Mixed Oxford/Pfizer vaccine schedules generate robust immune response against COVID-19, finds Oxford-led study

Alternating doses of the Oxford-AstraZeneca and Pfizer-BioNTech vaccines generate robust immune responses against COVID-19, according to researchers running the University of Oxford-led Com-COV study.

In a paper published on the Lancet pre-print server, they report that both ‘mixed’ schedules (Pfizer-BioNTech followed by Oxford-AstraZeneca, and Oxford-AstraZeneca followed by Pfizer-BioNTech) induced high concentrations of antibodies against the SARS-CoV2 spike IgG protein when doses were administered four weeks apart.

This means all possible vaccination schedules involving the Oxford-AstraZeneca and Pfizer-BioNTech vaccines could potentially be used against COVID-19.

Professor Matthew Snape, Associate Professor in Paediatrics and Vaccinology at the University of Oxford, and Chief Investigator on the trial, said: ‘The Com-COV study has evaluated “mix and match” combinations of the Oxford and Pfizer vaccines to see to what extent these vaccines can be used interchangeably, potentially allowing flexibility in the UK and global vaccine roll-out.

‘The results show that when given at a four-week interval both mixed schedules induce an immune response that is above the threshold set by the standard schedule of the Oxford/AstraZeneca vaccine. The investigators would like to thank the participants that made this important study possible.’

Of note is that the order of vaccines made a difference, with an Oxford-AstraZeneca/Pfizer-BioNTech schedule inducing higher antibodies and T-cell responses than Pfizer-BioNTech/Oxford-AstraZeneca, and both of these inducing higher antibodies than the licensed, and highly effective ‘standard’ two-dose Oxford-AstraZeneca schedule. The highest antibody response was seen after the two-dose Pfizer-BioNTech schedule, and the highest T cell response from Oxford-AstraZeneca followed by Pfizer-BioNTech.

Professor Matthew Snape said: ‘These results are an invaluable guide to the use of mixed dose schedules, however the interval of four weeks studied here is shorter than the eight to 12-week schedule most commonly used for the Oxford-AstraZeneca vaccine. This longer interval is known to result in a better immune response, and the results for a 12-week interval will be available shortly’.

Deputy Chief Medical Officer Professor Jonathan Van-Tam said: ‘Today’s data are a vital step forward, showing a mixed schedule gives people protective immunity against COVID-19 after four weeks.

‘Equally, they offer supportive evidence that the standard (non-mixed) JCVI recommendations for COVID-19 vaccination all produce highly satisfactory immune responses, for both main vaccines in use. Given the UK’s stable supply position there is no reason to change vaccine schedules at this moment in time.

‘The results for the 12-week interval, which are yet to come, will have an instrumental role to play in decisions on the future of the UK’s vaccination programme.

‘Our non-mixed (homologous) vaccination programme has already saved tens of thousands of lives across the UK but we now know mixing doses could provide us with even greater flexibility for a booster programme, while also supporting countries who have further to go with their vaccine rollouts and who may be experiencing supply difficulties.’

Professor Andrew Ustianowski, NIHR Clinical Lead for the COVID-19 Vaccination Programme and Joint National Infection Specialty Lead, said: ‘We know that the Oxford-AstraZeneca two-dose schedule is highly effective and has helped to save many lives. The fact we now know it works well, in terms of immune responses, when combined with the Pfizer vaccine provides researchers with the valuable knowledge that these vaccines could be used flexibly for those yet to be vaccinated in the UK and globally.

‘It would have been impossible to discover these results without the willingness and efforts of research participants across the country. Yet again they have worked alongside researchers to help find an end to the spread of COVID-19.’

In May, researchers reported preliminary Com-COV data revealing more frequent mild to moderate reactions in mixed schedules compared to standard schedules, however, these were short-lived in duration.

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

It aims to evaluate the feasibility of using a different vaccine for the initial ‘prime’ vaccination to the follow-up ‘booster’ vaccination, helping policymakers explore whether this could be a viable route to increase the flexibility of vaccination programmes.

The trial recruited 830 volunteers aged 50 and above from eight National Institute for Health Research (NIHR) supported sites in England to evaluate the four different combinations of prime and booster vaccination.

In April, the researchers expanded the programme to include the Moderna and Novavax vaccines in a new study, run across nine National Institute for Health Research supported sites by NISEC and backed through funding from the Vaccines Taskforce and the Coalition for Epidemic Preparedness Innovations.

The six new ‘arms’ of the trial each recruited approximately 175 candidates, adding a further 1070 recruits into this programme.

Both studies are designed as so-called ‘non-inferiority’ studies – the intent is to demonstrate that mixing is not substantially worse than not mixing – and will compare the immune system responses to the gold-standard responses reported in previous clinical trials of each vaccine.

If the studies show promising results, the Medicines and Healthcare products Regulatory Agency (MHRA) and the Joint Committee on Vaccination and Immunisation (JCVI) would formally assess the safety and efficacy of any new vaccination regimen.