As countries contend with limited supplies of Covid-19 vaccine, governments are grappling with whether to prioritize getting a first shot into as many arms as possible, or to take a slower approach that reserves some vials to deliver a second dose at the interval prescribed for attaining maximum protection. The U.K. has adopted the approach, calculating that vaccinating twice as many people is preferable to vaccinating half as many in the same time even if a smaller group’s protection would be stronger. Some scientists have cautioned that untested timing regimens have the potential to undermine confidence in vaccines and, worse, facilitate the emergence of dangerous new variants.

1. What’s the standard timing on vaccine doses?

Covid-19 vaccines made by Moderna Inc., Pfizer Inc.-BioNTech SE, and AstraZeneca Plc are administered in two doses. The recommended timing of the second dose varies depending on the vaccine, and is based on clinical trial data regulators used in their review process. In studies, the second Pfizer-BioNTech dose was given 21 days after the initial shot; Moderna’s was given 28 days later. Doses of AstraZeneca’s vaccine were scheduled 4 to 12 weeks apart across four trials.

2. Why is a second shot needed?

It’s not always. Vaccines are intended to hardwire immunological memory to generate a rapid, targeted and durable response by antibodies and T-cells to an invading foe. A single dose of the yellow fever vaccine provides lifelong protection, and Johnson & Johnson’s one-shot Covid-19 vaccine was found in late January to generate strong protection against severe disease in a large, late-stage trial. Booster shots are typically administered to give the immune system advanced “training” to make better antibodies. Some vaccines requiring multiple doses are administered four months apart to optimize immune memory. Some Covid-19 vaccines may work the same way, but it will take additional studies to know this for sure.

3. What’s the U.K. doing?

The National Health Service is scheduling doses of the AstraZeneca and Pfizer-BioNTech vaccines 12 weeks apart. By using shots that normally would have gone to people who have already received the first dose, the U.K. aims to give more people an initial dose. The strategy is supported by researchers studying the AstraZeneca vaccine, who found that vaccinating a large proportion of the population with a single dose, with a second dose given three months later, “is an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term.”

4. What’s happening elsewhere?

In the U.S., new guidance allows doses of the Moderna and Pfizer-BioNTech vaccines to be spaced out by up to six weeks if it’s impossible to get the follow-up shot on time (normally after three or four weeks). The Food and Drug Administration said slight delays shouldn’t affect the protection offered by the vaccine. France’s government announced Jan. 26 that it would not delay second doses, shunning the advice of its health authority and citing risks and uncertainties in the face of new viral variants. The European Medicines Agency said that changing how coronavirus vaccines are given to people raises the risk of reducing effectiveness.

5. What will delays do?

It’s hard to know without more research. Preliminary findings from the AstraZeneca trials found a single standard dose was 76% effective at stopping symptomatic infection 22-90 days after vaccination. That compares with 82% efficacy when two standard doses were given 12 weeks or more apart. Research published in early February showed the two doses were actually more efficacious when they were administered 12 weeks rather than six weeks or less apart. Data from the Pfizer-BioNTech trial found partial protection was achieved as early as 12 days after the first dose, but two doses were required to provide maximum efficacy, or 95% protection against disease. In a study in Israel analyzing the real-world effects of the Pfizer-BioNTech vaccine, symptomatic Covid-19 infections were reduced by 85% among health-care workers who got a single dose in the 15 to 28 days after their inoculation. It’s not clear if protection is sustained past that.

6. What are the risks of spacing out doses?

They’re medical, theoretical and social. The medical risk is that the first dose almost certainly won’t be as protective as two doses. Spacing out doses extends the period when people -- most of whom have been chosen to get vaccines quickly at this point for reasons of vulnerability -- will have suboptimal protection until they get their second dose. The theoretical risk is that a weak response to the virus in millions of people who have received just one dose would foster the emergence of new variants that could evade vaccine-induced antibodies. This would undermine a year’s work to develop safe and effective vaccines. The social risk is that mixed messages on the topic -- from governments, regulators, professional groups and drugmakers -- will make it more difficult to communicate with the public on vaccines that are already controversial, and shunned by some. There is also concern that inoculated patients may change their behavior in a way that increases the risk of spread, negating some of the benefits of vaccination.

7. What do others say?

Although AstraZeneca has been in favor of spacing out shots, Moderna and Pfizer have been more cautious. Pfizer said the safety and efficacy of its vaccine hasn’t been evaluated on different dosing schedules, and that it’s critical that health authorities carefully monitor the effects of any alternative regimens and ensure each recipient is afforded the maximum possible protection, “which means immunization with two doses of the vaccine.” Anthony Fauci, who heads the U.S. National Institute of Allergy and Infectious Diseases, said he’s worried about the push to stretch dosing schedules. The British Medical Association called for the U.K. to “urgently review” its decision to allow delays of the Pfizer-BioNTech vaccine. The U.K. physicians group supports delays of up to six weeks, but said Britain’s plan goes “well beyond” that.

8. Are there other options for economizing with vaccines?

It’s possible more shots could be extracted from available vaccine supplies by administering lower-strength doses, but more research is needed to determine the efficacy of such an approach. Encouragingly, a preliminary report of a mid-stage study of the Moderna vaccine showed a single, standard 100-microgram dose produced more antibodies compared with a 50-microgram shot, but the difference was less apparent after recipients had received a second inoculation.

(Updates section 5 with results of study in Israel)

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