Mixing COVID-19 vaccine doses leads to more reactions, study finds, which may be 'first sign of success'

Mixing different types of COVID-19 vaccines for two doses can hike the chance of someone having mild or moderate reactions like fatigue, headache or a fever, according to early results from a U.K. study, which is being watched closely by health officials in Canada and beyond.

The findings were published Wednesday as correspondence, not as a full study, in The Lancet — a peer-reviewed medical journal — and came from the Oxford Vaccine Group's Com-Cov vaccine trial, which is studying the use of different combinations of approved COVID-19 vaccines for first and second doses.

More than 800 participants, all aged 50 or older, were recruited in February, divided up, and given one of four dosing schedules at an either four- or 12-week interval:

• First and second dose of AstraZeneca-Oxford vaccine.

• First and second dose of Pfizer-BioNTech vaccine.

• First dose of AstraZeneca-Oxford vaccine, second dose of Pfizer-BioNTech vaccine.

• First dose of Pfizer-BioNTech vaccine, second dose of AstraZeneca-Oxford vaccine.

"Both of the mixed schedules caused more symptoms than the standard schedules," said study leader Dr. Matthew Snape, an associate professor in general pediatrics and vaccinology at the University of Oxford, during a media briefing on Wednesday before the publication of those early results.

"Most of these effects are mild," he said, though the findings did also show an increase in moderate reactions.

A feeling of feverishness, for instance, was reported by 34 per cent of those given a combination of AstraZeneca-Oxford first, then Pfizer-BioNTech as a booster — more than triple the 10 per cent of people who reported that reaction after getting two AstraZeneca shots.

Feverishness was also reported by a little over 40 per cent of those given Pfizer and AstraZeneca doses, nearly double the 21 per cent who had two rounds of Pfizer shots.

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

It also said it was "reassuring" the vaccine-induced symptoms were short-lived and that the limited data sparked no concerns.

Impact on immune response not yet known

The participant-blinded, randomized trial has been taking place at a network of trial sites across the U.K., with more findings to come. This first round only shows the impact on post-vaccination reactions — not the overall safety or effectiveness of each mix-and-match approach.

"Whether or not this will relate to actually an improved immune response, we don't know yet," Snape said. "We'll be finding out those results in a few weeks' time."

Snape also said this early research should encourage any regions considering a mixed dosage schedule to prepare for the impact on staffing levels at key sites like hospitals, since more post-vaccine reactions could mean more workers needing time off.

"You wouldn't want to immunize a ward full of nurses on the same day with a mixed schedule, because they may have high rates of absenteeism the next day," he said.

Further studies, including those incorporating vaccines manufactured by Moderna and Novavax, are ongoing, the Lancet correspondence noted.

McMaster University associate professor and infectious disease specialist Dr. Zain Chagla — who was not involved in the research — said long-term efficacy data from the trial will be crucial to determine how many COVID-19 cases could actually be prevented by a mixed dosing approach.

Even so, he said the results bode well for this being a viable strategy in Canada, and likened the aggressive reactions reported by those given two different doses to what's been observed when people who previously had COVID-19 are later vaccinated.

"This is probably the first sign of success," he said. "We know what we're aiming for here is a fairly profound immune response."

Small sample size

However, Horacio Bach, an infectious diseases expert at the University of British Columbia, warned the small size of the initial study does not make it possible to know whether some people would get severe reactions from mixing the two studied vaccines.

AstraZeneca-Oxford, for example, was tested during clinical trials in about 32,000 people, but rare blood clots were not detected until millions of people received the vaccine.

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That shot, which uses adenoviral vector technology, has been linked to a rare, but potentially severe, blood clotting condition known as vaccine-induced immune thrombotic thrombocytopenia (VITT). Shots based on mRNA technology — the vaccines approved from Pfizer-BioNTech and Moderna — have not been tied to VITT.

Canada's National Advisory Committee on Immunization (NACI) has suggested the AstraZeneca-Oxford vaccine should be sidelined in favour of the "preferred" mRNA options.

Bach also noted it's possible that knowing about an increase in adverse reactions from mixing vaccines could deter some people from getting a second dose, though symptoms following vaccination from even the seasonal flu shot do vary widely.

Canada exploring mixing doses

The early findings have emerged at a pivotal time in Canada's vaccine rollout, when health officials are now reviewing the emerging research on mixing various COVID-19 shots as multiple provinces are gearing up to start swapping in different brands for second doses.

On Wednesday, Saskatchewan's chief medical health officer said it's "likely" those who received AstraZeneca-Oxford as their first dose of COVID-19 vaccine could have Pfizer-BioNTech for their second due to supply issues, while Manitoba's medical officer of health noted that province is also exploring the prospect of using mRNA vaccines for second doses as well.

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The same day, Ontario's Health Minister Christine Elliott said the province is awaiting guidance from health regulators before deciding what to do with AstraZeneca-Oxford supplies after its use as a first dose was recently paused over blood clot concerns.

Ontario officials are also hoping to explore whether two different COVID-19 vaccines can be mixed.

Currently, all of the shots being used in Canada and the U.K. follow the same two-dose schedule, with a first dose followed by a booster dose later — with the exception of the one-dose Johnson & Johnson shot, which has been approved for use in Canada but has not yet been administered.