Scientifically Speaking | The emergence of Omicron was expected

Over time, mutations that confer a selection advantage are maintained. Of particular concern are the ones that lead to different amino acids in the spike protein. There are more than 30 changes to the spike protein and 15 that map to a key feature known as the receptor-binding domain in Omicron. Changes that make the receptor-binding domain attach tighter to the cell receptor have been observed for other variants so their individual effects can be predicted. However, many changes are new to Omicron and have not been encountered in any other variant of concern. There are also changes that lead to missing amino acids that alter the shape and the functional capacity of the spike protein.

In fact, Omicron is so heavily mutated that the standard RT-PCR detection tests don’t pick up one of the target diagnostic genes. In South Africa, the absence of this gene has been used to detect Omicron without the need to sequence the entire genome for all suspected cases.

Variants such as Delta that are better at transmitting and replicating inside cells change the parameters of the pandemic. A variant like Beta is significantly different at parts of the spike protein to earlier versions of the virus that antibodies recognize. This kind of a variant can evade some immune responses and is known as an “immune escape” variant.

The cumulative effects of mutations on Omicron spread and immune escape are being tested right now in labs around the world. These effects will be checked in modified and whole virus experiments, and ultimately by tracking the spread and clinical outcomes in people.

It is too early to know if Omicron will supersede Delta. Neither Lambda nor Kappa which made headlines earlier this year, were able to supplant Delta, which is still the predominant variant globally. But the emergence of another variant with multiple mutations sounds eerily familiar.

On October 13, in my column for Hindustan Times, I wrote that “new variants will emerge, and they may supplant Delta in the future. Where and when these variants will emerge is much harder to predict. We know that immunosuppressed individuals who received antibody therapy had persistent infections that lasted for months. In these people, viral lineages acquired many mutations and became variants. But variants can also emerge over time as a result of rapid spread through many people instead of in one person.”

There have been multiple, well-documented cases of SARS-CoV-2 variants emerging in immunosuppressed patients. These variants have a large number of mutations that have been seen in Alpha, Beta, Gamma, Delta and most recently in Omicron. In fact, a plausible theory is that Omicron originated somewhere in Africa in an immunosuppressed patient with poorly controlled human immunodeficiency virus (HIV) infection. Of course, until the index case is identified, this theory cannot be confirmed, but it fits with all known evidence.

Here’s why I think this is a realistic scenario for the emergence of Omicron. In healthy people who mount optimal immune responses, the virus is cleared quickly so it does not have much chance to acquire multiple mutations. The immune system deals with the equivalent of a knockout punch. In people who have no immune response, the virus doesn’t have evolutionary pressure to mutate; here the virus has an upper hand. But in people who are immunosuppressed, there is an uneasy struggle. During these chronic infections which can last over 100 days, SARS-CoV-2 has an opportunity to acquire more mutations. A highly mutated variant can emerge and (if the patient is not isolated) can spread to others.

The alarm bells were sounded over a year ago, when Bina Choi and colleagues at the Brigham and Women’s Hospital in Boston, Massachusetts published a report of an immunocompromised patient with SARS-CoV-2 infected that persisted for 152 days in The New England Journal of Medicine. The patient had a variant with 31 changes and three major deletions in the genetic sequence. The patient later died from pneumonia caused by Covid-19.

A few months later, Ravindra Gupta and his colleagues at Cambridge University published a worrying research article in Nature. Gupta’s team tracked mutations in an immunosuppressed patient with persistent SARS-CoV-2 infection over 101 days and found that the number of mutations exploded after convalescent plasma therapy.

A third study published in May in EBioMedicine by Jennifer Dien Bard and her team at Children’s Hospital in Los Angeles found three patients with cancer had developed variants with a constellation of mutations while they were on immunotherapy. Again, a common thread was that variants arose after persistent SARS-CoV-2 infections.

A feature that these variants share with Delta and with Omicron is the large number of mutations that result in changes in the spike protein. Some of these mutations are common across variants. For example, the 484 position of the spike protein is important in the binding of the virus and in antibody recognition. It is mutated in Delta and in Omicron. This commonality argues for a selective advantage for the 484 mutation that makes the variant better at displacing other circulating viruses.

From case reports, researchers have identified types of immunosuppression that have a heightened chance of giving rise to variants. These include patients who received convalescent plasma or antibody therapy but were unable to clear the virus in a short span of time. Long-term chemotherapy, the use of certain steroid hormones to dampen inflammatory responses, and immune-suppressing treatments have also been implicated.

Organ transplant recipients and those with HIV infection are also susceptible to chronic SARS-CoV-2 infection leading to multiple mutations accruing at once. These patients can be a source of new variants and if they are not kept in isolation, these variants can escape into the general population.

Transmission of new variants from patients should be prevented. Vaccination of immunocompromised individuals (with additional doses as necessary) should be prioritised. Unfortunately, the coverage of vaccines in Africa is low overall and most western nations have prioritised their own booster doses for healthy, low-risk individuals over first doses for those who are at high-risk in other countries.

The lessons are clear. We cannot turn back the clock on Omicron. But with appropriate health measures and equitable distribution of vaccines, we may be able to prevent other highly mutated variants from rapidly emerging.

Anirban Mahapatra, a microbiologist by training, is the author of COVID-19: Separating Fact From Fiction.

The views expressed are personal