As more countries look to "mix and match" two Covid-19 vaccine doses from different manufacturers, new research in The Lancet finds that pairing the Pfizer/BioNTech and AstraZeneca vaccines appears to increase the likelihood of mild to moderate side effects—but that no serious adverse outcomes were reported.

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Why scientists are intrigued by 'mixing and matching' vaccines

The early results stem from the ongoing Com-COV study, which launched in February to assess whether providing patients with one dose each of two different, two-dose Covid-19 vaccines could provide longer-lasting immunity, improve protection against new variants, or simply enable providers to swap vaccines if supplies are interrupted.

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According to MIT Technology Review, several nations—including the United States—already permit vaccine mixing and matching in certain, limited circumstances. For instance, in the United States, mixing and matching the country's two currently authorized two-dose vaccines—Pfizer/BioNTech and Moderna—is permitted in "exceptional situations," The Hill reports. In France and Germany, meanwhile, officials permit the use of an mRNA vaccine—such as Pfizer/BioNTech or Moderna—to young adults whose first dose was the AstraZeneca vaccine, citing concerns about rare blood clots.

However, MIT Technology Review reports that such an approach could become more common if mixing and matching Covid-19 vaccines is proven to boost the overall level or duration of immunity—as tantalizing, early evidence suggests might be the case.

For instance, a trial in China found that combinations of four different Covid-19 vaccines, when administered to mice, appeared to improve immune response. Experts believe the finding could stem from how different vaccines present their virus-fighting information in slightly different ways, potentially activating different parts of the immune system.

Accordingly, several trials—in addition to the Com-COV study—have been launched to examine the question, MIT Technology Review reports, including a study in Spain assessing the viability of mixing a first dose of AstraZeneca's vaccine with a second dose from Pfizer/BioNTech, as well as a study between AstraZeneca and Russia's Gamaleya Institute examining how AstraZeneca's vaccine works in combination with Russia's Sputnik V vaccine.

Details on Com-COV study

For the Com-COV study, which launched in February, researchers from the University of Oxford recruited 830 volunteers over the age of 50 into four groups. Members of different groups received:

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• Two doses of the Pfizer/BioNTech vaccine;

• Two doses of the AstraZeneca vaccine;

• An initial dose of the Pfizer/BioNTech vaccine and a follow-up dose of the AstraZeneca vaccine; or

• An initial dose of the AstraZeneca vaccine and a follow-up dose of the Pfizer/BioNTech vaccine.

The study was expanded in April to include an additional 1,050 volunteers to test other combinations of Covid-19 vaccines, including those from Moderna and Novavax. Ultimately, the study will "prioritize combinations … most relevant to the U.K. schedule," Matthew Snape, chief investigator of the trial, said.

According to Politico, all arms of the trial will test both 28-day and 12-week dosing intervals. Snape noted that the study would not look at efficacy in preventing real-world Covid-19 cases—he said both vaccines have already been proven to work—but rather primarily at the immune system's response to the various combinations, namely antibody levels and T-cell presentation over the course of a year following vaccination.

The researchers will also look for safety concerns, and they will retain blood samples to test the various combinations against future variants of the coronavirus.

The researchers said they expect to publish their first full results in June, BBC reports. Those findings will including information on side-effects and immune response with a 12-week interval, as well as the use of prophylactic acetaminophen to reduce side effects.

Early findings from Com-COV

The latest results, published as a research letter, provide a preliminary snapshot of the side effects for people who received mixed-and-matched shots and how they compared with those experienced by people who received two doses of the same vaccine.

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The researchers found that study participants who received a combination of Pfizer/BioNTech and AstraZeneca vaccines were more likely to report side effects than those who received two doses of either vaccine, but all reported adverse reactions were short-lived, and there were no serious safety concerns or hospitalizations. 

Specifically, the researchers found that about 10% of people who received two AstraZeneca vaccine doses four weeks apart reported feverishness, compared with about:

• 20% of people who received two Pfizer vaccine doses;

• 34% of people who received an AstraZeneca vaccine dose followed by a Pfizer/BioNTech vaccine dose; and

• 40% of people who received a Pfizer/BioNTech vaccine dose followed by an AstraZeneca vaccine dose.

Similarly, the researcher found that about 50% of people who received two AstraZeneca vaccine doses reported fatigue after the second dose, compared with:

• A little more than 50% of those who received two Pfizer/BioNTech vaccine doses;

• A little more than 60% of those who received a Pfizer/BioNTech vaccine dose followed by an AstraZeneca vaccine dose; and

• Nearly 80% of those who received an AstraZeneca vaccine dose followed by a Pfizer/BioNTech vaccine dose.

And according to the researchers, a little more than 30% of people who received two AstraZeneca vaccine doses reported headache, compared with:

• About 40% of people who receive two Pfizer/BioNTech vaccine doses;

• A little over 60% of people who received an AstraZeneca vaccine dose followed by a Pfizer/BioNTech vaccine dose; and

• A little over 60% of people who receive a Pfizer/BioNTech vaccine dose followed by an AstraZeneca vaccine dose.

"The same real differences applied for other symptoms such as chills, … malaise and muscle ache," Snape said. "One things it's telling us is that you wouldn't want to vaccinate a ward full of nurses on same day (with mixed doses of different vaccines), because you might have more absenteeism the next day" (Lonas, The Hill, 5/13; Collis, Politico, 5/13; Reed, BBC, 5/13; Willyard, MIT Technology Review, 5/6; Collis, Politico, 2/4).