Will a vaccine dosage delay cause a coronavirus escape mutant?

T.The pandemic has entered a new phase. Millions of people around the world are now receiving their first dose of a COVID-19 vaccine every day. In some countries, including the UK, millions wait up to 12 weeks before receiving their second dose. Vaccinating as many people as possible with initial doses before switching to the second doses is the fastest way to achieve a good level of protection in the population. However, some experts fear that this will be a huge experiment in virus development, with the possible consequences of which remain worryingly unclear.

Among those affected is Paul Bieniasz, a virologist at Rockefeller University. “Introducing a partially effective vaccination regime at the height of a widespread virus epidemic is just not a good idea if one of your goals is to avoid vaccine resistance,” he says.

Bieniasz explains that people waiting for their second dose may have sub-optimal immunity, which is selectively putting pressure on the virus. Should someone become infected in the time between the bumps, this pressure could allow the creation of a mutated version of SARS-CoV-2 that can shake off a person’s immune response – a so-called escape variant. Any such variant, which can also cause serious illness, could potentially trigger a whole new, devastating wave of infections and deaths.

In general, vaccine resistance in pathogens is rare.

Researchers say it is nearly impossible to know if this will happen, although historical cases of human pathogens developing vaccine resistance are rare.

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

Scientists advising the UK government have considered the same scenario. In an article published last month, they wrote, “In the short term, delaying the second dose should increase the likelihood of vaccine resistance somewhat.” However, quantifying the risk is almost impossible.

“We can’t really number it,” says Björn Meyer, virologist at the Pasteur Institute in Paris, about the risk of delayed dosing that leads to the development of an escape variant. Any time the virus replicates, there is a chance it could mutate into a more transmissible or deadly form. For a single person, the chances of this happening are negligible, but the picture changes a little when you consider that tens of millions of people are currently waiting for their second dose, Meyer notes.

Opportunity to escape

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

Virologists and immunologists do not yet know exactly in which environment a SARS-CoV-2 escape variant would most likely develop.

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

It is impossible to predict if this will happen as the clinical trials of COVID-19 vaccines do not provide data on how vaccine effectiveness changes when a second dose is given six weeks or later after the first dose.

“Beyond that, it’s just hard to tell, it’s everyone’s guess,” says Rasmussen.

It is crucial that virologists and immunologists do not yet know exactly in which environment a SARS-CoV-2 escape variant would most likely develop – in other words, which suboptimal immune response corresponds to the highest virus risk. Development of a successful escape variant. There are thousands of SARS-CoV-2 variants that are known to circulate around the world, but few of them are considered tangibly more transmissible. They could be viewed as partial escape variants, suggests Meyer, since they are less susceptible to neutralization by antibodies, but should not evade the broader immune response. Nobody knows under what conditions these variants could even arise.

Previous vaccine escape mutants

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

An article published in Royal Society procedure B. in 2017 by Penn State’s Andrew Read, an expert on the evolutionary genetics of infectious pathogens, and a colleague argued that vaccines may be less likely to cause pathogens to appear because they act early to prevent infection and transmission, and vaccines, too A variety of immune responses – from neutralizing antibodies to activating T and B cells. It is difficult for a virus to overcome a multitude of different immune response mechanisms, all of which work together. “Taken together, these features dramatically increase the time it takes for resistance to appear,” the authors write.

See “SARS-CoV-2 will not go away, experts predict”

That doesn’t mean it’s impossible. The hepatitis B virus appeared to develop resistance to recombinant vaccines in the 1980s, in part because the portion of the virus targeted by the vaccine-induced immune response was very small. Only a few mutations probably led to the emergence of an escape variant. Fortunately, the authors of a report on hepatitis B variants from 2015 write: “Despite all the concerns, the overall effect of the vaccine is currently evident [escape] Mutants appear to be low and pose no threat to public health or the need to change established hepatitis B vaccination programs. ”

Vaccination can affect virus transmission of pathogens that afflict people other than humans. Take the Marek virus, which infects chickens and some other birds. Although immunized poultry do not get sick, vaccines for the disease do not prevent the virus from spreading, which COVID-19 vaccines can do. “By keeping infected birds alive, vaccination improves the success of transmission and thus the spread of virus strains that are too lethal to survive in unvaccinated populations,” Read and colleagues conclude in a 2015 study.

Immunity at one dose

In contrast, there is evidence that current COVID-19 vaccines might actually reduce transmission and that delaying the second dose will not result in a significant decrease in immunity. A study published in Preprint on February 1st The lancet examined data from participants in the vaccine study at Oxford / AstraZeneca. The authors’ analysis of 88 study participants found that the effectiveness of the vaccine in reducing symptomatic infection reached 76 percent between 22 and 90 days after a single dose.

This could indicate that the risk of sub-optimal immunity after just one dose of a two-dose vaccine is actually rather low, says Lucy Walker of University College London. “Seventy-six percent vaccine effectiveness is respectable in its own right and would not be called ‘partial immunity’ in the context of other vaccines,” she says.

Another subgroup of 500 study participants who received both vaccine doses saw a 54 percent reduction in positive COVID-19 tests compared to the unvaccinated control population, regardless of whether they came off as symptomatic or asymptomatic. That could mean the vaccine can reduce transmission. If this is the case, this in turn would reduce the overall risk of flight options.

See “A Guide to Emerging SARS-CoV-2 Variants”.

“While this would be extremely welcome news, we need more data before this can be confirmed, so it’s important that we all continue to follow social distancing guidelines after vaccination,” said Doug Brown, executive director of the British Society for Immunology, in a statement to the Science Media Center. Brown is a trustee of the Association of Medical Research Charities in the UK.

Yale University immunologist Akiko Iwasaki notes that those who run immunization programs must weigh the known benefits of using vaccines to save lives versus the unknown likelihood of escape routes causing havoc.

“The British variant, for example, is more transferable. Many people will die from it if we don’t vaccinate now, ”she says. “Whether a dose promotes variants or not. . . That is still a theoretical argument. “

For Paul Bieniasz, however, the ideal approach would be to use interventions such as social distancing as a means of reducing virus transmission prior to using vaccines to avoid the risk of stimulating escape variants.

“Get the virus contained and then vaccinate your population,” he says.

Correction (February 4th): We mistakenly included Paul Bieniasz’s previous affiliation. The scientist regrets the mistake.

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