Correspondence
and we too hope that lessons will be
learned. However, we believe that
they will not achieve their aim by
calling for an independent and judge-
led statutory public inquiry. Although
such inquiries have their place,
experience would suggest that they
have proven to be particularly poor
in their evaluation of operational
matters.
Such inquiries have core weak­
nesses, including their desire to
allocate blame; their misuse of
hindsight and foresight, leading
to erroneous deductions; and their
failure to explain why a particular
approach was taken, given that it is
only through understanding the why
that we can prevent future failures.
Such inquiries also examine events
through the lens in which perfection
is possible; this false paradigm leads
to erroneous recommendations.
Furthermore, the recommendations
produced are often flawed because
they fail to appreciate the gaps
between knowing (ie, passive
learning) and doing (ie, active
learning).
The irony here is the call for
one imperfect system to examine
another in the vain hope that one
will perfect the other. Despite how
they are common practice, there
is little evidence that inquiries are
an effective way of learning opera­
tional lessons from past crises.
We must do better. Therefore, we
would support an examination
of the events from the past year;
however, we would also call for an
examination of the way in which
these inquiries are done to ensure
that they produce active rather than
just passive learning.
We declare no competing interests.
*Mike Lauder, Nigel Lightfoot
mal@alto42.co.uk
Alto42, Winchester SO23 8RB, UK (ML); Lightfoot
Associates, Newcastle, UK (NL)
1 Goodman J, de Prudhoe K, Williams C, of the
Covid-19 Bereaved Families for Justice.
UK COVID-19 public inquiry needed to learn
lessons and save lives. Lancet 2020;
397: 177–80.
www.thelancet.com Vol 397 March 6, 2021 879
Delayed second dose of
the BNT162b2 vaccine:
innovation or
misguided conjecture?
We strongly support vaccination
against COVID-19 with the Pfizer-
BioNTech COVID-19 mRNA vaccine
BNT162b2 when adhering to the
3-week dosing schedule that was
found highly effective in the phase 3
randomised clinical trial—regarded as
the gold standard. However we do
not support the second dose being
delayed to 12 weeks, as implemented
by UK Chief Medical Officers.1–3 The
latter followed recommendations by
the Joint Committee on Vaccination
and Immunisation (JCVI), based on
unplanned, retrospective analysis and
unwarranted assumptions.
The UK is currently the only country
to have adopted a maximal 12 weeks
delay. How science-led is the UK
strategy? Is it innovative and world-
leading, or scientifically fallacious,
resulting in an unproven dosing
schedule introduced without fully
informed patient consent? What are
the potential risks, for individuals and
the population?
The idea of protecting more of
the population by delaying the
second dose is predicated on a joint
statement by the JCVI and Public
Health England (PHE) that a first
dose provides 89–90% efficacy
(protection).4,5 This is contrary to the
clinical data or efficacy generated from
real-life clinical observational data
from Israel.6,7 How did the JCVI arrive
at their estimate of 89%?
The JCVI performed an
unplanned, retrospective analysis
of the randomised clinical trial
data. They compared COVID-19
cases in the vaccine group versus
the control group from a 6-day
window (15–21 days), selected
retrospectively after examining the
data. The resulting 89% efficacy
(95% CI 52–97) was based only on
roughly 20 events. Retrospective
analyses in therapeutic trials can be
hypothesis-generating but should
not be used to treat individuals. The
JCVI then made a major assumption
that the 89% effectiveness persists
from day 21 to day 85 in the absence
of the second dose,4,5 for which no
empirical evidence was adduced. In a
further major, incorrect assumption,
Oli Scarff/Getty Images
the JCVI stated “There is currently no
strong evidence to expect that the
immune response from the Pfizer-
BioNTech and AstraZeneca vaccines
differ substantially from each other”.5 Published Online
No scientific data on mRNA vaccines February 19, 2021
https://doi.org/10.1016/
exists to support this assumption. S0140-6736(21)00455-4
The available quality peer-reviewed,
published immunology data would
refute the assumptions documented
by the JCVI and PHE.4
mRNA vaccines had never been
used therapeutically in humans.
The JCVI assumption that mRNA
vaccines (BNT162b2 and Moderna’s
mRNA-1273 SARS-CoV-2 vaccine)
would behave similarly to the
AZD1222 viral vector DNA vaccine
developed by the University of Oxford
and AstraZeneca is not supported by
published evidence.8–10 Phase 1/2 trial
data of AZD1222 show a substantial
specific anti-virus spike protein T-cell
responses at day 7, which peaks at
day 14.8 This response is not seen
with BNT162b2. Furthermore, there
are marked quantitative differences
in the production and duration of
neutralising antibodies (NAbs).
The mRNA vaccines show marked
falls in NAb titres (compared with
the DNA vaccine) in the period
before the scheduled second dose
(day 22 and day 29 for BNT162b211,12
and mRNA-1273, 9 respectively),
something we have specifically
highlighted as occurring in all age
groups.3 Inevitably, NAb titres will
continue to fall during days 21–85,
leading to very reduced immunity
and increased risk to individuals of
infection, especially in frail older
people.
An efficacy of 52·4% was reported
out to day 22 for BNT162b2,13 and
 Correspondence
efficacy of 50–60% has been reported
in observational cohort studies from
Israel covering the same period. 6,7
UK’s delayed second dose strategy
for BNT162b2 is, in our view, a
misguided conjecture. It will yield
some protection for the individual
after a first dose: how much, and for
how long, is unknown and without
patient consent.
The population risk is that the
UK’s delayed second dose could
strongly favour the emergence of
consequential SARS-CoV-2 variants
resulting from sub-optimal or
partial immunity. The Government’s
Scientific Advisory Group for
Emergencies has also documented
concern about emergence of variants
as a result of the delayed second
dose.14
Sub-optimal vaccination will
create selective pressure facilitating
the emergence of vaccine-resistant
variants, which could result in a
persisting pandemic. New vaccines,
covering such variants, can be made
but will require time for testing, mass
production, and distribution.
We have no concerns regarding
the second dose of AZD1222 at
12 weeks, as this is supported by
evidence. However, if escape variants
arise due to sub-optimal dosing with
BNT162b2, they will likely be resistant
to other vaccines that target the same
viral spike protein.
In conclusion, we would strongly
recommend that the UK Government
reverts to the two doses in a 3-week
schedule (94% efficacy) for BNT162b2;
or, as recently supported by WHO and
the US Centers for Disease Control
and Prevention, adopt no more than
a 6-week delay to the second dose “in
exceptional circumstances”.15,16
We declare no competing interests.
*John F R Robertson, Herb F Sewell,
Marcia Stewart
john.robertson@nottingham.ac.uk
Graduate Entry Medicine Division, Royal Derby
Hospital, University of Nottingham,
Derby DE22 3DT, UK (JFRR, HFS); De Montfort
University, Leicester, UK (MS)
880 www.thelancet.com Vol 397 March 6, 2021
1 National Health Service. Letter to chief
executives of all NHS trusts and foundation
trusts. Dec 30, 2020.https://www.england.
nhs.uk/coronavirus/wp-content/uploads/
sites/52/2020/12/C0994-System-letter-
COVID-19-vaccination-deployment-planning-
30-December-2020.pdf (accessed
Feb 18, 2021).
2 Department for Health and Social Care.
Letter to the profession from the UK Chief
Medical Officers regarding the UK COVID-19
vaccination programmes. Dec 21, 2020.
https://www.gov.uk/government/
publications/letter-to-the-profession-from-
the-uk-chief-medical-officers-on-the-uk-
covid-19-vaccination-programmes/
letter-to-the-profession-from-the-uk-chief-
medical-officers-regarding-the-uk-covid-19-
vaccination-programmes (accessed
Feb 18, 2021).
3 Robertson JFR, Sewell HF, Stewart M, Kendrick D,
Agius RM. Covid-19 vaccines: to delay or not to
delay second doses. Jan 5, 2021. https://blogs.
bmj.com/bmj/2021/01/05/covid-19-vaccines-
to-delay-or-not-to-delay-second-doses/
(accessed Feb 17, 2021).
4 Public Health England. COVID-19: the green
book, chapter 14a. Feb 12, 2021.
https://assets.publishing.service.gov.uk/
government/uploads/system/uploads/
attachment_data/file/948757/Greenbook_
chapter_14a_v4.pdf (accessed Feb 4, 2021).
5 Joint Committee on Vaccination and
Immunisation. Independent report.
Optimising the COVID-19 vaccination
programme for maximum short-term impact.
Jan 26, 2021. https://www.gov.uk/
government/publications/prioritising-the-
first-covid-19-vaccine-dose-jcvi-statement/
optimising-the-covid-19-vaccination-
programme-for-maximum-short-term-impact
(accessed Jan 26, 2021).
6 Chodick G, Tene L, Patalon T, et al.
The effectiveness of the first dose of
BNT162b2 vaccine in reducing SARS-CoV-2
infection 13-24 days after immunization:
real-world evidence. medRxiv 2021;
published online Jan 29. https://doi.org/
10.1101/2021.01.27.21250612 (preprint).
7 Aran D. Estimating real-world COVID-19
vaccine effectiveness in Israel. medRxiv 2021;
published online Feb 11. https://doi.org/
10.1101/2021.02.05.21251139 (preprint).
8 Folegatti PM, Ewer KJ, Aley PK, et al. Safety and
immunogenicity of the ChAdOx1 nCoV-19
vaccine against SARS-CoV-2: a preliminary
report of a phase 1/2, single-blind, randomised
controlled trial. Lancet 2020; 396: 467–78.
9 Widge AT, Rouphael NG, Jackson LA, et al.
Durability of responses after SARS-CoV-2
mRNA-1273 vaccination. N Engl J Med 2021;
384: 80–82.
10 Walsh EE, Frenck RW Jr, Falsey AR, et al.
Safety and immunogenicity of two RNA based
Covid-19 vaccine candidates. N Engl J Med
2020; 383: 2439–50.
11 Mulligan MJ, Lyke KE, Kitchin N, et al. Phase I/II
study of COVID-19 RNA vaccine BNT162b1 in
adults. Nature 2020; 586: 589–93.
12 Collier DA, Ferreira IATM, Datir R, et al.
Age-related heterogeneity in neutralising
antibody responses to SARS-CoV-2 following
BNT162b2 vaccination. medRxiv 2021;
published online Feb 5. https://doi.org/
10.1101/2021.02.03.21251054 (preprint).
13 Polak FP, Thomas SJ, Kitchin N, et al.
Safety and efficacy of the BNT162b2 mRNA
Covid-19 vaccine. N Engl J Med 2020;
383: 2603–15.
14 Scientific Advisory Group for Emergencies.
SARS-CoV-2 immunity-escape variants,
7 January 2021. Jan 7, 2021. https://assets.
publishing.service.gov.uk/government/
uploads/system/uploads/attachment_data/
file/954990/s1015-sars-cov-2-immunity-
escape-variants.pdf (accessed Feb 18, 2021).
15 US Centers for Disease Control and Prevention.
Interim clinical considerations for use of
mRNA COVID-19 vaccines currently authorized
in the United States. Feb 10, 2021.
https://www.cdc.gov/vaccines/covid-19/info-
by-product/clinical-considerations.html
(accessed Feb 18, 2021).
16 WHO. Interim recommendations for use of the
Pfizer–BioNTech COVID-19 vaccine,
BNT162b2, under Emergency Use Listing.
Jan 8, 2021. https://assets.documentcloud.
org/documents/20445916/who-2019-ncov-
vaccines-sage_recommendation-bnt162b2-
20211-eng.pdf (accessed Feb 18, 2021).
Department of Error
GlobalSurg Collaborative and National Institute
for Health Research Global Health Research Unit
on Global Surgery. Global variation in
postoperative mortality and complications after
cancer surgery: a multicentre, prospective cohort
study in 82 countries. Lancet 2021;
397: 387–97—In figure 1 of this Article, the
1337 patients from 263 hospitals who had
surgery and were included in the analysis
should have been reported as having “gastric
cancer”. Additionally, members of the protocol
development group should have been
included in the GlobalSurg Collaborative and
National Institute for Health Research Global
Health Research Unit on Global Surgery study
group list, and the appendix has been
updated. These corrections have been made to
the online version as of March 4, 2021.
Voysey M, Costa Clemens SA, Madhi SA, et al.
Single-dose administration and the influence of
the timing of the booster dose on immunogenicity
and efficacy of ChAdOx1 nCoV-19 (AZD1222)
vaccine: a pooled analysis of four randomised
trials. Lancet 2021; 397: 881–91—In this Article,
in figure 3, some of the datapoints on the
graphs and the key on the left panel have both
been corrected. These corrections have been
made to the online version as of March 4, 2021,
and the printed version is correct.
Penninx BWJH, Pine DS, Holmes EA, Reif A.
Anxiety disorders. Lancet 2021; 397: 914–27—
In this Seminar, for figure 2, when comparing
various treatments with each other,
the intervention for SAD is now CBT
and the intervention for anxiety is now
CBT + medication. This correction has been
made to the online version as of March 4, 2021,
and the printed version is correct.