Omicron subvariant BA.5 more virulent, study in mice finds

Scientists have used engineered mice to compare SARS-COV-2 Omicron subvariants and found that the BA.5 strain was more virulent likely due to its ability to rapidly replicate early during infection.

The research, published in the journal Science Advances, addresses a challenge to studying and understanding rapidly evolving variants of concern due to a lack of animal models for running tests that could help explain why variants and subvariants each behave differently in people.

The genetically modified mice, called K18-hACE2, used in the research express a human receptor that allowed SARS-COV-2 to enter otherwise inaccessible mouse cells.

"One of the things we found is that the strain that causes more pathology, BA.5, replicates much faster early on during infection," said Avery August, a professor in the College of Veterinary Medicine (CVM) at Cornell University in the US.

"By doing that, the virus generates a really strong immune response, which then leads to increased pathology and symptoms compared to subvariants that don't replicate as fast," August said.

Prior to this study, there were no small animal models to study the new SARS-CoV-2 Omicron variants of concern, because no animals got sick with other variants, the researchers said.

"Our study allows us to use relatively older K18-hACE2 mice as a disease model to understand how the virus becomes pathogenic, and to test whether and how vaccines and antivirals work for the new Omicron sub-variants," said Hector Aguilar-Carreno, a professor of virology at CVM.

Early Omicron BA.1 and BA.2 subvariants also replicated and spread in the K-18 mice, but they caused minimal illness and death.

On the other hand, BA.5-infected mice exhibited significant weight loss, high pathology in lungs, high levels of inflammatory cells and cytokines, signaling proteins that are associated with inflammation.

While some 3-month old mice survived, all 5 to 8 month-old BA.5-infected mice died.

The animal model makes it possible for researchers to begin to tease apart components of the immune system that could be focused on or blocked to potentially lessen or eliminate disease, the researchers said.

Some scientists believe that targeting cytokines with drugs could provide a potential treatment that tempers the immune response and lessens symptoms, they said.

The researchers found many similarities between the mouse model and how these subvariants behave in humans, with BA.5 being more virulent in both. One big difference was that most people who developed illness from BA.5 didn't die, but in K-18 mice, the subvariant was particularly pathogenic and lethal.

An advantage of the mouse model is that all the mice are identical with the same genetic background. When studying humans, many variables such as previous conditions, genetics and whether someone has previously been immunised or infected can affect the pathological outcome of the disease.

Also, the mouse model allowed the researchers to examine disease in the lungs over time.

"With BA.5, we see more pathology early on during the infection compared to mice infected with other strains or the control mice, August said.

The team also found higher viral loads in the strain that caused more infection. Older mice were more affected by the virus than younger mice as well.