Gain-of-Function Research: Unproven Technique

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Science  18 Oct 2013:
Vol. 342, Issue 6156, pp. 310-311
DOI: 10.1126/science.342.6156.310-b

The letter “Gain-of-function experiments on H7N9” (R. A. M. Fouchier et al., 9 August, p. 612; published online 7 August) is based on unproven assumptions from previous H5N1 studies and on less-than-critical examination of the basic biology of influenza viruses (1). Furthermore, there is no scientific basis for the claim that gain-of-function (GOF) research on H7N9 may lead to development of more effective vaccines. There is a need to advance influenza vaccine development, but GOF experiments are unlikely to provide the required insights.

Influenza vaccines have been manufactured for many decades based on the isolation of a virus with a specific pandemic potential or seasonal prevalence. These isolates need to be propagated in eggs or, more recently, in cell cultures. Once obtained in sufficient quantities, vaccines are prepared either by inactivating the whole virus particle or isolating a particular fragment. Recently, a vaccine was produced by cloning viral hemagglutinin (2). It has so far been necessary to produce a new vaccine to protect against every influenza virus suspected of pandemic or seasonal threat, irrespective of the structure of viral hemagglutinin or detected mutations in its amino acid sequence.

Fundamental scientific studies have previously established that influenza viruses have high error rates in their viral polymerase and variation in their propensity to infect many avian and mammalian species. Furthermore, evolutionary pressures result in multiple reassortment and mutational events that follow no clear pathway and are impossible to predict or associate with a specific outcome in any population (3). Aside from its biosecurity and biosafety risks, GOF research is not based on scientific grounds, but rather on highly speculative assertions. Experience to date with H7N9 viruses in regard to neuraminidase inhibitor activity or the presence of certain hemagglutinin motifs are not novel findings (4). The previous GOF studies on H5N1 contributed little to the development of new vaccines or therapeutic measures. The current proposal is based on self-serving advocacy rather than a scientific determination.


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