Faced with the increased threat from a new variant and a health service under pressure, the UK’s top medical officers lengthened the gap between doses to allow more people to receive the first dose and therefore a certain level of protection.
A gap of 12 weeks, however, is a big difference to other jurisdictions and advice since set out by the WHO (the EU allows up to six weeks between doses; the US has said it will keep to the 3-4 week gap advised by manufacturers of its authorized vaccines; and the WHO says six weeks in exceptional situations for Pfizer/BioNTech).
Spacing out doses
The two main authorized vaccines in the UK are from Pfizer/BioNTech and AstraZeneca. While the strategy of spacing out doses has allowed the country to administer the first dose of the vaccine to a large number of people (6.8 million doses at the latest count, representing around 10% of the population), a 12 week delay for the second dose has not been backed up by clinical data to confirm efficacy.
The majority of participants in the Pfizer/BioNTech trials were given the second dose after a set 21 days (a small number of participants received the 2nd dose up to 42 days later). The WHO, consequently, has said that the second dose of the vaccine should be delivered 21-28 days apart, although can be delivered up to six weeks after in exceptional situations.
With the AstraZeneca vaccine, clinical trials looked at a variety of delays between doses (the WHO has not issued a position on dosage delays for this vaccine).
The UK's strategy of spacing out doses was set out at the end of December, with the WHO since publishing its advice on Pfizer/BioNTech on January 7. In light of the WHO recommendations - and with supplies of the vaccine under pressure across Europe - BMA has now written to the UK’s Chief Medial Officer to seek an ‘urgent review’ of the UK’s 12 week delay with this vaccine.
A BMA spokesperson said: “The BMA remains fully committed to supporting the Chief Medical Officer and the government in rolling out the vaccine as quickly as possible to protect the public and health care workers most at risk. This letter to the Chief Medical Officer represents part of an ongoing dialogue about the best approach to the rollout of the vaccine and shares with him the growing concern from the medical profession regarding the delay of the second dose of the Pfizer-BioNTech vaccine as the UK’s strategy has become increasingly isolated from many other countries.
“BMA members are also concerned that, given the unpredictability of supplies, there may not be any guarantees that second doses of the Pfizer vaccine will be available in 12 weeks’ time.
“The World Health Organisation has published its analysis of delaying the second dose and recommended that both doses of Pfizer-BioNTech should be given within 21-28 days, or as soon as possible thereafter. WHO has said that in exceptional circumstances this might be extended to within 42 days and there appears to be evidence for this in the Pfizer-BioNTech trial. However, the UK’s delay to 12 weeks goes well beyond even this timeline.
“The BMA supports giving a second dose up to 42 days after the first dose, in line with international best practice as this would still allow for a doubling of the numbers of people protected by vaccination within a given time period compared to the original a 3-week dose interval. The Association is urging the CMO to urgently review the UK’s current position of second doses after 12 weeks.”
Clinical trial data
Phase 3 dosage: The two doses were given 21 days apart in the Phase 3 trials, resulting in 95% efficacy.
Efficacy after one dose? Pfizer noted that partial protection from the vaccine appears to begin as early as 12 days after the first dose:“Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a vaccine efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the vaccine, starting as soon as 12 days after the first dose,” says the study published in the New England Journal of Medicine.
Phase 3 dosage: Clinical studies explored various dosing regiments with varying time between doses. In the two largest Phase 3 studies, one had a median interval between doses of 69 days and the other administered the second dose within 6 weeks.
Its primary efficacy analysis was based on participants who received either two standard doses or a half dose followed by a full dose: resulting in a pooled efficacy figure of 70.4%. The three trials that were initially designed to assess a single dose were amended to incorporate a booster.
“The timing of priming and booster vaccine administration varied between studies," notes the Phase 3 study published in The Lancet. "As protocol amendments to add a booster dose took place when the trials were underway, and owing to the time taken to manufacture and release a new batch of vaccine, doses could not be administered at a 4-week interval. 1459 (53·2%) of 2741 participants in COV002 in the LD/SD group received a second dose at least 12 weeks after the first (median 84 days, IQR 77—91) and only 22 (0·8%) received a second dose within 8 weeks of the first.
“The median interval between doses for the SD/SD group in COV002 was 69 days (50–86). Conversely, the majority of participants in COV003 in the SD/SD group (2493 [61·0%] of 4088) received a second dose within 6 weeks of the first (median 36 days, 32–58).”
A 'difficult and finely balanced decision'
On January 3, the independent Scientific Advisory Group for Emergencies (SAGE) committee backed the advice set out by the government's Joint Committee on Vaccination and Immunisation and chief medicial officers: saying that spreading out doses was justifiable in the context of the spread of the new, more transmissible variant of the virus (this advice was published before the WHO issued its guidance).
The committee noted that there are ‘sound reasons’ to delay a second dose of the AstraZeneca vaccine - including trial data - but notes the concerns raised over the delay in a second dose of the Pfizer/BioNTech vaccine.
These concerns included the lack of empirical evidence from clinical trial data on a delayed second dose; the organisational complexities of reorganising appointments; and the ethical consideration that patients were given the first dose on the understanding of receiving the second 21 days later.
However, it concluded: “While it is a very difficult and finely balanced decision, Independent SAGE endorses the decision to pursue coverage of as high a proportion of the population as possible, as quickly as possible as part of a comprehensive strategy."