'Mix and Match' COVID Vaccine Study Backs Flexible Second Dose Options

Peter Russell

December 07, 2021

New research supports adopting a flexible approach to 'mixing and matching' second doses of COVID-19 vaccines after a first dose of either the AstraZeneca/Oxford or Pfizer/BioNTech vaccines.

The results come from the University of Oxford's COM-COV2 trial that is investigating the use of different combinations of approved COVID vaccines for first and second immunisation doses.

The study, published in  The Lancet , found that a first dose of either the AstraZeneca or Pfizer vaccine, followed 8 to 12 weeks later by a second dose of the Novavax or Moderna vaccine, generated a robust immune response.

No safety concerns were raised in the trial that involved 1072 participants across 9 sites in England in April and May. However, more side effects were noted in those assigned to a heterologous schedule of the AstraZeneca and mRNA vaccines than those who received homologous vaccinations.

Non-inferiority Study

For the study, participants were randomly assigned to receive as a second dose either the same vaccine previously given, or either a Moderna or Novavax jab.

The single-blind, randomised, non-inferiority investigation found that a first dose of AstraZeneca followed by a second dose of either Moderna or Novavax induced a higher antibody response than a standard AstraZeneca/AstraZeneca schedule.

Prof Matthew Snape, who led the research, told a briefing hosted by the Science Media Centre: "The ratio of antibodies from this group that got Moderna as a second dose to those that got the Oxford/AstraZeneca as a second dose was 10 fold higher… and 2.8 fold higher if you've got Novavax as a second dose in terms of your binding antibodies, compared with a standard schedule of two doses of the Oxford/AstraZeneca vaccine."

Following up a first dose of Pfizer with a second dose of Moderna also boosted antibodies more effectively than a Pfizer/Pfizer schedule.

Prof Snape, a specialist in paediatrics and vaccinology at the University of Oxford, said this combination produced antibody levels "1.3 fold higher than if you received two doses of Pfizer vaccine".

However, while a Pfizer/Novavax schedule induced higher antibodies than observed in the AstraZeneca/AstraZeneca cohort, this combination was not as effective as having two doses of Pfizer.

AstraZeneca/Oxford Vaccine 'Good at Priming' Immune Response

According to Prof Snape, "all these schedules generated antibody concentrations above that of the licensed and effective two dose Oxford/AstraZeneca schedule", but that in terms of cellular immunity "having a first dose of the Oxford/AstraZeneca vaccine, followed by any of the other study vaccines, generates a particularly robust response".

An analysis of T cell response in the cohorts found that an adenoviral-vectored AstraZeneca first dose, followed by either the mRNA Moderna or recombinant nanoparticle protein-based Novavax as a second dose, was particularly effective.

Results from the AstraZeneca/Moderna cohort showed a T-cell response three and a half fold higher than those who received two doses of AstraZeneca, while the AstraZeneca/Novavax group had a T-cell response that was 4.8 fold higher.

By contrast, participants who received an mRNA vaccine as a first dose, followed by a second dose of Novavax, exhibited the lowest T cell response.

Prof Snape said the interpretation is that "the Oxford/AstraZeneca vaccine, using an adenoviral vector, seems to be very good at priming" and that "if you get it, then another vaccine as your second dose, whether it be RNA or protein, you get a really stonking T cell response – less so if you're primed with the RNA and then get a different vaccine as your second dose".

The researchers noted a gradual decrease in antibody concentrations over time. "If you have higher antibodies against the early pandemic strains, you'll still have antibodies against variants of concern, but there is clearly a drop off," said Prof Snape, who added that COM-COV was hoping to show results of vaccine effectiveness against the Omicron variant in the next few weeks.

The study authors conclude that: "While most high-income countries have completed

two-dose primary courses of COVID-19 vaccinations in adults, these data remain extremely relevant to the 94% of people in low-income countries who are yet to receive any doses."

Unlike the AstraZeneca and Pfizer vaccines, use of Novavax has yet to be approved by the UK regulator.

Expert Comment on Trial Results

Commenting on the study, that was funded by the Vaccine Task Force and the National Institute for Health Research, Penny Ward, visiting professor in pharmaceutical medicine at King's College London, said: "In the absence of agreed correlates of protection against infection, illness, and death with these vaccines, there is a tendency to use vaccine schedules which offer potential for a greater immune response.

"Based on this presumption, the immune response data suggests heterologous vaccination might have some benefits to offer in this respect, particularly for subjects receiving the viral vector vaccination as the first dose.

"Not surprisingly, the improved immunological response is accompanied by a greater potential for reactogenic effects, particularly systemic effects, occurring most frequently following a second dose with a mRNA vaccine."

She said that another potential benefit from the study would be that "individuals that have an allergic reaction to the first vaccine dose can be given an alternative vaccine type without, for the most part, losing the benefit of a second dose", while the same could be true for planning booster programmes.

Jonathan Ball, professor of molecular virology at the University of Nottingham, described the research as "fantastic" and said it was "great to finally see the data that was no doubt pivotal in deciding the UK's vaccine booster approach".

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