The Omicron Story: The Winter of Our Discontent

Larry Corey, MD

The Omicron wave has been shocking. We in the virology community knew the SARS-CoV-2 virus had an exceptional ability to mutate, but the pace of its evolution was surprising.

We were just as surprised by the even-faster speed by which this variant spread.

Omicron became the dominant variant almost two years into the pandemic because it’s more transmissible and able to escape immunity that people had developed from prior infection and vaccination.

The virus has made a lot of people sick. We’ve seen confirmed cases rise a breathtaking 10-fold over the Delta peak. Hospitals were overwhelmed. Tests, N95 masks, and vaccine boosters couldn’t arrive fast enough for many people.

It has brought us all a winter of discontent.

The Omicron variant was first recognized in mid-November in sub-Saharan Africa. It arrived in the United States, including my own city of Seattle, three weeks later. Omicron dampened the feelings of scientific accomplishment that had buoyed us all. Just 12 months prior, in December 2020, we celebrated the success, and the Emergency Use Authorizations, of the mRNA vaccines from Pfizer/BioNTech and Moderna.

The national vaccination program that ramped up in the first half of 2021 significantly curtailed the Alpha wave. The success of that campaign fueled hope that we were winning the war. Yes, the Delta variant arrived in late summer, creating a tsunami of infections, hospitalizations and deaths. But that tsunami came because we were unable to implement mandatory vaccination policy, and we had a large reservoir of unvaccinated people here, and around the world.

The Omicron variant’s ability to spread more rapidly than the Delta strain is disconcerting.

It leads me, today, to step back and ask: How did this occur?

I can look at my own thinking and writing. But if you don’t take action from thinking and writing, it doesn’t do much good, does it?

The Origins of Omicron

Some knowledgeable colleagues in the virology community say an animal reservoir likely played a role in Omicron’s genesis and the animal passed the virus to a human. That’s the zoonotic spread theory.

I have long suspected that it’s more likely that an immunocompromised person served as the critical host. I raised that possibility in Timmerman Report last July, and again with colleagues in the New England Journal of Medicine in August.

Researchers from South Africa published a preprint case report in June 2021 about an individual with HIV who was co-infected with COVID-19 and accumulated mutations of interest over a period of 200 days. More data have now arrived from South Africa, published this week in Cell Host Microbe, to strongly support this view that humans are the reservoir and genesis of Omicron.

My colleagues and I discussed saltational evolution and the rapid, multimutational steps that SARS-CoV-2 can take in immunosuppressed persons. (In biology, saltation, which comes from Latin saltus, “leap” or “jump,” is a sudden and large mutational change from one generation to the next.)

We showed that this happened with the Alpha variant in early 2021. While most of the variants that are generated in immune suppressed persons don’t jump to the community, some do. What defines the ones that do and those that don’t is unclear—much depends on the virus finding a way to persist, as well as to enhance its ability to spread to others.

With Omicron, it seems like it may have found an efficient and alternate way into the cells of our throats and noses and onward from there. Yes, it’s not as likely to cause pneumonia deep in the lower lungs as other strains—that’s good. But it’s adept at immune evasion.

There is no reason to believe the SARS-CoV-2 virus’s tricks are over.

The story of Omicron shows 50 mutations between its ancestral origin, nearly 20 of them 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 DNA exchange pieces of their genetic material with each other—essentially showing that they existed 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 someone who transmitted to another immune-suppressed person and it took a few weeks to emerge as BA.2? Hence there are two immune compromised persons but they are essentially epidemiologically related?

No one really knows the answers, and for Omicron it’s uncertain we will ever be able to decipher this. But the likelihood of two immune compromised people being in close contact is pretty high in townships and communities with high HIV prevalence.

But it’s clear Omicron variant 1, or BA.1, got into the population first because it spread throughout the world first. Now, some six weeks later, we’re seeing variant 2, or BA.2, start to emerge and take over. We initially thought BA.2 to be the weaker sibling, but as it turns out, it might be the stronger one because it’s 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—and it’s taken off by itself, after it learned how to become even more transmissible than its older sibling.

I’ll use a sports analogy. It’s like the Williams sisters, Venus and Serena. Venus was the initial breakout tennis star. Serena is younger, but eventually surpassed her sister, in time and space. And that looks to be the case with the Omicron siblings.

The analogy falls short though because you can get beaten by both Venus and Serena and I’m not sure you can get beaten by the Omicron variant BA.2 if you’ve had BA.1. I think our immune systems know how to play against BA.2 if we played against BA.1 since our cells are 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.

The good news is that our vaccine booster dose saves the day, taking efficacy against hospitalization from 70% to close to 90% and from infection from 40% to 70%. But Omicron is a  tougher adversary for the vaccines. There are still breakthrough cases of Omicron infection in people who received three vaccine doses. We saw very few breakthrough cases when the ancestral strain was circulating, and many people had two doses.

That’s what’s hard to like or accept. Why can’t we get back to December 2020 in our level of protection?

Powerful Treatments on the Way

Scientists have created a few new tools — primarily the monoclonal antibodies sotrovimab and Evusheld and the antiviral pill Paxlovid — but supply shortages are making it difficult to implement these treatments at scale.

Controlling an epidemic takes combination strategies, which my colleague Myron Cohen and I wrote about at the beginning of our battle with SARS-CoV-2 in May 2020 in Science, before we had medical countermeasures.

Behavioral measures such as social distancing reduce the risk of exposure. High-quality masks work. But people can’t be asked to maintain vigilance on non-pharmaceutical interventions forever.

The three primary biomedical interventions are vaccines, monoclonal antibodies, and antivirals. Vaccines and monoclonals came earliest and were hugely effective. Monoclonals have been shown to be effective for early outpatient therapy and as prevention for persons with high exposure or at greater risk (e.g., household exposure or immune compromised).

When available, monoclonals provide the backup treatment for the breakthrough infections. They are more expensive than vaccines but also highly effective in preventing hospitalization, death, and more recently for unvaccinated persons — reducing the risk of getting COVID-19. Their disadvantages are the requirement for more frequent administration and higher cost than vaccines.

The new tool that has emerged more recently are antiviral medicines. Few people were working on antiviral research against coronaviruses before SARS-CoV-2. The SARS-CoV-2 virus is complicated enough that figuring out what to target and what compounds would selectively inhibit the viral genes and not inhibit important proteins in our cells took time.

Remdesivir was one potential solution. An off-the-shelf drug initially tested for Ebola that had efficacy against other coronaviruses such as MERS, remdesivir has been useful in hospitalized persons and has been available since early in the epidemic. But we couldn’t build on this knowledge and needed a better drug against the viral protein. So, different targets of the viral life cycle needed to be evaluated.  

This is where Paxlovid, an inhibitor of the viral protease enzyme comes in. Unfortunately, little has been published on the drug yet, but in one study, when taken early after infection, the pill prevented hospitalization in nearly 90% of persons. This is a great outcome.

Importantly, it appears additional drugs against the viral protease enzyme are also emerging. Antiviral therapies will I think be a major part of the medical response tool kit. I believe it’s important for people to know there is an oral pill that can prevent severe disease progression if you get sick with SARS-CoV-2. Another antiviral drug called molnupiravir has also been discovered and authorized for Emergency Use by the FDA. It has its advocates and detractors; the main issue for my discussion of antivirals for COVID-19 is that recent data indicate it’s not nearly as good as Paxlovid. 

Peace of Mind

Why is conceptual reassurance from therapies needed? Obviously, it helps the unvaccinated, but it is important for vaccinated people as well. We have seen that for Omicron, even the vaccinated can get ill and some get pretty sick, especially the elderly and those who have several risk conditions for severe illness. Waning immunity increases this chance. Knowing there is a backup medicine has enormous implications medically and psychologically.

I think if we knew we had a therapy we could get at a pharmacy, whether a monoclonal injection or an oral antiviral pill that would keep us from getting really ill, our ability to cope with COVID-19 would markedly change.

Healthy people could start going to restaurants and feel closer to a sense of normalcy. For the less well, perhaps with rapid testing and the availability of these therapies, people would feel more comfortable in restaurants or at family gatherings. Flying on an airplane wouldn’t feel risky, nor would one feel like they might get trapped in another city or country in quarantine or worse, hospitalized.

Our options would expand, our economy open up fully, and our social well-being would improve.

When will this happen? These additional tools to ward off Omicron are to become widely available in April or May. They are, in some cases, more available than currently known. More education for physicians, pharmacists, and the public is needed.

What happens next with the virus?

What happens next is speculative but recognize that the virus has learned to select itself against many of the immune responses that we currently have. I think it’s hubris to feel confident that we know all of the virus’s immune-evasion strategies or all of its ways to increase its transmission efficiency. The host immune response that we avidly test is evasion of antibodies, but not the other factors that slow virus control especially escape from host non-antibody responses. These are less predictable.

One strategy I think must be pursued is to improve our vaccines so they prevent one from acquiring infection in the first place. No sickness, no breakthroughs, no hospitalizations, no complications. By not acquiring it, or just getting transient infection in the nose at a level not associated with high likelihood of transmission, we really get what people called “herd immunity” — immunity that stops the carriage to others. This is what I call population-based control of the epidemic. 

The monoclonal antibody work suggests that at really high neutralization titers, we appear to prevent people from acquiring the virus in the first place. We have some evidence that when the vaccine matched the ancestral strain, in the first couple of months, maybe 40% of the time it decreased acquisition.

My own bias is that if we could make vaccines that achieve the level of neutralization we see in the monoclonals — currently 10 times higher than we presently achieve — we might be able to prevent acquisition and truly reduce the widespread dissemination of disease.

There are a lot of people who will say to me, Larry, that’s just naïve—but I’ve always been an optimist. Conceptually, I think it helps in research to say, well, can our current technologies push our antibody titers to the circulating strain up a full order of magnitude? That’s ten-fold, so let’s say from 800 to 8,000 neutralizing titers in blood. Such titers appear to protect monkeys from experimental challenge in the nose…no virus is detected even with high-grade challenge.

I can’t guarantee this will happen in humans, but I can feel pretty comfortable that if I can maintain a level of 8,000 for a long period of time, I’d take that over 800. And it would be harder for a viral escape to occur, since as we’ve seen, the escapees generally originate in the immunocompromised population, which have low antibody and cellular immune responses. So, I do think it would help. It may require augmenting current vaccines with a mucosal vaccine delivered by drops or spray—these technologies exist. They need to be developed and administered.

Personally, I rank developing vaccines or vaccine regimens that achieve population control a higher priority than what people call universal coronavirus vaccines — a vaccine that might provide baseline immunity to all types of coronaviruses. Of course, accomplishing both goals is best.

Personal Reflection

Now, back to my own personal admonition of writing without action. I wrote about immunosuppressed people being an important source of new variants and needing better medical monitoring. I wrote the article mainly directed to cancer patients and what was going on in our country at that time. But having worked with HIV, I know that the very largest number of people who are immunosuppressed who walk our planet are the number of people with chronic, inadequately treated HIV. And in sub-Saharan Africa, that’s up to 20% of the population. This is twice as great as the number of immunosuppressed people in Europe or the United States.

Is it surprising then that the Beta and Omicron variants came from sub-Saharan Africa where population coverage of highly effective vaccines is less than 20% of the adult population?

We in the western world; governmental, pharmaceutical and, yes, our global health implementation bodies such as the WHO did not do enough to provide early enough access to effective vaccines. We have learned that the implementation of vaccine science is far behind the research discovery process. Moreover, African governments have also been, to this observer, passive in their insistence of protecting their citizens from this pandemic. Solving this inertia is perhaps our greatest current challenge.

This failure means we still have millions of immunocompromised, unvaccinated people walking around with a high likelihood of becoming the next host for a new variant.

We haven’t proven that vaccinating people will help reduce the emergence of Variants of Concern, but it’s pretty logical. It certainly couldn’t hurt and probably would help. And if that’s not true, then we should at least try and prove it one way or the other. Health services have gone down in low- and middle-income countries because of the COVID-19 epidemic. Most would argue that there’s an 80% likelihood vaccination would decrease the percent of people with persistent COVID-19 and hence, the milieu for generating multi-mutational variants of concern.

Nor is there proof yet that developing vaccine strategies for HIV-infected people would alter the emergence of variants. But, again, it’s logical and I could have raised our collective awareness about these issues sooner.

True, suggesting an idea in the summer of 2021 wouldn’t have changed what happened in November 2021. But there is a momentum for everything that leads to a call to action. I hope to build some more momentum for the idea of vaccinating immunocompromised people in need around the world, in the hope that it will compel us to determined action on global distribution of vaccines.

It is this reflection that leads to my personal “winter of discontent.”


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.

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