BUT WE DO KNOW EXPOSURE IS SUB-OPTIMAL:

For Osterholm, the emergence of these variants -- which came to be known as Alpha and Beta, respectively -- caused a "sea change."

"That's where, for me, I had to make a major adjustment in how I was looking at the pandemic," he said. "There were major changes occurring in transmissibility and in potential to cause serious illness."

Dr. Peter Hotez, a professor of virology at the Baylor College of Medicine, said mutations have been among "the most frustrating parts" of COVID-19.

At first, the mutations were predictable, with "similar types of amino acid substitutions," he said. But Omicron was a "game changer."

The new variant, which emerged around Thanksgiving 2021, had "significantly more mutations" than previous versions, particularly in the gene that encodes the spike protein that the virus uses to attach to cells, according to the US Food and Drug Administration. As a result, Omicron and its subvariants are adept at avoiding the antibodies people produce after vaccination or infection.

Osterholm said scientists are "still trying to understand" why these mutations occurred as the virus replicated inside humans.

"We're part of a natural experiment where that virus is going through all these genetic changes in us," he said.

It's impossible to anticipate how much more the virus might mutate in the future, and that might prolong the pandemic.

"Today, we still have a challenge of understanding what is going to happen in the future," said Osterholm. "Is there going to be a BA.8? Is there going to be a BA.9? Is there going to be Pi or Sigma?"

For much of the pandemic, experts claimed COVID-19 would stop spreading once we reached the tantalizing threshold of "herd immunity."

The concept is simple: once the majority of a population is immune to a virus -- by infection or vaccination -- there are too few hosts for the virus to continue to spread in the population.

In March 2020, Osterholm declared in the Washington Post that COVID-19 was bound to disappear "eventually" -- either through vaccination or through an accumulation of immunity against the virus.

"The virus will burn itself out as the spread of infection comes to confer a form of herd immunity on the population," he wrote.

Today, Osterholm believes the opposite.

He first felt "skeptical" of herd immunity in August 2020 after a report of reinfection indicated that immunity could wane. Once the variants took over, he said, "all bets were off."

"All the nails have been appropriately placed in the coffin of herd immunity," he said.

The concept of herd immunity only works for diseases like polio and measles because those viruses are "not evolving fast," said Hotez. For COVID-19, "with all the escape mutants, herd immunity proved a totally worthless concept."

Others argue that we have, in fact, achieved a kind of herd immunity.

"We can see that there is some immunity out there, and it is interfering with the transmission of the virus," said Dr. William Hanage, a professor of epidemiology at Harvard's T.H. Chan School of Public Health. "It's just not interfering with the transmission of the virus to make it go away."

Above all, individuals who have charted the course of COVID-19 have come to understand uncertainty.

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