Covid-19 Task Force member comment on dose spacing of vaccine

Professor Sheila Bird, formerly programme leader at the MRC Biostatistics Unit in Cambridge and member of our Covid-19 Task Force, has commented on the need for randomised trials to evaluate the strategy of delaying second dose of vaccine. 

This comment was originally published on the Science Media Centre on 4 January 2021 as part of expert comment discussing 'whether giving two doses of Covid vaccine separated by a longer period is sensible'.

'Often, decisions to safeguard public health have to be taken in the face of uncertainty. Importantly, however, when robust evidence can be got to evaluate those decisions, we should ensure that robust, randomized evaluation takes place from the outset. Hence, UK’s historic decision to prolong the inter-dose interval for the Pfizer/BioNTech mRNA vaccine from 21 days to nearly 12 weeks should be properly evaluated in the interest of both public health and scientific method.

'Robust randomized evaluation of policy-decision can be done relatively simply: randomize one quarter of those prioritized to be offered their 1st dose of BNT162b2 to receive the 2nd dose after 21 days versus three-quarters to receive their 2nd dose at around 12 weeks. Assume 160,000 1st doses of BNT162b2 are to be administered per week, then after 5 weeks some 200,000 citizens would have been randomized to receive the 1/22 day schedule versus 600,000 assigned to the 1/85 day schedule. This like-with-like powerful comparison will reveal how vaccine effectiveness actually compares during the weeks 4 to 9 after randomization, with answers (in terms of COVID-19 cases and hospitalizations) available by the week 12 after randomization began.

'An historic pandemic decision has been made to vary the dose-interval for the first mRNA vaccine authorized for use in UK. Let the UK’s second decision be randomized evaluation of the first.'

Longer version of Sheila’s thoughts:

MHRA’s Public Assessment Report Authorisations for Temporary Supply (under regulation 174 of the Human Medicines Regulation)recommendations by Joint Committee for Vaccination and Immunization.

Background: MHRA’s Public Assessment Report Authorization for the COVID-19 Vaccine AstraZeneca for active immunization of individuals >= 18 years old for the prevention of coronavirus disease 2019 (COVID-19) states: 'The vaccination course consists of two separate doses of 0.5 ml each. The second dose should be administered between 4 and 12 weeks after the first dose (see section 5.1).' Heterogeneity of dosing intervals across trials of the COVID-19 Vaccine AstraZeneca was more happenstance than by design and comparisons between-intervals did not have randomization as their underpinning. Nonetheless, MHRA granted the same laxity in dose-intervals as the trials had presented.

The MHRA’s corresponding text (last updated 31 December 2020) for the COVID-19 mRNA Vaccine BNT 162b2 reads: 'BNT162b2 is a vaccine indicated for active immunization of individuals 16 years of age and older to prevent COVID-19 caused by the SARS-CoV-2 virus . . . Following dilution with saline, BNT162b2 is given to you by an authorised practitioner as an intramuscular injection into the muscle at the top of the upper arm (deltoid muscle). You should receive two doses (each 0.3 mL) given 21 days apart.'

Public interest announcement: The Joint Committee for Vaccination and Immunization (JCVI) has, however, announced a major change from MHRA’s original authorization for temporary supply of BNT162b2. Instead of the second dose being received 21 days after the first, the dosing interval was extended to be from 3 weeks up to 12 weeks. And, in the interest of public health, the UK’s four Chief Medical Officers intimated on 31 December 2020 that UK’s inter-dose interval, including for BNT162b2, was likely to be maximal: 12 weeks.

The Pfizer/BioNTech mRNA vaccine is the first mRNA vaccine ever authorized in UK/USA. It was trialled in an exemplary and well-controlled manner so that, in particular, the scheduled interval of 21 days between doses was strictly adhered to. This was properly reflected in MHRA’s authorization for temporary supply and may contribute to BNT162b2’s higher vaccine efficacy – as the time interval for a mRNA booster injection may be critical for getting the best immune response. Moderna’s mRNA vaccine, authorised in USA, has a 28-day dose-interval. However, around 2,000 persons randomized in the Moderna randomized trials had received only one dose by the time of interim analysis: they have a key role in JCVI’s appraisal (see 2. Below).

More detailed explanation about JCVI’s rationale was needed: On 31 December 2020, a short statement (with Public Health England’s ANNEX A) was issued by JCVI. In respect of both vaccines, the Committee advised: 'initially prioritising delivery of the first vaccine dose as this is highly likely to have a greater public health impact in the short term and reduce the number of preventable deaths from COVID-19.'

Explanation in respect of JCVI’s advice on dose-interval extension for Pfizer/BioNTech mRNA vaccine was critical: it being the first mRNA vaccine ever authorized in UK/USA and having been authorised, as trialled, for 2nd dose at 21 days.

1. The JCVI summary states: 'models suggest that initially vaccinating a greater number of people with a single dose will prevent more deaths and hospitalizations than vaccinating a smaller number of people with two doses.' However, neither models nor time-varying assumptions about mRNA vaccine effectiveness during days 23 to 84 are detailed in ANNEX A, nor referenced.

2. JVCI’s considerations include that the Pfizer/BioNTech mRNA vaccine efficacy between dose 1 and dose 2 was 52% (95% CI: 29% to 69%);  but, allowing 14 days for immune response to develop, 89% (95% CI: 52% to 97%) between days 15 and 21; and 91% (95% CI: 74% to 97%) between days 15 and 28 (before booster dose takes effect). Lacking data beyond 28 days on BNT162b2, JCVI remarks: 'Similar findings were seen with the Moderna mRNA vaccine out to 108 days after the first dose (Annex A)”. However, ANNEX A cautions to the contrary: “These participants had a median follow-up time of 28 days (range: 1 to 108 days). The small, non-random sample and short median follow-up time** limits the interpretation of these results. There appears to be some protection against COVID-19 disease following one dose; however, these data do not provide sufficient information about longer term protection beyond 28 days after a single dose.'

3. JVCI’s considerations include: 'With most vaccines an extended interval between the prime and booster doses leads to a better immune response to the booster dose'. However, as no previous mRNA vaccine has been authorized, this statement cannot be read or interpreted as 'With most mRNA vaccines an extended interval . . .'

4. JVCI’s considerations include: 'The rate of vaccine delivery in the UK is currently limited by vaccine supply rather than by workforce capacity.' This is key as the alternative to a 12-week dose-interval for the mRNA vaccine would be to increase the volunteer workforce capacity. Evidence on supply issues was not adduced; and has been challenged.

** ie at the time of interim analysis of Moderna randomized controlled trial.


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