Omicron and its Subvariants: A Guide to What We Know

[Originally published: Dec. 2, 2021. Updated: Sept. 1, 2023]

Note: Information in this article was accurate at the time of original publication. Because information about COVID-19 changes rapidly, we encourage you to visit the websites of the Centers for Disease Control & Prevention (CDC), World Health Organization (WHO), and your state and local government for the latest information.

In the battle against COVID-19, Omicron has been a difficult opponent. The variant of the SARS-CoV-2 virus that causes COVID-19 first surfaced in the United States toward the end of 2021 and spread like wildfire, spawning new sub-strains—some more transmissible than others. Now, multiple Omicron subvariants are driving most of the COVID-19 cases in the United States.

The newest Omicron strain arrived in the United States this past summer. EG.5, or, informally, “Eris,” rapidly became the dominant SARS-CoV-2 strain in the country. While some experts believe EG.5 has been a possible factor in a summer uptick in COVID-19 cases and hospitalizations, scientists are still learning about its potential transmissibility and severity.

In August, the spotlight turned toward yet another Omicron strain, BA.2.86, unofficially nicknamed “Pirola.” Little is known about Pirola, and so far, there are relatively few reported cases, but it has been identified in several countries, including the U.S., suggesting it may be spreading more widely than people realize. Scientists are eager to learn about the more than 30 mutations seen in Pirola’s spike protein (compared to one mutation for EG.5). Spike proteins are how the coronavirus enters human cells, and while unconfirmed, more of them may mean there is a greater chance the strain will be more transmissible and more likely to cause severe disease.

Tracking Omicron and its variants can easily become confusing—even overwhelming, but Yale Medicine follows these variants, and the CDC provides weekly updates to track them.

Thomas Murray, MD, PhD, a Yale Medicine pediatric infectious diseases specialist, and Nathan Grubaugh, PhD, an epidemiologist at the Yale School of Public Health, commented on what we know so far.

First, some background. Omicron was initially identified in Botswana and South Africa in November 2021—although later reports showed earlier cases in the Netherlands. On December 1 of that year, the CDC confirmed the first case in the U.S., in an individual in California who had returned from South Africa in November. Omicron was the predominant strain in the U.S. by late December. As people around the world welcomed a new year (2022), the variant continued to surge more quickly than any previous strain in many areas. Both the WHO and the CDC classified it as a "variant of concern."

Except in rare cases, the original version of Omicron is no longer circulating—neither is the original strain of the SARS-CoV-2 virus and the early, more severe Alpha and Delta variants. But, as of early September 2023, CDC estimates showed a long list of circulating Omicron subvariants, including more than a dozen XBB strains. XBB.1.16 (or "Arcturus") was the prevalent strain before it was surpassed by EG.5.

From the beginning, two important questions about Omicron were top of mind for scientists, says Dr. Murray. As new variants have emerged, the first question has been how transmissible each one is compared to its predecessor.

According to the CDC, the Omicron variant spreads more easily than the original SARS-CoV-2 virus and Delta, an early variant. Omicron caused an alarming spike in COVID-19 cases in South Africa—they went from 300 a day in mid-November 2021 to 3,000 a day at the end of that month.

The second question has been whether Omicron and its subvariants are more likely than their predecessors to cause severe disease.

So far, Omicron strains have tended to be mostly mild, causing a runny nose, sore throat, and other cold-like symptoms, as opposed to lower respiratory tract symptoms. Experts say that the summer uptick in cases and hospitalizations in 2023 is much lower than COVID-19 spikes in previous years. But people 65 or older or who have a weak immune system are at higher risk of the virus traveling to the lower respiratory tract, causing severe illness. Some people infected with Omicron and its subvariants have still developed severe disease and had to go to the hospital, and some died. For that reason, experts continued to express concerns that a large volume of cases in a particular area could overwhelm medical centers, making it difficult to treat severe cases.

A new COVID-19 booster shot that is expected to become available in the fall of 2023 won’t be an exact match for EG.5, but experts expect it to help since it targets Omicron offshoot XBB 1.5, a close relative. Moderna announced that early clinical trials show that its booster shot will effectively target both the EG.5 and FL 1.5.1, another recent subvariant.

This past January, two studies suggested that the updated vaccine booster offered in fall 2022 (called a bivalent booster because it covered both the original SARS-CoV-2 strain and two Omicron subvariants, BA-4 and BA-5) continued to be effective against emerging Omicron strains. The New England Journal of Medicine (NEJM) published a study based on people 12 and older included in North Carolina’s state vaccine registry data that found it to be 58.7% effective against hospitalization compared to 25% for the monovalent one that preceded it; its effectiveness against infection was 61.8% compared to 24.9% for the monovalent. The study covered a period when Omicron BQ.1 and BQ.1.1 were also circulating, in addition to the strains the booster was designed to target.

Another study, from the CDC, assessed the bivalent vaccine’s real-world effectiveness against Omicron’s newest strains, XBB and XBB.1.5, in people who had previously received two to four monovalent vaccine doses. Scientists found that—at least for the first three months after vaccination—the updated booster’s effectiveness against the XBB subvariants was similar to what it was against BA.5.

Paxlovid, which is given in pill form early in the course of infection, is still prioritized by the National Institutes of Health (NIH).

Research published in the Annals of Internal Medicine in December 2022 suggests the drug can offer a substantial benefit as far as protection against severe illness and hospitalization among vaccinated people over the age of 50 (clinical trials had only reported on Paxlovid’s efficacy in unvaccinated people). Data for the study was gathered from a period between January and July 2022, when previous strains of Omicron were circulating. Another treatment, remdesivir, is also expected to be effective against Omicron.

Two other treatments, both monoclonal antibodies, had their FDA authorization halted until further notice in response to data that showed they were not effective against the Omicron subvariants that were currently circulating. In December 2022, the FDA withdrew its EUA for bebtelovimab, which was used as a treatment. It withdrew its EUA for Evusheld in January. The latter was the only option for pre-exposure prophylaxis (or preventive medicine) for immunocompromised individuals.

When they first started to study Omicron, scientists were concerned about a key distinguishing factor in the variant. Unlike Delta and other coronavirus variants, it carries an abundance of mutations—about 50 in all, including 26 that are unique to the variant—and more than 30 on the spike protein, which is the viral protein that vaccines train the immune system to recognize and attack. Grubaugh said some of Omicron’s enhanced transmissibility could come from its ability to evade some immune responses, especially in people who were previously infected but not vaccinated.

Scientists also wanted to know if these mutations indicated a possible reduction in the effectiveness of the COVID-19 vaccines and certain monoclonal antibody treatments. “We don’t really know how the mutations work together. Not everything is additive,” Grubaugh had said.

People need to understand that variants like Omicron are a natural part of the progression of the virus, Grubaugh says.

New variants aren’t surprising, he says. No one can predict how they might evolve—or if they will simply vanish at some point. “Delta was never going to be the last variant—and Omicron is not going to be the last one," Grubaugh says. "As long as there is a COVID-19 outbreak somewhere in the world, there is going to be something new that emerges.”

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