BA.4 and BA.5 — The Dominant Omicron Subvariants in the U.S.

Thanks to worldwide vaccination programs, the acute phase of the COVID-19 pandemic appears to be over. However, new sub-variants continue to emerge.

All viruses evolve and change over time, including SARS-CoV-2, the virus that causes COVID-19. Many of these changes have minimal impact on the characteristics of the virus, while others have significant effects. For example, certain mutations may allow it to spread more easily, cause more severe disease, or evade vaccinations and the effects of medications.

Since the beginning of the pandemic, researchers have identified numerous variants of concern. These included Alpha, Bata, Gamma, and Delta early in the pandemic. Then, in late 2021, doctors detected Omicron in South Africa and Botswana. Retrospective testing then identified earlier samples from people in England, South Africa, and Nigeria.

COVID-19 numbers increased explosively from when Delta was the predominant variant, and cases were falling. Experts estimated that Omicron could infect 3 to 6 times as many people as Delta over the same period.

Omicron mutations

Omicron stood out because of its incredible number of mutations. It had more than 50 compared to the original SARS-CoV-2 virus isolated in Wuhan, China, and around 12 were rare. Some had never been seen before.

Around 30 of Omicron’s changes involved amino acids in a particular part of the spike protein called the receptor-binding domain (RBD). The virus uses the RBD to attach to bind to receptors in human cell membranes called ACE2. Omicron has an exceptionally large number of changes within the RBD.

The RBD is a crucial target for COVID-19 vaccines. The reason being is that antibodies bind to it and help prevent the virus from infecting cells.

Experts are concerned that the various mutations may prevent antibodies generated through vaccination or natural infection from neutralizing the virus.

Following the original Omicron BA.1 variant, several further subvariants emerged — BA.2, BA.3, BA.4, and BA.5.

Omicron variants BA.4 and BA.5

The Centers for Disease Control and Prevention (CDC) now reports that Omicron subvariants BA.5 and BA.4 are the dominant strains of SARS-CoV-2 in the United States. They currently account for more than 9 in 10 cases.

Originally spotted in South Africa earlier this year, scientists aren’t sure if they mutated from the original, as some believe they likely evolved from the previously dominant BA.2 Omicron variant.

Because these new sub-variants have a high transmission rate, scientists must understand how current vaccines perform against them.

In a recent study, researchers tested antibodies from blood samples of people who had previously received three doses of an mRNA COVID-19 vaccine to see if they could neutralize the new subvariants. The researchers also collected blood samples from people who had received two mRNA vaccines but had previously contracted a non-Omicron SARS-CoV-2 variant.

The results suggested that compared to BA.2, the two new sub-variants were around four times more resistant to antibodies from fully vaccinated people.

As Omicron continues to mutate and evolve, it’s becoming more transmissible and more able to avoid the neutralizing effects of antibodies. However, scientists are not surprised at these effects.

If the immune systems of vaccinated people easily neutralize variants, it would be challenging for them to become the dominant strain. Therefore, the virus is more likely to evolve and mutate in ways that allow it to escape immunity from vaccines or natural infection.

How subvariants affect different countries

Countries have varying immune profiles against SARS-CoV-2 due to several contributing factors, including:

  • Number of people vaccinated.
  • Circulating virus strains.
  • Public safety measures.

Therefore, sub-variants BA.4 and BA.5 may affect countries differently. That said, it seems they contributed to a small increase in hospitalizations in South Africa, although the death rates were lower than the country’s previous Omicron wave.

Beyond South Africa, some countries are seeing a more significant impact from these new variations. For example, hospitalization and death rates in Portugal resemble those seen in the first Omicron wave despite high vaccination and boosting rates.

Experts believe that one explanation for the difference could be that Portugal has an older population. Generally, more elderly people mean more cases of severe disease.

Additionally, even though only half of South African adults are vaccinated, they experienced extremely high infection rates from earlier COVID-19 waves. Potentially, this hybrid immunity offers solid protection from severe disease, especially in older adults who are more likely to have been vaccinated.

How well do vaccines work against the variants?

Research suggests that although vaccination triggers antibodies, they are less effective at neutralizing BA.4 and BA.5 than earlier Omicron variants.

Potentially, this means that even vaccinated and boosted individuals could be left vulnerable to contracting multiple Omicron infections. Even individuals with both vaccination and previous Omicron infection-triggered immunity don’t produce antibodies that easily block BA.4 and BA.5 sub-variants. One reason for this may be their L452R and F486V spike mutations.

What’s next?

Scientists remain unsure as to the future of Omicron sub-variants. New sub-variants may continue to emerge, each more successful than the last, overcoming existing immunity. No one knows yet if the current sub-variants are the final that we’ll see, but it seems unlikely.

There also remains the possibility that variants from other branches of the SARS-CoV-2 genetic lineages could emerge, thereby creating a completely different variant that’s unfamiliar to immune responses.

Future variants may become more deadly even though it seems that successive COVID-19 waves are becoming milder.

Scientists are also unclear when a new variant may appear. There were only a few months of separation between the original Omicron variants and the emergence of BA.4 and BA.5 in South Africa.

Potentially, SARS-CoV-2 may evolve to resemble the other four seasonal coronaviruses (sCOVs) that cause the common cold and give rise to up to 30% of respiratory infections yearly. However, the big question remains whether COVID-19 infections will gradually become milder or will it remain a serious public health problem for the foreseeable future.


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