The FDA last month granted emergency use authorization to Pfizer/BioNTech and Moderna vaccines: specifying an interval of 21 days and 28 days respectively between the first and second dose. These intervals are the ones used in the vaccines’ Phase 3 trials, and yesterday were reiterated by the FDA.
Its position differs to the approach being taken in the UK, which is focusing on spacing out doses. The UK's chief medicial officers - faced with the increased threat from the more transmissible variant and a health service under pressure - now recommend that the gap between the first and second vaccine doses should be lengthened to allow more people to receive the first dose and therefore a certain level of protection.
They say the doses of both authorized vaccines in the UK – Pfizer/BioNTech and AstraZeneca – can be spread out with the second dose administered ‘within 12 weeks’. (Phase 3 trials for Pfizer/BioNTech had a gap of 21 days while for AstraZeneca the gap varied).
Meanwhile, Denmark has approved a delay of up to six weeks between the first and second dose of the Pfizer vaccine; while Germany is also reportedly considering authorizing a delay between doses.
FDA: 'We have committed time and time again to make decisions based on data and science'
The FDA notes discussions and media speculation about reducing the number of doses, extending the length of time between doses, changing the dose (such as using a half-dose), or mixing and matching vaccines in order to immunize more people against COVID-19.
While it deems these all ‘reasonable questions’ to consider in the context of clinical trials, in a statement published yesterday it says that suggesting any changes to the FDA-authorized dosing or scheduling of vaccines is ‘premature and not rooted solidly in the available evidence.’
“Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk, undermining the historic vaccination efforts to protect the population from COVID-19,” say FDA Commissioner Stephen M. Hahn, M.D., and Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research, in a statement last night.
“Using a single dose regimen and/or administering less than the dose studied in the clinical trials without understanding the nature of the depth and duration of protection that it provides is concerning, as there is some indication that the depth of the immune response is associated with the duration of protection provided. If people do not truly know how protective a vaccine is, there is the potential for harm because they may assume that they are fully protected when they are not, and accordingly, alter their behavior to take unnecessary risks.
“We know that some of these discussions about changing the dosing schedule or dose are based on a belief that changing the dose or dosing schedule can help get more vaccine to the public faster. However, making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.
"We have committed time and time again to make decisions based on data and science. Until vaccine manufacturers have data and science supporting a change, we continue to strongly recommend that health care providers follow the FDA-authorized dosing schedule for each COVID-19 vaccine."
UK defends second dose delay
In the UK, the focus is now on spreading out vaccine doses. 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 on Sunday: saying that spreading out doses was justifiable in the context of the spread of the new, more transmissible variant of the virus.
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."
The science: What exactly did the Phase 3 trials say?
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: Doses were administered 28 days apart, resulting in an efficacy figure of 94.5%. The primary endpoint of the study was prevention of COVID-19 with onset at least 14 days after the second injection.
Efficacy after one dose? In its Phase 3 study published in the New England Journal of Medicine last week, it notes that “results from a preliminary exploratory analysis suggest that some degree of prevention may be afforded after the first dose.”
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).”