian influenza virus toward greater virulence could happen."

The research has implications for human health, as well. The World Health Organization recently reported laboratory-confirmed cases in China of human infection with the avian influenza virus, including a number of deaths. "We humans never have experienced any contagious disease that kills as many unvaccinated hosts as these poultry viruses can, but we now are entering an era when we are starting to develop next-generation vaccines that are leaky because they are for diseases that do not do a good job of producing strong natural immunity -- diseases like HIV and malaria," Read said.

"Vaccines for human diseases are the least-expensive, most-effective public-health interventions we ever have had," Read said. "But the concern now is about the next-generation vaccines. If the next-generation vaccines are leaky, they could drive the evolution of more-virulent strains of the virus." He said it is critical now to determine as quickly as possible that the Ebola vaccines that now are in clinical trials are not leaky -- that they completely prevent the transmission of the Ebola virus among people. "We do not want the evolution of viral diseases as deadly as Ebola evolving in the direction that our research has demonstrated is possible with less-than-perfect, leaky vaccines," Read said.

The researchers recommend rigorous testing and vigilant monitoring of next-generation vaccines to prevent the runaway evolution of more-virulent strains of viruses that their research has confirmed can occur with leaky vaccines. "If some day we have a malaria vaccine or an HIV vaccine, of course we should use those vaccines, but we would be in significant danger if those vaccines turned out to be leaky and we had not developed effective ways to eradicate any strains that might become more virulent," Read said.

Read also recommends vaccination for individual protection. "When evolution toward more-virulent virus strains takes place as a result of vaccination practices, it is the unvaccinated individuals who are at the greatest risk. Those who are not vaccinated will be exposed, without any protection, to the hottest strains of a virus. Our research provides strong evidence for the importance of getting vaccinated."

In addition to Read, other members of the research team include Susan J. Baigent, Claire Powers, Lynda B. Kgosana, Luke Blackwell, Lorraine P. Smith, and Venugopal K. Nair at the Pirbright Institute in the United Kingdom; David A. Kennedy at Penn State University and the National Institutes of Health; and Stephen W. Walkden-Brown at the University of New England in Australia. The experiments were done in a specialized pathogen-containment facility at The Pirbright Institute in the United Kingdom.

Funding for this research was provided by the National Institutes of Health Institute of General Medical Sciences (R01GM105244) and by the U.K. Biotechnology and Biological Sciences Research Council as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program.

CONTACTS
Andrew Read: a.read@psu.edu, (+1) 814-867-2396 (office), (+1) 814-321-5004 (mobile)
Barbara Kennedy (PIO): science@psu.edu, (+1) 814-863-4682

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In this video Andrew Read discusses research that has important implications for food-chain security and food-chain economics, as well as for other diseases that affect humans and agricultural animals. Credit: Penn State University

Some Vaccines Support Evolution of More-Virulent Viruses
Video: Jul 27, 2015

https://www.youtube.com/watch?v=haRMKsI-jKY&t=271s

Why is it that super hot pathogens tend not
to evolve? Most infectious diseases of humans
do not kill all humans all the time. Why is
that? And the answer we would normally give
is that a super hot pathogen, one that kills
all of its hosts all the time is not going
to have an evolutionary future. It kills its
host it kills itself and that's the end of
it.
Now if that's true, and it seems like a reasonable
proposition what happens when you bring in
a vaccine that is going to keep the host alive
now that pathogen is not what wiped out if
the vaccine is keeping the host alive but
not stopping that pathogen from transmitting
on under those circumstances then you can
imagine these hot strains now persisting in
a population.
So broadly speaking with can think about two
types of vaccines. There are vaccines, which
stop the onward transmission of the pathogen
from the host. Those include things like smallpox,
polio, mumps, rubella, measles those sorts
of childhood diseases. The vaccines we have
in humans against those are very very good,
and they stop transmission but there's another
category of vaccines, which we call leaky
vaccines.
Which don't prevent that transmission. So
they protect the host but they allow some
transmission of that pathogen on to other
hosts. Those two types of vaccines the perfect
vaccine that stops transmission and the leaky
vaccines; they are going to have very different
outcomes.
The perfect vaccines stop evolution. They
don't allow the transmission so there's no
more evolution. The leaky vaccines, the ones
that allow this transmission on to new hosts
they allow evolution of these pathogens because
they can evolve from host to host, to host
and so change.
So the leaky vaccines are the ones that we're
concerned with. And Marek's disease virus
the vaccines against that sort. They protect
the host from death but they do not stop the
host from transmitting a virus on to another
chicken. Marek's disease virus which is a
herpes virus of chickens, its a big deal in
the poultry industry.
It used to be a very benign disease so in
the 1950's it did not cause much harm to chicken.
These days the strains that circulate kill
all unvaccinated birds in 10 days. Now what
caused that?
One possibility is that it was the vaccinations
used in the industry to protect the birds
against this disease.
So, we had this idea that evolution like this
could happen. That vaccines could drive more
pathogenic strains. So we've become very interested
in testing that and we've done that experimentally
now and what we find is that indeed these
super hot strains, these ones that kill everything
in 10 days that is not enough for transmission.
So if they kill everything in 10 days that's
the end of them.
If you keep them alive, the birds alive with
vaccines, those strains now can transmit because
their host doesn't die. We found precisely
what we predicted.
I think one of the important things to get
across here that even though the Marek's disease
virus evolved to be much much nastier then
it was, is that it isn't causing problems
for industry these days precisely because
of the vaccinations. So almost every bird,
every chicken in the world is vaccinated against
Marek's disease and that controls it. That
stops the birds dying. and so if you can vaccinate
all the hosts in a
Population and that protects them, it doesn't
matter if the thing has become more virulent.
So what are the implications of this? Well
first off there's a very real question whether
in the chicken industry Marek's disease virus
itself is going to get even nastier. The second
question is does this have any implications
for other diseases and agriculture? And I
think it does there are quite a few things
that we vaccinate against where the vaccines
are of these leaky types.
The one that particularly concerns me is Avian
influenza. So Avian influenza can come in
very high pathogenic strains and those ones
are of deep concern of industry all over the
world.
In the US and in Europe the birds that get
Avian influenza are culledso there is no evolution
because everything is dead, but in Southeast
Asia they vaccinate. And the vaccines leak.
So this sort of evolution could happen with
Avian influenza. And I think that's a very
real concern.
So it's natural to ask what this means for
human vaccines. Let me first say that there's
no question that vaccines are the cheapest
most effective public health interventions
we've ever had. The question is about next-generation
Vaccines things we might develop where the
immunity is not likely to be so good.
And we can imagine leaky vaccines.
So for instance I think it's very very important
that we determine as quickly as we can that
the Ebola vaccines that are currently under
trial are not leaky; that they prevent onward
transmission. We do not want the evolution
of diseases that pathogenic going in a direction
what we've seen in these chicken viruses.
If this sort of virulence evolution takes
place and when it takes place in response
to vaccination it's the unvaccinated that
are at the greatest risk. Those are the ones
who are going to be exposed to, with out protection,
to these hotter strains. So again an argument
for getting vaccinated.