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The Omicron Story: The Winter of Our Discontent, Part 1

Part I: Tracking Omicron’s Origins

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Authors:
Larry Corey, Professor of Medicine
February 17, 2022

This is the first of a three-part series.

The Omicron wave of the SARS-CoV-2 pandemic has been a shock to all of us. It’s not that we didn’t believe in the virus’s ability to mutate. It’s that we didn’t anticipate the virus’s rapid evolution and swift spread. Omicron’s effects are not just in the unvaccinated – even the vaccinated are experiencing breakthroughs; yes, they are not dying, but they are not partying either. This flood of cases – nearly a tenfold increase over Delta – has brought us all a winter of collective discontent.

From first being recognized in mid-November 2021 in sub-Saharan Africa to its arrival in the United States three weeks later – including in Seattle where I live – Omicron has been astounding. It tarnished the feeling of scientific accomplishment that has buoyed us all since December 2020 when the government granted Emergency Use Authorization (EUA) for the groundbreaking mRNA vaccines developed by Pfizer/BioNTech and Moderna.

The 2021 implementation of the national vaccination program dispatched the Alpha wave and fueled hope that we were winning the battle. Yes, Delta later created a tsunami of infections in our country that deflated that hope, but not because it broke through the efficacy of our vaccines. The problem was the nation’s inability to implement a mandatory vaccination policy, which allowed Delta to race through the national and global reservoir of unvaccinated people.

The Omicron variant’s ability to spread more rapidly than the Delta strain is disconcerting. It leads me to step back and ask: How did this occur? How did I fail to sound every alarm bell at my disposal when first sensing the potential for calamity? While some people believe an animal reservoir played a role in Omicron’s genesis, most people focused on the evolutionary biology of Omicron, including me, feel the data strongly point to humans as the reservoir and genesis of Omicron. My colleagues and I wrote a review article last summer about saltational evolution and the rapid, multimutational steps that SARS-CoV-2 can take in immunosuppressed persons. (In biology, “saltation,” derived from the Latin word for “leap,” is a sudden and large mutational change from one generation to the next.) We showed that this happened with Alpha. While most of the variants that are generated in immunosuppressed people do not jump to the community, some do. What defines the ones that do and those that do not is unclear – much depends on the virus finding a way to persist and to enhance its ability to spread. Omicron seems to have found an efficient and alternate way into the cells of our throats and noses and onward from there. While it is good that Omicron is not as likely to cause pneumonia as other strains, its adept immune evasion should tell us that SARS-CoV-2 virus’s tricks are not over.

The story of Omicron involves 50 mutations since its ancestral origin, with nearly 20 located in the immunodominant region of the receptor binding site. The genetic tree of Omicron points its origin way back to early 2020 in the time of B.1.1.7, or around the Alpha variant time frame. The phylogenetic tree also shows that the Omicron sub-variant 1 and variant 3 have recombination events – when two molecules of nucleic acid exchange pieces of their genetic material with each other. This essentially shows that they came into existence from the same person or from a small group of coinfected people. Variant 1 and variant 2 also have some recombination events that look like they also came from the same individual or small group of people. Were they the exact same individual? Or were they two people with similar evolutionary steps yet independent of each other? No one really knows, and for Omicron it’s uncertain we will ever be able to decipher this.

But it’s clear Omicron variant 1, or BA.1, entered the U.S. population first because it spread throughout the world first. Now, some six weeks later, we’re seeing variant 2, or BA.2, emerge and take over. We initially thought BA.2 to be the weaker sibling, but it might be stronger because it’s spread is more rapid. The best explanation we in the field can come up with is that BA.2 emanated from the same person or some small initial group of people that were infected with BA.1, and the virus evolved into BA.2 in another person, transmitting slightly later into the community – six or eight weeks later. It’s now taken off by itself, after it learned how to become even more transmissible than its older sibling.

I’ll use a tennis analogy. Consider the Williams sisters, Venus and Serena. The elder sister Venus was the initial star. But the younger sister, Serena, eventually surpassed her older sister. And that looks to be the case with the Omicron siblings. The comparison falls short though because you can get beaten by both Venus and Serena. That’s not quite true for Omicron’s BA.2 and BA.1 variants. Our immune systems know how to play against BA.2, especially if we first played against BA.1. Our cells would be left with the memory of playing the immune match with the virus – and that memory arms us against the other sibling. We’ll see how the cross-protection plays out. At present, very few BA.1-infected people have gotten BA.2.

Larry Corey, Professor of Medicine

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.