We Might Be Looking At COVID “Seasons” For Years To Come

“I know everybody wants great news, that we can be done with COVID and everything’s gonna be fine, but that’s not really true.”

The latest high-profile poster child for a COVID superspreader event was the playdate of the powerful — the storied Gridiron dinner in Washington, DC, that infected New York’s mayor, the US attorney general, and at least 70 others this month.

That outbreak points to the end of a long-sought lull in the deadly pandemic that has officially killed nearly 1 million Americans. Just how big a change it will herald, though, is hard to gauge.

“It’s really tough to say what is going to happen,” Anthony Fauci, President Joe Biden’s chief pandemic scientist, told BuzzFeed News. Virtually everyone across the country has some immunity to COVID from shots or infections, or both. “But there are going to be new variants.”

Despite the easing of mask guidelines and 95% of counties reporting “low” community risk rates, there are signs of another potential wave of COVID, with upticks in cases in New York and Washington, DC — homes to the Gridiron crowd. In the United Kingdom — the harbinger of past US surges — climbing cases from the BA.2 form of the Omicron variant last month reversed a similar lull there, with hospitalizations rising to levels seen during the first Omicron surge. One in 13 people in England was thought to be infected in the first week of April, according to the UK’s Office for National Statistics.

The striking and most welcome streak of US Covid hospitalizations going down every single day since mid-January continues, now well below the prior pandemic nadir, and even after facing BA.2 variant dominance in parts of the country weeks ago 👍

Twitter: @EricTopol

Only in the last three weeks, BA.2 has become the dominant variant in the US, now accounting for 86% of cases, according to the CDC. In that same time, US cases have hovered at around 28,000 new reports daily, a plateau in numbers that hasn’t been seen since last June. And daily hospitalizations, perhaps the most telling pandemic indicator, are down to around 1,400 a day in the US, less than a tenth of the rate at the height of January's Omicron spike. Still, there are cases rising in the Northeast, so much so that Philadelphia reinstituted its mask mandate on Monday.

“It does seem like what’s happening on the East Coast is nearing what has happened in Europe and in the UK, where BA.2 really did kind of pick up,” University of Arizona evolutionary biologist Michael Worobey said. “The good thing is that hospitalizations and deaths are not increasing nearly as much as with prior surges.” That break from the past, he added, could mark a turning point in the pandemic.

About 77% of the US population now has at least one vaccine shot, and more than 43% of the population is thought to have been infected at least once by the coronavirus, or SARS-CoV-2, providing some immunity. Add in warmer spring weather, curbing a virus that more easily spreads indoors, and crystal balls look hazy for April, although many observers expect at least some sort of COVID surge. Just how much is unclear.

“The more immunity we have in a population, and especially the more immunity we have to variants that are related to the thing that’s currently circulating, the less chance that I see of a major surge,” said Stephen Kissler of Harvard’s T.H. Chan School of Public Health.

While surges have come in the late summer and late winter in the US, he added, “early spring is sort of the time when we’ve seen the lower cases.”

Another question is how much immunity to BA.2 does past infection with the original Omicron BA.1 variant “sublineage” provide? BA.1 was only detected in November in South Africa before it rocketed around the world, causing tremendous surges. Omicron’s pronounced genetic differences from past variants — notably dozens of mutations on the spike protein it uses to first invade cells — let the virus evade treatment and vaccine defenses far more easily. BA.2’s mutations overlap to a large extent with BA.1, and a preliminary study released from Denmark suggests infection with the latter provides good “cross-reactive” protection against the former.

But even the experts disagree on what comes after BA.2. Some expect a split bump in cases, like University of Chicago infectious disease expert Emily Landon.

“I actually doubt that BA.2 is going to cause a major problem up in the northern half of the country, but it has a real potential to cause a surge in the South over the summer,” Landon said.

“I think there’s every reason to believe that that might happen and so, getting ahead of that, I certainly think anyone who wants to be protected should do that,” she added, referencing a second booster shot for those who are eligible.

Global counted covid deaths remain < 5000 a day. Not necessarily great news (that's 4500 moms, dads, brothers, sisters, kids every damn day) but far lower than we've seen. We do seem to be heading towards the end of this nightmare.

Twitter: @DFisman

Others are more worried about the chances of a sharper renewed surge like the one seen in the UK.

“BA2 is going to spread like crazy. I mean, it already is, and that is going to encourage the emergence of more variants,” said Theodora Hatziioannou, a virologist at Rockefeller University.

Some just acknowledge uncertainty.

“I don’t have the slightest idea what’s going on,” University of Arizona immunologist Deepta Bhattacharya said in regards to BA.2. “It’s not overtaking things nearly as quickly as I expected, and how it seems to be happening in Europe.”

Meanwhile, even as we wait to see whether BA.2 brings a surge back to the US, possible longer-term futures for the pandemic are swimming into view. Broadly, visions range from the coronavirus settling down into flulike seasonal appearances to more deadly new variant surges that continuously pop up over time.

One thing that isn’t going to happen, Fauci said, is the development of broad “herd immunity” in the US, once a long-sought-after goal in the beginning of the pandemic. The virus is too mutable — and natural immunity to the virus wanes too quickly — for herd immunity to offer the long-term protection that vaccines have against more stable viruses like polio and measles, he and his NIH colleagues wrote in a recent Journal of Infectious Diseases paper. There’s also the still-surprising fact that a significant portion of the population, just over 1 in 5 people, has not gotten a free vaccination against a deadly disease.

“We never expected that,” Fauci said.

The common cold–causing coronaviruses should have offered some clues that herd immunity was likely impossible, he added. These bugs regularly reinfect people within a year or two.

But it was a “gradual evolution” to realize that herd immunity wasn’t coming, as the Delta and Omicron variants drove surges and vaccine shots stalled, Fauci said. Despite early hopes, he added, “that’s not really a possibility now.”

Heading into whatever wave BA.2 brings, the US is looking at a more complicated COVID future. Or futures. Here are some possibilities:

Seasonal COVID

Like the virus’s runny nose and sore throat–causing cousins, many experts agree that SARS-CoV-2 may very well settle into a seasonal pattern, surfacing during certain months then retreating into the dark again. But how this pattern materializes, and when, is still up in the air.

It’s possible different parts of the country will see “opposite seasonality” that’s dependent on when people spend the most time indoors, Kissler said. Florida, for example, tends to see high coronavirus transmission in the summer when people escape the heat for indoor air conditioning. More northern states may see traditional spikes in cases in the winter for the same reason, providing immunity that lasts through their summer. Still, it’s possible that may not even be the case because SARS-CoV-2 “is just so incredibly infectious,” Kissler said.

Determining COVID’s seasonality is a bit more complicated than that of the common coronaviruses, which are more predictable in that their variants closely resemble previous dominant strains, Bhattacharya said. A lot of experts assumed this would be the case with SARS-CoV-2, but “weird jackpot events like Omicron” raised doubts that this new virus would mirror its predecessors.

“Maybe the common coronas were like this at the beginning, too, when no one was looking, and lacked the capability to look,” Bhattacharya said, “but it’s hard to know if it’s that or if there is something fundamentally different about SARS-CoV-2.”

Even if COVID morphs into a seasonal illness, we still won’t know what to expect or prepare for, at least not any time soon, Landon said. Each year so far has brought about two major waves of infections, with some smaller surges sprinkled throughout. So COVID could emerge from the shadows once or twice annually, she said, “but it’s not 100% predictable where the biggest peaks are going to hit and when.”

Permanent COVID Season

Every year, the flu kills tens of thousands of mostly older people, but also some children and other vulnerable individuals. A worse future for the pandemic might see the coronavirus ceaselessly bubbling along and causing similar deaths in a kind of permanent COVID season.

“We don’t like to talk about it, but we have lots of everyday illnesses that still kill people,” Fauci said. “RSV (respiratory syncytial virus) kills children as well as the elderly.”

That may be the future of a “settle in” strategy for dealing with the pandemic like we endure colds and flus, Fauci added, which he doesn’t think is a good idea.

“People will still get seriously ill,” he said.

“There is no reason to think this is going to become the cold,” said Worobey, the viral evolution expert. “From what I can see, it's going to be much more problematic than flu, which is a shitstorm every year, increasingly, killing up to 80,000 people in the US, which is a lot of people. And I think SARS-COV-2 is poised to be considerably worse than that.”

In this future of a perpetual COVID season, people will get very sick unexpectedly from the coronavirus, perhaps ending up with disabling long COVID symptoms, or dying, while others remain unscathed.

“We know some people are just intrinsically more vulnerable,” Temple University pulmonologist Steven Kelsen said.

In a recent JCI Insight study of 61 healthcare workers, Kelsen and his colleagues tested participants’ antibodies after the first of a two-shot Pfizer-BioNTech mRNA vaccine. They found that half of the hospital workers who had prior infections developed stronger antibodies similar to those seen in the fully vaccinated. That’s good news for giving people even just one shot around the world (as well as for vaccinated people who had breakthrough infections in the recent Omicron surge).

But the study also pointed to something more worrisome: a highly uneven waning of those protective antibodies. Some people’s antibodies lasted a long time, while others faded fast. “That suggests there are people out there more vulnerable to infection than anyone might suspect,” Kelsen said.

Without some check on their antibodies to identify who needs a booster, those people might regularly fall victim to COVID, even as most everyone else sees SARS-CoV-2 as less of a problem. The FDA’s March 29 call for people over 50 and those at high risk to get a second booster strikes Kelsen as a good first step for addressing this possibility, but he worries about people outside those categories who, for whatever reason, have antibodies that fade uniquely fast, leaving them more likely to suffer an infection.

“We need to personalize vaccinations for these people,” Kelsen said. “I don’t see that happening right now.”

New Deadly Variants

In a worst-case scenario, variants like Omicron throw cold water on hopes of a long-term lull in the pandemic after BA.2 passes or even settles in like other common diseases, experts say. Lulls followed by eruptions of immune-evading variants could be the new normal, bringing more deaths among the unvaccinated and vulnerable.

“I think we will see ‘blips’ where there are more cases going forward as new variants emerge,” Fauci said.

The Delta variant arose in India and Omicron emerged in Africa, where broad swaths of unvaccinated people gave the virus countless opportunities to mutate, he noted.

“Anywhere you have large pockets of unvaccinated people that give the virus room to evolve we could see dangerous new variants,” he added.

In a recent New York Times essay, experts on viral evolution led by the University of Chicago’s Sarah Cobey suggested that new variants might arrive with the regularity of the flu changing every winter. While Omicron had 15 mutations of its genes that helped it evade current vaccines, there’s room for nearly 2,000 more, they estimate.

“There’s no reason, at least biologically, that the virus won’t continue to evolve,” they wrote.

Even now, scientists are watching BA.4 and BA.5 versions of the Omicron mutation, which possess a mutation called “F486V” associated with even more evasion of current vaccines.

Wanted to add details about F486V mutation in the new BA.4 and BA.5 lineages of #Omicron (see nice thread by @Tuliodna below). F486V could lead to more antibody escape from serum elicited by current vaccines / early infections. (1/n) https://t.co/xOR5KmlHcZ

Twitter: @jbloom_lab

While BA.2 seems to be causing only increases in cases on the East Coast right now, without an uptick in hospitalizations and deaths, that is more a reflection of past vaccinations and infections with the BA.1 Omicron variant, rather than an indicator of the future, Worobey said. Omicron itself was likely a “blast from the past,” a variant that picked up its mutations in a single ill person, steadily accumulating them until it emerged ready to run rampant across the globe.

In the early stages of an infection, the body’s antibodies match up to locations on the “spike” proteins projecting from the virus, gumming up any docking with cells. Omicron’s mutations changed the topography of the spike enough to better evade those antibodies. There’s no reason not to think that thousands of people infected for the long-term with the earlier Alpha or Beta variants are steadily mutating versions of those bugs, one of which will emerge — a lottery winner in the game of evolution — to defeat antibodies now aimed against Omicron.

“You have to be humble — no one knows exactly what is going to happen,” Worobey said. “But it is clear the virus has acquired mutations.”

Given that it took Omicron more than two years to emerge, Fred Hutchinson Cancer Research Center biostatistician ​​Trevor Bedford has suggested that one of these new Omicron-like surprise variants shouldn’t emerge every year. Instead, statistics show they will likely arise anywhere from 18 months to 10 years apart. For that reason, Bedford favors switching to boosters based on Omicron, which appears to be the dominant variant, for now.

Others, like Hatziioannou of Rockefeller University, think switching to variant-specific boosters may be more beneficial in pulling the pandemic’s reins if given to specific people, such as those who have already been vaccinated and boosted with the original vaccine. She’s more hesitant, however, about the benefits of giving shots based on Omicron to the unvaccinated, who don’t have vaccine-induced protection for either of the previous variants.

The Only Safe Bet Is Vaccination

“There’s going to be different sorts of dynamics in different places, sort of different patterns of spread across the year,” said Kissler, the disease modeler. Because of that, “weather reports” of pandemic conditions, looking at wastewater surveillance, hospital numbers, and other indicators, might just become part of our lives.

“One of the best things that we can do to help manage continued outbreaks is to just continue informing people how much COVID is currently circulating in their community,” he said. “A lot of data suggests that people do tend to sort of adjust their behavior accordingly.”

The only indisputable observation that experts have is that vaccines save lives. The rate of COVID hospitalization was five times higher among unvaccinated people in February, the most recent month tabulated by the CDC, and the split has been even higher in the past.

That leaves open the question of whether a second booster shot, now allowed for those 50 and older, is needed for everyone.

“I would say for the majority of the population, three doses is a must. But I’m not certain a fourth dose is required right now,” said Hatziioannou, who added that she’s a “bit skeptical” that any future variant will achieve complete resistance to the currently available COVID vaccines.

“The immune responses we are mounting right now have such enormous breadth that they can touch even very divergent coronaviruses,” she said, such as SARS-CoV-1, which was first identified in China in 2003. “It gives me hope that our immune responses, at least in terms of protection from severe disease and death, will be maintained.”

Many experts are especially interested in more ambitious vaccines aimed against a plethora of variants, or more broadly a “pan-coronavirus” vaccine that would protect against a SARS-CoV-3 or SARS-CoV-4, now likely evolving in a bat somewhere, Worobey said, threatening to someday wreak more havoc.

For now, Fauci said he will happily take a vaccine that is effective against a broader spectrum of variants. Some research is looking for one of these aimed against unchanging parts of the spike protein that seem to resist mutation. Others look to release a mosaic of variant spikes that tip the immune system to all the evolutionary pathways open to SARS-CoV-2. A shot like that, aimed against SARS-CoV-2, would be a lot quicker to develop rather than one aimed against every single kind of coronavirus out there, where more than 4,000 different kinds have been isolated from bats.

“At this point, I’ll take a single over a home run, if we can get it,” Fauci said.

In the meantime, as we wait to see the effects of BA.2 infecting politicians and ordinary people alike in the US, experts say the pandemic looks far from over.

“I know everybody wants great news, that we can be done with COVID and everything’s gonna be fine, but that’s not really true,” Landon said. “I don’t think right now for most people in most parts of the country, it’s not a higher-risk time, but that doesn’t mean that there won’t ever be another high-risk time.” ●