The G2P2 virology consortium: keeping pace with SARS-CoV-2 variants, providing evidence to vaccine policy, and building agility for the next pandemic

Since arising in China from a single zoonotic event in 2019, SARS-CoV-2 variants of concern (VOCs) have evolved through mutation and selection with Alpha, Delta, and Omicron becoming sequentially dominant worldwide, contrasting with other VOCs that have been regionally dominant e.g., Beta in South Africa and Gamma in South America. VOCs have evolved independently from the early virus (Wuhan), rather than sequentially from one to another, potentially implying differing pathways to dominance as each VOC has been replaced by a "fitter" VOC to drive new waves of infection. This pattern of evolution can be explained by immune escape combining with adaptive changes to the human host to confer more efficient replication and transmission in humans.
The deployment of effective vaccines has significantly reduced COVID19 associated hospitalisation, morbidity and mortality, yet high infection rates persist even in vaccinated/infected populations thus providing the opportunity for further viral evolution and the genesis of novel VOCs. Indeed, what is being observed with SARS-CoV-2 is consistent with previous work in other seasonal respiratory infections, showing that immune responses reduce symptoms from a second infection but are less effective at suppressing re-infection and inhibiting onward transmission.
The Omicron VOC represents the first substantial antigenic shift, with >30 mutations in Spike rendering the virus markedly less sensitive to neutralisation by antibodies induced by vaccination and/or prior infection. Importantly, Spike adaptation to escape human immunity was linked to increased replication in vitro and in vivo, and reduced pathogenicity in humans as well as animal models (though immune memory also presumably contributes to reduced Omicron pathogenicity in humans). Since the emergence of the first Omicron isolate, BA.1, further Omicron subvariants have evolved, yielding a series of sub-lineages, BA.1-5, and now BQ.1.1 and XBB, that co-circulate and recombine thus acquiring additional adaptive mutations. These mutations have enhanced replication, transmission and escape from the host adaptive and innate immunity.
In sum, the ongoing sequence diversification and evolution of SARS-CoV-2 as it transitions to endemicity, together with the inevitable waning of adaptive immunity at the level of individuals and populations, raise the very real possibility that the pathogenicity and transmissibility of future VOCs may increase, thus increasing disease burden and intensifying the pressures on health systems globally. Indeed, as of Jan 2023, there were over 11,000 hospitalisations due to COVID19. In preparing for the emergence of a new VOC, our consortium will work collaboratively to: 1) rapidly risk-assess new variants as they arise for increased transmission and pathogenesis; and 2) define and mechanistically dissect the viral sequence signatures/ patterns that are carried by VOCs and that underpin phenotypic changes. These data will help provide early warning as constellations of mutations of concern arise, and inform the scientific and public health responses to novel VOCs, providing scientific evidence to policy aimed to for example intensify vaccination programmes and/or refine the vaccines themselves.

Our overarching aims are organised into two overlapping and complementary modules.
1. Response Mode: real-time assessment of the pathogenicity and transmission potential of emerging VOCs;
2. Mechanistic insight into SARS-CoV-2 biology: in vitro, in vivo and machine learning approaches aimed to determine the mechanistic basis for the evolving biological phenotypes of VOCs, and identify mutational signatures of concern.
Our consortium will continue to work together with UK-HSA to horizon scan SARS-CoV-2 sequence information that corresponds with epidemiological signals. We will compile a weekly report on the circulating SARS-CoV-2 variants in the UK (using sequence data reported by COG-UK) and globally (using sequence data reported in GISAID). The report will highlight mutations with functional or antigenic potential impact on SARS-CoV-2 biology.
Once a signal is detected, we will mobilise G2P2 and carry out a series of rapid risk assessments based on analyses of virus replication and initial characterisation of host responses in vitro and in vivo assessment of pathology and transmission in animal models.
Using assays employed for the Response Mode work above, and experiments that allow more detailed phenotyping of virus growth, innate immune evasion, transmission and pathology. We will conduct mechanistic experiments with virus isolates and reverse engineered viruses aimed to experimentally link variants genotype to phenotype.
We have developed different recombinant SARS-CoV-2 viruses carrying any mutation of interest, allowing us to generate to date 100+ viruses. In addition, we have rescued "backbones" for SARS-CoV-2 variants of concerns (VOCs) such as Alpha, Beta, Gamma, Delta, and Omicron (and related sub-lineages) and a panel of 20 SARS-CoV-2 B.1 (ancestral) viruses carrying the spike gene from different variants. We have also created recombinant viruses that express reported genes that allow us to track virus spread in vitro and in vivo.