As of the end of January, SARS-CoV-2 has demonstrably infected more than 100 million individuals globally. It has killed more than 2 million. And the long-term sequelae of COVID infections – to say nothing of the health consequences of grief, social isolation and widespread economic distress – are still unfolding and will be for years to come.

To speak of opportunities amidst this cataclysm is to risk being tone-deaf. And yet, perhaps in the vein of “growth experiences” aka traumatic events, there are learnings to be had from SARS-CoV-2 that can mitigate this pandemic – and hopefully, the next one as well.

Mutations in SARS-CoV-2 are at once a challenge, a fact of life and an opportunity. In a Perspective published in the Jan. 29, 2021, issue of Science, researchers from Emory University wrote that “methods development over the past 10 to 15 years, the widespread avail ability of sequencing technologies…. mean that more can be learned from viral genomes than ever before.”

Fact of life

Genomes mutate. On the macro scale, that is what keeps life alive, because it enables species to adapt to changing circumstances. Most individual mutations are either harmful or neutral, reducing fitness or leaving it unchanged.

Viruses, which are at the very border between life and nonlife, mutate a lot. And viruses with RNA genomes have a high mutation rate within the viral world.

For an RNA virus, in fact, SARS-CoV-2 has a lower-than-average mutation rate. The workhorse enzyme for copying its genome has a proofreading mechanism, which reduces the number of errors that occur during viral replication. This means that SARS-CoV-2 mutates at about half the speed of influenza, and a quarter the speed of HIV – though still many times faster than DNA-based viruses, which have more elaborate mechanisms to prevent errors during replication.

Opportunities

Sharon Peacock, professor of public health and microbiology at the University of Cambridge, said that using variant data “is about being a genetic detective.”

As SARS-CoV-2 moves through its constant cycles of replicating itself, an average of one to two mistakes occur every month, Peacock told the audience at the 2021 annual meeting of the American Association for the Advancement of Science. And as those mistakes accumulate, the viruses develop “something like a genetic barcode.”

SARS-CoV-2 sequence

Those barcodes can be used at many different scales.

At the national and international level, Peacock showed sequencing data by the COVID-19 Genomics Consortium (COG-UK) showing how SARS-CoV-2 was introduced into different areas, data which “speaks to the sort of actions required at borders.”

In two different samples in the entire U.K. and Scotland, respectively, genomes sequenced during the now-ongoing second wave that began in the fall of 2020 were genetically distinct from those driving the first wave of spring 2020, suggesting summer holiday travel, rather than a result of a return to indoor living in the fall, as a major driver of the second wave.

Peacock also described the sequencing of a case cluster of infections in dialysis patients at a Cambridge hospital in the spring of 2020. Unexpectedly, the infections occurred not while patients were in the hospital ward, but during transportation to and from their appointments. The hospital changed its transportation protocols as a result of the study – an example, she said, of “how sequencing can be used at the local level for public health benefit.”

Peacock said that those opportunities were underpinned by technology advances in sequencing and analysis.

While sequencing HIV took three years, the first SARS-CoV-2 genome sequence was released online within three weeks of the beginning of that pandemic. The Institut Pasteur published the first sequence from a European case five days after the French Ministry of Health confirmed the first French cases.

And computational methods now allow the simultaneous analysis of thousands, or even tens of thousands of sequences.

A mutation can be both a clinical challenge and a tracking opportunity. Under certain circumstances, for example, reduced sensitivity to a mutated protein can lead to improved detection of the variant virus.

Such is the case for Thermo Fisher Scientific Inc.’s Taqpath COVID-19 Combo Kit and Applied DNA Sciences Inc.’s Linea COVID-19 Assay Kit. Both detect multiple targets, including one in the spike protein that is mutated in B.1.1.7, the more transmissible strain that is now the dominant lineage in the U.K. The tests have reduced sensitivity to their spike protein target, but not to their other targets, in B.1.1.7.

As a result, B.1.1.7 samples may show up as “a pattern of 2/3 positive targets showing the S-gene drop out (reduced sensitivity with the S-gene target), when using the Taqpath COVID-19 Combo Kit, and a pattern of 1/2 positive targets showing the S-gene drop out when using the Linea COVID-19 Assay Kit,” the U.S. FDA wrote in a Jan. 8, 2021, letter to clinical laboratory staff and health care providers. The agency recommended that when such a pattern is observed, labs “should consider further characterizing the specimen with genetic sequencing” if rapid whole genome sequencing is accessible at their institution, and reaching out to the U.S. CDC otherwise.

Opportunities do not have to translate into better public health outcomes. The U.K., for example, has sequenced roughly 5% to 6% of all cases, a far higher proportion than any other country. But it has handled the pandemic poorly from a public health perspective.

R0 (R-nought), the average number of new infections resulting from each case, which is a measure of how contagious a virus is, can also be estimated more accurately from sequencing than via epidemiology. Caseloads are affected by reporting rates as well as R0– in the most extreme case, reporting rates are always zero before a new variant has been identified. So, sequencing “may be particularly useful in the early stages of virus circulation when a large proportion of identified cases may be new introductions and when reporting rates are likely to be low,” the Emory team wrote in Science.

Challenge

Clinical challenges arise when the virus mutates in a way that makes it more dangerous in any number of ways. For SARS-CoV-2, the worrisome mutations to date have made the virus more transmissible, leading to new spikes in caseloads. In addition to causing more severe disease, the most common of these variants, the B.1.1.7 variant, contributes to higher death rates by pushing up the overall caseload, thus overburdening hospital systems.

Mutations can also increase the severity of disease. As with COVID-19, the 1918/1919 Spanish flu pandemic, had several waves, with the second being far deadlier than the first. In 1918, though, the line from mutations to higher death rates was direct – the mutated virus of the second wave was more lethal.

Finally, mutations that occur in parts of the virus targeted by drugs and vaccines can reduce their effectiveness. This is the case for the E484K mutation. The virus variant B.1.351, which includes E484K, is the dominant variant in South Africa. Novavax Inc.’s and Johnson & Johnson’s vaccines were less effective – though still effective – in trials in South Africa than in Europe and the U.S., while Astrazeneca’s candidate did so poorly that the country has halted its rollout.