G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation

There have been almost 100 million cases of SARS-CoV-2 infections world-wide, with more than two million deaths to date. It seems certain that this virus will permanently establish itself in the human population and become endemic, meaning that multiple strategies and measures will be needed to prevent, control and treat SARS-CoV-2 infections for the foreseeable future.
For all viral infections, the outcomes in terms of disease, recovery, viral persistence or onward transmission are dictated by the balance between virus replication and the immune responses of the infected individuals. As SARS-CoV-2 continues to circulate in people this balance will change over time; On one hand the virus that emerged from an animal source may further adapt to its new human host and on the other hand the acquired immune response in the human population will accumulate potentially limiting viral spread.
New variants of SARS CoV-2 with mutations in the genome (different 'genotype') will emerge and some may have altered biological properties ("phenotype"): including transmitting between humans more readily, exacerbating or attenuating disease and mortality, spreading to other animal species (to establish non-human reservoirs) or evading human immunity that is acquired through natural infection or vaccination. The latter is a particular concern at this moment in time given that population-level immunity is increasing as a result of high virus circulation and vaccination programs. Many variants of SARS-CoV-2 are now appearing globally, and the rational assessment of the risks they pose to society requires an evidence-based scientific understanding of any causative changes in biological properties.

The Genotype-to-Phenotype UK National Virology Consortium (G2P-UK) will address this critical knowledge gap by leveraging the combined virological expertise of ten leading research centres to undertake a suite of directed and complementary experimental tests that will link SARS-CoV-2 sequence variation to virus behaviour and function. Tests will include the detailed assessments of virus growth using a series of laboratory models of infection, susceptibility of viruses to inhibition by human immune mechanisms including antibodies, evaluations of the functionality of individual virus proteins, and virus propagation and transmissibility using established small animal models. Co-ordination within G2P will be achieved through upfront agreed methodologies and standards, the free exchange of materials, specimens and know-how, regular scientific meetings and a dedicated consortium website.

SARS-CoV-2 variants of concern that warrant focused investigation will be prioritised through co-ordinated workings with scientists at another consortium, COG-UK, who are responsible for virus surveillance and keeping track of emerging virus variants. Variants of concern will be selected on criteria that include altered disease outcomes, rapid emergence or spread, infections in the context of pre-existing immunity, apparent or inferred escape from immunity, or resistance to anti-viral drugs.G2P will also engage closely with other key UK organisations and scientific consortia including UK-wide Public Health laboratories and UK-CIC (Coronavirus Immunology Consortium), as well as other leading groups working in the UK and internationally, to gather the most holistic and incisive evaluation of the biological phenotypes of variants of concern and the associated risks they carry. These conclusions will be shared rapidly and openly with key groups such as NERVTAG and SAGE to inform national pandemic management and strategies for patient treatment, diagnostics, population-level surveillance, infection control and vaccination.

SARS-CoV-2 has caused 1.4 million deaths and has devastated economies worldwide. As SARS-CoV-2 replicates and spreads, its RNA genome inevitably mutates. Mutations may confer altered properties of potential concern to human health, such as increased pathogenicity or transmissibility, or reduced sensitivity to prior immunity or antiviral drugs. Importantly, the imminent roll out of vaccination campaigns could provide strong selection pressure for escape from vaccine-induced immunity.

We are a consortium ("G2P-UK") of UK virologists who will work openly with COG-UK and UK-CiC, to establish an experimental pipeline and shared resources (reagents, methodologies and model systems) to rapidly define the phenotypic impacts of SARS-CoV-2 mutations as they emerge. With three interconnected work packages we will obtain and distribute clinical isolates and engineered SARS-CoV-2 mutants (WP1), test the functional properties of the mutations in in vitro assays (WP2) and characterise their phenotype in culture and animal model systems (WP3).

The choice of strains and mutations will be informed by a joint working group that includes COG-UK members. Current virus strains will be immediately introduced into the pipeline, to accumulate a baseline of underpinning knowledge about SARS-CoV-2 behaviour, to validate the consortium working relationships and to seed mechanistic studies suitable for further research. Then, as variants of concern are detected, they will be prioritized for co-ordinated investigation in real time.

By interpreting the biological consequences of SARS-CoV-2 mutations we will inform on the associated risks and vulnerabilities related to public health policy and clinical practice, including treatment strategies, diagnostics and infection control, and vaccination.