Comment on "Gain-of-Function Research and the Relevance to Clinical Practice".

To the Editor—Kilianski et al [1] highlight clinical applications of gain-of-function (GOF) research on viruses and suggest that the present US government funding moratorium hinders progress in such research. Those concerned about biosafety risks of certain GOF experiments have used the term “potential pandemic pathogens” to denote the small subset of GOF research that poses a risk of widespread transmission of a highly virulent pathogen [2, 3]. The National Science Advisory Board on Biosecurity refers to this small subset as GOF research of concern (GOFROC) [4]. The funding pause, which initially covered 18 National Institutes of Health (NIH)–funded influenza virus and coronavirus projects, was reduced to 11 projects by December 2014. For comparison, a search of the NIH Reporter Database shows well over 200 projects naming influenza virus or coronaviruses in the title or abstract; thus the funding moratorium affects <5% of research on these viruses funded by the NIH.

Kilianski et al cite 5 categories of GOF research that can have clinical benefits. First they mention the development of animal models for coronaviruses. However, development of an animal model of MERS coronavirus infection was specifically removed from the funding pause [5], and SARS coronavirus GOF studies (not designed for the development of an animal model) have been published during the pause [6] with US government funding.

Next, they mention vaccine development. While enhancement of vaccine strains to enhance production is technically a GOF, it is widely agreed to be low risk, high benefit, and not GOFROC [4]. This distinction has been noted by the Infectious Diseases Society of America, among others [7].

Next, they describe the generation of escape variants from therapeutics or immunity as a form of GOF that can be important to development of treatments or preventive measures. Such efforts may be valuable, but I am unaware of any such experiments that have been blocked by the present funding pause. Some such experiments might be risky and considered GOFROC and might pose particularly challenging test cases for risk-benefit analysis.

Finally, they cite the use of the results from GOFROC experiments to inform disease surveillance, prioritizing surveillance, and perhaps prevention and control measures for strains that show genetic changes that have been observed to confer increased transmission in ferrets during GOFROC experiments. Indeed, public health officials from the United States have indicated [8, 9] that they use the mutations identified in the noted GOFROC experiments on influenza A(H5N1) virus [10, 11] to prioritize surveillance. Given that no pandemic of A(H5N1) influenza has occurred, there is no rigorous way to identify whether incorporating that information has improved the outcome of surveillance. Indeed, there are reasons to think that prioritizing strains showing those mutations might in some cases be misleading (Table 1). Moreover, each of the variants identified as potential risk indicators in the GOFROC experiments had previously been identified as such in safe, non-GOFROC studies by using alternative approaches [24], as shown in Table 1.

Table 1.

Prior Studies That Identified Mutations of Concern That Were Later Identified in GOFROC Studies, And Exceptions to The Idea That They Are Associated With Increased Risks

Mutation Identified to Prompt Enhanced Concern That Was Derived From GOFROC Studies [8, 9]	Prior Studies Not Involving PPP Creation That Identified These Mutations	Exception
Hemagglutinin (HA) Q222L (influenza A[H5N1] virus)	[12–18]	Context dependence: changes do not quantitatively shift receptor binding in related H5 influenza virus strains [18]
HA S133A, S135N, S123P, S155N	[14, 19]	…
HA T156A, Q222L (influenza A[H7N9] virus)	[20, 21]	…
Polymerase B2 subunit PB2 E627K, D701N	[22]	Misleading inference: both absent in 2009 pandemic influenza A(H1N1) virus [23]; could have led to its misclassification as low risk

Abbreviations: GOFROC, gain-of-function research of concern; PPP, potential pandemic pathogen.

GOF is undeniably a valuable technique for microbiological research, including applied research with direct benefits for public health. This fact is accepted by most, if not all, critics of GOFROC or potential pandemic pathogen research. When weighing the benefits of GOFROC against those of alternative approaches [25], the issue is not whether GOF can be useful, which it often can be, but whether the risks of GOFROC are justified by unique benefits that cannot be achieved by safe approaches. Of the examples of public health or clinical benefits cited by Kilianski et al, some are not the result of GOFROC. Of those that are, the surveillance benefits at least can and have been achieved through alternative, safer means.