Vaccine shortages and distribution delays are hampering efforts to curb the SARS-CoV-2 pandemic. So some scientists have suggested postponing the second shots of two-dose vaccines to make more available for people to get their first doses. The original recommended interval was 21 days between doses for the Pfizer vaccine and 28 days for the Moderna shots, the two currently authorized in the U.S. Now the U.S. Centers for Disease Control and Prevention has updated its guidance to say that people can wait up to 42 days between doses, though the agency still advises individuals to stick to the initial schedule. And developers of the University of Oxford–AstraZeneca vaccine—which is authorized for use in the U.K.—suggest even longer stretches are possible, saying their shot performs better when its doses are spaced 12 weeks apart. Their data is in a new preprint paper, released before peer review. So what gives? How long can you go on a single shot and still stay safe? And what happens if your second shot isn’t available on time? Scientific American explores the potential risks and benefits of delaying vaccine doses.

Why do you need two shots?
Vaccines are designed to create immunological memory, which gives our immune system the ability to recognize and fend off invading foes even if we have not encountered them before. Most COVID vaccines elicit this response by presenting the immune system with copies of the novel coronavirus’s spike proteins, which adorn its surface like a crown.

Two-shot vaccinations aim for maximum benefit: the first dose primes immunological memory, and the second dose solidifies it, says Thomas Denny, chief operating officer of the Duke Human Vaccine Institute. “You can think of it like a gradient,” he adds. One dose of the Pfizer vaccine can reduce the average person’s risk of getting a symptomatic infection by about 50 percent, and one dose of the Moderna shot can do so by about 80 percent. Two doses of either vaccine lowers the risk by about 95 percent.

Why does the CDC now allow up to 42 days between doses of the Pfizer and Moderna vaccines?
The agency updated its initial guidance after it received feedback that some flexibility might be helpful to people, especially if there are challenges around returning on a specific date, says CDC spokesperson Kristen Nordlund. While the U.K. is recommending dose stretching as a deliberate strategy to get more first shots in more arms, the CDC is suggesting it as an option to make scheduling second shots less onerous. In the U.S., the vaccine rollout has been painfully slow: two months after the first shots were given to the public, only about 3 percent of the population has received both doses of a vaccine. And as vaccine producers struggle to keep up with demand, experts believe some compromises are necessary to ensure people are fully vaccinated. “We need to make the best decision with the resources we have,” says Katherine Poehling, a pediatrician at Wake Forest Baptist Health, who is on the CDC’s Advisory Committee on Immunization Practices. “If there’s plentiful vaccine, it might take a different approach than if the vaccine is limited.... But you do need the second dose.”

What kind of protection do you have until day 42?
According to data from the Pfizer and Moderna trials, protection kicked in about 14 days after the first dose, when the curve showing the number of infections in the nonvaccinated group kept swinging upward while the curve for the vaccinated group did not. For both vaccines, a single shot protected almost everyone from severe disease and, as noted, was about 50 percent (Pfizer) or 80 percent (Moderna) effective in preventing COVID altogether. Though most trial participants received their second vaccine on day 21 or 28, some waited until day 42, or even longer. The number of outliers is too small to draw definitive conclusions about the impact of prolonging the two-shot regime, however. For example, of 15,208 trial participants who received the Moderna vaccine, only 81 (0.5 percent) received it outside the recommended window.

“We don’t have the greatest science, at this point, to say we are 100 percent comfortable doing a booster 35, 40 days out,” Denny says. “We are deferring to the public health concerns and the belief that anything we can do right now is better than nothing.”

If people are only partially immunized with one dose, could that fuel more dangerous coronavirus variants?
That is a real concern, according to Paul Bieniasz, a retrovirologist at the Rockefeller University. Early in the pandemic, there was little pressure on the novel coronavirus to evolve because nobody’s immune system was primed against infection, and the microbe had easy pickings. But now millions of people have become infected and have developed antibodies, so mutations that give the virus a way to evade those defenses are rising to prominence. “The virus is going to evolve in response to antibodies, irrespective of how we administer vaccines,” Bieniasz says. “The question is: Would we be accelerating that evolution by creating country-sized populations of individuals with partial immunity?”

Just as not finishing your entire course of antibiotics could help to fuel antibiotic-resistant bacteria, not getting fully vaccinated could turn your body into a breeding ground for antibody-resistant viruses. But Trevor Bedford, a computational biologist at the Fred Hutchinson Cancer Research Center who tracks viral mutations, has tweeted that the pace of evolution is not only determined by the weakness or strength of the immune system. It is also affected by the sheer number of viruses circulating in the population, he wrote. Without widespread immunizations, the latter amount—and the number of variants that might beget a more formidable virus—will continue to grow.

Could a longer interval between first and second doses make a COVID vaccine more effective?
That result is possible. All COVID vaccines are not created equal, and the optimal dosing schedule depends on the specific design. Some vaccines are based on fragile strips of genetic material known as mRNA, some rely on hardier DNA, and others use protein fragments. These cores can be carried into a cell sheathed in a tiny lipid droplet or a harmless chimpanzee virus.

Given such differences, Denny is not surprised that the DNA-based Oxford-AstraZeneca vaccine was tested and found effective with a space of 12 weeks between shots. That is about three to four times longer than the recommended intervals of the mRNA-based Moderna and Pfizer vaccines. In time, researchers may find that dosing schedules that are slightly different from the ones tested in the first clinical trials are more effective. “You could have done dosing studies for two years, but that would not be the most responsible thing to do in a world like this,” Denny says. “Don’t let the perfect be the enemy of the good.”

The author would like to acknowledge Rachel Lance for suggesting a source of information that was included in the story.

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