San Francisco Chronicle - (Sunday)
Mutating virus casts cloud over forecasts
But ‘doomsday scenario’ seems unlikely, experts say
At the very end of a Stanford panel about coronavirus variants last week, someone finally posed the question that seems to haunt everyone now: Just how much worse than the highly infectious delta variant can this virus get?
The answers were both cautiously reassuring and disconcertingly unsatisfying. The “doomsday scenario,” in which a variant is completely resistant to antibodies and remains highly transmissible, is unlikely, said Arjun Rustagi, an infectious disease fellow at Stanford. But beyond that, many experts were wary about guessing.
“This virus has a massive genome. There’s still room for it to play, and it’s really hard to make predictions on where it’s going to go,” Dr. Catherine Blish, an infectious disease expert and Rustagi’s mentor, said Wednesday during Stanford grand rounds, an educational panel for medical students and physicians.
In an interview earlier, she was more bluntly
averse to making a prediction. “We have no idea what’s going to happen next. It’s hard to imagine it can get much more transmissible than it is with delta,” she said. “But the only consistency of these past almost two years of pandemic is how often I’ve been wrong.”
Delta has rampaged across the globe since its first appearance in India just six months ago, tearing through unvaccinated populations and upending public health responses even in communities like the Bay Area, which had seemed to be wrestling the pandemic under control.
The delta variant is thought to be twice as infectious as the original strain of the coronavirus. It’s not as transmissible as measles, a virus that causes systemic infection and that can spread farther and faster than any other known pathogen.
But with delta, “we are now looking at the most infectious respiratory virus in our history,” said Dr. Warner Greene, a senior investigator at the Gladstone Institutes, a UCSF-affiliated research center in San Francisco. “We’re in unprecedented transmission here.”
And, he added, no one can yet answer perhaps the next most logical question: “Will there be an heir to delta that will be even more transmissible?”
Variants have become a defining feature of this pandemic, as the coronavirus rapidly mutates and spawns new versions of itself that make it both harder to contain and potentially more lethal. In fact, the first variant to dominate worldwide included a key mutation that may have made it easier to generate even more mutations, and faster.
Concerns over variants largely fall into three broad categories: that they will evade vaccines or natural immunity; that they will become more infectious; and that they will cause more severe disease. So far, a few variants have shown signs of immune resistance, though not enough to seriously undermine the vaccines. A few studies have suggested that delta may cause more severe disease, but many experts say they need more evidence.
Several variants have proved more infectious than the original virus, but none as dramatically as delta. Whether the next variant could outpace delta isn’t clear. It’s not impossible, but as long as delta has a strong foothold there may not be much pressure for it to mutate to become even more infectious.
In a way, infectious disease experts say, it hardly matters if a virus is as contagious as the flu or chickenpox or measles — any variant might be contained with the same mix of vaccination, social distancing and masks.
Instead, a main concern is that delta will develop mutations that allow it to retain its high infectiousness and also evade vaccines or cause much more serious illness. But such combinations may never happen, some experts say. That’s because mutations often come with concessions, trading one trait for another.
Sometimes those trade-offs are easy to explain. For example, a mutation that causes more severe disease may come at a cost of less transmission, because people who are very sick, or dead, don’t infect others very easily.
But for reasons that aren’t entirely clear, mutations that make coronavirus variants resistant to antibodies may also make them less contagious.
“As you get one property you may gain something, but you may lose something at the same time,” Greene said. The endgame for this virus, some experts believe, is a variant that is highly transmissible but will cause only mild symptoms, similar to the common cold.
It would probably take years to reach that point. “But ultimately it settles into a symbiotic relationship, where the virus gets to replicate and the host gets to not die,” Greene said.
Delta may already have made concessions to become so infectious. It has more than a dozen mutations, including at least two that appear to make the virus better able to attach to human cells. Another mutation may make the virus better able to hide from the body’s rapid immune response, giving it a head start on replication.
But a few studies have suggested that those mutations may also make delta less able than other variants to resist antibodies. It’s possible, some experts say, that the coronavirus won’t ever mutate in such a way that it’s both highly infectious and vaccine-resistant.
Even the variants that have shown some resistance to antibodies aren’t able to fully escape the vaccines, and there are signs that the cellular immune response — by way of T cells and B cells that fight off serious disease — are much more durable than antibodies, experts say.
“It doesn’t look like this virus has many ways of evading immunity,” Shane Crotty, an infectious disease expert at the La Jolla Institute for Immunology, said Thursday during a panel discussion about delta at UCSF. “It may not have many tricks left.”
Still, Crotty added, that’s not something he’d bet on. Delta already proved that the virus can mutate suddenly and unexpectedly. It’s hard to rule out any potential combination of mutations that could make it more dangerous, Crotty and other experts said.
“We could get a combination of mutations that may still have the transmissibility and be more resistant. I don’t think that’s out of the realm of possibility at the moment,” said Dr. Benjamin Pinsky, who runs the Stanford Clinical Virology Laboratory.
A handful of variants collectively known as “delta-plus” — because they share the delta mutations, plus an additional mutation associated with vaccine resistance — have been identified in the Bay Area, including in Pinksy’s lab. But so far they’re not taking off like delta has.
If there’s an upside to delta becoming dominant, it may be that it’s preventing other, more problematic variants from getting a foothold, some experts say. As recently as a few weeks ago, Pinsky regularly would identify variants known to be somewhat vaccine resistant — not just delta-plus, but others like lambda and beta, which raised alarm in other parts of the world. But none has been able to compete with delta.
Across California, delta shoved aside all other variants almost completely over the course of just two months. In July, it made up more than 86% of all cases that were genomically sequenced in the state. In the Bay Area, many labs say it’s closer to 100% now.
“Delta definitely is edging out all the other variants,” said Stacia Wyman, senior genomics scientist at the Innovative Genomics Institute at UC Berkeley. “And if delta is going to go crazy, at least it’s not killing everybody.”
The next few months, or perhaps far longer, will be a constant game of surveillance as scientists watch for variants. Pinsky already has his eye on one — so new it doesn’t yet have a Greek letter name — with mutations that may make it vaccine resistant. It was first found in Colombia, and cases have been creeping up in Florida, where the pandemic is raging among the unvaccinated.
His Stanford lab has picked up a few Bay Area cases recently.
“Whether that gains foothold here, I don’t know. It seems like delta is still more transmissible, so maybe that will tamp it down,” Pinsky said. “But I’m not willing to commit and say we’re at the end of what this virus can do, as far as optimizing to infect us. I think it would be unwise to predict that.”