September 2, 2013

New Gain of Function Experiments Proposed for H7N9 Influenza Virus

A declaration of intent to conduct “gain-of function” experiments on the novel avian influenza A(H7N9) virus has been published by scientists who wish to alter the genetic composition of the viruses to determine what genetic changes/mutations correlate with altered function. Gain of function (GOF) experiments on pathogens alter existing properties and can result in the creation of more dangerous pathogens; the goal is to gain insights into the relationship between genetics (structure) and function. The H7N9 virus emerged earlier this year in China, and to date the World Health Organization reports 135 human cases, with 44 fatalities. This new effort to study H7N9 is proposed by a consortium of scientists, including Ron Fouchier and Yoshihiro Kawaoka, who were the principal investigators for the experiments on HPAI H5N1 viruses that produced viruses with potentially increased human to human transmissibility. Those earlier experiments raised such an alarm that publication of the research was halted in the U.S. while the NSABB federal advisory committee evaluated the risk of publication (both were eventually published). The proposed experiments fall into the category of DURC (dual research of concern), defined as such: 
Dual use research of concern(DURC) is a subset of dual use research defined as life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security. 
The declaration of intent by the scientists is presumably an attempt to increase transparency and invite deliberation at the front end of the process and avoid the panicked reaction that followed the announcements of the earlier H5N1 experiments in 2011. The authors also include materials outlining the biosafety precautions that would accompany the experiments. Early official reaction from the CDC and NIH declares that such experiments will receive extra scrutiny before U.S. government funding will be made available, according to recently issued federal guidelines for DURC issued earlier this year. The CDC has also issued specific biosafety guidelines for working with the H7N9 virus. The following kinds of gain-of-function experiments were announced in the letter: 
•Immunogenicity. To develop more effective vaccines and determine whether genetic changes that confer altered virulence, host range or transmissibility also change antigenicity. 
•Adaptation. To assist with risk assessment of the pandemic potential of field strains and evaluate the potential of A(H7N9) viruses to become better adapted to mammals, including determining the ability of these viruses to reassort with other circulating influenza strains.
•Drug resistance. To assess the potential for drug resistance to emerge in circulating viruses, evaluate the genetic stability of mutations conferring drug resistance, and evaluate the efficacy of combination therapy with antiviral therapeutics. Also, to determine whether A(H7N9) viruses could become resistant to available antiviral drugs, and to identify potential resistance mutations that should be monitored during antiviral treatment.
•Transmission. To assess the pandemic potential of circulating strains and perform transmission studies to identify mutations and gene combinations that confer enhanced transmissibility in mammalian models (such as ferrets and guinea pigs).
•Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the haemagglutinin cleavage site, that would enable circulating A(H7N9) viruses to become more pathogenic. 
These proposed experiments – altering the critical variables of spread and virulence for the viruses, changing drug resistance and  vaccine susceptibility – will likely produce viruses that are potentially more dangerous than those we currently know about. The stated goal of such work is to learn which mutations alter the risk profile of a virus – confer pandemic potential – and use that knowledge to design vaccines or discover antivirals that can respond to these viruses. Further, it is argued that ongoing surveillance efforts can be focused on identifying virus isolates that display such mutations and pose an elevated public health risk, although this point is contested by other scientists. It’s not clear whether the NSABB will be involved at this early stage – to date, it has not advised on the merits of funding specific experiments which can be characterized as DURC. The recent tightening of federal review of such research will be put to the test with these proposed experiments as the investigators seek U.S. funds. With respect to the publication of results, the influenza researchers anticipate the possible fallout: 
To advance A(H7N9) virus research, findings should be shared in refereed publications. Investigators agree to adhere to guidelines for responsible communication of results and every effort will be made to put the results in context and reduce sensationalism. 
The questions that were raised by the H5N1 influenza controversy  - what criteria are to be used when evaluating the funding for DURC or what conditions need to attach to such funding – will now surface with this H7N9 research declaration – and their resolution might establish a template for future research proposals.

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