LONDON – A new national consortium of virologists has been set up to systematically assess how mutations in SARS-CoV-2 affect key outcomes such as effectiveness of vaccines and therapies, transmissibility of the virus and the severity of COVID-19 infections.

Now is the critical time to do this, as the level of both natural and vaccine-conferred immunity that might drive natural selection is increasing, said Wendy Barclay, head of the department of infectious disease at Imperial College London, who is leading the G2P-UK (Genotype to Phenotype-UK) project.

“The virus has circulated in humans for more than a year; we’re in a phase where the virus is constantly throwing up new variants and we need to gear up to assess the risk they pose, and to understand the mechanisms by which they act,” Barclay said.

The consortium gets off the ground as new variants are emerging that appear to be more infectious, such as 501.V2, first detected in South Africa; B.1.1.7, first picked up in the U.K. in September and now accounting for more than 50% of cases in the country; and most recently a new variant found in Brazil that has worrying mutations.

The Brazil variant contains 17 unique amino acid changes and three deletions, including mutations of putative or known biological importance, such as E484K in the receptor binding domain of the spike protein by which the virus enters the human host cell, and K417T, which possibly allows the virus to escape some monoclonal antibody therapies.

Finding variants that matter

SARS-CoV-2 has been mutating ever since it emerged a year ago, but with increasing levels of immunity in the human host it is now under selective pressure and new variants identified by genome sequencing are more likely to have phenotypic consequences that increase viral fitness.

G2P-UK will consult with researchers in the UK COVID-19 genetics consortium, which to date has sequenced more than 156,000 SARS-CoV-2 samples from patients, to look for variants that could have important consequences, such as those associated with fast-spreading virus clusters.

The huge amount of viral sequencing carried out in the U.K. has caused a bottleneck in interpreting it, and the aim of G2P-UK is to speed things up, said Barclay. Many variants will mean nothing, but there may be one that enables the virus to escape from the immune response, that affects transmission, or that will allow SARS-CoV-2 to cross to other animals.

The 10 institutes that are part of G2P-UK will assess the biological significance of variants, working in parallel to conduct in vitro assays assessing replication in human cell lines, the effect on antibodies from people with immunity, spike protein antigenicity and receptor binding.

Variants of most concern will be further assessed in animals to see if virus mutations alter the immune response, the effectiveness of vaccines and therapies, the impact on disease severity and how readily variants transmit by direct contact or airborne routes.

Setting up a streamlined and coordinated national program using different methods and assays to simultaneously study variants of concern will produce faster and more reliable results, to inform public health policy and clinical practice, said Ottoline Leyser, chief executive of UK Research and Innovation, the agency funding the research. “This is critical research, which will feed into government decision-making on a daily basis,” she said.

Michael Malim, head of the school of immunology at King’s College London, co-lead on the project, reckons it will take two to three weeks to carry out in vitro work to assess if any particular variant is more dangerous. “We aim to assess [changes] as they arise,” Malim said. “We need to know if variants are less sensitive to the immune response generated by vaccines.”

It may ultimately become possible to predict likely escape variants directly from sequence data, which would speed up the process. In a paper in the Jan. 15, 2021, issue of Science, scientists at the Massachusetts Institute of Technology reported that by adapting algorithms originally used for natural language decoding, they were able to predict likely escape variants in SARS-CoV-2, as well as influenza and HIV.

Most mutations are deleterious to fitness, because the resulting protein is no longer functional for one reason or another. The authors reasoned that this situation is analogous to sentences, where the change of a single word can either result in a sentence that is still meaningful – though its meaning is different – or one that no longer conforms to the rules of grammar. For example, in the sentence “Sally ate eggs for breakfast,” replacing “eggs” with “cereal” will still result in a meaningful sentence. Replacing “eggs” with any number of words, though, – for example, “any,” number,” “of,” or “words” – will not produce a functional sentence.

An early warning from minks

The variant that alerted researchers to need to set up a coordinated system for interpreting the significance of genotypic changes was the Danish mink virus, which arose in densely farmed mink and spread back to the local community.

That has a mutation, Y453F, in the spike protein receptor binding domain. “We showed the spike protein had mutated in such a way that it bound more effectively,” said Bryan Charleston, director of the Pirbright Institute, a lab that specializes in viral diseases in livestock and their potential to spread humans.

Pirbright has a number of animal models in which ACE2, the receptor through which SARS-CoV-2 attaches to host cells, is expressed. “So we can understand the threat of a variant moving into another species, and also if [a variant] binds more effectively to the human receptor,” Charleston said.

G2P-UK will be able to respond to concerns about variants with “solid evidence” said Massimo Palmarini, director of the center for virus research at Glasgow University, also a co-lead in G2P-UK. Looking into the phenotypes of variants that are causing the most infections, it will be possible to say if there is a biological basis for this, or if it due to a founder effect, in which one person spread the infection to many more.

The World Health Organization (WHO) currently is considering how to establish a global surveillance system to track SARS-CoV-2 variants of interest, in the same way as it tracks which influenza viruses are circulating to inform the design of vaccines each flu season.

G2P-UK is feeding into the draft plan, which Barclay said will require in depth understanding of the ways in which differences in genotype impact on the phenotype. The question is, “How big will the difference need to be to update a vaccine on a global level?” she said.

As yet, there is no internationally approved definition of “variant of concern,” though WHO has called for such a definition to be agreed through consultation. There also is no agreement on consistent nomenclature for variants, and here again, WHO is trying to create a standard.