What We Know About Omicron BA.4 and BA.5

Two new Omicron subvariants—BA.4 and BA.5—now account for 13% of new COVID-19 cases in the United States, a sizable leap from early May when the variants only accounted for 1%, according to data from the Centers for Disease Control and Prevention (CDC).

Early research indicates that the newer versions may be more transmissible and more likely to cause breakthrough infections than earlier forms of Omicron.

While BA.2.12.1 remains dominant in the U.S. this week, experts are concerned about how quickly the newer subvariants are gathering speed here. 

Researchers are working to unravel the characteristics that make BA.4 and BA.5 unique. Preliminary data from lab studies suggest the variants have evolved to spread more easily, better skirt immune defenses, and make people sick.

“It is a game of mutations,” Kamlendra Singh, PhD, a professor of molecular microbiology and immunology at the University of Missouri, told Verywell. “In other words, where the mutation is and in what kind of environment that mutation is found—that's the whole game.”

Scientists first detected BA.4 and BA.5 in South Africa early this year and the variants have since become dominant in the country. The surge in infections was not as high as seen in prior waves, perhaps due to existing immunity. Still, they drove an uptick in cases and hospitalizations, suggesting they could be more transmissible than Omicron BA.2.

BA.4 and BA.5 still only account for a relatively small fraction of the cases globally, but the variants have been detected in at least 46 countries, according to an international database.

In the U.S., the South is seeing the highest proportion of BA.4 and BA.5 cases—the variants account for one in five cases in that region, according to the CDC.

Omicron Is Getting Better at Evading Immune Responses

When Omicron first emerged, it appeared to cause less severe disease, even though it was more transmissible than the Delta variant.

Researchers in Tokyo said the new versions of Omicron may be more likely to cause disease than the last, according to a preprint study. In lab tests, when unvaccinated people recovered from BA.1 or BA.2 infections, they did not have sufficient antibodies to protect against BA.4 and BA.5, Kei Sato, PhD, a virology professor at the University of Tokyo and lead author on the study, told Verywell in an email.

Sato’s team also found that BA.4 and BA.5 replicated more readily in human lung cells and caused more severe disease in hamsters than BA.2 did. These preliminary findings suggest the risk of BA.4 and BA.5 to global health “is potentially greater than that of original BA.2,” the authors wrote.

Many of the mutations in the Omicron variants allow the virus to escape immune defenses. While antibodies are trained to recognize certain characteristics of the COVID-19 virus, the newer variants may evolve to a point where they become unrecognizable to existing antibodies.

Another pre-print study indicates that even in people who are vaccinated and boosted, monoclonal antibody treatments are significantly less effective against BA.4 and BA.5 than against BA.2.12.1—the version that is currently dominant in the U.S. In preliminary lab tests, researchers said that only bebtelovimab appears to stay potent against both BA.2.12.1 and BA.4/5.

Despite these initial reports, scientists won’t know exactly how BA.4 and BA.5 behave without more clinical data. 

Real-world data on BA.4 and BA.5 is limited, but other countries can provide some clues. In Portugal, for instance, BA.5 has already overtaken BA.2. There, BA.5 appears to be spreading about 13% faster than BA.2.

Identifying a Key Mutation for Viral Fitness

As Omicron variants evolved, they developed new mutations while hanging onto some of the changes that helped the older variants take over.

“Many Omicron variants, both Omicron and sub-lineages of Omicron, have mutations from all prior four variants of concern—Alpha, Beta, Gamma, and Delta,” Singh said.

For instance, BA.4 and BA.5 retained some of the mutations in Delta, including a part of the genome called the L452 residue. This mutation tweaks the spike protein to help the virus to better attach to the ACE2 receptor in human cells and cause sickness.

A slight chemical change in the L452 residue means the virus can better bind to the ACE2 receptor and enter cells. This specific mutation is so indicative of a variant’s fitness that the World Health Organization placed BA.4 and BA.5 as Variant of Concern lineages that require prioritized attention and monitoring.

Will BA.4 and BA.5 Cause a New Wave?

The U.S. is already experiencing an Omicron wave, Singh said. The seven-day average of cases was more than 100,000 in the first week of June, up from about 30,000 in the first week of April.

As to whether the spread of BA.4 and BA.5 will cause an even greater uptick in cases and hospitalizations, however, is still to be seen.

The upside is that people in the U.S. are more protected now. Over 70% of Americans older than five are now fully vaccinated and some 146 million people may have been infected with COVID-19 since the start of the pandemic.

With this combined immunity from vaccination and natural infection, many people in the U.S. have some degree of protection against serious illness from future Omicron variants.

Vaccine manufacturers are developing an Omicron-specific vaccine that is intended to produce antibodies that could defend against current and future variants more effectively than the original COVID-19 vaccines do.

On Wednesday, Moderna announced the results for the phase 3 clinical trial of its new bivalent COVID-19 booster, which is designed for both the original COVID-19 virus and Omicron.

Singh said it’s unclear how effective Omicron-specific vaccines will be. Much will depend on the comorbidities and immunity of each individual.

It takes at least six months for a vaccine manufacturer to reformulate and prepare a new version of mRNA COVID-19 vaccine. Given how quickly the virus mutates, a vaccine formula that was once highly effective can quickly become obsolete.

“It’s like a game of hide-and-seek. The virus is much faster than we can make the vaccinations,” Singh said. “We cannot keep up. No [vaccine] company can keep up with the changes this virus is making. It's impossible. They're so fast and so complex.”