Does BA.5 cause more severe disease than earlier Omicron subvariants?

With the Omicron subtype BA.5 rapidly becoming dominant in the United States a small body of research has begun to reveal the unique properties of this novel SARS-CoV-2 variant. Two recent preprints have described how BA.5 is more immune-evasive than prior iterations of the virus and how it could lead to more severe disease.

According to the latest variant-tracking estimates from the Centers for Disease Control and Prevention (CDC) the BA.5 Omicron variant accounts for the majority of SARS-CoV-2 infections in the United States. BA.5 has quickly taken over in predominance from BA.2.12.1, which had briefly ruled over BA.2, following the first Omicron BA.1.1 wave at the beginning of the year.

Each iteration of Omicron has displayed substantially distinct mutations, but so far no subsequent Omicron wave has been as severe as that first sweep across the world after its initial emergence in late 2021. BA.5 however, has triggered a wave of infections and hospitalizations larger than many countries have experienced in months, and scientists are playing catch-up to understand the unique characteristics of this new mutation.

BA.5 and immune evasion

What is perhaps most clear about BA.5 (and its structurally similar sibling BA.4), is this subvariant has developed the ability to evade pre-existing immunity. One early study, published in Nature, demonstrated BA.5 can effectively escape antibodies generated by both vaccine-induced immunity and prior BA.1 infection. More specifically, the research suggested those vaccinated individuals who experienced a BA.1 infection early this year may have little immune protection from a BA.5 infection.

Another recently published study affirmed the vaccine-escape properties of BA.5. The research, from Columbia University, found BA.4 and BA.5 were four times more resistant to vaccine-induced antibodies compared to the original Omicron variant.

“Our study suggests that as these highly transmissible subvariants continue to expand around the globe, they will lead to more breakthrough infections in people who are vaccinated and boosted with currently available mRNA vaccines,” said David Ho, lead on the study.

So it is clear BA.5 is likely leading to a spike in SARS-CoV-2 infections both by hunting down those individuals who, so far, had avoided Omicron infection, and reinfecting others for the second or third time. But a much more difficult question to answer is whether BA.5 generates more severe disease compared to prior variants.

What's happening in other countries?

South Africa was one of the first countries to experience a BA.5 wave, which peaked back in May. At the height of the wave both hospitalizations and deaths were slightly lower compared to the country’s first Omicron wave in late 2021.

While some experts are pointing to this data as evidence BA.5 leads to even milder illness than the first iteration of Omicron, others suggest predictions of disease severity based on the experience of individual countries is useless at this point in time. Tulio de Oliveira, an epidemic scientist in South Africa, said the severity of BA.5 in South Africa was likely a result of the country’s unique type of hybrid immunity.

South Africa has an extraordinarily high degree of past exposure to SARS-CoV-2, experiencing multiple waves from different variants over the past two years. De Oliveira said the intrinsic severity of a given variant cannot be divorced from the novel recipe of pre-existing immunity it encounters in a geographical population.

“Now [severity] is a property not only of the variant itself, but the variant and the population that it encounters,” De Oliveira said to The Guardian. “We believe that this hybrid immunity in South Africa is what kept our BA.4 and BA.5 wave with very low hospitalizations and deaths.”

It’s also worth pointing out South Africa kept widespread COVID-19 restrictions in place over the course of its BA.5 wave. Indoor mask mandates and limits on gathering sizes were only lifted in late June as the wave finally slowed down.

In contrast, Portugal has been another country facing an early BA.5 wave and its experience has been much more challenging. At its peak deaths and hospitalizations from BA.5 equalled the heights seen with the first Omicron wave.

Speaking to Healthline, infectious disease expert Amesh Adalja suggested BA.5 hit Portugal harder than South Africa because early SARS-CoV-2 variants hadn’t spread through the population. Looking to the local landscape, Adalja speculates the United States may follow the South African experience more than the Portugal one, based on prior exposure to the virus over the pandemic.

“In Portugal, hospitalization numbers rose [with BA.5], but they had less severe prior Omicron variant waves,” Adalja said. “I think the US is likely to follow the South African path with infections rising but largely being decoupled from hospitals being overwhelmed as immunity from prior Omicron variants coupled to Paxlovid and monoclonal antibodies will be operative.”

But the threat of a new variant on a population level is very different to the threat of a new variant on an individual level. And here the intrinsic properties of the virus certainly play a role.

How is BA.5 different?

Two new preprint studies, both yet to be peer-reviewed and published in a journal, offer insights into the novel characteristics of BA.5. And both suggest it is plausible to presume it may lead to more severe disease than prior Omicron variants.

A study out of Japan posted in late May offered the first clues to BA.5’s pathogenicity. The study demonstrated BA.5 had the ability to replicate significantly faster in human lung cells compared to BA.2.

It was then shown that BA.5 was significantly more pathogenic in hamsters compared to BA.2. These animal tests also affirmed BA.5 did generate more severe lung infections in the animals compared to BA.2.

Speaking to the Japanese press, Kei Sato, one of the researchers on the project, made clear these animal test were conducted on completely immune-naive subjects. So again, they cannot offer clues as to how BA.5 affects humans with different combinations of vaccine- or infection-induced immunity.

A more recently posted preprint, from a large team of researchers in Australia, explored the novel mechanisms by which BA.5 enters human cells. Using genetically engineered cell lines the study demonstrated BA.5 has “switched tropism,” meaning it has regained the ability to enter human lung cells in a way not seen in SARS-CoV-2 variants since Delta.

In a series of tweets, Australian researcher Stuart Turville said the switch back to some of the Delta-like mutations in BA.5 resembles a viral yo-yo. And although BA.5 still shares “phenotype aspects” of BA.2, it has picked up some of the “old habits” of Delta.

“BA5 isn’t quite Delta yet but is on its way (sits in between Delta and BA2 in its ability to engage the Ace2-TMPRSS2 pathway),” tweeted Turville. “A p681r change would be very interesting to see if it can “yo yo” fully from BA2 to the tropism of Delta again.”

Ultimately, it’s impossible to offer a simple answer to the question of BA.5’s severity. As with the entire pandemic to date, many will still experience mild, acute infections, while others will end up in hospital. And with the number of COVID-19 hospitalizations high around the world it is clear BA.5 is a new kind of threat we have yet to fully understand.

Nathan Grubaugh, an epidemiologist at the Yale School of Public Health, said vaccinations and boosters are still the most effective things people can do to protect themselves and others. And the one thing experts are certain of is BA.5 will not be the last coronavirus variant we have to deal with.

“Delta was never going to be the last variant – and Omicron is not going to be the last one,” said Grubaugh. “As long as there is a COVID-19 outbreak somewhere in the world, there is going to be something new that emerges.”