Q&A: How Many COVID-19 Variants Like Delta Are Possible?


Johns Hopkins University

William Moss, MD, MPH, is Executive Director of the International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health.

SARS-CoV-2, like all viruses, is constantly mutating – a process that has spawned 11 different named variants of the virus during the pandemic so far. The fastest spreading of those has been Delta, a much more transmissible variant that is thriving in a world where only about 13% of the international population had been vaccinated by mid-July. Even nations with successful vaccination programs are struggling to contain surges driven by Delta, which has spread to at least 100 nations, according to the World Health Organization. Delta is now the most common variant in the United States, where more than half of the population was still unvaccinated in mid-July.

Do viruses always morph into so many variants?

There is an enormous amount of genetic diversity with all viruses, and they are always mutating. These mutations arise from errors when a virus replicates its genome. Given the tremendous amount of transmission of SARS-CoV-2 around the world, I don’t think it’s surprising that we’re seeing more transmissible variants such as Delta.

But the virus doesn’t have an infinite capacity to become more and more transmissible or continually evade our immune responses. It has to be able to bind to our host cell receptors, and there is only so much it can do to improve that binding. It may still have tricks it can pull off, but there are also evolutionary constraints on how much it can mutate in ways beneficial to the virus.

How are variants identified and tracked?

The U.S. Centers for Disease Control and Prevention established a three-tiered classification system for variants: Variants of Interest, Variants of Concern, and Variants of High Consequence.

Variants of Interest are viruses that have genetic mutations that could be compatible with either increased transmissibility, more severe disease, the ability to escape immunity, or the ability to escape our diagnostics. They have mutations that we think could possibly do that.

Variants of Concern are ones that have actually demonstrated at least one of those properties. It’s not that they just have genetic mutations that could have those properties –they’ve actually been observed demonstrating one of them.

Variants of High Consequence would be viruses that cause severe disease in fully vaccinated individuals and would require us to change our vaccines. We haven’t had any classified in this category yet. Viruses missed by diagnostic tests also fall within this category.

Why are variants named by Greek letters?

The World Health Organization came up with the Greek letter naming. They did that for two reasons. The official viral nomenclature with the numbers and the letters was just hard for people to say and track. They also don’t want to name variants after the places where they were first identified to avoid stigmatizing that location.

The places where these genetic mutations are first identified are not necessarily where they first evolved. It’s solely a function of how much genotyping countries are doing. The Alpha variant, or B.1.1.7, was first identified in the United Kingdom but that doesn’t mean it first evolved there. The U.K. has been far out in front in terms of genotyping. It could have evolved somewhere else and the country of its origin didn’t detect it.

However, I do believe the Delta variant did evolve in India where it was also first identified because of the tremendous amount of transmission that was going on in that country. That much transmission allowed the virus to mutate and evolve to be more transmissible.

Who is actually looking for these genetic mutations?

Both academic and public health institutions are conducting the sequencing needed to find variants. The process requires two pieces. You must have the laboratory technology to fully sequence the virus, and you must have the bioinformatics to process and interpret the genomic data.

The CDC has been criticized, and rightly so, for not sequencing as many viruses as it should have earlier in the pandemic. In the U.K., the COVID-19 Genomics UK (COG-UK) Consortium has been doing the sequencing there. It’s a bit easier for them to do it because it’s a smaller nation with a national health system.

There are databases where everyone is supposed to submit their genomic sequences. Now these are huge databases, and you can track the evolution of these viruses.

Does every mutation render the virus more deadly?

The vast majority of mutations are actually deleterious to the virus. They’re dead ends. And many mutations are neutral. But then you get these rarer mutations that are advantageous to the virus. The way evolution works is that if there’s a mutation that allows a variant to be more transmissible it’s going to take over and the other strains with other mutations will fall away.

The rate of mutation in SARS-CoV-2 hasn’t changed. It’s just that we’re giving the virus more opportunities to mutate and evolve more transmissible variants, especially with these big surges in cases where there are many unvaccinated people. It becomes an amplifying cycle: you get a more transmissible variant that then causes more infections and that gives that variant more opportunity to mutate and evolve again.

The Delta Plus variant is an example of this. Someone has called it a variant on a variant on a variant. They build on each other. The Delta Plus has one additional mutation over the Delta variant. But that mutation is in the spike protein, the critical place where the mutations are occurring because that’s what allows the virus to bind to our cells. But it’s also where our neutralizing antibodies are attaching.

The Delta Plus has this one mutation that was seen in a number of other strains, but most notably in the Beta variant that was first identified in South Africa and that people think may help confer some escape from prior immunity. That’s why the Delta Plus is of such concern because it acquired this additional mutation.

How are the mutations constrained?

The reason I say there are constraints is that some mutations are evolving to help the virus bind more tightly to our host receptors. But that’s where vaccines are also targeted. That’s where these evolutionary constrains come in. The spike protein in the virus can’t change too much to escape our immune responses because if it does it won’t bind to our host cell receptors. Maybe it can evolve to bind a little more tightly, but it can’t completely change, or it won’t be able to bind. By being fully vaccinated you’re getting more antibodies in both magnitude and diversity. You are diversifying your immune response so that it can attack different parts of the virus with more antibodies and immune cells.

Which vaccines are most effective against Delta?

There is emerging evidence that the mRNA vaccines, particularly the Pfizer vaccine, are effective against the Delta variant, particularly against severe disease in persons who are fully immunized. For two doses of the Pfizer mRNA vaccine, there is a slight reduction in protective efficacy against any symptomatic disease. In the U.K., one study showed it was 88% effective against symptomatic disease with the Delta variant. Some other studies have shown lower effectiveness, including data from Israel that received a lot of attention.

But if you look at severe disease or hospitalizations, it’s about 96% effective, according to the early data coming out of the U.K. And that’s an important point. Sure, we want these vaccines to be protective against mild, even asymptomatic infection, because that will help reduce transmission. But what’s really important is that the Pfizer vaccine remains very highly protective against hospitalization, or severe disease.

That’s why it’s so important to get both doses. Early U.K. data identified a much lower efficacy – 33% — against symptomatic disease after only a single dose.

Will the United States escape Delta-driven surges seen around the world?

This pandemic is not over until it’s over everywhere. The Delta variant highlights why the United States really needs to step up and do more than it’s doing to fight the pandemic globally by getting vaccines out to the world.

We are fortunate that the mRNA vaccines remain highly protective against the Delta variant. But what we don’t want is a Delta Plus Plus or any variant that evades vaccine-induced immunity because that would be a major setback.

Delta shows us that the game is not over yet. We’re seeing more highly transmissible variants. And Delta will hit hard the unvaccinated communities and individuals in the United States. We’re going to see that increasingly. It’s now making up about 30% of all infections in the United States.

Perhaps we’ve moved too quickly in opening up and unmasking because it will be very hard to walk back if we need to in some communities, particularly if hospitals and intensive care units again are overwhelmed. We need to be open as individuals and as communities to the fact that we may need to return to some basic but highly effective public health measures if we experience a resurgence because of the Delta or another variant.