On Omicron

We have seen​ plenty of viral variants, some with Spike genes of sufficient interest to merit a Greek letter. Spike is the virus’s entry weapon, and the bit of the virus that’s targeted by vaccines. If your antibodies block Spike, you block the virus – and if Spike has mutated, it may have become better at dodging those antibodies. Delta has been the most vicious variant so far, with a Spike that allows it to enter cells more efficiently and brush off some antibodies. The strange Spikes of Epsilon, Zeta, Eta etc all passed by without great alarm, none of them able to compete with the Delta variant. There were worries that the next serious variant might be a descendant of Delta: one version with an extra couple of mutations has been slowly gaining ground, but there are no reasons to believe it will escape vaccine-induced immunity any more than its parent did. There was perhaps a sense of complacency about further variants in general. Since Delta, every variant from Epsilon to Kappa has been downgraded, with Lambda and Mu still designated as merely 'Variants of Interest'. If the mighty Delta could be crushed by the first-generation vaccines, albeit in three doses, what hope for the Nu variant when it came along? But Nu was too much like the English ‘new’, and Xi too much like the president of the People’s Republic of China; so we arrive at Omicron.

On 23 November a postdoctoral researcher at Imperial noticed a cluster of unusual Sars-CoV-2 genomes. The earliest sequence was from 11 November. There were a lot of mutations in the Spike protein, some of them in places that we know might enhance the ability of the virus to transmit, and others in places known to be the targets of neutralising antibodies. Several of them had cropped up in studies trying to determine what a worst case scenario vaccine-escape mutant would look like.

The news isn’t all bad. Delta is still (for now) the main circulating Sars-CoV-2 variant – outside Southern Africa, it’s several orders of magnitude more prevalent than Omicron. Delta has been a huge threat. It transmits more efficiently than the previous variants of concern and partly evades vaccine-induced immunity: the protective effect of two doses, strong against previous variants, is more modest against Delta. The vaccines we have are all based on the original ‘Wuhan’ Spike. It was conceivable that a third dose of ‘Wuhan’ vaccine would induce more antibodies to the original Spike but wouldn’t cross-protect against Delta. As it turns out, a third dose broadens the neutralising power of the vaccines so that Delta is very effectively blocked. It’s too early to say how well they will work against Omicron.

On 25 November, South African scientists raised the alarm. They had already spotted the new variant and were tracking its progress; 77 sequences had been collected in Gauteng Province between 12 and 20 November. One of the deletions in Spike was familiar from the Alpha variant (the one that ruined Christmas last year). By pure chance, it interferes with one of the popular commercial PCR tests for the virus. The test targets three viral genes including Spike (S). If the other two genes are detected, but S fails, it still counts as an infection (you need two out of three to identify a positive). This S gene target failure (SGTF) can be used to track a variant’s spread. We could see Alpha gaining ground by SGTF a year ago. When Delta took over in May, SGTFs became rare. Last month SGTF became dominant in Gauteng, then elsewhere in South Africa, and there are now clear signs of a fourth wave of infections in South Africa.

There was immediate action. On 26 November the World Health Organisation declared Omicron a variant of concern. In the UK, travel from Southern Africa was heavily restricted, masks became mandatory on public transport and in shops, PCR tests rather than the less sensitive lateral flows were required for travel, and a campaign was launched to deliver a third dose of vaccine to all adults. There are also efforts to track and isolate suspected cases of Omicron.

The rationale for the travel ban is that the majority of cases are thought to be in Southern Africa. There hasn’t been much SGTF elsewhere, and it’s estimated that the variant originated some time between late September and October. Thanks to surveillance in South Africa, we have caught this very quickly. There are, however, cases in the UK and elsewhere without obvious connections to Southern Africa. Restricting travel will reduce the number of cases that start a new Omicron wave, but it won’t prevent it. It’s a delaying tactic, and whether it is justified depends on what we do with the borrowed time. As Tulio de Oliveira, one of the leading South African scientists working on Covid, pointed out, ‘border restrictions deter nations from alerting the world to future variants. They will also slow down urgent research because few planes carrying cargo – including lab supplies needed for sequencing – are now arriving in South Africa.’ I hope the restrictions will be short term; if not they will be short-sighted.

As I write, knowledge of the Omicron variant has been in the public domain for ten days. It has gone from being a furrow in the brow of a worried virologist to a global threat in a very short time. There are a lot of unanswered questions. What about severity: might it be ‘milder’? What about lateral flow tests: will they still detect it? What about the antivirals: will they still work? Where did it come from: human or animal? Most important: will the vaccines still work?

Let’s tackle that last one first. The vaccines will definitely still work, we just don’t know to what extent. If you haven’t yet had your third dose, get it as soon as you reasonably can. If you’ve not had your first dose, get it today. South African scientists have already posted a pre-print showing that Omicron appears more likely to infect previously infected people – the first empirical confirmation that this variant will at least partly escape immunity. It’s very early days to assess the extent to which it escapes, but it would be a major surprise if it wasn’t substantially less well neutralised by antibodies generated by the vaccines. Researchers (including the team I work with at the Crick Institute) are rushing to quantify this. The first studies may report in a matter of days, and we will begin to get an idea of just how bad it could be.

Might Omicron be ‘milder’? There’s no reason to think so. Viruses evolve to optimise transmission within a population. For viruses that are not immediately lethal to their hosts, there is no evidence that they evolve to become less pathogenic. Immunity, acquired by vaccination or infection, makes people less likely to become severely unwell if they are infected again. If a virus appears to become ‘milder’, it’s usually because of partial immunity in previously infected or vaccinated individuals. Most of the South African population has been either previously infected or vaccinated: reports claiming that most Omicron cases are ‘mild’ reflect this, and we cannot yet infer anything useful about the intrinsic ability of the virus to cause disease. Cases in Gauteng have risen rapidly, and so have hospitalisations. This is very early in the Omicron wave; deaths will follow. We can hope the rates will be lower than expected, or we can fear they will be higher – but neither hope nor fear has any rational basis at this point.

There are some potentially important mutations to parts of the virus other than Spike. Lateral flow tests target N, a protein in the virus that’s more abundant than Spike and less variable. Omicron has a couple of mutations in N. It’s likely that most lateral flow tests will maintain their sensitivity but that hasn’t yet been quantified and it’s possible that one or more proprietary devices may suffer. This is a good reason, along with SGTF, to prefer PCR tests for travellers just now.

What about antivirals? They can be helpful if given very early. There are two new drugs which can be given as tablets and will probably be available soon. Molnupiravir – named after Thor’s hammer, as the marketing people would have you believe it does to the virus what Mjölnir does to giants in the Prose Edda (or, let’s face it, to bad guys in Marvel movies) – is unlikely to be affected. Probably the same is true for Pfizer’s Paxlovid. There are some artificial neutralising antibodies on the market already, which have been shown to be very effective in some circumstances against earlier variants. Because they target Spike, some of them are likely to be less effective against Omicron.

Viral origins aren’t always easy to determine. It’s interesting that Omicron has arisen not from Delta but from a different branch of the Sars-CoV-2 evolutionary tree. Delta has had plenty of opportunity to become its most transmissible version. There are suggestions that Omicron might have been transmitted to an animal reservoir (reverse zoonosis), and then jumped back to humans. It’s not impossible, but I doubt it. It seems more likely that Omicron arose as the virus lingered in an immunosuppressed individual, gradually acquiring all the mutations it needed to escape ineffective immunity – plenty of such cases have been described. Untreated HIV is the most prevalent cause of immunosuppression in Southern Africa: yet another reason, if any were needed, to take global health inequality more seriously.

Still, it seems that only a modest quantity of neutralising antibodies is needed to prevent Covid-19. Three doses of vaccine, in people with normal immune systems, provide enormous amounts of antibodies to previous variants: they will be less effective against Omicron, but the hope is that they might still be enough. Other aspects of vaccine-induced immunity that help protect against severe disease (mediated by our T and B cells) will still work. The next generation of vaccines may include Spikes from multiple variants and should possess an even broader neutralising capability. The antiviral drugs will be useful. We aren’t going back to square one, but some hospitals are already struggling. Many intensive care beds are still occupied by unvaccinated adults infected with Delta. Also at high risk are immunocompromised people whom we must do all we can to protect. Get your third jab.

3 December

Listen to Rupert Beale discuss this piece with John Lanchester and Thomas Jones on the LRB Podcast.