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Mixing doses of the Pfizer and AstraZeneca COVID-19 vaccines produces a strong immune response, a major study has found, in a finding that should make it easier for governments to vaccinate more people faster. The results may also have some implications for how governments choose to roll out booster jabs to ensure people maintain immunity in years to come.

Receiving an initial dose of the Pfizer vaccine followed four weeks later by a dose of the AstraZeneca vaccine, or vice-versa, produced a higher level of antibodies against SARS-CoV-2, the virus the causes COVID-19, than simply administering two doses of the AstraZeneca vaccine with the same four-week time gap.

But the mixed dosing results were best, the researchers said, when the AstraZeneca vaccine was given first followed by the Pfizer vaccine. In that case, the antibody levels were about nine times higher than with two AstraZeneca doses.

Alternating the doses in that way, the scientists also found, produced an even better T-cell response—a key part of immunity in which specialized “killer cells” learn to recognize and attack pathogens—than giving two doses of the Pfizer vaccine.

Two doses of the Pfizer vaccine, however, produced a higher antibody response than with any of the mixed dosing schedules. As a result, the researchers said that two doses of the Pfizer vaccine were probably superior to mixing it with the AstraZeneca vaccine.

Booster considerations

Despite the findings, Matthew Snape, an associate professor of pediatrics and vaccinology at the University of Oxford, who headed the study, said he wouldn't recommend altering the approved dosing regimens, in which two doses of the same vaccine are given, unless adequate supplies of those vaccines were not available or a particular person had an allergic reaction to the first vaccine type they'd been given.

In such cases, he said, the study was critical for showing that "resilience and flexibility" could be achieved by mixing vaccine types between doses.

Snape said that, while the results could help scientists think about future booster doses, any decisions about which vaccines to use and when should be guided by real-world data on patients becoming infected and ill following initial vaccinations. He said the antibody and T-cell data from blood tests, such as those conducted in this research, was too limited—and too difficult to correlate with specific immune protection for different age groups—to use it as a basis for making decisions about booster shots.

Also, on June 28, a separate University of Oxford study found that a third dose of the AstraZeneca vaccine, given at least six months after the second dose, increased antibody levels six fold and maintained the same T-cell response compared to the second dose. The third dose also resulted in more antibodies able to neutralize the prevalent variant strains of the virus, including the Delta variant, officially known as B.1.617.2, which is now the predominant strain in the U.K. It was also effective against the Alpha, also called the Kent or U.K. variant, and the Beta, or South African, variant.

The mixed dosing study Snape lead, called Com-COV, was funded by the U.K. government. The results were published June 28 on a website run by the prestigious medical journal The Lancet, but are not yet peer-reviewed.

The T-cell finding may be important because it is known that the antibody response to SARS-CoV-2 fades over time, while scientists believe that T-cells retain the ability to respond to pathogens the body has encountered before for much longer periods. They may also offer critical protection against new variants of the virus causing severe disease, even in cases where new mutations render the antibodies less effective at preventing infection.

While the study results so far only looked at this mixed dosing with a four-week interval between jabs, the scientists are doing further research examining a 12-week interval. That’s because, when it first began immunizing people, the U.K. extended the recommended period between doses to between eight and 12 weeks, to stretch its limited vaccine supply so as to provide more people with first jabs.

“The results for the 12-week interval, which are yet to come, will have an instrumental role to play in decisions on the future of the UK’s vaccination program,” Jonathan Van-Tam, England’s deputy chief medical officer, said in a statement.

The separate Oxford study of the AstraZeneca vaccine found that delaying the second dose even up to 45 weeks after the first dose produced an antibody response that was four times greater than with the 12-week interval.

Van-Tam also said the U.K. currently had enough vaccine supplies to provide two doses of the same vaccine to all adults, so the results of the trial would not have an immediate impact on the country’s vaccination policy.

But this is not the case in other parts of the world, where the findings may help them cover more of their population with limited vaccine doses. "These types of studies are really important to inform the best use of the vaccines that we have available, especially in low and middle income countries," Snape said.

“Heterologous dosing”

The COM-CoV study had previously reported that mixing vaccine doses appeared to be safe, with no serious side effects, although the researchers did find that people were more likely to experience uncomfortable flu-like symptoms, such as fever, muscle aches and lethargy, when mixing vaccines. The scientists described these symptoms as “mild to moderate” and “short-lived,” lasting at most a few days.

The “heterologous dosing” study initially recruited 830 volunteers, all aged 50 and above, at eight different sites throughout England, and trialed four different combinations of the AstraZeneca and Pfizer vaccines. In April, the study was expanded to include the Moderna and Novavax vaccines as well, across nine different sites, with an additional 1,070 people recruited to take part.

In addition to the British government-funded study on heterologous dosing, AstraZeneca has been conducting its own study looking at the immune response when one dose of its vaccine is used in combination with a dose of the Russian-made Sputnik V vaccine.

The Pfizer vaccine, which the company jointly developed with the German firm BioNtech, and the AstraZeneca vaccine, which that company co-developed with scientists from the University of Oxford, both work by inducing the body's cells to produce the spike protein found on the surface of the coronavirus. Exposing the body to this spike protein, without the coronavirus itself being present, allows parts of the immune system to recognize a real coronavirus infection and have tools ready to fight it off.

But the AstraZeneca vaccine and the Pfizer vaccine use different technologies to deliver the instructions to the body to make the spike protein. Pfizer's vaccine, as well as Moderna's, use messenger RNA (mRNA), a set of instructions to make the protein that is directly absorbed into the body's cells. The AstraZeneca vaccine, meanwhile, uses a genetically-modified chimpanzee virus, called an adenovirus, to carry the instructions for the spike protein into the body's cells.

These two different technologies seem to produce slightly different immune responses, with studies showing higher antibody levels and immunity produced by the mRNA-based vaccines.