Eeek!

Biologists​  love abbreviations, but we often use them clumsily. What may sound like catchy acronyms to one group of researchers are tiresome jargon to colleagues in related fields. Fruit fly geneticists have taken whimsy to absurdity: MAD stands for ‘Mothers Against Decapentaplegic’. The ‘decapentaplegic’ bit comes from a mutant fly that doesn’t correctly form fifteen (deca-penta) important structures that go on to become legs, wings, antennae etc. The ‘Mothers Against’ bit is a joke that may have been funny in 1995. Immunologists tend towards the impenetrably boring. We’ve named messenger molecules between white blood cells ‘interleukins’, and given each of them a natural number. Logical enough, but we’ve now got up to IL38, and it’s almost impossible to recall what each of them does. Not to be outdone, molecular epidemiologists have come up with such names as B.1.1.7. That’s the Sars-CoV-2 variant now dominating the pandemic in the UK (and Ireland, Denmark, Israel and soon Germany and much of the rest of the world). The variant that’s dominating in South Africa is B.1.351, or 20H/501Y.V2 if you prefer. At least in Brazil what would have been B.1.1.28.P1 has been allowed to drop its cumbersome honorific and become plain old P1.

If biologists get befuddled it’s hardly a surprise that the public and politicians are confused too. These names are hard to remember and to pronounce, so in the UK we refer to B.1.1.7 as the Kent variant. Elsewhere in the world it’s known as the UK variant, or ‘British virus’. Toponyms in virology can quickly become problematic: Trump often spoke of the ‘Wuhan virus’, the ‘Chinese virus’ and then ‘Kung flu’.

When Matt Hancock announced the appearance of a new variant of concern on 14 December, there was scepticism from many. Was it just an excuse for the failure of the ‘tier’ system that had been put in place after the November ‘lockdown’? The variants that had emerged until that point weren’t much to be concerned about. Scientists were frequently correcting misapprehensions that a new ‘strain’ of coronavirus had been discovered, when all that was happening were a few biologically insignificant mutations in the virus that allowed its transmission to be tracked. Under these circumstances, unmemorable names (letter point something point something else) were an advantage. It seemed improbable, though, that the health secretary was imagining the emergence of a more transmissible variant; he was more likely to be trying to persuade his cabinet colleagues of the need for further restrictions.

A more transmissible virus is a disaster. We knew that in theory in December, and found out for real in January. Measures needed to be put in place immediately to prevent its spread. What happened instead was a modest strengthening of the tier system and a tightening of the holiday relaxation plans. ‘Boris Johnson battles experts to save Christmas,’ the Express trumpeted. Peace on earth and goodwill to all men were sacrificed for a few days’ shopping.

Uncontrolled spread – as we knew it would – led to an even greater wave of infections, hospitalisations and deaths than last spring. Children were sent to school for one day before the necessary ‘lockdown’ was reimposed. The impulse to keep schools open where possible is laudable; children have been educationally disadvantaged by online-only learning and don’t often get seriously ill with the virus. They can, however, efficiently spread it to one another and to potentially more vulnerable adults. The single day of mixing in January will have contributed nothing to their education but will have caused many deaths.

Further deaths can be prevented by vaccines. The highly successful Moderna and BioNTech/Pfizer vaccines, as well as the SARS-CoV-2 virus itself, are composed of messenger RNA, the same stuff that carries genetic messages from the DNA in a cell nucleus to the ribosomes elsewhere in the cell, the molecular machines that decode the messages and make proteins. All the vaccines aim to generate immune responses to the viral protein known as Spike, the sugar-coated switchblade that the virus has evolved to force its way into our cells.

We can describe proteins as strings of letters, with each letter representing a different amino acid. Each has different chemical properties, and many of them can be additionally modified (for example with sugars). Spike consists of a string of 1273 amino acids folded up into a tightly packed protein. It can adopt a variety of folded shapes to achieve its biological purpose: to insert itself, like a flick knife, into the outer membranes of our cells and pull them apart. Structural biologists at the Francis Crick Institute have catalogued ten different conformations that Spike adopts to achieve this goal – complicated and fascinating stuff. This gives antibodies plenty of chances, however, to stick to Spike in such a way as to disrupt it: if you wanted to stop someone jabbing you with a flick knife, you could blunt the blade, jam the switch or remove the spring. To be really sure, you could do all three. A good vaccine elicits just this kind of response: antibodies that bind to multiple different sites in Spike so that if a new variant comes along it still isn’t dangerous.

The Kent variant, B.1.1.7, has eight changes to the amino acid code for Spike. We represent these changes by listing the letter for the amino acid in the original Wuhan variant, its numbered position in the protein, and the letter for the new amino acid. N501Y, for example, means that in position 501, asparagine (N) has been replaced by tyrosine (Y). This helps the Kent variant stick better to cells, and is probably part of the reason it’s spreading faster. Fortunately it’s still very susceptible to the vaccines, all currently based on the original Wuhan strain. You could think of it as a flick knife with a sharper blade – but the blade can still be blunted, and if you jam the mechanism, it’s still jammed.

The variant circulating in South Africa (B.1.351) and the P1 isolate from Brazil have both acquired E484K – a change at position 484 from glutamic acid (E) to lysine (K). It’s a change from acid to alkali, from a highly negative charge to a highly positive charge. Antibodies stick to proteins partly on the basis of charge: opposites attract, so an antibody that sticks to Spike close to position 484 will probably have a positive amino acid at its binding interface to help stick to the Wuhan Spike’s E. If it instead encounters the positive K, the antibody will be repelled. This one mutation does seem to impair antibody binding, and is making vaccines less effective. In one study in South Africa, the Oxford/AstraZeneca vaccine didn’t show a convincingly protective effect against the B.1.351 variant. The numbers were small and there was a very wide margin of uncertainty, but the South African authorities are switching to other vaccines which have shown more evidence of effectiveness. It’s likely, though, that all the vaccines will still generate some useful immunity via antibodies sticking to other parts of Spike, and by other forms of immunity that don’t rely on antibodies.

There are several examples of the Kent variant having also acquired the E484K mutation. Some virologists have started to describe the variants by nicknames based on the Spike mutations. N501Y is known as ‘Nelly’, and E484K as ‘Eeek’. These mutations are happening among many different lineages, a phenomenon known as convergent evolution. This happens when a mutation confers a selective advantage, so it’s a flag that something may be really different about these variants. The biology of the virus is much more complicated than Spike variants. It’s quite possible we will see variants emerge over time with mutations in other genes that confer a different kind of selective advantage: for example, they might allow the virus to antagonise the immune system better. What’s really critical for humanity in the next stage of the pandemic, however, is how well the vaccines protect against the emerging variants. That means that Spike variants are the main thing we must look out for.

We have a lot of highly effective vaccines. For all the failures of the UK response, the vaccine rollout has been among the best in the world. The Vaccine Taskforce, led by Kate Bingham, got on with its job well in advance of knowing whether vaccines would be effective. Her background in biotech venture capital proved relevant for making massive bets on biological products of uncertain efficacy. The NHS and many unpaid volunteers who are currently delivering the vaccinations are doing a magnificent job. More than 90 per cent of over-seventies have had their first injection, hugely exceeding expectations. The UK’s calculated gamble to delay a second dose of the Pfizer vaccine from three to up to twelve weeks is probably also well judged. There is a theoretical risk that this delay will help generate vaccine-resistant mutants, but a recent paper in the Lancet analysing data from Israel suggests that the first dose alone offers 85 per cent protection against symptomatic disease from fifteen days after it is administered. Simon Stevens, the head of NHS England, quoted Churchill as he turned to the prime minister with the plea: ‘Give us the tools … and we will finish the job.’

We must finish the job. The biggest risk to the success of the vaccination programme is easing restrictions too early. The E484K (Eeek!) variants are already worrying as partial immune-escape mutants. But updated vaccines that target Nelly and Eeek will be available by the autumn, existing ones are already effective, and for the virus to evolve to escape the vaccines completely seems unlikely: it would need simultaneously to evolve a variety of mutations that block multiple different antibodies. Every time someone is infected, there is a tiny chance of such a set of mutations occurring. It’s been compared to buying the virus a lottery ticket. Winning the lottery isn’t lucky if you can buy thirty million tickets. We should therefore pursue a very cautious strategy and not allow uncontrolled spread in younger people even if older and more vulnerable people have been vaccinated. Effective testing regimes, though not a panacea, can help with establishing more normal education and a better functioning economy until the vaccines have been administered to the great majority of adults.

What might the end of the pandemic look like? There are two main possibilities. The first, and most likely, is that Sars-CoV-2 becomes an endemic coronavirus that gives rise to large numbers of infections in winter. Vaccinated or previously infected people may get infected again, but because they have some measure of immunity their infections will be mild, much as with the four seasonal coronaviruses we have lived with for decades. Unvaccinated people and an unlucky few whose immunity isn’t protective may become seriously ill. Elderly people, those with certain underlying conditions and healthcare workers will need a booster every now and then. Seasonal coronaviruses tend to rise in two-yearly cycles, so it could be that a booster is needed every other year.

The second, more desirable outcome is that we treat Sars-CoV-2 a bit like measles, and try to stamp it out as completely as we can. I’ve seen erroneous commentary that this isn’t possible because measles doesn’t mutate as fast as Sars-CoV-2. In fact, measles intrinsically mutates faster; it just makes more errors as it replicates because, unlike coronavirus, it doesn’t bother with proofreading. The real reason for the near elimination of measles is that its equivalent of Spike is more constrained by the structures it must form and by the multiple different types of neutralising antibodies induced by the vaccine. Near elimination of Sars-CoV-2 could be equally possible if updated, highly effective vaccines prevent the virus and any evolving variants from spreading. With better vaccine technology we might be able to direct a very strong antibody response to the bits of Spike that the virus can’t do without; alternatively, there might be a vaccine that covers a wide range of different Spike variants – so wide that there is no way for the virus to evolve to escape them all.

In either case, we should push for a global effort to reduce the spread of the virus and ensure that vaccines are available and administered in resource-poor settings as well as highly developed economies. A strong case for this can be made on the basis of enlightened self-interest, but after so much suffering and death some genuine altruism wouldn’t go amiss.

19 February