Recent studies have suggested a mix-and-match approach to vaccine dosing could induce a better immune response.
To return to some semblance of normal life after Covid-19, the global population must be vaccinated against the virus. While some countries’ inoculation programmes are steaming ahead, a number of obstacles are preventing shots getting into arms worldwide, from hesitancy and safety concerns to manufacturing and supply constraints.
Mixing different Covid-19 vaccines has emerged as a potential solution to these problems. All currently available vaccines – minus Johnson & Johnson’s one-shot jab – must be given in two doses; the first dose primes the immune system, while the second dose boosts this response.
Not only would mixing vaccine doses give global vaccine rollouts a much-needed push, but studies have suggested it could offer better protection against Covid-19, too.
Mixing AZ and Pfizer jabs: does it work?
All research into vaccine mixing is in the early stages, but a preliminary study by University of Oxford scientists in June found that mixing the AstraZeneca (AZ) and Pfizer vaccines generated a robust immune response against the virus, inducing higher antibodies than an AstraZeneca-only, two-dose schedule.
Researchers conducting the Com-COV (Comparing Covid-19 Vaccine Schedule Combinations) study found the order of immunisation also had an impact, with AZ followed by Pfizer showing a better immune response out of the two mixed dosing regimens.
Professor Matthew Snape, 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.”
A more recent trial conducted in South Korea has shown that a mixed vaccination, with AZ as the first dose and Pfizer as the second, induced neutralising antibody levels six times higher than those seen after two doses of the AstraZeneca jab.
The study also analysed the dosing regimens’ effect on coronavirus variants of concern. According to the Korea Disease Control and Prevention Agency, none of the groups demonstrated reduced neutralising activity against the Alpha variant first identified in the UK, but the neutralisation titre decreased by 2.5 to six-fold against the Beta, Gamma and Delta variants, first detected in South Africa, Brazil and India respectively.
Studies in Spain and Germany have found that a mixed dosing regimen elicits a better immune response than administering two doses of the AstraZeneca vaccine.
Is mixed dosing safe?
The vaccines assessed in these studies – Pfizer’s Comirnaty and AstraZeneca’s Vaxzevria – are used widely in vaccination programmes across the globe, having been found safe and highly effective in protecting against Covid-19.
The Oxford Com-COV study observed four serious adverse events across all participant groups but stated none “were considered related to immunisation”. An independent data safety monitoring board reviewed the trial’s safety data, and local trial-site physicians oversaw all adverse events in real-time.
Com-COV researchers did note in an earlier study that 30 to 40% of those who received mixed doses reported fevers after their second shot, compared to 10 to 20% of those who received the same vaccine for both doses. This could be attributable to the shorter, four-week interval between doses that was used during the Oxford study. Safety data from a cohort with a 12-week dosing interval is still to come.
Research into the safety of mixing vaccine doses is early and ongoing. The key studies demonstrating the efficacy and relative safety of the mixed AZ-Pfizer regimen have been carried out on relatively low patient populations – 463 in the case of the four-week Com-COV group and 499 in the South Korean study, of whom only 100 actually received mixed doses. As Com-COV chief investigator Matthew Snape acknowledged in late June, studies with low populations “do not pick up on your one-in-1,000 side effect, let alone your one-in-50,000 side effect”. Expanded studies on much larger groups will clearly be needed to definitively test the safety of vaccine mixing.
What about other companies’ vaccines?
Oxford University’s initial mix-and-match study, Com-COV1, is focused on mixing the AstraZeneca and Pfizer jabs. Com-COV2, however, is evaluating the safety and immunogenicity of combining the Moderna and Novavax vaccines with a first dose of either the Pfizer or AstraZeneca jab.
The researchers say that as more Covid-19 vaccines become available, the number of jabs included in the vaccine mixing study may increase. Dose-mixing studies testing other vaccine combinations are also ongoing around the world, including a Moscow trial of an AZ-Sputnik V combination, as well as a Philippines-based study mixing Sinovac’s CoronaVac jab with six other vaccines.