Could delaying a second vaccine dose lead to more dangerous coronavirus strains?

Spiking COVID-19 cases, slow vaccine rollout and the emergence of more transmissible coronavirus variants in some countries have sparked debate among scientists over the best way to protect people with recently authorized vaccines. 

One idea involves delaying when people receive the second of two required vaccine doses, so that more people can receive the doses that are currently available. 

That’s happening in the United Kingdom, where researchers have raised concerns about a new coronavirus variant that appears to be more contagious than other versions. Officials there are opting to extend the time between each vaccine dose from three or four weeks to up to three months (SN: 12/22/20). 

In the United States, on the other hand, officials strongly recommend that states stick to the regimen that the U.S. Food and Drug Administration authorized in December — two shots spaced three weeks apart for Pfizer-BioNTech’s vaccine and four weeks apart for Moderna’s. 

On January 12, the Trump administration announced it was no longer holding back second shots of COVID-19 vaccines, several days after President-elect Joe Biden suggested he would release all the shots. While that may speed protection for more Americans, it also raises the possibility that people might not get their second doses on time, if manufacturing problems arise.  

The possibility that second doses could be delayed has some experts concerned because it might lead to millions of people walking around with only partial immunity to the coronavirus, a condition that could be ripe for harmful mutations of the virus to arise.

Delaying the second shot is a gamble, says Ramón Lorenzo-Redondo, a virologist at Northwestern University Feinberg School of Medicine in Chicago, particularly without a lot of evidence suggesting how well one dose works. Officials “shouldn’t gamble [their] best tools” to fight the pandemic, he says. “We don’t want to fuel [potential viral evolution] by doing suboptimal immunization of the population.”

How that fueling of virus evolution could happen comes down to the immune system. If people have full immunity as a result of vaccination, their immune response is likely to be robust, spawning large numbers of neutralizing antibodies, for example, that stop viruses from getting into cells and heading off harmful mutations before they arise. But if people have partial immunity, that immune response is likely to be weaker. 

It’s like when doctors encourage patients to finish a full course of antibiotics, Lorenzo-Redondo says. In that case, eliminating susceptible bacteria with a full course could help lower the chance that stragglers build up resistance.

For the COVID-19 vaccine, if people’s second doses are delayed long enough — akin to not finishing a full complement of antibiotics — it’s possible that low numbers of neutralizing antibodies triggered by only one dose may only partially fight an infection. That might provide more time for variants of the virus with immune-dodging mutations to arise and thrive and be transmitted to other people.

If immune-dodging variants do arise as a result of shot delays and spread to lots of people, that could deal a blow to vaccines’ effectiveness. For example, if mutations arose that prevented vaccine-induced antibodies from binding to the virus, or caused antibodies to bind less tightly, that virus variant may be more likely to infect cells than variants without the mutation and thus cause disease, Lorenzo-Redondo says. With cases surging in many places, including the United Kingdom and the United States, the coronavirus could have even more chances to accumulate vaccine-evading mutations than it would if case numbers were lower.

For now, it’s unclear how protected vaccinated people are after a single shot and for how long. Trial participants who received Pfizer-BioNTech’s vaccine had low levels of neutralizing antibodies 21 days after the first dose, researchers reported in the Dec. 17 New England Journal of Medicine. But clinical trial results from both the Pfizer-BioNTech and Moderna vaccines suggest that protection begins around two weeks after the first dose — Pfizer-BioNTech’s vaccine had an efficacy of around 50 percent after the first dose and Moderna’s had around 80 percent efficacy (SN: 12/18/20). It’s unknown how durable that protection might be, says Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago, but it would be weird to see it fade quickly. 

Cobey is one of the scientists who isn’t worried about the risk of a long delay between shots.  Instead, expanding how many people get the first dose could actually help control how much the coronavirus changes, she says. That’s because even the partial protection that people may get from a single dose “will almost certainly lower the prevalence of infection,” she says. Fewer infections overall would mean fewer coronavirus variants in general circulating among people. By virtue of numbers, the coronavirus then may not accumulate as many mutations that could help it evade immune systems.

And even if a virus accumulates mutations that help it dodge the immune response as a result of the dose delay, such changes might in turn damage essential viral functions like breaking into and hijacking a host cell. A virus that can escape immunity, for instance, might end up being less transmissible. For now, it’s unclear what might happen with the coronavirus, which in general mutates more slowly than other similar viruses thanks to a unique proofreading enzyme that acts as a spell-check for the letters that make up the coronavirus’s genetic blueprint (SN: 1/28/20).

What’s more, the immune responses that a person makes also don’t attack just one part of a virus. Antibodies, for instance, including those induced by vaccines, hit many different parts of viral proteins, making it harder for the virus to escape. And over time antibodies can get better at their job (SN: 11/24/20). So, most mutations are unlikely to render antibodies completely ineffective. 

“You put that all together and it’s a pretty high barrier” for virus evolution to work around, says Adam Lauring, an infectious disease physician and virologist at the University of Michigan Medical School in Ann Arbor. 

In lab experiments, for example, COVID-19 patient serum that harbors myriad coronavirus antibodies still stops the coronavirus from infecting cells in a dish, even if there are viral mutations, researchers reported in a preliminary study posted January 4 at bioRxiv.org. While a few mutations — including one present in a coronavirus variant now circulating in South Africa — made antibodies in the serum less effective at stopping viruses from infecting cells, the serum’s virus-halting activity didn’t outright disappear. 

Still, that doesn’t mean potentially risky viral evolution as a result of delaying doses is not going to happen. “I think this is something we need to study and we need to look at for sure,” Lauring says. For now, “I’m not sure we know enough that we can really confidently say what one or other [vaccine-dosing] strategy is going to do.”