Authors: Melissa Healy August 13, 2022 la times

For more than two years, Cathy Baron and Sara Alicia Costa managed to duck the coronavirus. But despite their being fully vaccinated and boosted, the Omicron variant finally caught them.

Baron is an actress and dance instructor who lives in Santa Monica. Costa is an architect in Austin, Texas. Both are 40 and healthy. But the two friends saw two very different sides of the variant they expected to be gentler on its victims than earlier strains.

For Costa, the Omicron variant lived up to its reputation for mildness, causing headaches and “something like a crummy cold” for a couple of days. She was visiting Baron and surfing in Santa Monica a week after testing positive.

Baron’s illness was deeply chastening. She was flattened for several days with a high fever and debilitating muscle aches and was too exhausted to teach her pole dancing class for three weeks. Two months later, she’s still coping with fatigue, brain fog and episodic coughing fits. She hopes never to repeat the experience.

Baron and Costa are what scientists would dismiss as an “n of 2.” If their experience were a study, the sample size would be far too small to draw any conclusions, especially one as important as whether the Omicron variant really is less virulent than the SARS-CoV-2 variants that came before it.

And yet, their contrasting experiences are as telling as many of the research studies conducted to date that have tried to determine how dangerous Omicron really is.

“It’s an excellent question,” said Dr. Stanley Perlman, a University of Iowa virologist and a leading expert on coronaviruses. Many researchers think they know the answer, and “I think it’s true” that the Omicron variant is causing milder illnesses, he said. But the true picture is “not clear,” he cautioned.

Omicron arrived in the United States at a time when 60% of Americans had the protection of COVID-19 vaccines and roughly a third of Americans (including some who’d been vaccinated) had a past infection. Not only was there a high level of population immunity, those who did become ill had access to treatments that weren’t available to people sickened by the initial strain from Wuhan, China, or the Alpha and Delta variants that followed.

Perhaps these are the reasons why those infected with Omicron have tended to experience milder illnesses.

“It’s widely said that Omicron is inherently less pathogenic, but there is no real evidence for that,” said Dr. Christopher Chiu, a COVID-19 researcher at Imperial College London.

“Comparisons with Delta are like apples and oranges,” he said. “Delta was circulating at a time when many were still not vaccinated or previously infected. In contrast, Omicron is largely causing breakthrough infections in people who already have partial protection from immunity conferred by vaccines or infection.”

Since its earliest appearance in November, researchers have seen that compared with previous variants, Omicron was less likely to send infected people to the hospital or to their graves.

First in South Africa and later in communities across America, the new variant bucked expectations spawned by earlier surges. In the two to three weeks after Omicron cases spiked, hospitalizations and deaths rose as well — but more slowly, and they’d topped out at lower levels.

Still, as Americans have learned from hard experience, the Omicron variant is a highly capable killer. Just over 200,000 of the country’s COVID-19 deaths are likely attributable to some version of the Omicron variant, which arrived here around Thanksgiving and became dominant in January.

And don’t forget, Perlman added: It’s still killing some 400 people a day in the United States.

How much of Omicron’s supposed mildness should be credited to the protective effect of vaccines is not really known.

During June, the Centers for Disease Control and Prevention concluded that COVID-associated hospitalizations among unvaccinated adults were 4.6 times higher than they were among vaccinated people. But the picture is muddier than such data would suggest.

Americans’ immune profiles run the gamut, making it hard to slot people into neat categories and compare how they fared when infected by different variants. Those who’ve been vaccinated are experiencing various degrees of waning immunity, even if they’ve been boosted. The same goes for people who’ve recovered from infections. The readiness of their immune systems depends on how long ago they had the infection, what variant infected them, their vaccination status, and factors like age and the medications they take.

With so many variables to consider, it’s hard for researchers to draw a clean comparison between Omicron and its predecessors. But they’ve tried.

In one study published in Nature, scientists showed that Omicron was drawn to a wide range of human tissues. When observed in petri dishes, the variant established itself in cells that mimicked the upper airways of the respiratory system, though with less gusto than the Delta variant. In addition, Omicron was far less adept at infecting lower airway cells, including lung tissue, than either Delta or the original SARS-CoV-2 strain that left Wuhan.

And in studies that infected animals such as hamsters and genetically engineered mice, the Omicron variant caused less weight loss (a proxy of severe disease) and touched off less inflammation in the lungs than either Delta or the original strain.

Adding to the uncertainty is the fact that coronavirus testing was undergoing sweeping changes just as the Omicron variant took hold. As at-home testing ramped up and fewer new infections were reported to public health agencies, the relationship between cases on the one hand and hospitalizations and deaths on the other — a previously dependable measure of a variant’s ability to sicken — became less reliable.

The Omicron variant’s astonishing infectiousness and propensity to spin off new subvariants complicate the picture even more. In a recent meeting convened by the Food and Drug Administration, even experts from the agency shrugged when asked to compare the subvariants.

Collectively, those Omicron subvariants muscled Delta aside so quickly that doctors and researchers didn’t have time to collect groups of similar patients, genetically sequence the viruses that infected them, and compare how their illnesses proceeded.

That’s the kind of study that might shed light on the divergent experiences of Cathy Baron and Sara Alicia Costa. They’re a seemingly well-matched pair of healthy 40-year-old women, yet Omicron attacked one of them like a lion and treated the other like a lamb. With the experiences of hundreds or thousands of people thrown in, such research might reveal factors that nudge an Omicron infection in one direction or the other.

There is a more direct way to learn how Omicron compares to earlier variants in its ability to sicken and kill. Researchers could deliberately infect volunteers with different versions of the coronavirus and track their physiological responses to infection over the course of an illness.

Chiu and his colleagues at Imperial College London have just such an undertaking in mind. They are planning “human challenge” studies involving the Delta and Omicron variants to mirror one already conducted with the original version of the virus.

The resulting data could yield a clearer picture of exactly how Omicron behaves in healthy humans, and how a prior infection or different levels of vaccination affect an individual’s illness.

Chiu said a new study would seek to enroll people who gained immunity through vaccination, a past infection, or a combination of both. That would give them more insight into whether so-called hybrid immunity is an important bulwark against becoming sick in the Omicron era.

If research confirms that the Omicron variant is indeed milder than its predecessors, and that getting it confers some protection from future illness, some may conclude it’s time to let the virus spread.

Baron would take some convincing of that.

“When people say, ‘let’s just let it rip’ and allow ourselves to get infected over and over again — that’s scary to me,” she said. “I don’t want to just let it rip. I don’t want to get it again.”