The pandemic has entered a new phase. Millions of people around the world are now receiving their first dose of a COVID-19 vaccine each day. In a few countries, including the UK, millions will wait for up to 12 weeks before they receive their second dose. Vaccinating as many people as possible with initial doses before moving on to second doses is intended as the fastest means of inducing a good level of protection within the population. But some experts say they worry that this constitutes a giant experiment in viral evolution, where the potential consequences remain troublingly unclear. 

Among those concerned is Paul Bieniasz, a virologist at the Rockefeller University. “Rolling out a partially effective vaccine regime in the peak of a highly prevalent viral epidemic is just not a great idea if one of your goals is to avoid vaccine resistance,” he says.

There’s a chance, Bieniasz explains, that people waiting for their second dose may have a sub-optimal level of immunity that places selective pressure on the virus. If someone were to become infected during the interval between jabs, that pressure could allow for the emergence of a mutant version of SARS-CoV-2 able to shake off a person’s immune response—a so-called escape variant. Any such variant that also proved capable of causing severe disease could potentially spark a whole new, devastating wave of infections and deaths.

Researchers say it’s almost impossible to know whether this will happen, though historical cases of human pathogens evolving vaccine resistance are rare. 

Anthony Fauci, President Joe Biden’s chief medical adviser on COVID-19, said last month at a virtual World Economic Forum panel that delaying the second dose of a COVID-19 vaccine could increase the likelihood of an escape variant emerging. “It may not be the case, but it gets risky,” he told the audience. 

Scientists advising the UK government have considered the same scenario. In a paper published last month, they wrote, “in the short-term, delaying the second dose would be expected to somewhat increase the probability of emergence of vaccine resistance.” But quantifying the risk is nigh on impossible.

“We can’t really put a number on it,” says Björn Meyer, a virologist at the Pasteur Institute in Paris, referring to the risk of delayed dosing leading to the evolution of an escape variant. Every time the virus replicates there is a chance that it could mutate into a more transmissible or more deadly form. In a single individual, the odds of this happening are vanishingly small but the picture changes somewhat when you consider that tens of millions of people are currently waiting for their second dose, notes Meyer.

Opportunity for escape

Almost all vaccines in use at the moment require two doses, including Pfizer/BioNTech’s, Oxford/AstraZeneca’s, Moderna’s, Russia’s Sputnik V, and Sinopharm’s products. Meyer adds that the second booster dose has the effect of raising the amount of antibodies in people’s blood but it also improves affinity maturation, in which B cells produce antibodies that are especially effective at binding to the virus and blocking infection. 

It’s possible that, should a second dose be delayed beyond the manufacturer-recommended schedule of, for example, 21 days for the Pfizer/BioNTech vaccine, antibody levels might gradually come down somewhat and provide a suitable environment for escape variant emergence, says Angela Rasmussen, a virologist at Georgetown University’s Center for Global Health Science and Security. 

It’s impossible to predict whether that will occur because the clinical trials of COVID-19 vaccines do not provide data on how the efficacy of vaccines changes when a second dose is administered six weeks or later following the first dose. 

“Beyond that, it’s just really hard to say, it’s anybody’s guess,” says Rasmussen.

Crucially, virologists and immunologists don’t yet know exactly what sort of environment would be most likely to prompt a SARS-CoV-2 escape variant to evolve—in other words, what level of suboptimal immune response equates to the highest risk of the virus evolving a successful escape variant. There are thousands of SARS-CoV-2 variants known to be in circulation around the world, but just a few of them are thought to be noticeably more transmissible. They could be thought of as partial escape variants, suggests Meyer, because they are less susceptible to neutralization by antibodies but are not thought to evade the broader immune response. Nobody knows what conditions allowed for the emergence of these variants in the first place. 

Past vaccine escape mutants

In general, vaccine resistance among pathogens is rare. Famously, vaccines have succeeded in keeping the highly infectious measles virus at bay since the inoculations were first introduced in the 1960s. And Meyer notes that, while influenza viruses are known to mutate rapidly, their many variants are not generally thought to have evolved as a result of vaccination programs.

A paper published in Proceedings of the Royal Society B in 2017 by Penn State’s Andrew Read, an expert on the evolutionary genetics of infectious pathogens, and a colleague argues that vaccines may be less likely to cause the emergence of pathogen resistance because they act early to prevent infections and transmission, and vaccines also induce a wide variety of immune responses—from neutralizing antibodies to T and B cell activation. It’s hard for a virus to overcome a variety of different immune response mechanisms all working in unison. “Together, these features drastically increase the time until resistance emerges,” the authors write. 

That doesn’t mean it’s impossible. The hepatitis B virus appeared to evolve resistance to recombinant vaccines in the 1980s partly because the part of the virus targeted in the vaccine-induced immune response was very small. Just a few mutations likely led to the emergence of an escape variant. Reassuringly, the authors of a 2015 review of hepatitis B variants write: “Despite concern, at present the overall impact of vaccine [escape] mutants seems to be low and they do not pose a public health threat or a need to modify the established hepatitis B vaccination programs.” 

Vaccination can influence viral transmission of pathogens that plague other animals besides humans. Take Marek’s disease virus, which infects chickens and some other birds. Although immunized fowl don’t get sick, vaccines for the disease do not prevent the virus spreading, something that is a possibility for the COVID-19 vaccines. “By keeping infected birds alive, vaccination substantially enhances the transmission success and hence spread of virus strains too lethal to persist in unvaccinated populations,” Read and his colleagues conclude in a 2015 study.

Immunity at one dose

In contrast, there are signs that the current COVID-19 vaccines might in fact reduce transmission, and that delaying the second dose does not lead to a significant decline in immunity. A study posted as a preprint February 1 in The Lancet examined data from participants in the Oxford/AstraZeneca vaccine trial. The authors’ analysis of 88 trial participants found that vaccine efficacy, in terms of reducing symptomatic infection, reached 76% between 22 and 90 days following a single dose. 

This could indicate that there is actually a rather low risk of suboptimal immunity arising after just one dose of a two-dose vaccine, says Lucy Walker of University College London. “A vaccine efficacy of 76% is respectable in its own right and wouldn’t be talked about as ‘partial immunity’ in the context of other vaccines,” she says.

There was also a 54% reduction in positive COVID-19 tests among a different subgroup of 500 trial participants who received both doses of the vaccine, regardless of whether they presented as symptomatic or asymptomatic, when compared with the unvaccinated control population. That could mean that the vaccine is able to reduce transmission. If it does, that would in turn reduce the overall risk of escape variants emerging.

“While this would be extremely welcome news, we do need more data before this can be confirmed, and so it’s important that we all still continue to follow social distancing guidance after we have been vaccinated,” says Doug Brown, the chief executive of the British Society for Immunology, in a statement to the Science Media Centre. Brown is a trustee of the Association of Medical Research Charities in the UK.

Immunologist Akiko Iwasaki of Yale University notes that those running vaccination programs must weigh the known benefits of using vaccines now to save lives, versus the unknown probability of escape variants causing havoc.

“The UK variant, for example, is more transmissible. Many people are going to die from that if we don’t vaccinate right now,” she says. “Whether one dose encourages variants or not . . . that’s still a theoretical argument.”

But for Paul Bieniasz, the ideal approach would be to use interventions such as social distancing as a means of reducing viral transmission before deploying vaccines, to avoid the risk of stimulating escape variants. 

“Get the virus clamped down, then vaccinate your population,” he says. 

Correction (February 4): We mistakenly included Paul Bieniasz’s former affiliation. The Scientist regrets the error.