As some experts continue to warn of very rare side effects associated with the AstraZeneca vaccine, Canadian health officials are now reviewing the research on mixing various COVID-19 shots.
A study of a "mismatched" vaccine regimen is underway in the U.K. — but some scientists say there's reason to believe that administering two doses of different products could boost a person's immune response beyond what can be achieved by giving the same shot twice.
The National Advisory Committee on Immunization (NACI) caused some confusion earlier this month when it said the viral vector shot from AstraZeneca is not the "preferred" product given its associated risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) — a condition that causes blood clots. That warning came out after hundreds of thousands of Canadians had received the AstraZeneca vaccine already.
According to the Ontario Science Table, estimates of the frequency of VITT in individuals who have received the AstraZeneca vaccine now range from 1 case in 26,000 to 1 case in 127,000 doses administered.
The risk of developing this side effect, combined with an uncertain delivery schedule for future supply, has prompted some provinces to consider pausing AstraZeneca vaccinations altogether.
Dr. Brent Roussin, Manitoba's chief provincial public health officer, said Sunday a temporary suspension "has been discussed at many levels, and certainly discussed at our provincial program right now."
Christine Elliott, Ontario's health minister, said Monday that recipients of the AstraZeneca vaccine may receive a different shot for their second dose.
While the AstraZeneca product has been deemed safe and effective repeatedly by Health Canada regulators, some people who already have received that vaccine are now looking at their options.
What does the research say about mixing vaccines?
Researchers at Oxford University in the U.K. launched a study in early February to explore the possible benefits of alternating different COVID-19 vaccines. According to the lead scientists, the study is "looking for clues as to how to increase the breadth of protection against new virus strains."
The study — otherwise known as the COVID-19 Heterologous Prime Boost study, or "Com-COV" — is collecting data to determine whether receiving two different types of vaccine generates an immune response at least equal to the response that follows receiving the same product twice. (A "heterologous" vaccination regimen is one that uses more than one product.)
Some early results may be available soon; the study team told CBC News it's "anticipating sharing data in the next week or so."
All of the shots currently in use in Canada and the U.K. follow the same two-dose schedule, with a "prime" dose followed by a second "boost" dose some weeks later. (The one-dose Johnson & Johnson shot has been approved for use in Canada but it has not yet been administered.)
The Oxford researchers are evaluating the effects of vaccine combinations — comparing the results of a first dose of the AstraZeneca vaccine followed by either the Pfizer vaccine or a second AstraZeneca dose, or a first dose of the Pfizer vaccine followed by either the AstraZeneca or a second dose of the Pfizer.
A second study, called Com-COV 2, includes the products from Moderna and Novavax as booster vaccines.
Jonathan Van-Tam is the deputy chief medical officer for England and one of the senior officials responsible for this study. He said this research will "give us greater insight into how we can use vaccines to stay on top of this nasty disease."
"It is possible that by combining vaccines, the immune response could be enhanced, giving even higher antibody levels that last longer," he said in a statement. "Unless this is evaluated in a clinical trial, we just won't know."
Dr. Helen Fletcher is a professor of immunology at the London School of Hygiene and Tropical Medicine in the U.K. She said a "mismatched" vaccine program would deliver some practical benefits — vaccine delivery logistics would be greatly simplified — but there could be another good reason to pursue a mixed-dose regimen.
The prospect of a 'stronger immune response'
"I'm excited about the study because I think it's likely that the immune response will be even better if you mix and match vaccines," Fletcher said in an interview with CBC News.
"Mixing vaccines could give you a stronger immune response, or it could give a broader type of immune response — generating a wider range of antibodies, or T cells as well as antibodies. It's also possible that a mix and match regimen could strengthen our immune response against virus variants because of this stronger or broader immunity."
Vaccines teach the immune system — which includes both antibodies and T-cells — to recognize part of a virus. A T cell is a type of white blood cell that responds to viral infections and boosts the immune function of other cells.
A single dose of either the AstraZeneca or Pfizer shots has been found to generate a significant antibody response to the novel coronavirus. But a recent study by the U.K. Coronavirus Immunology Consortium and the University of Birmingham found that the AstraZeneca vaccine may actually induce a stronger cellular immune response than the Pfizer shot.
So a combination of the two shots "could lead to a higher quantity of antibody, but it can also broaden the immune response," Fletcher said.
Is there any history of mixing different vaccines like this?
Yes. Fletcher said people have been combining vaccine types for several decades in an effort to boost immune responses to malaria, tuberculosis, HIV and cancers.
A mixed vaccine regimen was approved for Ebola last year.
"When we give immunizations to infants, we use several different types of vaccine over a period of months and years with no safety concerns," Fletcher said.
Are there any risks associated with a mismatched regimen?
Fletcher said there have been no reports of any side effects beyond the ones already reported when the vaccines are administered individually.
"The Com-COV study will, of course, be looking very closely at safety and it's great that this is being carefully monitored as part of a clinical trial, but I would not anticipate any safety problem with mixing vaccines," she said.
Different vaccines administered as part of a two-dose regime do not directly interact with each other, as the vaccine particles are swiftly cleared by the immune system within days of immunization, Fletcher said.
"There's no remaining vaccine mRNA or vaccine viral vector around when you give a second dose," she said.
Jorg Fritz, a microbiology and immunology professor at McGill University, said he doesn't see why there would be any additional danger involved in receiving two different vaccines.
Fritz said he also thinks it would be better to mix two vaccines that use different technologies than to wait too long to give the second shot.
"I think it's more important to get a booster vaccination to have a more robust and more durable immune response against the viral proteins than using the same technology," Fritz told the Canadian Press.
What have Canadian officials said about this?
Dr. Theresa Tam, Canada's chief public health officer, said last week the current guidance is for AstraZeneca recipients to get a second dose of the same product, but NACI is now reviewing the Oxford research on mixing AstraZeneca with an mRNA shot.
"There will be further advice forthcoming on that second dose based on the evolving science. We should watch this space," Tam said.
"All of the vaccines being used in Canada are targeting the virus' spike protein, so I think the science will look not just at whether the mixed schedule is safe, but whether that's actually an even better approach than using exactly the same vaccine for the two doses. Those questions remain to be answered."
Would we have enough mRNA doses for a mix-and-match program?
Probably. According to Health Canada, at least 1,540,000 AstraZeneca doses have been administered in Canada as of May 1. Thousands of Canadians have been vaccinated since then.
With delivery of millions more mRNA shots expected over the coming months — Pfizer alone will deliver 2 million shots each week in May before ramping up to 2.4 million a week next month — there should be enough shots on hand to vaccinate AstraZeneca recipients with a second dose of a second product.
But provinces may have to hold back some Pfizer supply to make this work.
Canada has ordered 48 million Pfizer doses — 5.5 million were delivered in the January-through-March period, 24.2 million will arrive in the second quarter of this year and 18.3 million more are to follow between July and September.
That's enough shots to vaccinate 24 million people with two doses. If some of that product is earmarked for people who already have doses of AstraZeneca, that leaves less product for first doses.
Moderna is also expected to deliver 12.3 million doses of its mRNA product in the April-through-June period, with millions more doses expected in the third quarter of this year.
Maj. Gen. Dany Fortin, the military commander leading vaccine logistics at the Public Health Agency of Canada, said last Thursday that officials are "only starting to do deliberate planning on second doses."
"What I would tell you is provinces and territories have a good handle on what they need. They keep tabs on who is getting which vaccine," he said. "Everybody is working on a very deliberate plan making sure people get the right vaccine when they're supposed to receive it."
Will Canada shorten the time between shots?
Possibly. NACI said in early March that, given the limited vaccine supply, provinces and territories may want to wait up to 16 weeks between first and second doses to give more people at least some level of protection.
The provinces have since followed this guidance, with a few exceptions. For example, many long-term care home residents have been fully vaccinated on the timeline recommended by the vaccine makers. Pfizer calls for a second dose 21 days after the first, while Moderna stipulates the second shot should come 28 days later.
Ontario announced Monday that it would begin offering second doses to some high-risk groups this week.
"As more vaccines come in, that interval can be shorter," Tam said.