Mixing Covid-19 vaccines increases the risk of unpleasant, short-term side-effects such as fatigue and fever, according to a UK trial in which people received different jabs for their first and second doses.

Preliminary results from the study run by Oxford university, published in The Lancet, showed a downside to vaccine mixing that the researchers had not expected, although the adverse reactions were shortlived. Mixed dosing is under consideration in several parts of the world, either because of safety concerns about the Oxford/AstraZeneca jab or to help spin out scarce supplies.

“The results from this study suggest that mixed dose schedules could result in an increase in work absences the day after immunisation,” said Matthew Snape, chief investigator on the trial, adding that it could be particularly important for planning the vaccination of healthcare workers.

Several European countries, including France and Germany, are offering a second dose of a different vaccine to younger people who received a first jab of the AstraZeneca shot that has been associated with rare cases of a serious blood clotting disorder. Some Canadian provinces are also considering mix and match vaccine schedules to make the most of available supplies.

The Com-Cov study has recruited 830 volunteers over the age of 50, who received four different combinations of AstraZeneca and Pfizer shots.

The mixed schedules — AstraZeneca-Pfizer or Pfizer-AstraZeneca, known technically as a heterologous boost — were much more “reactogenic” than two doses of the same shot. Symptoms such as fatigue, feverishness, chills, malaise and headache were reported two to three times more frequently by participants who received mixed doses. For example, 34 per cent of people who received an AstraZeneca shot followed by a Pfizer jab felt feverish, compared with 10 per cent who got two AstraZeneca doses.

“These data suggest that the two heterologous vaccine schedules in this trial might have some short-term disadvantages,” the Oxford researchers said. “Routine prophylactic use of paracetamol after immunisation could help mitigate these and is being studied in Com-Cov participants.”

Short-term side-effects of vaccination normally arise from a reaction by the innate immune system, Snape said. But the researchers had no immediate explanation for why this would be stronger when doses are mixed.

The scientists also warned that the side-effects of the mixed vaccine schedules might be worse for younger people, who tend to have more active immune responses, than for the study group, who were all over 50.

The primary aim of the Com-Cov study was to discover whether mixed schedules produced stronger long-term immune protection against Covid. Those results will take longer to compile and Snape cautioned against drawing conclusions about protection from the short-term reactogenicity data.

Professor Andrew Ustianowski, National Clinical Lead for the UK National Institute for Health Research Covid Vaccine Research Programme, said the results were “very important” for understanding how best to vaccinate the population. “These findings need to be combined with future results on the effectiveness of these combinations against Covid-19,” he said.