We’re approaching the year-and-a-half mark of the globe’s collective experience with the SARS-CoV-2 virus and the Covid-19 pandemic it has triggered. At this point, it’s fair to assume people the world over are asking themselves the same two questions: How will this end? And when?
There may have been a fleeting chance humans could have halted spread of SARS-2 and driven it back into nature, as happened with its cousin, SARS-1. But that door was firmly shut long ago. It also seems that another option — vaccinating our way out of the pandemic — is an expensive toll highway that few countries will be able to access in the near term.
That probably sounds bleak, but don’t despair. The truth of the matter is that pandemics always end. And to date vaccines have never played a significant role in ending them. (That doesn’t mean vaccines aren’t playing a critical role this time. Far fewer people will die from Covid-19 because of them.)
But there were no flu vaccines in 1918, when the world didn’t yet know that the great influenza was caused by a virus, H1N1. In 1957, when the H2N2 pandemic swept the world, flu vaccine was mainly a tool of the military. In the pandemic of 1968, which brought us H3N2, the United States produced nearly 22 million doses of vaccine, but by the time it was ready the worst of the pandemic had passed, and demand subsided. That “too little and too late” phenomenon played out again in 2009, when the world finally had the capacity to make hundreds of millions of doses of H1N1 vaccine; some countries canceled large portions of their orders because they ended up not needing them.
How did those pandemics end? The viruses didn’t go away; a descendent of the Spanish flu virus, the modern H1N1, circulates to this day, as does H3N2. Humans didn’t develop herd immunity to them, either. That’s a phenomenon by which a pathogen stops spreading because so many people are protected against it, because they’ve already been infected or vaccinated.
Instead, the viruses that caused these pandemics underwent a transition. Or more to the point, we did. Our immune systems learned enough about them to fend off the deadliest manifestations of infection, at least most of the time. Humans and viruses reached an immunological détente. Instead of causing tsunamis of devastating illness, over time the viruses came to trigger small surges of milder illness. Pandemic flu became seasonal flu.
The viruses became endemic.
If the pattern holds, and it is expected to, SARS-2 will at some point join a handful of human coronaviruses that cause colds, mainly in the winter, when conditions favor their transmission.
When will that happen? That’s the big, unanswerable question. “I thought that we’d be out of this acute phase already,” admitted Maria Van Kerkhove, the World Health Organization’s leading coronavirus expert. Van Kerkhove’s thinking, though, is influenced by her adamant view that the world could stop the pandemic if countries would only take the steps countries like New Zealand, Vietnam, and others have done, and bring transmission under control.
“There’s nothing — there’s nothing — including the virus variants, that suggests we couldn’t be out of the acute phase already,” she told STAT in a recent interview. “Because this is controllable.”
Experience from the last four pandemics — the ones mentioned above — would suggest that viruses morph from pandemic pathogens to endemic sources of disease within a year and a half or two of emerging. But all of those pandemics were influenza pandemics. A different pathogen could mean we’ll see a different pattern.
There may well have been previous coronavirus pandemics; there’s a school of thought that a pandemic in 1889, known in medical histories as “the Russian flu,” might actually have been caused by one of the human coronaviruses, OC43. All four of the human coronaviruses are assumed to have jumped to people from an animal species; OC43 is believed to have come from cattle, potentially in the late 1800s. But this is in the realm of theory, not conclusive fact, having occurred before the era of modern virology.
There’s no historical record of how much illness and how much severe illness those other coronaviruses caused when they started to infect humans or how long it took for them to settle into an endemic state. As such, the flu pandemics are the closest thing we have to road maps. “In recent history, everything has been influenza and the timeline has been within a couple of years,” said Jennie Lavine, a biology research fellow at Emory University who was the first author of a modeling paper published in Science that envisioned how the pandemic might end.
Lavine and her co-authors predicted that as older adults — most susceptible to hospitalization and death with Covid — acquire experience coping with the virus, it will no longer induce severe disease, at least not in most of those people. (Nothing is absolute; flu, for instance, occasionally kills previously healthy people.)
That immune system training will likely turn future Covid-19 infections into the equivalent of a cold, the authors concluded. Over time, as a degree of protection becomes more standard in adults, the people who will most commonly catch Covid will be young kids, in whom infections even now are rarely serious. That’s the pattern with human coronavirus infections.
“I think the scenario … remains the most likely one,” said Marc Lipsitch, an infectious diseases epidemiologist at Harvard’s T.H. Chan School of Public Health. “That essentially, almost everybody has some form of immunity from natural infection and/or vaccination and/or one followed by the other, and that that will persist long enough so that they don’t get really sick when they get it again. And then we transition to endemicity.”
Lavine is unfazed by the notion that SARS-2 could still be with us when the pandemic is over.
“It’s not a death sentence in any way, shape, or form to say we’re not going to have herd immunity,” she said. “It just means it’s going to become endemic and then the question is, is it going to be mild and endemic, or is it going to be severe and endemic? And I would say my odds are on mild and endemic at some point. I think that seems really, really likely.”
Lavine is not alone in thinking we’re not going control spread of SARS-2 through herd immunity. Earlier this spring, Jonathan Yewdell, a senior investigator in cellular biology and viral immunology at the National Institute of Allergy and Infectious Diseases, published an opinion piece in the journal PLOS Pathogens arguing that coronaviruses don’t trigger the kind of long-lasting immune protection we’d need for herd immunity to take hold.
Endemic SARS-2 would have a seasonal pattern, spreading in the winter months when kids are in school and when we spend more time indoors in proximity to each other. Florian Krammer, a vaccinologist at the Icahn School of Medicine at Mount Sinai in New York, said that early on some of these seasons may be more severe than others — but not pandemic severe.
“If this thing becomes seasonal and you have countries where the vaccination rate is low and the immunity background is low, those seasons in the beginning might be a little bit stronger. In countries where vaccination rates are high, they might be very low,” said Krammer.
He and others told STAT this transition will play out at different times across the globe. “I think we will see a huge difference between the West and everybody else who kind of didn’t get enough vaccines,” Krammer said. “Although there might be countries like Iran, where the infection rates have been incredibly high, and I think they have by now so much background immunity that if they bring it down now, it’s unlikely to come back as a wave.”
Lavine believes the shift could happen fairly soon in countries like the United States that have had both high levels of infections and large numbers of vaccinated people.
“In the U.S., I would say that is not far off,” she said. “Not to say that it’s just going to disappear, but the idea that it would no longer be this kind of pathogenic scourge, I think we might not be too far from that.”
There are some experts who are more cautious about the timeline. Historian John Barry, who wrote the definitive account of the Spanish flu, “The Great Influenza,” noted there are significant differences between Covid infection and transmission and influenza infection and transmission. The incubation period — the time from exposure to illness — is longer with Covid. People are sick for longer; they’re infectious for longer, too.
“This is like influenza moving in very slow motion,” Barry said. Influenza pandemics have abrupt endings to their waves, with transmission dying out in any given location in a matter of weeks. That has not been the case with Covid. Instead, human behavior — societal shutdowns and reopenings — appear to be driving patterns.
Lipsitch worries that the recent explosive waves in Brazil and India are reason for us to be wary about forecasts that a transition might be near. Both had experienced substantial transmission early in the pandemic, yet have been walloped by second waves triggered by mutated viruses, so-called variants of concern.
“I think we do have to have some account of how it’s taking this whole year with multiple waves and still there’s no real evidence that it’s ending on its own in any country. And I think that a slower natural history is probably a piece of it,” he said. “It’s been niggling at me.”
Cécile Viboud, an infectious diseases modeler who has extensively studied flu pandemics, also believes the pandemic ends with SARS-2 being endemic. But she’s not sure when.
“I’m trying to be cautious, because I’ve always been an optimist and during Covid-19 I’ve been proven wrong,” said Viboud, who is based at the National Institutes of Health’s Fogarty International Center.
She suggested it’s possible that the four seasonal coronaviruses, the ones that cause colds, were always milder than Covid. Or that SARS-2 will continue hurling variants at us — especially once it comes under pressure to evolve when large swathes of people are vaccinated. “So I think we have to be cautious. We only have like 15 months of data or something, right?”
Mike Ryan, head of the WHO’s Health Emergencies Program, agreed.
“We don’t know where we are, because this is the first pandemic of a SARS coronavirus,” he said. “From my perspective, crystal-balling it … we’re not even close to the end of it.”
Ryan picks up Van Kerkhove’s refrain, arguing countries shouldn’t be waiting for vaccines or for the virus to transition into an endemic mode. They should be using the other tools that have been shown to stop transmission, he said. “I think we can get to very high levels of disease control, so much so that this ceases to be a pandemic in the sense that it ceases to be … causing disease and deaths and filling up our hospitals. So, in that sense it ceases to be a public health crisis.”