Bond LSC and UNMC scientists explain mutations unique to the Omicron variant

Austin Spratt Protein Models
Austin Spratt, undergraduate mathematics student in the Kamlendra Singh lab, shows protein models of the Omicron spike protein and the receptor it attaches to when infecting cells. “The genetic codes are used to identify the mutations, and then we use the structure to see how it would change over time. It’s going to give us more information about new mutations that occur,” Spratt said. | Photo by Cara Penquite, Bond LSC

By Cara Penquite | Bond LSC

It took eight days for Kamlendra Singh and his team to crack the code behind the Omicron COVID-19 variant. Although usually characterized by months of waiting, the peer-review process matched their pace, publishing their research a week later.

“That’s how quick it went because the editors and the general [scientific community] recognize that it’s very timely and important research,” said the Bond Life Sciences Center principal investigator.

Discovering 46 genetic mutations in the Omicron variant, their research explains Omicron’s ability to efficiently infect cells and evade antibodies. Their explanation predicted Omicron’s possibility for increased transmissibility a couple weeks before the beginning of the late December surge of COVID-19 cases  in the U.S. The work published online December 10, 2021, in the Journal of Autoimmunity.

“You will see a lot of infections now because the vaccine-induced immune responses are not able to control the [Omicron] infection,” said Siddappa Byrareddy, a collaborator on the project and Professor and Vice-Chair of Research in the Department of Pharmacology Experimental Neuroscience at the University of Nebraska Medical Center (UNMC).

Genetic mutations to the spike protein on the surface of the virus increase Omicron’s ability to infect cells and evade antibodies. In Omicron, the mutations allow for a stronger bond between the spike protein and the healthy cell. The spike protein acts as a key enable the virus to get inside the cell by attaching to receptors on the surface of healthy cells. Once inside, the virus hijacks the cell and uses it to create more copies of the virus.

“What happens is, these mutations are in the receptor-binding domain. Which means, when these two things come together, when the spike protein tries to attach to the ACE2 receptor, these mutations cause it to bind more. When that happens, we have increased transmissibility or increased infectivity,” said Saathvik Kannan, a Hickman High School sophomore, and lead author from the Singh lab involved in identifying the mutations.

The spike protein is also the primary point of contact for antibodies designed to neutralize the virus. Since antibodies are not universal, the immune system must be exposed to a virus, either through infection or vaccination, before creating antibodies to neutralize that virus. Omicron’s mutations in the spike protein make it different from other variants of COVID-19, so antibodies that can neutralize other variants seem to be less effective in preventing Omicron infection.

“Antibodies are very specific. Any one mutation can completely abolish the binding,” Singh said.

While antibodies from previous infection or vaccination may not prevent Omicron transmission, Byrareddy emphasized that they are still decreasing hospitalization.

“Even though the vaccines are not effective [against Omicron] transmission, they still help the immune response to fight against the virus. That’s why we don’t [see] a lot of hospitalization,” Byrareddy said.

One potential solution to mitigate Omicron’s effect would be to create an Omicron-specific vaccine. While a new vaccine could decrease Omicron transmission, Singh warns that it would not necessarily prevent the emergence of further variants. This is a particular concern with Omicron because of its many versions.

“We’re seeing different Omicron versions where you have the Omicron, but with a couple changes. Those couple changes are making a big impact.” said Austin Spratt, another Singh lab researcher and MU undergraduate studying mathematics involved in the project.

Spratt’s role in the project was to create computer simulations of the spike proteins to see models of the mutations.

“[Omicron] has bigger mutations and different flavor mutations [than previous variants], and there are starting to be subcategories of that,” Spratt said.

Singh and Byrareddy’s labs are taking their research in the direction of antivirals with the hope of creating a drug that could reduce COVID-19 symptoms. The antiviral would block receptors on the surface of healthy cells so that the virus’ spike protein will not fit anymore. Without a key to get into the cells, the virus would not take over the cells.

While antivirals would not cut out all variants, Spratt believes they could help the problem as they did with other pandemics such as the Spanish Flu.

“I think it’s possible that they create antivirals that will slowly but surely cut out variants over time,” Spratt said.

This research published in the Journal of Autoimmunity December 10, 2021, under the title “Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing antibodies.”