What happens if you mix COVID-19 vaccines, receiving a first dose of one jab and a second dose of a different inoculation? Scientists want to know.

Why? Because mixing doses might give governments more flexibility to stretch available vaccine supplies across populations, ensuring more people get vaccinated and doses won’t go to waste. There’s also speculation that, at least for some of the vaccines, receiving a second dose of a different vaccine might produce a stronger immune response.

Finally, if COVID-19 becomes endemic —as many experts think is likely— and people need frequent booster shots to retain immunity, then it is possible people will need to receive boosters of a different shot than they received initially.

The U.K. government is sponsoring one of the earliest and largest clinical trials of this kind of mixing, which experts call “heterologous dosing.” And the very first preliminary results from that study are in: People who received the Pfizer vaccine followed by the AstraZeneca jab or vice versa, were more likely to experience uncomfortable reactions to the second dose than people who received two doses of the same vaccine, researchers at the University of Oxford reported in a research note published in the peer-reviewed medical journal The Lancet.

These reactions included flu-like symptoms, such as fever, muscle aches, lethargy, and a general feeling of being unwell. The scientists said that none of these side effects were severe, describing them as “mild to moderate.” They also said the symptoms were short-lived, lasting at most a few days and that there had been no other safety concerns so far with mixing the Pfizer and AstraZeneca vaccines.

More frequent and pronounced reactions could lead to higher rates of absenteeism from work on the day after the second inoculation. This could be an important consideration, especially when governments were vaccinating healthcare workers, according to Matthew Snape, a University of Oxford professor of paediatrics and vaccinology who is leading the mixed dose clinical trial. The scientists also cautioned that the study only included people over the age of 50 and that it is possible that younger people might react differently.

Early days yet

Data on whether the mixed dosages produced a comparable or better immune response in those vaccinated is not yet available, the researchers said, adding that they “hope to report these data in the coming months.”

In the meantime, they said they had adapted the trials to study if offering volunteers the over-the-counter pain medication paracetamol (acetaminophen) reduced the side effects experienced with the second dose.

The British study is being carried out by the National Institute for Health Research. The initial study of the AstraZeneca and Pfizer vaccines involved more than 800 volunteers recruited across eight different sites in England. In April, scientists expanded the research to look at the Moderna and Novavax vaccines too, with a further 1,050 volunteers recruited. These volunteers would receive either the AstraZeneca or Pfizer vaccine first, followed either by the same vaccine for their second dose, or a dose of either the Moderna or Novavax jabs.

Separately, AstraZeneca is conducting a clinical trial to look at the effect of mixing doses of its vaccine with the Russian Sputnik V vaccine.

Scientists say this kind of mixing-and-matching is possible because most of the COVID-19 vaccines approved for use so far all elicit an immune response to the same part of the coronavirus: the spike protein.

Researchers are particularly interested in seeing if mixed dosing regimens confer a better immune response for the vaccines that use a modified adenovirus to deliver instructions to the body’s cells to produce the spike protein. The AstraZeneca vaccine, Johnson & Johnson vaccine, and the Sputnik V vaccine each use a different kind of adenovirus.

Scientists speculate that, after the initial injection of the adenovirus-based vaccines, a person’s body develops an immune response to the adenovirus as well as the coronavirus spike protein. This immune response is problematic because it may mean that when the person receives the second dose of an adenovirus-based vaccine, the immune system targets and disables the adenovirus before it can deliver the instructions to the body’s cells to make the coronavirus spike protein, making the second jab less effective, according to Stephen Griffin, an associate professor of medicine at the University of Leeds who is not affiliated with the clinical trial. By using a different adenovirus for the second dose or a different vaccine technology, it is hoped this can be avoided.

This same issue does not seem to affect vaccines, such as Pfizer’s and Moderna’s, that use messenger RNA (mRNA) to deliver instructions to the body’s cells to make the coronavirus spike protein. That mRNA is delivered encased in a tiny envelope of fat, called a lipid nanoparticle, that the body’s immune system does not seem to recognize as a foreign invader.