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expert reaction to preprint on immune response in delayed second dose and third doses of the Oxford-AstraZeneca vaccine

A preprint, an unpublished non-peer reviewed study, looks at tolerability and immunogenicity after a late second dose or a third dose of the Oxford-AstraZeneca COVID-19 vaccine.

This Roundup accompanied an SMC Briefing.


Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice, Immediate past Chair of the BMA Public Health Medicine Committee, said:

“When the first Covid-19 vaccines became available, there was a lot of discussion about how we could use them most effectively. I have commented on this previously.2 3

“One of the particular issues was that the phase 3 trials had used particular prime-boost intervals; and some considered that those must be, somehow sacrosanct. That any variation from those intervals might render the vaccines ineffective.

“We know a great deal about how the immune system interacts with diseases, and have decades of research into how it interacts with vaccines. Concerns as above did not generally come from vaccinologists. We know that extending the prime-boost interval enhances the immune response. We can’t be certain how long this continues for; but it is one of the rules of thumb that applies to prime-boost vaccines that, while you risk reducing vaccine efficacy if you give booster doses sooner than recommended, you can extend the prime-boost interval almost indefinitely (certainly for at least a decade) without a reduction in the efficacy of the booster; and, certainly for a year or so, increasing the prime-boost interval enhances booster efficacy.

“With the human papillomavirus 2-dose vaccine regime, for example, if the second dose is given before the recommended 6-month interval, guidance recommends that an additional dose be given at least 6-months after the priming dose.4

“It was right, at the turn of the year, to make judgements based on this knowledge of vaccines.

“But it is always best to test ones assumptions, to ensure that they were correct.

“This paper does just that.

“It found that – entirely as expected – there was an increased antibody response if the second dose was delayed. The limitations of the trial (the time between the trial starting and publication) could mean that this could only be observed for up to about 45 weeks, but there is no reason to expect this improvement to fall away if and when the trial is extended for longer.

“There was limited data, so the authors were unable to comment on the effect of delaying the second dose on the T-cell response.

“The other question the authors sought to answer related to the effect of a second, later booster dose. As any vaccinologist would expect, a subsequent booster dose further enhanced the antibody responses; and here the authors had sufficient data to demonstrate also an increase in T-cell responses.

“This paper’s findings, therefore, are no surprise to vaccinologists. They confirm what we had predicted. But it remains very important to check that our predictions were correct, and this paper does just that.”


  1. Cunningham AM, Flaxman A, Marchevsky N, Jenkin D, Aboagye J, Aley PK, et al. Tolerability and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 (AZD1222) (Manuscript draft- embargoed until 28 Jun 2021): Oxford Vaccine Group, 2021 (28 Jun 2021).
  2. English PMB. The UK’s vaccine approach isn’t ‘anti-science’. The Spectator 2021; Updated 04 Jan 2021; Accessed: 2021 (04 Jan): (
  3. English PMB. The UK approach to COVID-19 vaccination: why was it so different? Drugs in Context 2021;10:2021-4-5. (
  4. Public Health England. Chapter 18a: Human Papillomavirus (HPV). Immunisation against infectious disease (“The Green Book”) 2019; Updated 12 Jul 2019; Accessed: 2019 (16 Jul): 1-19 (



Tolerability and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 (AZD1222)’ by Amy Flaxman et al. is a preprint



All our previous output on this subject can be seen at this weblink:



Declared interests

None received.

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