October 4, 2022

A wave of COVID infections caused by the BA.5 subvariant has peaked. All over the world daily new cases, hospitalizations and deaths they come down.

But the SARS-CoV-2 virus is almost certainly here to stay. Another wave is all but inevitable as new variants and sub-variants mutate, compete for dominance and find new transmission paths.

How quickly this wave comes and how bad it gets is likely due to a genetic competition between different mutations of the new coronavirus. If we’re lucky, a milder form of the virus wins – and buys us time to prepare for one worse form of the virus that is almost certainly coming, sooner or later.

If we are unluckythis worst comes sooner.

The scientific community takes nothing for granted. “What we’ve learned from this pandemic is to expect the unexpected,” Cindy Prince, an epidemiologist at the University of Florida, told the Daily Beast.

BA.5, an offshoot of the basic Omicron variant, was still dominant when epidemiologists began looking for the version of COVID that might come post BA.5. They have identified two main possibilities.

The best of the possible possibilities is another form of Omicron, a variant that our immune system recognizes and knows how to defeat. The worst is some brand new variant that can escape our antibodies. A variation of Pi, Rho or Sigma if you will.

Any outcome is possible. The one thing experts don’t expect is for… COVID to disappear. “The virus has always found a way to survive,” John Schwarzberg, professor emeritus of infectious diseases and vaccinology at the University of California-Berkeley School of Public Health, told the Daily Beast. “I don’t see anything to suggest that he’s not going to continue to do that.”

BA.5 is the third major subvariant of Omicron, itself the third major variant of the virus after Alpha and Delta. The BA.1, Omicron’s entry-level line, went mainstream late last year, replacing the Delta models.

BA.1 was not as deadly as Delta was, mainly due to widespread vaccine immunity and prior infection. The worst day for BA.1 deaths, 13,000 on 9 February, was less devastating than the worst day for Delta deaths, 18,000 on 20 January.

But the BA.1 was way more contagious than Delta. Some epidemiologists described it as the most contagious respiratory virus they had ever seen. BA.1 led to a record wave of infections that peaked at nearly 4.1 million new cases worldwide on January 19.

But if we have Pi, Rho or Sigma, prepare for possible disaster.

The BA.1 wave saw two smaller increases in cases as new sub-variants of Omicron took over. BA.1 cases declined in February. BA.2 drove them back in March. BA.2 infections decreased in May. BA.5 drove them back in June.

The BA.5 surge peaked with 1.6 million new cases on July 20 and 4,500 deaths on July 27. Now infections and deaths are decreasing pretty much everywhere that isn’t Japan.

The relative decline in COVID belies what, by our pre-pandemic standards, is still suffering. “It reflects what we have faced in recent years that we could be in a situation with more than 120,000 known new infections per day, more than 43,000 hospitalizations per day – with 5,000 in ICU – and 450 deaths per day. [in the U.S.] and to be in a mindset where we think, “This isn’t that bad, we’ve seen worse,” Anthony Ahlberg, an epidemiologist at the University of South Carolina, told The Daily Beast.

And the suspension is temporary. If the past 32 months are any guide, the next wave of COVID will build this winter. The only variable is the form of the virus. Is the next dominant form of SARS-CoV-2 the fourth major subvariant of Omicron? Or an entirely new variation?

Discrimination counts for a lot. All sublines of Omicron share some key mutations, especially around the spike protein of the virus, the part of the pathogen that helps it grab onto and infect our cells.

By now billions of people have antibodies that recognize these mutations, whether the antibodies come from one of the safe and highly effective vaccines or from past infections. It is the steady build-up of immunity over the past two years that has kept death rates low even as infection rates rise. Many people have contracted COVID since last winter—some for the second or third time. Most had mild cases.

If one more Omicron descendant becomes dominant in the coming months, this trend must to continue. Will exist probably to be a weekly increase in cases. But the deaths could increase slightly.

Our antibodies are ready, said Edwin Michael, an epidemiologist at the Center for Global Health Infectious Disease Research at the University of South Florida, who has built sophisticated computer models to simulate the COVID pandemic.

“Naturally acquired immunity is long-lived, estimated at 2.5 years in our models, and therefore new infections occur mainly in those who lose their vaccine-induced immunity, which decays more quickly,” Michael told the Daily Beast. “This results in a steady but smaller rise and fall in cases, the fluctuations or oscillations becoming progressively smaller in magnitude over time until an apparent endemic steady state is reached.”

But if we have Pi, Rho or Sigma, prepare for possible disaster.

New variants of a virus become dominant through radical mutations that significantly change the way the pathogen behaves and give it an advantage over its predecessors. With each new variant, there is a chance that it has changed so much that our antibodies no longer recognize it. “A significant genetic change that would greatly increase its ability to infect humans regardless of vaccination status and previous infections,” according to Alberg.

Epidemiologists call this “immune escape.” It’s the nightmare scenario when it comes to viruses.

Michael modeled the wave of a large variant of immune evasion. How bad it gets depends on whether the new variant evades the vaccine-induced antibodies, the natural antibodies from a previous infection, or both. “If immune evasion acts similarly in both forms of immunity, then significantly large repetitive waves will form depending on the precise rate and strength at which evasion occurs,” Michael said.

There are reasons to believe that another Omicron subline is more likely to follow. Geneticists scrutinizing virus samples have noted four forms of Omicron vying for dominance in recent weeks. BA.5, of course. But also BA.5.2, BA.2.75 and BA.4.6.

BA.5.2 is a slightly mutated form of BA.5 and probably doesn’t have enough advantages to outperform its predecessor, Kristian Andersen, director of infectious disease genomics at the Scripps Research Translational Institute in California, told the Daily Beast. “So I think we’ll see BA.2.75 or something completely different take over.”

This “something completely different” has yet to show up in viral surveillance, which means BA.2.75 may have a head start.

If there is a wildcard, it might be BA.4.6, a sub-variant of BA.4, which is a close cousin of BA.5. “We don’t know much about .4.6 in terms of structure,” Swartzberg said. It is possible that BA.4.6 mutated for significant immune evasion, despite the fact that it was just another subvariant of Omicron. “We could wish for a new sub-variant of Omicron that is so successful at evading immunity [that] it could be a serious problem for us.”

“Be careful what you wish for,” Swartzberg joked.

However, as long as Omicron and its progeny dominate, there is a decent chance that the next wave of COVID will be quite small. That buys us time to prepare for the wave after that—and the increased chance, over time, that some immune-evading variant will eventually emerge.

No one expects another round of major lockdowns, even with a highly immune-evasive new form of COVID raging across the globe. Instead, our best tool against Pi, Rho, or Sigma may be the new formulations of messenger-RNA vaccines from Moderna and Pfizer.

mRNA is inherently flexible. It is a plug-and-play delivery system for tiny bits of genetic material that trigger a specific immune response. Change the genetic material and you change the vaccine—and the antibodies it elicits.

Current mRNA vaccines were designed for the Alpha variant, although they still work very well against Delta and Omicron. Anticipating that an immune evasion variant is coming, both Pfizer and Moderna are working on new “multipotent” vaccine formulations with broader efficacy against an even wider range of SARS-CoV-2 variants.

But these new formulations are not quite ready. Both Moderna and New York, Massachusetts-based Pfizer have conducted large-scale trials of their multivalent vaccines, but the US Food and Drug Administration is still reviewing the data.

Whether and when the FDA approves new vaccine mixes, a requirement for health agencies in many other countries to do the same, could depend on whether and when an immune escape variant emerges. Swartzberg said the new jabs could receive FDA approval in about a month.

Obviously, regulators would prefer to study the new formulations without the pressure of a large increase in infections and deaths. And they might just figure it out if the next wave is a BA.2.75 wave instead of something potentially much worse.

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