One vaccine dose is better than none, right? Well, that depends.

On Dec. 30, the United Kingdom approved its second vaccine, one developed by Oxford University and pharmaceutical company AstraZeneca. The UK government also announced that from now on, it'll prioritize the first doses of its vaccines. That means it'll vaccinate as many people as possible with their first dose, even if they have to wait up to 12 weeks to get their second. UK officials reason that although it might be better for any one person to receive a second dose promptly, spacing out the doses may end up saving more lives. President-elect Joe Biden also plans to change the U.S.'s policy of holding back a second dose for each person who receives a first dose. Although the time between doses is set to stay the same, the strategy would run the risk of delaying a second dose if production can't keep up.

Currently, it's unclear how effective these strategies would be. Although there are other multi-dose vaccines that recommend at least one dose in some cases and two in others, the diseases they prevent and the vaccines themselves are very different from the ones for COVID-19, which means scientists can't look to them for insights. There's some evidence that a single dose of the new vaccines could effectively protect people for the 12-week period between doses or possibly longer, but those predictions are based on either calculations or subsets of data. To know for sure if a single dose of a COVID-19 vaccine is effective either on its own or with a long delay before the second dose as compared to a shorter time, scientists would need to run more clinical trials. These trials would be crucial; given on its own, an effective single dose given to twice as many people could save lives.

First there's the question of how long one can wait between doses. In other vaccines, like the HPV vaccine, a longer time between doses actually makes the vaccine more effective after both doses. But there's no data specific to any COVID-19 vaccine on how delaying the second dose might affect how well the vaccine works after the second dose.

Then, there's the question of whether a single dose can work on its own. The Oxford-AstraZeneca vaccine, which is only approved in the UK, has two doses, as do two approved in both the U.S. and the UK: one by pharmaceutical companies Pfizer and BioNTech and one by biotech company Moderna. While most Oxford-AstraZeneca participants in the British trial waited between nine and 12 weeks to get a second dose of the vaccine, no current trial has independently examined the question of if a single dose of the vaccine would be effective, even for just twelve weeks. For the two other vaccines, scientists didn't test such a long delay between doses. Pfizer and BioNTech's vaccine has a second dose given three weeks after the first, while Moderna's second vaccine dose is given after four weeks.

The first dose of all of these COVID-19 vaccines is the primary shot; the second re-introduces the virus so that the immune system can better “remember” how to respond. For a first dose alone to be effective, scientists would have to show that a second dose isn't necessary to "jog the memory" of the immune system.

UK officials emphasize that everyone who receives a first dose of the vaccine will still receive a second within 12 weeks, but even so, many infectious disease experts question the strategy. Dr. Anthony Fauci, the top expert on infectious diseases in the United States, told CNN that he “would not be in favor of” the UK’s strategy. “We want to stick with what the science tells us,” he said. For now, that's that the two vaccines approved in the U.S. are the most effective with three or four weeks between doses.

“We don't know, on the basis of the clinical trial, how effective that first dose is without the second,” says Mark Cameron, an immunologist at Case Western Reserve University.

So far, data suggests that the Pfizer-BioNTech vaccine is 52% effective after the first dose, although that was only based on a subset of people who contracted the virus in the days between the two shots in the trial (some of whom got the vaccine). The UK’s Joint Committee on Vaccination and Immunisation has said that the Pfizer-BioNTech vaccine may provide short-term protection about 90% effectively. The Oxford-AstraZeneca was 73% effective in a subset of trial participants after one shot.

Although it's unclear how the UK came up with a 90% efficacy rate for the Pfizer-BioNTech vaccine, some infectious disease experts have come up with a similar 80 to 90% efficacy rate. Both doses of the vaccine have a delayed effect, so experts got this higher rate by looking at how effective the vaccine was shortly after the second dose, when the first dose is thought to have taken effect but the second has not yet. In Moderna's three trials, the vaccine seemed effective in 80 to 90% of about 2,000 participants who got just one dose of its vaccine and never got the second. But while these results are promising, none involve full clinical trials — only calculations and small groups of people from larger, two-dose trials.

Scientists also don’t know how long immunity will last after two doses of the vaccine, let alone one. Cameron notes that, although it's rare, people have become re-infected with COVID-19. Some studies have also shown that COVID-19 antibodies (immune cells that help fight disease) can decrease quickly, although that may not decrease one's immunity.

There’s reason to believe the second dose of the vaccine increases not just how well it works, but how long a person will be protected for, says Mandy Muller, a virologist at the University of Massachusetts, Amherst. After the first dose of a vaccine, antibodies flood the immune system, providing an initial response to the virus. But a second dose of a vaccine can lead to the production of immune cells called memory B cells, which make the immune system better able to recognize and respond to a virus in the future.

Early data from COVID-19 vaccine trials also indicated that the immune response was stronger after a second dose.

Beyond this general principle, data from previous vaccines don’t provide much insight into any COVID-19 vaccine. The MMR vaccine, which protects against the measles, mumps, and rubella, is at least over 75% effective against all three diseases after just one dose. As such, adults who haven't gotten the vaccine before need at least one dose, rather than the two recommended for children, who often have weaker immune systems. But the MMR vaccine is made from weakened, live viruses, which makes it much different than any of the COVID-19 vaccines. In fact, the three vaccines approved in the U.S. and the UK use two technologies that been used in either no or very few previous vaccines.

“These vaccines are totally different,” says Dr. Joel Greenberg, a pediatrician and chair of the department of pediatrics at Michigan State University College of Osteopathic Medicine. “They don’t have the same mechanism or anything,” he says.

The Moderna and Pfizer-BioNTech vaccines use a bit of the virus’s genetic material, called RNA, instead of a whole virus, and AstraZeneca’s uses what’s called a viral vector — an entirely different virus that's had some of its genetic material replaced with genetic material similar to that of the virus that causes COVID-19. There's never been an approved RNA vaccine before, and the first adenovirus vector vaccine, used to prevent Ebola, was only approved in July.

There’s also never been a vaccine for a coronavirus, says Cameron. Any vaccines being developed for SARS, another serious coronavirus, were stopped after the 2003 outbreak was contained and there were very few cases. Another serious coronavirus, MERS, also has no approved vaccine.

Still, the idea of giving twice as many people at least partial protection from the virus is appealing. In a new study that has not yet been reviewed by other scientists, Laura Matrajt, an applied mathematician at the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center, examined what might be the best strategy. She found that if a COVID-19 vaccine were highly effective after one dose, a single-dose strategy vaccinating twice as many people while skipping the second dose would save lives, especially alongside effective social distancing. Matrajt emphasizes that models like hers have a lot of assumptions baked into them — assumptions that don't necessarily mimic what actually occurs in the real world. For instance, the model assumes the vaccination rate would be around 300,000 people per week, which is on par with the UK's vaccination rate and substantially lower than the U.S.'s, but still higher than in many countries.

Regardless, Matrajt says having data on exactly how effective a vaccine would be after one dose could save lives. A new, more contagious variant of the virus also makes it more urgent that people receive a vaccine as soon as possible. It’s leading some to raise another possibility — that providing partial immunity to COVID-19 could give an already mutated virus a leg up on becoming resistant to the vaccine. And although it’s hard to say how likely that is, it’s a legitimate concern, says Cameron.

In people who are infected after receiving a single dose of the vaccine, “the virus would have a very strong interest in evolving in a way that would protect it from whatever leftover immunity that person would have,” says Muller. But others disagree. Greenberg, for instance, doesn’t think this is particularly likely.

"It's not like the virus knows there's a vaccine out there," he says. He also noted that the virus started mutating well before there were any COVID-19 vaccines.

There are some reasons why the UK’s strategy might work better there than in the U.S., says Cameron. The population is much lower, so producing enough vaccines to provide everyone with a second dose within 12 weeks could be more realistic. Matrajt also noted that the UK has more of a unified social distancing policy, whereas the U.S. has different policies in each state. Since her model shows that social distancing is crucial to a single-dose strategy, it’s possible that the UK is better suited for it. But without more data on how well a single dose works, it's impossible to know.

Although vaccinating a huge number of people will be an immense challenge, for now, the U.S. actually has enough to give millions of people both doses. The difficulty has been in actually vaccinating people. As of Jan. 8, although about 22 million doses of the vaccine had been distributed to states, only about 6.7 million people had received at least one dose. The Trump Administration had previously said that 20 million people would be vaccinated by the end of December 2020.

“Hopefully, in a few months, when the vaccine is up to supply and distribution, we won't have to debate,” says Cameron. But problematic shortages could still emerge as countries attempt to vaccinate more of their population.

If a shortage does cause more debate, he says, there's only one way to find out if giving just one dose or delaying the second could work. New clinical trials would have to test how effective a single dose is as well as other proposals for conserving vaccines, like giving two half-doses. Cameron emphasizes that research for any vaccine doesn’t stop after approval, and that’s extra true with COVID-19. Scientists need more time, observations, and data to make any decisions on changing the way we give these vaccines.