A version of this editorial appears in the February 2013 issue of Nature Medicine.
Last January, scientists voluntarily imposed a pause on research that could lead to the generation of highly pathogenic avian influenza viruses with increased transmissibility to mammals. Now, new restrictions currently under debate further risk stalling progress in avian flu research.
In late 2011, a firestorm erupted around two papers under peer review on highly pathogenic avian influenza (HPAI) H5N1 viruses. Both identified mutations that would permit airborne transmission of the viruses to ferrets. Although the viruses were not highly pathogenic in the ferrets, the papers sparked concerns that the mutant H5N1 viruses might have pandemic potential.
The concerns are not unwarranted given the history of H5N1 infections. The case fatality rate due to H5N1 in humans exceeds 50%, yet only 610 infections have been recorded since 2003, in part because of its low capacity for human-to-human transmission. However, there is fear that avian influenza could acquire the mutations necessary to rapidly transmit among humans, similar to seasonal influenza. Therefore, a better understanding of the mutations necessary to facilitate transmission of H5N1 in mammals and their effects on the fitness of the virus is considered by many to be crucial in developing countermeasures in the event of an avian flu pandemic.
Not everyone agrees on the utility—or ethicality—of this type of research, which led to the research embargo and delayed publication of both papers. (They were ultimately published in May and June of 2012 in Nature and Science, respectively.) The research pause was intended to allow researchers to communicate the rationale and the safety measures in place for undertaking experiments with H5N1 and to allow governments to consider whether new policies are necessary for funding such research. Yet the original 60-day moratorium, which was only lifted in January 2013, albeit not in the US, lasted more than a year, and the US Department of Health and Human Services (HHS) has recently recommended new regulations that would restrict all research using highly pathogenic H5N1 viruses, regulations that could hamper efforts aimed at protecting humans.
Due to its potential effects on animal health and safety, HPAI is classified as a US Department of Agriculture (USDA) select agent. Low pathogenicity strains are excluded from this designation. Since October, HHS has sought public comment on whether to make HPAI H5N1 viruses a tier 1 HHS select agent, a designation currently restricted to a handful of agents (including the Ebola and smallpox viruses and Bacillus anthracis) that are considered to present “the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence”.
The new designation might require that H5N1 research in the US be done in a biosafety level 4 (BSL-4) laboratory, rather than in an enhanced BSL-3 facility where it is currently performed, as well as more background screening of personnel and enhanced security measures. Canada has ruled that research on mammalian transmissible H5N1 viruses must be done in a BSL-4 lab, whereas The Netherlands has determined that enhanced BSL-3 containment measures suffice. Additional review measures have also been proposed for US National Institutes of Health grants involving studies that would increase mammalian transmissibility of H5N1, and they would entail an extra review step by the HHS if the studies met certain criteria. These regulatory efforts aim to prevent the accidental or intentional release of avian flu, but the unintended consequences are clear: researchers in the US would have less access to facilities in which to carry out H5N1 studies, restricted funding of some studies, lengthy review processes and more obstacles to international collaboration. As the US is the major funder of H5N1 studies, these impediments will have a crippling effect on H5N1 research.
Academics have weighed in on both sides of the argument. The Infectious Diseases Society of America concurs that H5N1 should be an HHS select agent because of its potential risks to human health and concerns surrounding the development of mammalian-transmissible strains. In contrast, the American Society for Microbiology does not support the change, given that circulating H5N1 strains are poorly transmissible among humans and that the USDA select-agent designation sufficiently addresses the biosafety and biosecurity needs. Sanofi Pasteur, Novartis Vaccines and MedImmune, in turn, have requested that attenuated H5N1 strains and low-pathogenicity avian influenza viruses be exempt from the HHS select-agent list, as their inclusion could hamper vaccine development. In 2012, these vaccine manufacturers were awarded contracts by the HHS valued at up to $22 billion to develop medical countermeasures against H5N1. How global pandemic preparedness might be affected by the proposed changes is unclear.
What is clear is that avian flu research has been set back, and further deliberation and a more restrictive funding and regulatory environment will exacerbate matters. In our view, the only way to guard against a biomedical disaster is through more research and greater knowledge—not by making certain types of research nonpermissible or unattainable. In June 2012, Science published a follow-up paper by the two labs at the heart of the debate, in which surveillance data showed that only three additional mutations would be required to convert some circulating strains of HPAI H5N1 into highly transmissible forms, based on the mutations identified in the original two publications. The findings underline the importance of continued research on mammalian-transmissible H5N1 viruses. What we don’t know can hurt us. Shouldn’t that be the lesson learned?