'Mix and match' coronavirus vaccine doses linked to more side effects

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Cropped image of nurse injecting Covid-19 Vaccine to a patient. Female healthcare worker is working at hospital. She is holding syringe.
Scientists are investigating the efficacy and safety of administering the Pfizer-BioNTech coronavirus vaccine followed by a University of Oxford-AstraZeneca booster, and vice versa. (Stock, Getty Images)

Mixing and matching different coronavirus vaccines as part of the two-dose schedule may cause more side effects, research suggests.

Scientists from the UK's National Immunisation Schedule Evaluation Consortium (NISEC) are investigating the effects of administering the Pfizer-BioNTech vaccine as a first dose, followed by a University of Oxford-AstraZeneca booster jab, and vice versa.

While these are not the regimens on which the jabs were approved, many are optimistic that alternating doses may lead to a more potent immune response.

Amid growing concern the Oxford-AstraZeneca vaccine causes blood clots in a small minority of patients, Germany, France and Sweden are just a few of the countries "advocating" for a mix and match approach in young people.

Read more: Two Pfizer jabs over 95% effective against Kent coronavirus variant

The NISEC scientists' 13-month study was only initiated in February 2021, but preliminary safety data suggest alternating doses leads to a higher incidence of mild side effects, like feeling hot, tired or achy.

The observed adverse events were not serious, with none of the study's participants being hospitalised with post-jab complications.

Corona virus
Mixing and matching vaccines as part of the two-dose schedule may lead to a more potent immune response against the coronavirus. (Stock, Getty Images)

"There is significant international interest" in a mix and match jab approach "to mitigate against supply shocks or shortages that might otherwise reduce the speed of vaccine rollout", the scientists wrote in The Lancet.

As well as the Pfizer-BioNTech and Oxford-AstraZeneca jabs, the Moderna vaccine is also approved in the UK to ward off COVID-19, the disease caused by the coronavirus.

The Moderna vaccine was only recently rolled out and is therefore not included in the NISEC analysis.

Read more: One in 14 in hospital with COVID had first vaccine

The scientists are comparing the effects of alternating Pfizer-BioNTech and Oxford-AstraZeneca jabs against giving the same vaccine in the two-dose regimen.

In the study, all the jabs are being administered either four or 12 weeks apart, but only the former was included in the preliminary safety analysis.

The UK's three vaccines were approved based on a dosing interval of around three weeks, but this has been extended to up to 12 weeks to maximise the number of people having a first jab.

All the NISEC study participants are aged 50 or over, with no serious underlying health issues.

Watch: Do coronavirus vaccines affect fertility?

Seven days after their second vaccine, the participants self-reported any side effects they had experienced.

Of the 110 participants who received the Oxford-AstraZeneca vaccine followed by the Pfizer-BioNTech booster, 37 (34%) endured feverishness, defined as feeling hot but not necessarily measuring as having a fever on a thermometer.

This is compared with 11 of the 112 (10%) participants who had the Oxford-AstraZeneca jab twice.

Read more: Sore arm most common coronavirus jab side effect

Feverishness was reported by 47 of the 114 (41%) participants who had the Pfizer-BioNTech vaccine followed by the Oxford-AstraZeneca jab, compared to 24 of the 112 (21%) who received two Pfizer-BioNTech vaccines.

"Similar increases were observed for chills, fatigue, headache, joint pain, malaise and muscle ache," wrote the scientists.

All the side effects generally occurred within 48 hours of being vaccinated.

The participants were told paracetamol may ease their side effects, but "were not actively counselled to medicate".

Among those who had the Oxford-AstraZeneca vaccine twice, more than a third (36%) took the over-the-counter painkiller within 48 hours of having their second dose.

This is compared to more than half (57%) who had the Oxford-AstraZeneca jab followed by a Pfizer-BioNTech booster.

Just over two in five (41%) who had two Pfizer-BioNTech vaccines took paracetamol within 48 hours of their second jab, compared to three in five (60%) who had the Pfizer-BioNTech jab followed by the Oxford-AstraZeneca booster.

When it comes to blood clot concerns, no cases had been reported in any of the participants at day seven after their second vaccine.

Thrombocytopenia is the unusual form of blood clot being linked to the Oxford-AstraZeneca jab. It is defined as clots with low platelets, the cells that promote clotting following a bleed.

Watch: What is long COVID?

Speaking of the overall results, lead author Professor Matthew Snape – from the University of Oxford – said: "It's a really intriguing finding. It's not necessarily something we were expecting."

Although it is unclear why the higher incidence of mild side effects is occurring, mixing the vaccines may better stimulate the innate immune response.

Innate immunity refers to the non-specific defence mechanisms that are triggered within hours of an infection taking hold, like inflammation. 

The adaptive immune response is more specific, releasing infection-fighting antibodies, T cells and B cells.

The scientists have stressed that more side effects does not necessarily mean an individual is better protected against the coronavirus.

The team has also warned the reported adverse events may be more common in younger people, who tend to have a more robust immune response.

A "more complete safety dataset" will be reported "shortly". The immune outcomes of mixing and matching the vaccines are expected to be released in June.

In the meantime, the scientists have concluded the approach could have "some short-term disadvantages".

"You wouldn't want to immunise a ward of nurses with mixed schedules because you may have [a higher rate of] absentees the next day," said Prof Snape.

The scientists are investigating whether the mixed approach is linked to more time off work or an individual seeking medical care.

They are also looking into whether routinely recommending paracetamol post-jab helps to ward off an increase in side effects.

"Regardless, it is reassuring all symptoms were short lived," wrote the scientists.

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