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expert reaction to launch of COVID-19 alternating dose vaccine study (heterologous prime-boost vaccination) in the UK, the Com-COV study

A clinical trial looking into alternating COVID-19 vaccine doses, the Comparing COVID-19 Vaccine Schedule Combinations (Com-COV) study, has launched today in the UK.

This Roundup accompanied an SMC Briefing.


Dr Andrew Garrett, Executive VP, Scientific Operations, ICON Clinical Research, said:

“This is a welcome announcement and the trial represents a positive step forward, both in the UK and internationally.  It initiates the next stage of vaccine development, which is to establish optimal dosing for approved vaccines and their combinations.  The trial is aimed at determining immunological response as an indicator of clinical effectiveness, and as such the number of participants required is notably fewer compared with a phase III placebo-controlled vaccine trial, that requires in the region of 30,000 participants.  Blood samples will be taken over time to measure antibody levels in the participants, and adverse reactions will also be recorded.  The importance of using randomization cannot be over-emphasised as the means of establishing causality in relation to the impact of the selected dosing intervals and two-dose combinations.  A such this trial requires consenting volunteers.  However the trial should be attractive to potential volunteers as all participants will receive two doses of an approved vaccine, or their combination.  The trial is due to begin enrolling in mid-February and is targeting volunteers over the age of 50, many of whom will not yet be eligible for vaccination.  There are 8 distinct combinations being evaluated in a 800 participant factorial design with 100 participants per combination.

“There remain many unanswered question, and new questions will emerge, so it is important for the UK to create an experimental framework to continue to gather objective vaccine evidence to support public health policy.  This trial represents an important step in the right direction.”


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

“The antigen used in all of the vaccines currently licensed in the UK is exactly the same spike protein, so the immune system will recognise it and can be expected to respond at least as well if a different product is used for boosting as it would if the same vaccine as in the original dose were used.

“It is also the case that many vaccines work better if a different vaccine is used for boosting – an approach described as heterologous boosting.  Examples include hepatitis B, where some people respond poorly to vaccination but better if a heterologous booster is given; and some of the candidate vaccines for a better tuberculosis vaccine – I’ve provided a few example references in my blog:

“We have seen that the Sputnik vaccine uses a form of heterologous boosting – it is a vector vaccine, and the vector is different for the two doses.  This seems to have been done partly out of concern that the immune system might recognise the vector virus used, reducing the efficacy of the booster dose.

“We have also seen that the AstraZeneca vaccine appears more effective with a longer prime-boost interval1.  This was no surprise to vaccinologists – it is to be expected.  The short prime-boost interval in the initial vaccine trials was presumably chosen because the efficacy of vaccination after a single dose was not predicted to be as high as it has turned out to be, to provide better initial immunity, at the expense of longer term immunity.  So that the trial is looking at different intervals is interesting, and should yield some valuable data.  Perhaps, if the recent paper confirming the benefit of the 12 week interval (and the efficacy of the first dose of vaccine for at least 12 weeks) had been available when the trial was being designed, an even longer interval – perhaps 6 months – might have been chosen (dropping one of the shorter intervals).

“While current guidance permits a different dose of vaccine to be used, it still recommends that the same product is used if possible, so this trial is not part of the general vaccine roll-out.”

1 Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, 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. 2021; Updated 01 Feb 2021; Accessed: 2021 (03 Feb): (



Declared interests

Dr Andrew Garrett: “I am employed by ICON which is a Contract Research Organization.   ICON provides pharmaceutical services to the pharmaceutical and biotechnology industries.  ICON conducts clinical trials on behalf of Sponsors, including vaccine trials.  I am a member of the UK Statistical Authority’s (UKSA) Research Accreditation Panel.”

None others received.




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