In the early days of the pandemic, before the new virus had a name, people who had studied coronaviruses offered reassuring predictions about the stability of the virus, which has implications for how often people might be reinfected and how frequently vaccines would need to be updated.

Coronaviruses don’t change very quickly, they aren’t as mutable as, say, influenza viruses, those experts said. In fact, the spike protein on the virus’ exterior, the one that attaches to human cells and triggers infection, cannot change too much without losing its ability to infect, they assured the rest of us.

That was the dogma. Then came the variants: Alpha, Beta, Delta, and Omicron, with its mind-boggling array of mutations. Since it emerged in late 2021, Omicron has splintered into a seemingly endless succession of subvariants, which continue to mutate and evade immunity induced by prior infection and immunization.

Many of the people STAT interviewed cited SARS-CoV-2’s evolution as their biggest surprise of the pandemic. “It’s been wild, in my view,” said Marion Koopmans, head of virology at Erasmus Medical Center in Rotterdam, the Netherlands.

Anthony Fauci, retiring head of the National Institute of Allergy and Infectious Diseases, also listed it as his number 1 surprise. “What has surprised me most about Covid is the continual evolution of new variants leading to an unprecedented persistence of the pandemic phase over three years,” he said.

Michael Diamond, a viral immunologist at Washington University, scoffed when he recalled the early proclamations about the virus’ inability to mutate much. “At some point we’re going to run out of mutational space. Well, we haven’t run out of that yet, which was surprising to us, I think, that the virus is still flexible enough to be able to accommodate these mutations. And not only do that, but increase transmissibility and increase immune escape concurrently.”

The erroneous prediction was predicated on what, after the fact, was clearly a flawed idea — that the evolutionary rate seen when a virus was moving through a totally naïve population would remain the evolutionary rate when the virus faced the challenge of infecting people who had some vaccine- or infection-acquired immunity, said Paul Bieniasz, a virologist at Rockefeller University.

Bieniasz was surprised by the role immunocompromised people — people who, once they contracted Covid, could not shake the infection for weeks, sometimes months — played in driving evolution of the virus. That phenomenon is believed to be responsible for another of the surprises about SARS-2 evolution. Most viruses evolve in a stepwise fashion known as “drift,” adding change after change to an existing strain. But some of the Covid variants look more like old versions of the virus were hyper mutated, possibly in a persistently infected person. When those viruses started to spread, they replaced the viruses that had been circulating. The Alpha, Beta, Gamma and Omicron variants of concern are examples of this type of evolution, called saltation, Thomas Peacock and colleagues wrote in a preprint article posted in late November.

“The reality is that SARS-CoV-2 had a much greater capacity for adaptation than I expected,” said Vineet Menachery, a coronavirus expert at the University of Texas Medical Branch. “While this fact was exacerbated by slow uptake and delivery of vaccines, the truth is that the sheer amount of virus and replication provide enough replication cycles to … select for mutations that provided fitness and immune evasion advantages.”

The susceptibility of the public to charlatans
First it was a malaria drug, hydroxychloroquine. Then it was ivermectin, a drug used to eliminate parasitic worms. Heavenly silver. Bleach. Ultraviolet light. Urine therapy. The list goes on.

The Covid pandemic has been a field day for quacks and crooks. They’ve made a killing.

It is ever thus, some would surely say. But Bieniasz has been stunned by the degree to which a not-small portion of the population has been taken in by hucksters — and by the inability of the scientific community to break that spell.

“The sort of willingness of Joe Public to listen to anybody with a large Twitter following has just shocked and appalled me,” Bieniasz said. He sees this as a consequence of a huge loss of trust in the scientific community.

The reverberations of this loss of trust continue, even though the acute phase of the pandemic appears to be subsiding.

Malia Jones, an assistant professor in community and environmental sociology at the University of Wisconsin-Madison, studies vaccine hesitancy and rejection. She spoke to parents this autumn who refused to get their kids vaccinated against flu. The reason? A rumor that the government is bottling Covid vaccine in flu vaccine vials to surreptitiously increase Covid vaccination rates among kids.

“What? Imagine the coordination it would take to pull that off. It’s just impossible,” she sputtered. “And illegal, and a lot of other stuff, too. But also just really implausible. It’s not the way the world works.”

Unhelpful public health approaches
Bhattacharya has two very active sons, now aged 9 and 11. When schools closed and activity opportunities shrank, he wanted to take them to play tennis. But the nets were removed from local tennis courts to discourage people from using them. “Policy choices like that I think were unfortunate. That then really brought a lot of ill will to anything [public health officials] tried to do subsequently.”

Richard Hatchett worked in the George W. Bush White House on pandemic preparedness, studying the control measures that were used during the 1918 Spanish flu pandemic. His work was pivotal in reminding the world that non-pharmaceutical interventions — the types of measures Cowling was writing about in the WHO report — could reduce transmission of respiratory pathogens. Still, he was surprised at how bluntly they were applied. A future goal should be to figure out how to use non-pharmaceutical interventions “with greater subtlety and finesse to interrupt transmission but not destroy economies,” Hatchett said.