On November 30, 2022, the Food and Drug Administration (FDA) deauthorized bebtelovimab for emergency use in the United States. This was the last monoclonal antibody drug authorized by the FDA to treat COVID-19. The decision was made because it is not expected to neutralize new Omicron subvariants.

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Healthcare workers wearing personal protective equipment at a temporary holding area for patients displaying COVID-19 symptoms wait outside the Accident and Emergency Department at Prince of Wales Hospital in Hong Kong, China, on February 16, 2022. Bertha Wang/Bloomberg via Getty Images
  • The BA.2 subvariant of Omicron, or the “stealth” variant, has been outcompeting the previously dominant BA.1 subvariant in several countries.
  • Recent studies suggest that BA.2 has a competitive advantage over BA.1, mostly due to its increased transmissibility.
  • The BA.2 variant may also be slightly better at evading immunity than BA.1, which could be contributing to its rapid spread.
  • Although BA.2 is more contagious than BA.1, clinical data do not suggest a significant difference in disease severity.

Coronavirus data

All data and statistics are based on publicly available data at the time of publication. Some information may be out of date. Visit our coronavirus hub for the most recent information on COVID-19.

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The Omicron variant, which researchers first sequenced in South Africa and Botswana in November 2021, was found to be more transmissible but cause less severe disease than its predecessor — the Delta variant.

Owing to being more contagious, Omicron rapidly supplanted Delta as the dominant variant worldwide. Currently, it accounts for 99% of all sequenced cases.

Moreover, since it emerged, scientists have categorized Omicron’s subvariants or lineages into three groups: BA.1, BA.2, and BA.3.

Although the BA.1 subvariant started as the dominant Omicron lineage across the globe, since December 2021, the proportion of COVID-19 cases linked to the BA.2 variant has been rapidly increasing.

This has raised concerns about the severity and transmissibility of BA.2. Here’s what researchers have found so far:

BA.2 has been especially prominent in countries in Southeast Asia, Africa, and Europe. Recent analyses have indicated that it has displaced BA.1 as the dominant Omicron sublineage in Denmark, Singapore, India, South Africa, and Austria. The rapid ascent of BA.2 is illustrated by the increase in its prevalence from 20% in the last week of December 2021 to 66% by the third week of January 2022 in Denmark.

The proportion of BA.2 cases in the United States remains low at 3.8% so far, but health experts expect it to rise.

Preprint studies that are yet to be peer reviewed have characterized differences between the BA.1 and BA.2 subvariants, which may explain why the latter is outcompeting its sibling variant.

Although BA.2 shares many of BA.1’s mutations, the two subvariants differ by 28 mutations, some of which are responsible for the rapid surge in BA.2 cases.

Notably, the mutations unique to these subvariants are also present in the spike protein, which mediates the entry of SARS-CoV-2 into cells and is the target of COVID-19 vaccines. Specifically, BA.2 carries eight new mutations in the spike protein but lacks 13 mutations that the BA.1 spike protein harbors.

The rapid surge in the prevalence of BA.2 in multiple countries suggests that this variant is more contagious than BA.1. One study estimates that BA.2 is up to 33% more transmissible than BA.1 and considers that its spread could be a serious issue for global health in the near future.

Moreover, a nationwide study comparing the spread of the BA.1 and BA.2 variants in Danish households in late December 2021 and January 2022 suggested that the latter was more contagious. The study found that the secondary attack rate, which measures the probability of transmission of the virus to household members, was 39% for BA.2 and 29% for BA.1.

The study also reported that fully vaccinated and booster-vaccinated individuals were less likely to pass on or contract an infection due to either subvariant compared with unvaccinated individuals.

In addition, unvaccinated individuals were more likely to spread the BA.2 subvariant to their household members than BA.1.

The household transmission data from the Danish study also showed that both vaccinated and unvaccinated individuals were more susceptible to a SARS-CoV-2 infection due to BA.2 compared with BA.1.

The relative increase in susceptibility to the BA.2 variant was greater in vaccinated individuals than unvaccinated individuals. In other words, it was more adept at evading the immune protection offered by vaccines to cause an infection.

Speaking to Medical News Today, the co-author of this study, Dr. Frederik Plesner Lyngse, a researcher at Copenhagen University, said, “[BA.2] possesses immune-evasive properties that reduce the protective effect of vaccination against infection, but [does] not increase its infectiousness from vaccinated persons with breakthrough infections.”

“All individuals are more susceptible to BA.2 compared to BA.1, unconditional on their vaccination, previous infection status [or both]. Unvaccinated individuals are more infectious if they [acquire an infection] with BA.2 compared to BA.1, while vaccinated individuals (vaccination and/or previous infection) that have a breakthrough infection are less infectious if [they contract an infection] with BA.2 compared to BA.1.”
– Dr. Frederik Plesner Lyngse

The levels of antibodies that can bind and neutralize SARS-CoV-2 tend to predict the extent of protection from infection. Two studies have independently shown that individuals immunized with mRNA vaccines showed significantly lower levels of neutralizing antibodies against the BA.1 and BA.2 subvariants than the original wild-type SARS-CoV-2.

Receiving a third shot as a booster also increased neutralizing activity against these Omicron lineages, but the neutralizing antibodies levels in response to BA.2 were slightly lower than BA.1.

Dr. Lyngse said they found that “vaccinations work in both reducing susceptibility (probability of [acquiring infection]) and infectiousness (probability of [causing infections in] others) — and that boosters reduce it even more.”

Given the modest difference in neutralizing activity against BA.2 and BA.1, Dr. Dan Barouch, a virologist at Harvard Medical School and author of one of the above studies, noted:

“The ability of BA.2 to outcompete BA.1 is probably due to increased transmissibility of the virus, rather than additional immune escape beyond BA.1.”

Do treatments work against BA.2?

Researchers developed the currently available COVID-19 vaccines to elicit an immune response against the wild-type SARS-CoV-2 spike protein. The lower neutralizing antibody response against BA.1 and BA.2 in fully vaccinated individuals likely reflects the high number of mutations in the Omicron spike protein.

These mutations on the Omicron spike protein also explain why most of the monoclonal antibodies that were effective against previous SARS-CoV-2 variants have diminished neutralizing activity against BA.1.

Sotrovimab was one of the few monoclonal antibodies that retained neutralizing activity against this variant.

Recent studies have shown a significant decline in the neutralizing activity of sotrovimab against the BA.2 variant. The AstraZeneca antibody combination Evusheld and the Eli Lily antibody bebtelovimab are two authorized antibodies that still retain activity against both BA.1 and BA.2 variants.

In light of the ability of these Omicron subvariants to evade most therapeutic monoclonal antibodies, scientists fear that further mutations in the SARS-CoV-2 spike protein could render all currently available monoclonal antibody treatments ineffective.

A recent laboratory study suggests that a BA.2 infection may cause more severe illness than BA.1. The study showed it replicated much faster than BA.1 in cultures of upper and lower respiratory tract cells.

Subsequent experiments in hamsters also suggested that BA.2 had a superior ability to replicate and spread in the lungs than BA.1. It also caused more lung damage and had greater adverse effects on lung function in these experiments.

However, data on disease severity in humans so far suggest that the BA.2 variant does not cause more severe illness than BA.1.

A study that researchers conducted in South Africa evaluated the risk of hospitalization due to BA.1 and BA.2 infections between December 5, 2021, and January 29, 2022, when the prevalence of BA.2 infections in the country grew from 3% to 80%. Upon analyzing the outcome of 95,470 COVID-19 cases, the study found that a similar proportion of individuals with BA.1 and BA.2 infections required hospitalization.

A statement by the World Health Organization (WHO), citing this study and other unpublished real-world evidence from the United Kingdom and Denmark, noted that BA.2 variant may not differ from BA.1 in its ability to cause severe illness in humans.

The discrepancy between the laboratory study and real-world clinical data could be due to the inability of the animal model to recapitulate all aspects of COVID-19 in humans.

Dr. Larry Corey, a virologist at Fred Hutchinson Cancer Research Center in Seattle, said, “Currently, there is no evidence either from South Africa or places in the U.S. that suggest differences in the clinical spectrum and course between BA.1 and BA. 2.”

“The BA.2 epidemic has had a 6–8-week later start, so severity data do lag behind. But to date, there is no evidence of significant differences, and cross-protection between the two variants seems in the short term quite high,” he told MNT.