Rupert Beale · On Omicron · LRB 4 December 2021

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WI have seen the mailLots of viral variants, some containing spike genes of enough importance to merit the Greek letter. Spike is the virus’s entry weapon, the part of the virus that vaccines target. If your antibodies block the spike, you block the virus — and if the spike mutates, it might be better at blocking those antibodies. Delta has been the most aggressive form to date, with Spike allowing it to enter cells more efficiently and get rid of some of the antibodies. The strange spikes of Epsilon, Zeta, Eta, etc. passed without much warning, and none of them were able to compete with the Delta variant. There have been concerns that the next dangerous variant might be delta descendent: one version with two additional mutations is slowly gaining ground, but there are no reasons to believe it would escape vaccine-induced immunity any more than her father did. There may have been a sense of satisfaction with the other variables in general. Since delta, the classification of each variable has been lowered from epsilon to kappa, with Lambda and Mu still being classified as only “variables of interest”. If the Great Delta could be crushed by first-generation vaccines, albeit in three doses, what was the hope for the Nu variant when it came? But Nu was a lot like the English word “new”, and Xi was a lot like the president of the People’s Republic of China; So we get to Omicron.

On November 23, a postdoctoral researcher at Imperial University noticed a set of unusual genomes of Sars-CoV-2. The earliest sequence was from 11 November. There have been a lot of mutations in the spike protein, some in places we know might enhance the virus’s ability to be transmissible, others in places known to be targets for neutralizing antibodies. Several of them have appeared in studies trying to determine the worst-case scenario a vaccine escape mutant would look like.

The news isn’t all bad. Delta remains (for the time being) the main circulating variant of Sars-CoV-2 – outside of South Africa, it is several times by volume more prevalent than Omicron. Delta was a huge threat. It transmits more efficiently than earlier variants of concern and partially avoids vaccine-induced immunity: the protective effect of two doses, strong against earlier variants, more modest against delta. All of our vaccines are based on the original Wuhan spike. It was conceivable that a third dose of the ‘Wuhan’ vaccine would induce more of the original Spike antibodies but would not protect against Delta. As it turns out, a third dose extends the equivalent power of the vaccines so that delta is blocked very effectively. It is too early to say how well they will work against Omicron.

On November 25, South African scientists sounded the alarm. They had already discovered the new form and had been following its progress; 77 sequences were collected in Gauteng Province between 12 and 20 November. One of Spike’s omissions was familiar from the Alpha variant (which ruined Christmas last year). By pure chance, it interfered with one of the common 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 is still considered an infection (you need two out of three to determine positivity). Failure of the S gene target (SGTF) can be used to track variant propagation. We could see Alpha gain ground by the SGTF a year ago. When Delta took over in May, SGTFs became scarce. Last month, the 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 November 26, the World Health Organization declared Omicron to be the worrisome alternative. In the UK, travel from South Africa was severely restricted, masks became mandatory on public transport and in stores, PCR tests were required for travel rather than less sensitive side flows, and a campaign was launched to introduce a third dose of the vaccine to all adults. There are also efforts to trace and isolate suspected cases of Omicron.

The rationale for the travel ban is that the majority of cases are believed to be in southern Africa. There was not much SGTF elsewhere, and it is estimated that the variant arose sometime between late September and October. Thanks to monitoring in South Africa, we figured this out pretty quickly. However, there are cases in the UK and elsewhere without clear links to South Africa. Restricting travel will reduce the number of cases starting a new wave of Omicron, but it will not prevent it. It’s a delay tactic, and whether it’s justified depends on what we’re doing with the wasted time. Tulio de Oliveira, one of the leading South African scientists working on Covid, also noted that “border restrictions prevent countries from alerting the world to future variables. It will also slow down urgent research because a few planes carrying the cargo – including laboratory supplies needed for sequencing – are now arriving in South Africa. I hope the limitations are short term; If not, they will be shortsighted.

As I was writing, knowledge of the Omicron variant was in the public domain for ten days. He’s gone from being a furrow of a worried virologist to a global threat in no time at all. There are many unanswered questions. What about the severity: Could it be “moderate”? What About Lateral Flow Tests: Will You Still Find It? What about antivirals: will they still work? Where did it come from: human or animal? Most important: Will vaccines still work?

Let’s deal with the latter first. Vaccines will certainly still work, but we don’t know to what extent. If you have not yet taken your third dose, get it as soon as possible. If you haven’t taken your first dose, get it today. South African scientists have already published a print version showing that Omicron appears to be more susceptible to previously infected people – the first experimental confirmation that this variant will escape at least partially from immunity. It is still too early to assess the extent of its escape, but it would be very surprising if it is not well neutralized by the antibodies that vaccines generate. Researchers (including the team I work with at the Crick Institute) are quick to determine this. The first studies may be reported in a matter of days, and we’ll start to get an idea of ​​how bad it could be.

Could Omicron be milder? There is no reason to believe that. Viruses evolve to improve transmission between populations. For viruses that are not immediately fatal to their hosts, there is no evidence that they evolve to become less pathogenic. Immunity, acquired through vaccination or infection, makes people less likely to become very unwell if they become infected again. If the virus appears to be becoming ‘milder’, it is usually due to partial immunity in previously infected or vaccinated individuals. Most South Africans have previously been infected or vaccinated: reports claiming that most cases of Omicron are ‘mild’ reflect this, and we cannot yet conclude anything useful about the intrinsic capacity of the virus to cause disease. Cases in Gauteng have risen rapidly, as have hospital admissions. 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 there is no rationale for hope or fear at this point.

There are some mutations that are potentially important for parts of the virus other than the spike. Lateral flow tests target N, a protein in the virus that is more abundant than Spike and less variable. Omicron contains two mutations in N. This is a good reason, along with SGTF, to now favor PCR tests for travelers.

What about antiviruses? It can be useful if given very early. There are two newer drugs that can be given in tablet form and will likely be available soon. Molnupiravir – named after Thor’s hammer, marketing people want you to believe it does to the virus what Mjölnir does to the giants in Ida prose (Or, let’s face it, for the baddies in the Marvel movies) — you’re unlikely to be affected. The same may be true of Pfizer’s Paxlovid. There are already some synthetic neutralizing antibodies on the market, which have been shown to be very effective in some conditions against the above variants. Since they target Spike, some of them will likely be less effective against Omicron.

It is not always easy to identify viral origins. It is interesting that Omicron arose not from delta but from a different branch of the Sars-CoV-2 evolutionary tree. Delta has had plenty of opportunities to become its most portable version. There are suggestions that Omicron may have been transferred to an animal tank (reverse zoonosis), and then jumped back to humans. It’s not impossible, but I doubt it. It seems more likely that Omicron arose when the virus remained in an immunosuppressed person, and gradually acquired all the mutations it needed to escape from ineffective immunity – many of these cases have been described. Untreated HIV is the most prevalent cause of immunosuppression in South Africa: another reason, if anything, to take global health inequality more seriously.

However, only a modest amount of neutralizing antibodies appears to be needed to prevent Covid-19. Three doses of the vaccine provide, for people with normal immune systems, massive amounts of antibodies to the former variants: they will be less effective against Omicron, but the hope is that they may still be sufficient. There will still be other aspects of vaccine-induced immunity that help protect against severe disease (mediated by our T cells and B cells). Next-generation vaccines may include spikes of multiple variants and should possess a broader neutralizing ability. Antiviral drugs will be helpful. We won’t go back to square one, but some hospitals are already struggling. Many intensive care beds are still occupied by unvaccinated adults with delta disease. Also, immunocompromised people are at great risk and we must do everything we can to protect them. Get a third hit.

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