It Ain’t Over Til It’s Over

Larry Corey, MD

If you’re still curious about COVID-19, then good for you. Many people apparently have stopped paying attention, but COVID-19 remains a relevant topic.

Here’s where things stand this fall with viral variants and our countermeasures.

We are starting a period of the Omicron epidemic in which the numbering is no longer B1, B2, B3, B4, B5. We’re into the Omicron subvariants—BA.5, BA.4.6, BQ.1.1, BQ.1, BF.7, BA.2.75.2, BA.2.75, BA.4.6., and XBB.

All of this nomenclature which, of course doesn’t make much sense to any of us, indicates that we’re getting the strain variation that we saw in South America early on with Lambda. When you look at the diversity of the viruses with these Omicron subtypes, we’re starting to see some commonality of changes in the spike protein, especially in regions associated with immune escape. This is a phenomenon called convergent evolution. These alterations are happening in many places around the world. Localized variants are acquiring unique but sometimes common mutations, indicating the virus is evolving in an effort to escape immunity.

We’re probably at the time now where we need to just track the mutational changes in the spike protein and give less credibility to the names. What seems more meaningful are the strains that “take over” geographically that have high reproductive rates. Some of these variants possess reproductive numbers that are remarkably fast — similar to what we saw at the beginning of the Omicron wave in November/December 2021. Genomic surveillance is telling us about localized outbreaks such as BQ1.1 in Europe and some parts of the US and XBB in Singapore.

To date, the pattern has been for each local outbreak to grow for a few weeks. These outbreaks appear to be shorter in duration than what we saw with the Delta wave from 2021, and certainly the first part of Omicron.

A Better Prepared Population

This makes sense when you consider the overall increase in COVID-19 immunity in the population. There are fewer and fewer people immunologically naive to SARS-CoV-2; more and more people are seeing reinfection; and more and more reinfections on top of vaccination. The likelihood is that on a population basis, we would see an immune response threshold that cuts down the duration of shedding and therefore a reduced rate of transmissibility. The level of immunity that shuts down transmissibility is now being reached much sooner. I suspect we will see epidemic waves in most countries that are measured in 2 to 3 months rather than 4  to 8 months.

United States, the Outlier?

My one caveat on this is when you consider the United States: we as a country have had sustained outbreaks with each of the variants. Delta lasted a long time, six to nine months; Omicron BA.1, six months; B4/5, six months. Whether we see the peak and fall, like Singapore, or chronic lingering outbreaks this winter remains to be seen.

We’re already seeing this fall, and I predict will be true for winter also, an uptick of what some are already calling the “tridemic” of RSV converging with COVID-19 and the flu. Mask-wearing has gone back to being a stigmatizing behavior and people have gone back to pre-pandemic activity—just walk around any US airport, restaurant, or urban public space.

When kids were wearing masks, RSV and influenza were close to non-existent in the school setting.

Why? Because masks are effective. Now, we’re seeing our pediatric hospitals flooded with RSV because children haven’t had it in two and a half years. Older kids are getting their primary infection, and secondary transmission is occurring in families with higher inoculum loads. Those who are involved in the respiratory care of children, and their parents, are going to have a banner year in taking care of people. And COVID-19 will still be around.

Winter Surge

I suspect that we will see — in mid-to-late December — a pretty significant upswing in hospitalizations and deaths in the adult population mostly related to COVID-19. I fully expect that hospitalizations will go from 3,500 to 7,000 a day and deaths likely from 350 to 600 each day. Some of this may be due to Influenza A and RSV, but most will, in my opinion, be COVID-19/Omicron.

Omicron has silently impacted the very elderly (75 and over) with hospitalizations, especially if they aren’t boosted. So, if we don’t see more uptake of boosting, we’ll see a fair amount of hospitalization and some mortality from Omicron and even perhaps flu, although this year’s flu vaccine seems to be reasonably matched to what we expect to see as the circulating strains of influenza A.

Understanding the population impact between COVID-19, RSV, and influenza will be interesting and valuable. We haven’t had to do that yet because there’s been only COVID-19 the past two winters. Now we have a multifactorial issue.

What about COVID-19 Vaccination?

All the data say that the bivalent vaccine gets you to produce new antibody-producing cells to Omicron strains, and yes, you will also make antibodies to the ancestral strain. But it also starts you off with Omicron B cells. There are data that show a full monovalent Omicron boost gives better antibody magnitude than the bivalent booster, and those neutralizing antibody titers likely that will be matched and surpassed with a second monovalent Omicron boost. Some of the cross-reacting ancestral antibodies still bind to Omicron virions so they might not neutralize, but binding antibodies can also be useful making it less transmissible and in making immune complexes which help enhance T cell responses.

So, I can see no reason not to get vaccinated with the new bivalent vaccine.

People talk a lot about where the next variant will be coming from. In the past, each major variant has come from something we call “saltational” evolution. That means that someone with persistent COVID-19 developed an inadequate immune response and the variant escaped with a large number of mutations. Omicron clearly came from clade C SARS-CoV-2 variant 8 to 12 months after its emergence; it had 18 mutational changes from its nearest relative, and it didn’t have these intermediary cousins prior to its appearance. That indicates it emerged from a single person or a small number of individuals.

What’s the probability of this happening again? We don’t know, but there are precious few SARS-CoV-2 viruses from outside the Omicron family circulating in the world at the moment. It doesn’t mean they aren’t there—and that there isn’t a possibility that another zoonotic jump to humans couldn’t occur—but all of the data suggest that the strains that are going to occur are emanating from Omicron, because it’s the only thing around. Thus, I think we need to concentrate on Omicron. Maybe it can accommodate another massive “saltational jump” of say 10 or more mutations that introduce a dominant new variant; or maybe the virus can sustain this constant evolution to escape from immune responses incrementally.

Monoclonal Antibodies Lost

The biggest danger I see now is the dwindling availability of monoclonal antibodies to treat serious infections. A combination of monoclonal antibodies, tixagevimab and cilgavimab (Evusheld), has been a valuable tool for protecting immune compromised patients.

Unfortunately, it has been lost. The new Omicron subvariants escape it. This is an incredible loss—one that I think has been underappreciated by the public. AstraZeneca’s Evusheld has played a vital role in prophylaxis for the highly immunocompromised patients who will never respond to vaccination. Evusheld has been effective in reducing infections, keeping these people healthy, keeping them out of the hospital, and alive. Many can’t take effective antivirals when they get infected, so they have a double whammy—no response to vaccination and they face potential organ loss because they need to come off immune suppressive medications for extended time periods in order to use Paxlovid. 

I’m concerned. When you look at the monoclonal antibody field, every single monoclonal antibody within the last three years has dropped out: the Lilly monoclonals, bamlanivimab/etesevimab and also bebletovimab; Regeneron’s casirivimab/imdevimab (brand name REGEN-COV); VIR/GSK’s sotrovimab; and now AZ’s Evusheld.

It’s very tough for a company to financially invest in a product that only has a market shelf life of a year or year and a half. The only way we can handle that is to have society—and the government—underwrite the manufacturing of the monoclonals for this important population. Evusheld, at its peak, averaged a million doses a month; and it’s probably been underutilized.

My philosophy for the severely immunocompromised and the frail elderly is to give them effective antibodies; quit flogging them with a vaccine with limited efficacy.

So, settle in this winter, get the Omicron bivalent vaccine booster shot, keep the antivirals close, get tested when you feel sick to determine what you have, and don’t be ashamed to wear a mask. 

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 Center.

You may also like

SARS-CoV-2: Where Did It Come From and Where Does It Go Next?
Making Clinical Trials More Diverse: Michele Andrasik on The Long Run
When Does COVID Normalcy Begin?
A Long Hauler, Two Years Later