Omicron Hits the Mutation Jackpot

SWPRS | 28 Nov 2021

The South African Omicron variant is the first coronavirus variant to achieve immune escape from all three major antibody classes. Is it finally time to panic?

Back in July, SPR presented a framework developed by the Bloom lab to easily identify the immune escape potential of new coronavirus variants based on three major antibody classes targeting the coronavirus receptor binding domain (see updated table above).

At the time, we noted that none of the existing coronavirus variants had achieved escape from all three major antibody classes, although variants from South Africa (Beta), Brazil (Gamma), Nepal (Delta+) and Peru (Lambda) had already escaped two out of three antibody classes.

We also noted that “such a triple-escape variant may arrive next autumn or winter and could potentially lead to increased rates of vaccine breakthroughs and re-infections, especially in regions that have not yet faced the Brazilian or South African class 2 escape variants.”

The new Omicron variant, detected just a week ago in South Africa, now has become the first variant to achieve such an immune escape from all three major antibody classes, including a double mutation in the important class 2 region of the receptor binding domain (see table above).

Although the final results are not yet available, this likely means that existing coronavirus vaccines, which are still based on the original 2019 Wuhan variant, will have significantly lower (but not zero) neutralization effectiveness against the Omicron variant.

Natural immunity against re-infection may also decrease somewhat, especially in places that have not yet faced the Brazilian or South African ‘class 2’ escape variants, which is the case in Europe, the United States, and large parts of Asia. Nevertheless, natural immunity is likely to remain stronger than vaccine-induced immunity, thanks to a broader antibody response, a stronger T-cell response, and first-line mucosal immunity.

Besides immune escape, the second key aspect of any new variant is transmissibility: will the Omicron variant be able to displace existing variants and assert itself? Initial data from South Africa indicates that Omicron has fully displaced Delta in just two weeks (see also:

The South African Delta wave had already ended in late October, but since mid-November, local infections have indeed increased again. However, the mere fact that a new variant is displacing a previous variant after some time does not prove that it is any more transmissible: influenza virus variants displace each other all the time without increasing their (absolute) infectiousness.

The third key aspect is virulence and disease severity, which is primarily determined by receptor binding affinity (see figure below). There is currently no evidence that Omicron is any more virulent than previous variants. In fact, actual clinical differences between coronavirus variants (including Delta) have so far been much smaller than is often claimed by various news outlets.

In conclusion, Omicron certainly has the potential to establish itself, although it may face continued competition from some Delta subvariants. Based on current evidence, Omicron does not seem to make much of a difference in terms of disease severity, transmission or covid risk groups, but it appears likely that vaccines will have to be updated to maintain high effectiveness.

As noted back in July, the novel coronavirus has already played many of its best ‘cards’ in terms of immune escape mutations. In terms of receptor binding affinity, there are a few more options left (see chart below). The arrival of immune-escape variants once again highlights the importance of early outpatient treatment of high-risk covid patients, regardless of vaccination status.


1) Coronavirus escape mutations (per antibody class and overall)

A mutation at position 484 has the strongest overall immune escape effect.

Coronavirus escape mutations, per antibody class and overall (Bloom lab)

2) Coronavirus mutations increasing or decreasing ACE2 receptor binding affinity

Mutations increasing (blue) or decreasing (red) ACE2 receptor binding affinity. An increased receptor binding affinity may increase or decrease virulence and infectiousness.

Coronavirus mutations and their effect on ACE2 receptor binding affinity (Starr et al.)

3) RNA vaccines: Reduced neutralization against new virus variants

Covid RNA vaccines: reduction in neutralization of variants (x-fold reduction). P.1/P.2: “Brazilian” variants; B.1.351.V1-3: “South African” variants (Source: Garcia-Beltran).

Covid RNA vaccines: Reduction in neutralization of variants (x-fold reduction). P.1/P.2: “Brazilian” variants; B.1.351.V1-3: “South African” variants (Source: Garcia-Beltran)

See also

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