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London volunteers help confirm flexible second dose options in COVID-19 vaccine study

  • First dose of Oxford-AstraZeneca or Pfizer-BioNTech followed nine weeks later by second dose of Novavax or Moderna COVID-19 vaccines generated a robust immune response.
  • Oxford-AstraZeneca followed by Moderna/Novavax schedules induced higher antibodies and T-cell responses than two-dose Oxford-AstraZeneca schedule.
  • Pfizer-BioNTech/Moderna induced higher antibody and T-cell responses than the two-dose Pfizer-BioNTech schedule.
  • Pfizer-BioNTech/Novavax induced lower antibody and T-cell responses than the two-dose Pfizer-BioNTech schedule, although the schedule still induced higher antibodies than the two-dose Oxford-AstraZeneca schedule.

Following up first doses of the Oxford-AstraZeneca or Pfizer-BioNTech vaccines with second doses of the Moderna and Novavax jabs will generate robust immune responses against COVID-19, according to the Com-COV 2 study run at St George’s University Hospitals NHS Foundation Trust, Guy’s and St Thomas’ NHS Foundation Trust and University College London Hospitals NHS Foundation Trust.

In a paper published in the Lancet, they report that participants receiving a first dose of Oxford-AstraZeneca or Pfizer-BioNTech generated a robust immune response when immunised nine weeks later with a second dose of COVID-19 vaccines manufactured by Novavax or Moderna.

More than 400 people took part in London, with a total of 1,070 participants involved nationally. No safety concerns were raised in this study, across nine National Institute for Health Research-supported sites.

The study, led by researchers at the University of Oxford, therefore supports flexible use of these vaccines in primary immunisation schedules, which is crucial to help rapid deployment of these vaccines, especially in low-and middle-income countries where vaccine supply may be inconsistent.

Professor Matthew Snape, Associate Professor in Paediatrics and Vaccinology at the University of Oxford, and Chief Investigator on the trial, said: “Thanks to studies such as these, we are now getting a more complete picture of how different COVID-19 vaccines can be used together in the same vaccine schedule.

“Encouragingly, all these schedules generated antibody concentrations above that of the licensed and effective two dose Oxford-AstraZeneca schedule. When it comes to cellular immunity, having a first dose of the Oxford-AstraZeneca vaccine followed by any of the other vaccines generates a particularly robust response.

“It’s only through the inspiring efforts of the Com-COV2 participants and study teams that we can generate this data; this will help get the world immunised against COVID-19 as quickly as possible.”

Of note is that the primary vaccine made a difference to the immunogenicity of the various schedules:

  • Oxford-AstraZeneca followed by Moderna/Novavax schedules both induced higher antibodies and T-cell responses than the licensed and highly effective ‘standard’ two-dose Oxford-AstraZeneca schedule.
  • Pfizer-BioNTech/Moderna induced higher antibody and T-cell responses than the standard two-dose Pfizer-BioNTech schedule.
  • Pfizer-BioNTech/Novavax induced lower antibody and T-cell responses than the two-dose Pfizer-BioNTech schedule, although this schedule still induced higher antibodies than the two-dose Oxford-AstraZeneca schedule.
  • Blood samples taken from participants were tested for their effectiveness against the Wild-Type, Beta and Delta variants – while it was observed that the vaccines’ efficacy against the variant strains had decreased, this was a consistent trend across the mixed schedules.

In addition, a significantly higher number of short-lived vaccine reactions were reported in volunteers who received a second dose of Moderna compared to those who received two doses of either Oxford-AstraZeneca or Pfizer-BioNTech.

Professor Matthew Snape said: “Using different types of vaccines within the same schedule as we have done here (for example mRNA vaccines, viral-vector vaccines or protein-based vaccines) is a relatively novel approach to immunisation.

“As well as providing evidence for flexibility in deployment, these results suggest this approach can also help generate better immune responses. This has implications beyond COVID-19, and will inform new approaches to immunisation against other diseases that are, as yet, not vaccine preventable.”

Professor Andrew Ustianowski, National Clinical Lead for the UK NIHR COVID Vaccine Research Programme, said: “We really cannot thank the volunteers and staff involved in studies such as Com-COV2 enough. The continued effort from everyone within the study helps to gather more important information on the immune response of these vaccine dose combinations.

“This is another set of positive findings discovered by the UK research community, supported by the NIHR, which could be applied globally. Results such as these will help to shape guidance nationally and internationally, allowing more populations to be better protected from COVID-19.”

Professor Paul Heath, Principal Investigator of the trial at St George's, University of London and St George's Hospital, said:

“While there are some interesting differences shown between the combinations of vaccines studied in Com-COV2, the most important conclusion of this study is that robust immune responses are generated by all combinations. These results will facilitate flexible use of COVID-19 vaccines in primary immunisation schedules around the world.”

Anna Goodman, Consultant in Infectious Diseases at Guy’s and St Thomas’, was the local Principal Investigator for the study. She said: “We are so grateful to those who made the Com-COV2 trial possible - particularly those locally who gave up their time to participate in this study.

“It is almost exactly one year since the first COVID-19 vaccines were licensed for use, with vaccine regimes which involved receiving two doses of the same vaccine. So we were pleased when the first part of the Com-COV trial showed us that when we gave for example the Oxford-AstraZeneca followed four weeks later by Pfizer-BioNTech, we saw strong immune responses.

“It’s been really exciting in this follow up trial to see that we can combine a range of different vaccines with a nine week interval between doses and see excellent immune responses. It shows us for the first time that a strong immune response occurs when the two vaccines given are Oxford-AstraZeneca or Pfizer-BioNTech followed by Novavax or Moderna nine weeks later. This introduces new options for the first two doses of vaccine and globally could provide flexibility where it is needed.”

The study was designed as a so-called ‘non-inferiority’ study – the intent is to demonstrate that mixing is not substantially worse than the standard schedules – and compares the immune system responses to the gold-standard responses reported in previous clinical trials of each vaccine.

A brief Com-COV timeline

The University of Oxford is leading the Com-COV 2 study, run by the National Immunisation Schedule Evaluation Consortium (NISEC) and backed by £7 million of government funding from the Vaccines Taskforce.

Data from the original COMCOV study in adults has shown that mixed schedules involving Pfizer-BioNTech and Oxford-AstraZeneca induced high concentrations of antibodies against the SARS-CoV2 spike IgG protein when doses were administered four weeks apart. This study has informed immunisation practices globally and already resulted in two publications in the Lancet.

In September, the programme was further expanded to test multiple options for second dose COVID-19 vaccines in young people aged 12 to 16 years.