Maria Sundaram, PhD, an epidemiologist and postdoctoral fellow at the University of Torontos Dalla Lana School of Public Health, watched from afar in March and April as many of her friends and family in the United States received their first and second doses of a COVID-19 vaccine.

It was a very interesting mix of emotions, says Sundaram, who grew up in the United States. Many of us have experienced vaccine envy, watching other people get a vaccine before us, [but there was] simultaneous relief that my friends were getting protected.

Meanwhile, in Canada, vaccine supply remained scarce. Despite purchasing more than five times the number of vaccine doses needed to cover its entire population, the Canadian government experienced challenges obtaining the vaccines from the European countries that were manufacturing them. As a result, it lagged behind other wealthy countries on vaccination rates for months until the supply began to increase in May.

Finally, in mid-May, Sundaram who works for a hospital but does her research from home was able to get a dose of the Pfizer COVID-19 vaccine and was given an appointment for her second dose in September.

The four-month gap between doses more than three months longer than the 21 days that the company recommends based on clinical trial data was a result of the Canadian governments decision to focus on giving first doses to as many people as possible before administering second doses (except to those in the highest risk groups, such as people living in long-term care facilities). The delayed second dose strategy followed that of the United Kingdom, which faced a surge caused by the alpha variant in the early months of 2021 but broke from the United States strategy of sticking to the dosing regimen tested in clinical trials.

Theres been a bit of luck involved in the approach that Canada has used.

Eric Arts, PhDProfessor and Canada research chair in viral control at Western University in London, Ontario

The decision was controversial. At one point, even Canadas chief scientific advisor, Mona Nemer, PhD, called it a population level experiment when speaking with CBC News.

Still, faced with a COVID-19 surge in March and April that strained hospitals and a lack of vaccine supply, Canada took a risk.

They had to come up with strategies that would provide some protection, says Alon Vaisman, MD, an infectious disease physician at University Health Network at the University of Toronto. The thinking was, Can I protect both of us at 80% [efficacy] versus me at [almost] 100% [efficacy] and you at 0%? That was the philosophy.

Now, as Canadas vaccination rate has skyrocketed in recent weeks covering nearly 70% of the population with at least one dose, passing the United States 55% and most other nations and its cases and hospitalizations have tapered, it seems that the risk is paying off.

Theres been a bit of luck involved in the approach that Canada has used, says Eric Arts, PhD, a professor and Canada research chair in viral control at Western University in London, Ontario. It was an approach that was quite successful.

Many scientists, including top U.S. infectious disease expert Anthony Fauci, MD, have said that the best vaccination strategy is to adhere as closely as possible to the dosing regimen tested in the clinical trials: two doses of the Pfizer vaccine spaced 21 days apart or two doses of the Moderna vaccine spaced 28 days apart.

We feel strongly that we will go by the science, which has dictated for us the optimal way to get the 94 to 95 percent response, which is, in fact, durable for the period of time that weve been following it, Fauci explained at a White House press briefing on Feb. 3.

ICUs were full, people were being helicoptered out. It [was] extremely important to use every tool in our tool box.

Maria Sundaram, PhDEpidemiologist and postdoctoral fellow at the University of Torontos Dalla Lana School of Public Health

But the United States, which contracted with manufacturing plants on its soil, had access to far more doses more quickly than Canada. Although vaccines in the United States were initially limited and reserved for people in higher risk categories such as front-line workers and older adults, there was enough supply to make all adults in the country eligible for a shot by mid-April.

At that time, Canada was at the peak of a third wave of cases that was threatening to overwhelm its hospitals in some regions.

In Toronto, we had a very serious situation, Sundaram recalls. ICUs were full, people were being helicoptered out. It [was] extremely important to use every tool in our tool box.

Anticipating this, Canadas National Advisory Committee on Immunization recommended extending the time between first and second doses to four months on March 3 even longer than the three months that the United Kingdom had implemented.

The data supporting that was pretty much nonexistent, Vaisman says. There was a small gamble taken on what the efficacy was going to be like.

The decision was ethically complicated, according to Jonathan Kimmelman, PhD, director of the Biomedical Ethics Unit at McGill University in Montreal.

One of the variables that was not nailed down [in clinical trials] was how long you should wait between the first and second dose to maximize the effect, he explains. There was incredible pressure to get the vaccine out.

In a perfect world, Kimmelman says, the clinical trials would have tested spacing out the vaccine doses at different intervals to see which one was most effective. Instead, researchers focused on testing the shortest effective interval.

Still, all clinical trials have limitations.

This is no different for public health than it is for medicine, he explains. When you run a clinical trial of a drug, its rare that [doctors prescribe] that drug under the exact conditions of the trial.

In fact, some scientists said that further spacing out the doses would likely increase the effectiveness of the vaccines.

The government didnt work independently; they consulted a lot with the scientists and vaccinologists, says Arts. A lot of my colleagues felt that the rapid immunization between first and second doses was not necessary. You want to boost a secondary response with a vaccine. If you immunize too quickly from first dose, your primary response hasnt come down yet [and its] not always very efficient.

And as more data have emerged from the delayed dosing, it seems that spacing out the doses can result in a stronger immune response. One study in the United Kingdom released in May found that people over the age of 80 who received two doses of the Pfizer vaccine 12 weeks apart had three times more antibodies than those who received the doses three weeks apart. Another U.K. study at the University of Oxford found that further spacing between doses of the AstraZeneca vaccine also increased antibody production.

Canada also took a different approach than the United States by advising people that they could mix and match their vaccines: People who had received an AstraZeneca COVID-19 vaccine for the first dose could choose either the Pfizer or Moderna mRNA vaccine for the second dose, and those who received a first dose of one mRNA brand could get the other for the second dose. This change came about as a result of some controversy surrounding the safety of the AstraZeneca vaccine in some populations earlier this year as well as shortages of the Pfizer vaccine for some time.

[Mix-and-matching] provided a lot of flexibility. It ensured vaccines werent staying in freezers where they dont offer protections.

Craig Jenne, PhDAssociate professor in the Department of Microbiology, Immunology, and Infectious Diseases at the University of Calgary in Alberta

The shift allowed Sundaram to get her second vaccine dose months ahead of her scheduled appointment by switching to Moderna. Because of her knowledge of how other vaccines have been mixed in a similar way in the past and her understanding of how vaccines work, she was confident the two mRNA vaccines were essentially interchangeable.

Historically, we havent been watching the developing of vaccines, she explains. We havent asked, Hey, what brand is this flu shot?

Another University of Oxford study found that mixing a dose of the AstraZeneca vaccine with a dose of the Pfizer vaccine elicited a strong immune response, although there have been few real-world studies about the efficacy of mixing the two types of vaccine.

[Mix-and-matching] provided a lot of flexibility, says Craig Jenne, PhD, an associate professor in the Department of Microbiology, Immunology, and Infectious Diseases at the University of Calgary in Alberta. It ensured vaccines werent staying in freezers where they dont offer protections.

While the single doses of COVID-19 vaccine have helped protect Canadas population so far, the focus is now pivoting to ramping up second doses even, in many cases, cutting short the four-month delay.

This change is being made to stay ahead of the highly transmissible delta variant, which was first identified in India and quickly became dominant in the United Kingdom and the United States. Laboratory studies are finding that single doses of the Pfizer, Moderna, and AstraZeneca vaccines are providing far less protection against this variant. One study in England suggested that one dose of the AstraZeneca or Pfizer vaccine could provide as little as 33% effectiveness against symptomatic disease from the delta variant, compared with 50% against the alpha variant. However, two doses remained 60% and 88% effective, respectively.

One of the most challenging things about infectious disease pandemics is that the last inches are exactly as hard as the first hundred miles. Were not safe until all of us are safe.

Maria Sundaram, PhDEpidemiologist and postdoctoral fellow at the University of Torontos Dalla Lana School of Public Health

As of July 9, Canada was quickly gaining on the United States fully vaccinated rate of 47% of the population, which has now slowed to a crawl. On June 1, less than 6% of Canadas population was fully vaccinated, but on July 8, it had reached 40%, according to Our World in Data.

Arts compared the United States and Canadas vaccine strategies to the fable about the tortoise and the hare, saying that although the United States had a quick start like the hare, Canadas slower approach seems to be poised to win the proverbial race because of less vaccine hesitancy.

If everyone who got the first dose gets their second, well be OK, Vaisman says.

But successfully ending the pandemic cannot be done by individual countries, Sundaram cautions. As long as the virus is allowed to spread in unvaccinated communities, it has the opportunity to mutate and potentially evade vaccine protection.

Canada ordered a lot of vaccines, and that came at a cost to a lot of other countries, she says. One of the most challenging things about infectious disease pandemics is that the last inches are exactly as hard as the first hundred miles. Were not safe until all of us are safe.

Read more:
Canada took a risk delaying second COVID-19 vaccine doses. Now, its vaccination campaign is one of the best in the world - AAMC