Why Omicron Will Be The Last COVID Variant of (Major) Concern

In my last post, I argued

“I’m not worried about another, more contagious variant emerging. Omicron is that variant.”

I further argued that we were on the verge of achieving a type of herd immunity in the US.

Several people asked a good question about my rosy prediction. In an interconnected world with dismal vaccination rates in many poor countries, won’t future variants continue to emerge? Don’t we first have to distribute effective vaccines to everyone? Doesn’t herd immunity have to be global?

The answer (as with so many things) is both yes and no.

What is a variant?

Every time a living thing reproduces, it copies its genetic material (either DNA or RNA). When DNA or RNA is copied, mistakes can happen. Those mistakes are called mutations, and they are the source of variation in all living things. Because viruses reproduce so quickly and in such great numbers, mutated versions of the virus, which we call variants, are being born all the time.

Because mutations are random, most of them are either harmful or irrelevant to the virus. So most new variants either die immediately or get diluted into obscurity. Rarely, mutations are helpful in some way to the virus’s ability to reproduce. If a set of mutations accumulate that give the virus an advantage over previous versions, then it might start to succeed—and get noticed. (The CDC has a nice, short video using branches of a tree to help describe what variants are. Watch it here.)

Scientists monitor coronavirus variants by sequencing viral RNA from infected people. When a new variant is identified, they analyze the location and nature of the mutations and make their best guess whether the variant is one to worry about, or not. In increasing order, they label the degree of worry as: variant being monitored; variant of interest; variant of concern; and variant of high consequence. (Source: CDC; click for details of what distinguishes each category)

The omicron variant of SARS-CoV-2 is a variant of concern because it is more transmissible—that is, it’s highly contagious compared to other versions of the virus.

There have been other variants of concern. Only delta and omicron remain in this category; all others have been downgraded.

There have been NO coronavirus variants of high consequence (thank goodness).

Where do COVID variants come from?

Every time the SARS-CoV-2 coronavirus reproduces, it’s possible for a new variant to be born. So the more people who are infected, the more viral reproduction, and the more opportunities for a variant of concern to emerge. By that logic, failure to vaccinate people in all countries worldwide should be a big risk to us all.

But it’s not that simple, because not every infected person is equally likely to produce a dangerous variant.

Let me explain.

In the beginning of the pandemic, humans were naïve, defenseless prey. The virus had it easy, and didn’t have to be very good at its job. Small changes in the virus could make big improvements in its ability to reproduce, and give a variant a competitive advantage over others. A couple of mutations here and there, the low-hanging fruit of evolution, could lead to a new variant of concern. The likelihood of this happening was directly related to the number of infections happening on the planet: more infected people, more risk.

As time has gone by, however, the virus has gotten stronger, so there’s less room for improvement. Easy, small changes to the RNA have all been tried. To become significantly more dangerous to humans, the virus must accumulate more complex sets of mutations.

The alpha variant of concern, first discovered in November 2020, had about 15-18 mutations that affect the structure of the virus. The omicron variant (November 2021) has at least double that number.

So how does a virus accumulate a whole set of dangerous mutations?

Some viruses—most notably, influenza—can actually swap gene sequences with each other, like cards in a deck. This is why epidemiologists (still) worry so much about a flu pandemic. I don’t think coronaviruses have this ability. SARS-CoV-2 has to mutate, mutate, mutate at random; not get killed; and then undergo natural selection for mutation collections that help the virus to reproduce.

These steps toward evolution are unlikely to happen in a person with a robust immune response. If a healthy, vaccinated person gets infected, their immune system will destroy the virus before it has time to do all that mutating and selecting. If a person is young, otherwise healthy, and unvaccinated, their immune system may take a little longer but the result is the same: not enough time for the virus to evolve a complex dangerous variant inside their body.

The situation is different in hosts with a dysfunctional immune response, where the immune system is not strong enough to clear the virus, but is strong enough to keep the host alive. The coronavirus can persist in their bodies for months, providing an environment in which the virus can experiment with new combinations of mutations. This is currently the most popular theory to explain the origin of the omicron variant: that it quietly evolved over time in a person with a compromised immune system, who may or may not have been vaccinated against COVID. You can read more about it here.

Another plausible theory is that omicron evolved in an animal host. We know that SARS-CoV-2 can infect a wide range of mammals, including mink, deer, big cats, bats, gorillas, and hamsters (source). It’s possible that the virus spent months evolving in one of these species, and then jumped back into humans. (In fact, this is my biggest concern for the sudden appearance of a new variant of high consequence.)

Whether future variants come from immunocompromised human hosts or from animals, vaccinating the vast majority of healthy humans everywhere on earth doesn’t directly fix the problem. Successful vaccination campaigns in poor countries can indirectly decrease the risk from these sources by reducing overall community transmission.

Will there be a worse variant than omicron in the future?

I can think of three definitions of “worse”: more contagious (infecting more people); causing more severe disease (killing a higher proportion of those infected); and immune escape (outwitting the vaccines). These are interrelated but I’ll consider them as separate properties of the virus.

Transmissibility:

Thanks to the omicron variant, the US has recorded an average of >800,000 new COVID cases every day over the past week. (NYT) This already-huge number doesn’t even include most at-home rapid tests, and the many infected people who are not tested at all. Could the virus mutate to become even more contagious than this? I suppose it could, but would it matter? Already, over 65 million Americans have had a documented positive COVID test. About 250 million have had at least one dose of a COVID vaccine (NYT). These groups overlap, but no matter how you look at it, a substantial majority of our population now has at least some immunity against SARS-CoV-2. The omicron surge should make us relatively resistant to any future variants. Unless a future variant also evades the immune system, simply being more infectious won’t be enough to cause a big surge in a population with this level of immune protection.

Lethality:

I can easily imagine variants that are more deadly than any we’ve seen so far, but would any such variant “succeed”? It’s unlikely, because evolution favors variants that reproduce best, not ones that are more virulent. In other words, natural selection “doesn’t care” whether the virus makes its host sicker, unless the sickness somehow promotes spread of the virus to fresh hosts. A set of mutations could emerge that generate a particularly deadly form of COVID but there’s no reason why that variant would out-compete a highly contagious but milder variant like omicron.

Also, lethality is a property of both the virus and the host. As the host population gets vaccinated and antiviral drugs become accessible (Paxlovid), I don’t expect we will see any future variants cause death at a higher rate than the delta variant.

Immune escape:

This is the most worrisome of the three issues. A future variant could evolve with changes in the spike protein that hide it from the antibodies generated by the vaccines. This is called immune escape. The virus is under a lot of pressure to find this escape route when most of its potential hosts have immunity. But the threat can be overstated.

• The immune response is not an on/off switch, it’s a dimmer switch. A new variant could evade some antibodies, but not all of them. People would still have some protection. And antibodies are only one part of the response. T cells are powerful protectors against COVID, and they are much harder for the virus to escape with mutations in the spike protein.
  1. Manufactured monoclonal antibodies used as a COVID treatment are a different story. They are relatively easy for the virus to evade, and most do not work against omicron. Ask me if you want a technical explanation for why this is.
• There are biological limits to how much the spike protein of the virus can mutate before it doesn’t work anymore. This protein is the “key” the virus uses to “unlock” the cells in the human respiratory tract. If it evolves to escape detection by antibodies, the tradeoff could be reduced infectivity. In other words, the coronavirus that causes COVID can only evolve so far until it no longer causes COVID.

We do have a tool to deal with immune escape if it happens. The mRNA vaccines can pretty easily be modified to match any future variants with a booster.

The odds are in our favor

If you find someone on the internet hyperventilating about a new variant, pay no attention at first. Mutations will continue to happen. New sequences of the coronavirus will be identified. What matters is how those variants actually behave in the wild. Whether a new variant beats the odds and becomes a threat to us will be revealed within a few weeks of discovery. So unless you’re a public health professional whose job it is to figure this stuff out, don’t bother with early or sporadic panic-reports (such as the ones I’m seeing right now on “deltacron”). If there’s a problem, you’ll know soon enough.

In summary, I think omicron will be the last variant of the SARS-CoV-2 coronavirus to cause major disruption and a substantial surge in deaths in the United States. Vaccination, and widespread natural infection by omicron itself, will leave the population in a position of relative immune strength. While we won’t reach true “herd immunity” where the virus dies out for lack of hosts, I don’t think we’ll see a surge of hospitalizations and deaths like this one again.

Let’s all hope I’m right.

Questions? amy@amyrogers.com

Amy Rogers, MD, PhD, is a Harvard-educated scientist, novelist, journalist, and educator. Learn more about Amy’s science thriller novels at AmyRogers.com.