The U.K. recently made the controversial decision to delay administration of the second dose of the Covid-19 vaccines. The U.K. has approved vaccines from Pfizer/BioNTech, Moderna, and Oxford/AstraZeneca, all of which require two doses, administered at least 21 days apart. The decision will allow the doses to be administered up to 12 weeks apart.
This choice is controversial for a number of reasons. Critics argue that the data from the clinical trials don’t support such a move, and it’s not known what will happen if the protocols are changed. Though U.K. medical officers argue that the first dose will provide the “majority” of immunity, some say this partial protection may not be enough. Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, has advised against delaying the second dose in the U.S.
Some have raised the concern that delaying the second dose of the vaccine could create conditions that lead to a vaccine-resistant strain of the virus. On January 1, Rockefeller University virology professor Paul Bienasz, PhD, tweeted a document with the caption “Musings of an anonymous pissed off virologist,” in which he criticized the plan to delay the second dose because of its potential to lead to a vaccine-resistant strain of SARS-CoV-2. Here’s a passage from the full piece, a tongue-in-cheek missive sarcastically explaining how one might create a such a mutant:
Finally, and here’s the kicker: having developed a remarkable two-dose vaccine, that is extraordinarily effective, ADMINISTER IT TO MILLIONS OF PEOPLE — BUT DELAY THE SECOND DOSE. Generating a pool of hosts with just the right amount of neutralizing antibody to apply selection pressure, but also maintain sufficient levels of partially antibody-resistant virus to allow onward transmission is key here. We might not achieve this shortly after the first dose, but if we let immunity wane for a little while, say 4 to 12 weeks, we just might hit the sweet spot.
Retweeting Bienasz, virologist Angela Rasmussen, PhD wrote: “The real ticking time bomb is the selection pressure of an incomplete vaccine dosing regimen.”
A resistant strain that develops in this way is sometimes known as an “escape mutant.” To understand how they come about, think about the way vaccines are meant to work: A vaccine elicits the immune system’s antibody response, which goes on to neutralize all the virus particles in the body. Antibodies recognize virus particles by targeting specific molecules on the particle known as antigens. But viruses mutate. If one does so in a way that changes its antigens and renders it unrecognizable to the antibody, then it becomes vaccine resistant: an escape mutant.
Ideally, a vaccine would cause all the virus particles in the body to be neutralized in one fell swoop, so that none of them get a chance to mutate. But when a vaccine is only partially administered, the antibodies that are produced may wane. Waning antibodies, wrote Rasmussen, creates “a large pool of people with insufficient antibodies to be efficacious but sufficient to select escape mutants.”
Quick note about the term “selection pressure”: It’s an evolutionary biology term referring to anything that changes the likelihood that a population will survive and reproduce. Antibodies apply selection pressure on the virus, making them less likely to survive. But the pressure from an incomplete dosing regimen, as Rasmussen explained, may allow mutants to escape and proliferate.
Put very succinctly by science journalist Melinda Wenner Moyer in an excellent article on virus evolution for Quanta, “A vaccine is a novel selection pressure placed on a pathogen, and if the vaccine does not eradicate its target completely, then the remaining pathogens with the greatest fitness — those able to survive, somehow, in an immunized world — will become more common.”
Keep in mind that this possibility remains hypothetical right now.
“It is conceivable that people who have only one shot of the vaccine… can become infected, resulting in an escape mutant,” said Yale immunologist Akiko Iwasaki, PhD, in an interview with Vox. “This is purely hypothetical at this time, as we have yet to see such escape mutants arise from naturally infected people who have suboptimal immunity.”
Acknowledging this possibility, the U.K.’s chief medical officer Chris Whitty, MD, said on Wednesday that people have raised concerns about the “theoretical risk that by having this longer gap you could actually lead to a slightly increased risk of an escaped mutant.” He continued, “That is a real worry but quite a small real worry within the system.”
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