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Preserving pathogens with pandemic potential
Newsdesk
Preserving pathogens with pandemic potential Recent lapses in safety protocols have motivated some to question the wisdom of work with so-called laboratory-only pathogens. Do the benefits outweigh the risks, asks Talha Burki. For more on the CDC’s anthtrax incident see http://www.cdc. gov/media/releases/2014/ p0711-lab-safety.html For a study of transmission of H5N1 between ferrets see Science 2012; 336: 1534–41
Thomas Frey/epa/Corbis
For the second study of transmission of H5N1 between ferrets see Nature 2012; 486: 420–28
Experiments involving pathogens that do not exist outside the laboratory, but harbour pandemic potential have long been a source of controversy. Experts have struggled to balance the risks of an accidental, or indeed deliberate, laboratory release against the potential benefits of the research. There are questions over whether publishing genetic information about destructive viruses amounts to offering budding bioterrorists an instruction manual. Over the past few years, arguments have centred on gain-of-function studies involving influenza viruses genetically modified to enhance transmissibility. Recent breaches in protocol at the US Centers for Disease Control and Prevention (CDC) have kept the argument alive. It has caused something of a split in the scientific community, with each side attracting high-profile support. A pair of studies involving the creation of airborne H5N1 viruses that spread from ferret to ferret helped bring the matter to a head. In late 2011, the US National Science Advisory Board for Biosecurity decided to suppress the studies, and researchers in the field agreed on a voluntary moratorium. “I can’t think of another pathogenic organism that is as scary as this one”,
A biohazard sign on the door of a special secured laboratory testing H5N1 samples
1048
noted the Board’s head, Paul Keim. The papers were eventually published in full in 2012 (the idea of redacting the text had initially been mooted).
“There are questions over whether publishing genetic information on destructive viruses amounts to offering budding bioterrorists an instruction manual.” The US National Institutes of Health subsequently amended its funding policies for “dual research of concern”. The amendments stressed the necessity for stringent safety standards for institutions involved in gain-of-function influenza experiments. Funding would only be disbursed after assessment of the risks and benefits, and on the basis that the latter exceeded the former. The USA funds much of the research into laboratory-only pathogens. “We fully acknowledge that this research—as with any work on infectious agents—is not without risk”, wrote proponents of gainof-function research last year, in a letter announcing the end of the moratorium. But they added that “virus transmission studies are essential for pandemic preparedness and understanding the adaptation of influenza viruses to mammals”. Harvard University’s Marc Lipsitch countered that “there are dozens of safe research strategies to understand, prevent, and treat pandemic influenza. Only one strategy—creating virulent contagious strains—risks inciting such a pandemic”. Lipsitch is a founding member of the Cambridge Working Group, whose call for a curtailment of studies involving potential pandemic pathogens pending a “credible assessment of the risks, potential
benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches” has been endorsed by more than 200 scientists from around the world. These arguments were first rehearsed after the eradication of smallpox. In September, 1978, medical photographer Janet Parker became the last person to die from smallpox after she contracted the disease at the University of Birmingham. The laboratory on the floor below that on which Parker was working was researching smallpox. In the aftermath of her death, it was agreed that all remaining stocks of the variola virus should either be destroyed or removed to two laboratories, one at the CDC, and the other at the Russian State Research Centre of Virology and Biotechnology. The eventual aim was total destruction of the virus. WHO, which oversees smallpox research, even went so far as to set a deadline for destruction of Dec 31, 1993. But in 1992, a defector who had worked on the Soviet biological warfare programme told US authorities that the Soviet Union had weaponised the smallpox virus, and that countries in the region might retain supplies. Research into antivirals and improved vaccines suddenly seemed more vital. After the 2001 anthrax attacks in the USA, interest in smallpox research again picked up. Since then, WHO has continually postponed any decision on destroying the remaining stocks, with poorer member states tending to favour immediate destruction and the USA and Russia in favour of continuing research efforts. So how long do these efforts need to continue? Two promising antiviral agents are on the verge of being
www.thelancet.com/infection Vol 14 November 2014
Newsdesk
licensed, there are plenty of options in terms of effective and safe vaccines, as well as perfectly adequate diagnostic tests. The two WHO smallpox advisory committees met last year. One concluded that the live variola virus was no longer scientifically necessary; the other affirmed that the virus was still needed for the development of antivirals. “The arguments can go on ad infinitum”, said David Heymann, chairman of the UK Health Protection Agency. “The real question is whether it is relevant any more now that the virus sequence is fully known”. The genome was sequenced in 1994. Unlike the poliovirus, the smallpox virus has never been reconstructed, but it is theoretically possible. Such an undertaking is probably out of reach for most non-state actors for now, but over time it might become achievable. “I would have supported previous destruction, but now it is a question that needs to be reviewed in light of the fact that it can be genetically developed de novo”, Heymann told TLID. Moreover, an accidental release can be managed with little difficulty. “Smallpox is very easy to contain— every infection is clinically expressed and the vaccine can modify the course of infection up to 4 days after exposure”, explains Heymann. Established procedures of isolation and containment, and the presence of a reliable vaccine, mean that the chances of a pandemic resulting from a laboratory infection are extremely low. None of which is the case for influenza. Gain-of-function experiments are typically done in biosafety level 3+ facilities (the highest rating is 4). Assuming an infection rate of two per 1000 lab-years and ten laboratories engaged in such work, Lipsitch calculates that the chances of an accidental infection over 10 years is 20%. It is tricky to define the probability of such an infection leading to extensive spread of the virus, but estimates suggest at least 10%. It has been suggested that the
1977–78 H1N1 epidemic originated as a laboratory release. Couple this with the fact that there are about 1500 high containment laboratories in the USA, roughly four times the number of a decade ago, and the CDC’s estimate that there have been 269 accidents involving dangerous pathogens in the past 4 years, and the picture darkens (although the exact nature of these accidents is unclear). Moreover, the USA has arguably the highest safety standards in the world. Other countries might be more lax in their precautions.
“For very cutting-edge research, almost by definition, you cannot do risk–benefit analysis because you don’t always know what the risk is...” Lipsitch notes that, unlike with smallpox, there is no global prospective process for ensuring gain-of-function experiments are reviewed in advance. “This is a problem for public health”, says Lipsitch. “There should be a public discussion with the widest variety of specialists and with the numbers involved, which has really been lacking so far—neither the risks nor the benefits have been quantified in any way.” Adolfo Garcia-Sastre (Mount Sinai Hospital, New York City, NY, USA) points out that the 1977 H1N1 release took place in a different era. “At that time, these viruses were not under biocontainment; the proliferation of biocontainment laboratories have reduced, not enhanced, the possibility that something like what happened in 1977 could happen now”, he said. Garcia-Sastre remains certain of the value of gain-of-function research. “People thought the H5N1 viruses could never become transmissible in mammals—but we know now that there is no structural or genetic impediment for the viruses to become transmissible by aerosol, so therefore we need to do as much as possible to contain them”, he said. But he agrees that this is a subject that should not be decided
www.thelancet.com/infection Vol 14 November 2014
solely by virologists. “It is very important to reach a consensus and to continually engage in questions over biocontainment levels and whether particular experiments are needed or not”, he said. This, however, should be done in a timely fashion. “If we take too long to reach a consensus then research slows down, and that is going to impact on our understanding of the biology of viruses that could become pandemic.” The University of Florida’s Grant McFadden notes that it has not been established that the enhanced H5N1 virus is more dangerous to human beings then the versions currently circulating in the wild. It is one of many imponderables for those attempting to sift risks and benefits. “For very cutting-edge research, almost by definition, you cannot do risk–benefit analysis because you don’t always know what the risk is, and you certainly can’t predict the benefits”, he explained. He advocates a different approach. “Instead of thinking about risks for which there are no data, we should allow fundamental research to go on if the containment facilities are appropriate”. McFadden reckons developed countries have a reasonable record for biosafety, and that improvements in technology, regulation, and equipment should see this continue. “I have relatively few concerns about breaches from these facilities—they’ve become very good at containing organisms.” Lipsitch is unconvinced. “We have enough experience with highcontainment labs to estimate the probability of infections—the numbers we have published are bestcase estimates, the real probability could be considerably higher”, he said. “Potential pandemic pathogens present almost unprecedented levels of risk to the public if they do get out—we have an ethical responsibility to vigorously seek safer ways to gain scientific and public health benefits.”
For more on the 1977 influenza epidemic see N Engl J Med 2009; 361: 279–85
Talha Burki 1049
Preserving pathogens with pandemic potential Recent lapses in safety protocols have motivated some to question the wisdom of work with so-called laboratory-only pathogens. Do the benefits outweigh the risks, asks Talha Burki. For more on the CDC’s anthtrax incident see http://www.cdc. gov/media/releases/2014/ p0711-lab-safety.html For a study of transmission of H5N1 between ferrets see Science 2012; 336: 1534–41
Thomas Frey/epa/Corbis
For the second study of transmission of H5N1 between ferrets see Nature 2012; 486: 420–28
Experiments involving pathogens that do not exist outside the laboratory, but harbour pandemic potential have long been a source of controversy. Experts have struggled to balance the risks of an accidental, or indeed deliberate, laboratory release against the potential benefits of the research. There are questions over whether publishing genetic information about destructive viruses amounts to offering budding bioterrorists an instruction manual. Over the past few years, arguments have centred on gain-of-function studies involving influenza viruses genetically modified to enhance transmissibility. Recent breaches in protocol at the US Centers for Disease Control and Prevention (CDC) have kept the argument alive. It has caused something of a split in the scientific community, with each side attracting high-profile support. A pair of studies involving the creation of airborne H5N1 viruses that spread from ferret to ferret helped bring the matter to a head. In late 2011, the US National Science Advisory Board for Biosecurity decided to suppress the studies, and researchers in the field agreed on a voluntary moratorium. “I can’t think of another pathogenic organism that is as scary as this one”,
A biohazard sign on the door of a special secured laboratory testing H5N1 samples
1048
noted the Board’s head, Paul Keim. The papers were eventually published in full in 2012 (the idea of redacting the text had initially been mooted).
“There are questions over whether publishing genetic information on destructive viruses amounts to offering budding bioterrorists an instruction manual.” The US National Institutes of Health subsequently amended its funding policies for “dual research of concern”. The amendments stressed the necessity for stringent safety standards for institutions involved in gain-of-function influenza experiments. Funding would only be disbursed after assessment of the risks and benefits, and on the basis that the latter exceeded the former. The USA funds much of the research into laboratory-only pathogens. “We fully acknowledge that this research—as with any work on infectious agents—is not without risk”, wrote proponents of gainof-function research last year, in a letter announcing the end of the moratorium. But they added that “virus transmission studies are essential for pandemic preparedness and understanding the adaptation of influenza viruses to mammals”. Harvard University’s Marc Lipsitch countered that “there are dozens of safe research strategies to understand, prevent, and treat pandemic influenza. Only one strategy—creating virulent contagious strains—risks inciting such a pandemic”. Lipsitch is a founding member of the Cambridge Working Group, whose call for a curtailment of studies involving potential pandemic pathogens pending a “credible assessment of the risks, potential
benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches” has been endorsed by more than 200 scientists from around the world. These arguments were first rehearsed after the eradication of smallpox. In September, 1978, medical photographer Janet Parker became the last person to die from smallpox after she contracted the disease at the University of Birmingham. The laboratory on the floor below that on which Parker was working was researching smallpox. In the aftermath of her death, it was agreed that all remaining stocks of the variola virus should either be destroyed or removed to two laboratories, one at the CDC, and the other at the Russian State Research Centre of Virology and Biotechnology. The eventual aim was total destruction of the virus. WHO, which oversees smallpox research, even went so far as to set a deadline for destruction of Dec 31, 1993. But in 1992, a defector who had worked on the Soviet biological warfare programme told US authorities that the Soviet Union had weaponised the smallpox virus, and that countries in the region might retain supplies. Research into antivirals and improved vaccines suddenly seemed more vital. After the 2001 anthrax attacks in the USA, interest in smallpox research again picked up. Since then, WHO has continually postponed any decision on destroying the remaining stocks, with poorer member states tending to favour immediate destruction and the USA and Russia in favour of continuing research efforts. So how long do these efforts need to continue? Two promising antiviral agents are on the verge of being
www.thelancet.com/infection Vol 14 November 2014
Newsdesk
licensed, there are plenty of options in terms of effective and safe vaccines, as well as perfectly adequate diagnostic tests. The two WHO smallpox advisory committees met last year. One concluded that the live variola virus was no longer scientifically necessary; the other affirmed that the virus was still needed for the development of antivirals. “The arguments can go on ad infinitum”, said David Heymann, chairman of the UK Health Protection Agency. “The real question is whether it is relevant any more now that the virus sequence is fully known”. The genome was sequenced in 1994. Unlike the poliovirus, the smallpox virus has never been reconstructed, but it is theoretically possible. Such an undertaking is probably out of reach for most non-state actors for now, but over time it might become achievable. “I would have supported previous destruction, but now it is a question that needs to be reviewed in light of the fact that it can be genetically developed de novo”, Heymann told TLID. Moreover, an accidental release can be managed with little difficulty. “Smallpox is very easy to contain— every infection is clinically expressed and the vaccine can modify the course of infection up to 4 days after exposure”, explains Heymann. Established procedures of isolation and containment, and the presence of a reliable vaccine, mean that the chances of a pandemic resulting from a laboratory infection are extremely low. None of which is the case for influenza. Gain-of-function experiments are typically done in biosafety level 3+ facilities (the highest rating is 4). Assuming an infection rate of two per 1000 lab-years and ten laboratories engaged in such work, Lipsitch calculates that the chances of an accidental infection over 10 years is 20%. It is tricky to define the probability of such an infection leading to extensive spread of the virus, but estimates suggest at least 10%. It has been suggested that the
1977–78 H1N1 epidemic originated as a laboratory release. Couple this with the fact that there are about 1500 high containment laboratories in the USA, roughly four times the number of a decade ago, and the CDC’s estimate that there have been 269 accidents involving dangerous pathogens in the past 4 years, and the picture darkens (although the exact nature of these accidents is unclear). Moreover, the USA has arguably the highest safety standards in the world. Other countries might be more lax in their precautions.
“For very cutting-edge research, almost by definition, you cannot do risk–benefit analysis because you don’t always know what the risk is...” Lipsitch notes that, unlike with smallpox, there is no global prospective process for ensuring gain-of-function experiments are reviewed in advance. “This is a problem for public health”, says Lipsitch. “There should be a public discussion with the widest variety of specialists and with the numbers involved, which has really been lacking so far—neither the risks nor the benefits have been quantified in any way.” Adolfo Garcia-Sastre (Mount Sinai Hospital, New York City, NY, USA) points out that the 1977 H1N1 release took place in a different era. “At that time, these viruses were not under biocontainment; the proliferation of biocontainment laboratories have reduced, not enhanced, the possibility that something like what happened in 1977 could happen now”, he said. Garcia-Sastre remains certain of the value of gain-of-function research. “People thought the H5N1 viruses could never become transmissible in mammals—but we know now that there is no structural or genetic impediment for the viruses to become transmissible by aerosol, so therefore we need to do as much as possible to contain them”, he said. But he agrees that this is a subject that should not be decided
www.thelancet.com/infection Vol 14 November 2014
solely by virologists. “It is very important to reach a consensus and to continually engage in questions over biocontainment levels and whether particular experiments are needed or not”, he said. This, however, should be done in a timely fashion. “If we take too long to reach a consensus then research slows down, and that is going to impact on our understanding of the biology of viruses that could become pandemic.” The University of Florida’s Grant McFadden notes that it has not been established that the enhanced H5N1 virus is more dangerous to human beings then the versions currently circulating in the wild. It is one of many imponderables for those attempting to sift risks and benefits. “For very cutting-edge research, almost by definition, you cannot do risk–benefit analysis because you don’t always know what the risk is, and you certainly can’t predict the benefits”, he explained. He advocates a different approach. “Instead of thinking about risks for which there are no data, we should allow fundamental research to go on if the containment facilities are appropriate”. McFadden reckons developed countries have a reasonable record for biosafety, and that improvements in technology, regulation, and equipment should see this continue. “I have relatively few concerns about breaches from these facilities—they’ve become very good at containing organisms.” Lipsitch is unconvinced. “We have enough experience with highcontainment labs to estimate the probability of infections—the numbers we have published are bestcase estimates, the real probability could be considerably higher”, he said. “Potential pandemic pathogens present almost unprecedented levels of risk to the public if they do get out—we have an ethical responsibility to vigorously seek safer ways to gain scientific and public health benefits.”
For more on the 1977 influenza epidemic see N Engl J Med 2009; 361: 279–85
Talha Burki 1049