Safety-relevant research in virology

Safety-relevant research in virology

Call for a rational discourse on the risks and opportunities of gain-of-function research in virology

The Society of Virology (GfV) e.V. welcomes the great public interest in virological research. With this position paper, the Society addresses media representatives, scientists and interested parties and summarizes the proven regulatory framework for gain-of-function (GoF) research. At the same time, the GfV promotes a rational and objective discourse on the risks and opportunities of GoF in virological research.

Media reports on the risks and necessity of research on viruses and the structural measures to control, monitor and reduce the risks of this work have increased significantly during the SARS-CoV-2 pandemic. In particular, the term "gain-of-function" is often used in an undifferentiated way, giving the false impression that this method is mainly used by researchers to increase the pathogenicity of pathogens.

What does GoF research mean in virology and why is it necessary?

Viruses have the ability to constantly change their genetic material through mutations. This is part of their natural evolution, for example to adapt to new hosts, to evade the defense mechanisms of the immune system or to develop resistance to antiviral drugs. The acquisition of GoF mutations, which have a positive effect on virus replication, is therefore an intrinsic ability of viruses. However, GoF is also an integral part of research. The addition of properties such as heat resistance in plants or the production of immune cells (CAR-T cells) that can fight tumors also fall into this category. In virological research, GoF stands for a scientific method in which changes are introduced into the genetic material of a virus in order to give the virus a new property or to enhance existing properties of the virus. In principle, this can be done using two different experimental approaches: Either through targeted changes to the genetic material using molecular biological methods of genetic engineering. One example is the insertion of genes for fluorescent proteins into a virus genome using genetic engineering, which makes it easier to identify infected cells in laboratory experiments. This does not increase pathogenicity. Or cultivating the virus in a modified environment, whereby certain mutations are selected (adaptation). An example of this would be the selection of resistance to antiviral drugs, or of immune escape variants by propagating a virus in the presence of a neutralizing antibody (e.g. after vaccination). This type of research is important in order to understand how viruses can adapt to the human immune response or develop resistance to antiviral therapies and what measures can protect against them. Many drugs or vaccines would not be available today and we would not be able to assess the pandemic potential of viruses that are already circulating in nature. However, the use of GoF methods on viruses does not usually lead to an increase in pathogenicity. If changes are introduced that could possibly increase the risk potential of a pathogen due to altered transmissibility, reduced sensitivity to drugs or increased pathogenicity potential, this research falls into the area of additionally regulated "safety-relevant research" and is also referred to as GoF research of concern (GoFRoC).

GoF in virological research

Virological studies with GoF aspects are also carried out in the context of questions of viral pathogenicity, cell tropism or the transmission mechanisms of viruses. For example, viruses can be genetically modified in such a way that they bind to a different cell receptor and thus preferentially infect other cell types. In zoonosis research, this method helps to find out which change in the receptor binding site of an animal pathogenic virus enables it to jump from animals to humans. In many laboratories, research is being carried out into how mutations occurring in nature influence the properties of viruses, which allows an assessment of whether these viruses circulating in the wild can pose a risk to humans. This research is also crucial in the international preparation for future pandemics ("pandemic preparedness"). However, the amplification or addition of properties (gain) is often at the expense of the viral ability to multiply, so that these modified viruses have a lower risk potential than the original viruses.

GoF research cannot be completely replaced by alternative methods

A significant proportion of questions on pathogens can and are investigated in alternative and simplified experimental models (surrogate models) or by bioinformatic simulation studies (in silico analyses), which replace experiments with pathogenic viruses. Often, for example, closely related viruses or replication models are available that have a lower pathogenicity or do not form infectious virus particles and can therefore be processed in a laboratory with a lower safety level. However, the holistic breakdown of complex pathogenicity mechanisms is not always possible with alternative methods. Certain questions, such as the contribution of individual viral activities to transmissibility or to certain disease patterns, can only be answered through experiments with infectious viruses.

GoF research is used to combat diseases and for the prevention/early detection of pandemics

Viruses with GoF modifications are used to fight cancer and other diseases (Masemann et al. 2017). A genetically modified herpes virus is used, for example, in the treatment of malignant melanoma (Robinson et al. 2022). The Ebola vaccine based on an attenuated vesicular stomatitis virus and the SARS-CoV-2 vaccine based on an adenovirus are the results of GoF experiments (Marzi et al. 2015; van Doremalen et al. 2020). GoF can also be used safely and effectively in pandemic control and prevention. In the case of newly emerging mutations in the genome of circulating human and animal viruses, the effect of these mutations on the pathogenicity of the virus can be investigated using GoF research. Such experiments are always initially based on a risk assessment by the researcher and the responsible regulatory authorities. Due to a possible increase in pathogenicity, such experimental work is carried out in safety laboratories at the level corresponding to the risk. The findings can help to assess an increase in the pandemic potential of a pathogen at an early stage, as is currently the case with highly pathogenic influenza viruses in birds, for example.

Safety-relevant research on viruses is closely regulated

In German-speaking countries, all scientific research or diagnostics involving pathogens (including genetically modified ones) is subject to mandatory notification and approval. In contrast to the USA, this also applies to industrial (privately funded) research. Internationally, pathogens are divided into risk groups based on their potential risk to humans, animals and the environment. This results in safety levels 1 (no risk) to 4 (high risk) (international = Biosafety Level 1-4). A laboratory for safety-relevant research must meet structural and safety requirements that are monitored by the authorities and must be approved by the supervisory authorities for safety levels 3 and 4. In these laboratories, the safety standards are so high that unintentional escape of pathogens is reliably prevented if handled properly. In addition, very strict access regulations apply to these laboratories. All experimental work must be supervised by competent persons and there are strict regulations on the necessary professional qualifications that researchers must acquire for pathogen testing under the Infection Protection Act. Reliability and work experience are the decisive criteria. Only appropriately trained personnel who are regularly instructed on the safety standards to be observed are permitted to work in safety laboratories. Genetic engineering and virological research projects in level 3 and 4 safety laboratories must be notified to and approved by the relevant authorities before work begins. These authorities check whether the safety level is appropriate and regularly monitor whether the laboratories meet all safety requirements. However, new pathogens and the rapid technological progress of genetic engineering processes require a case-by-case assessment of safety-relevant research projects and may also lead to an adjustment of safety measures. From safety or protection level 3, the nationally recognized interdisciplinary committee of experts, the Central Commission for Biological Safety (ZKBS) in Germany and the Federal Expert Commission for Biological Safety (EFBS) in Switzerland, are always consulted. The ZKBS and EFBS also issue recommendations and statements on the necessary safety measures when dealing with various pathogens.

What responsibility do scientists and research institutions bear?

The initial assessment of planned research projects and the weighing up of the risk against the gain in knowledge is initially the responsibility of the scientist leading the project. If the experiments fall into the area of safety-relevant GoF research, two approaches are taken in Germany to ensure the greatest possible safety: i) when using genetic engineering, the current Genetic Engineering Act (GenTG) and its regulations must be complied with, for which the project leader is subject to a demonstrable training and documentation obligation. In addition, it must be checked whether alternative methods can be used and what measures must be taken to reduce risk. This risk analysis is always reviewed by the ZKBS from security level 3. ii) When applying for research funding, the applicant must submit their own assessment and substantiate this with a vote from a Commission for Ethics in Research (KEF). Both statements are then reviewed by experts in the field of research. In Germany, Switzerland and Austria, 120 institutions already have such or comparable commissions to evaluate safety-relevant research in various disciplines. Between 2020 and 2021, 35 security-relevant cases across various disciplines were discussed in KEFs in Germany. 17 of these were assessed positively without restrictions, while in 11 cases additional precautionary measures were recommended to further reduce risk. In at least 2 cases, a research project was advised against (German National Academy of Sciences Leopoldina and German Research Foundation (DFG), 2022). The activities of the KEFs are supported by regular events (KEF forums) at which safety-relevant projects and their assessments are presented and discussed. These meetings are organized by the Joint Committee for Security-Related Research of the DFG and Leopoldina.

The safety regulations for risk research have proven their worth

In the opinion of the GfV, the current safety standards and regulatory mechanisms for GoF research on viruses in German-speaking countries are appropriate and exemplary by international standards. The GfV does not consider a tightening of the guidelines for the regulation and evaluation of safety-relevant research to be expedient, but recognizes the danger of a disproportionate regulation and slowing down of necessary translational and basic research in virology, which aims to protect and maintain human and animal health, also in international comparison. In contrast, the GfV recommends that the proven evaluation of safety-relevant research projects at individual case level by KEFs, the DFG review boards and the Joint Committee be maintained. In addition, the GfV advocates a continuous discourse on the safety and risks of GoF and GoFRoC, e.g. those arising from new technologies or newly emerging viruses.

Left:

• Federal Institute for Occupational Safety and Health (BAUA): https://www.baua.de/DE/Themen/Arbeitsgestaltung-im-Betrieb/Biostoffe/Einstufung.html
• Central Commission for Biological Safety (ZKBS): https://www.zkbs-online.de/ZKBS/DE/Home/home_node.html
• Bavarian Office for Health and Food Safety (LGL Bayern): https://www.lgl.bayern.de/rubrikenuebergreifende_themen/gentechnik/gentechnische_arbeiten.htm#sicherheitsstufen
• Joint Committee on the Handling of Security-Related Research (AG): https://www.sicherheitsrelevante-forschung.org
• Federal Expert Committee for Biological Safety (SECB): https://www.efbs.admin.ch/de/startseite

References:

1. Masemann D, Boergeling Y, Ludwig S. (2017) Employing RNA viruses to fight cancer: novel insights into oncolytic virotherapy. Biol Chem. 398(8):891-909. doi: 10.1515/hsz-2017-0103
2. Robinson C, Xu MM, Nair SK, Beasley GM, Rhodin KE. (2022) Oncolytic viruses in melanoma. Front Biosci. 27(2):63. doi: 10.31083/j.fbl2702063.
3. Marzi A, Robertson SJ, Haddock E, Feldmann F, Hanley PW, Scott DP, Strong JE, Kobinger G, Best SM, Feldmann H. EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science. 2015 Aug 14;349(6249):739-42. doi: 10.1126/science.aab3920.
4. van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato VA, Bushmaker T, Flaxman A, Ulaszewska M, Feldmann F, Allen ER, Sharpe H, Schulz J, Holbrook M, Okumura A, Meade-White K, Pérez-Pérez L, Edwards NJ, Wright D, Bissett C, Gilbride C, Williamson BN, Rosenke R, Long D, Ishwarbhai A, Kailath R, Rose L, Morris S, Powers C, Lovaglio J, Hanley PW, Scott D, Saturday G, de Wit E, Gilbert SC, Munster VJ. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020 Oct;586(7830):578-582. doi: 10.1038/s41586-020-2608-y
5. German National Academy of Sciences Leopoldina and German Research Foundation (2022): Joint Committee on the Handling of Security-Relevant Research - Fourth Activity Report as of November 1, 2022. Halle (Saale), 86 pages.

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