While the typical approach for COVID-19 vaccinations is using the same brand for each dose, given at specific intervals, Canada has been exploring mixing doses on top of delaying second shots up to four months — two big bets that could pay off. Before vaccine shipments started ramping up, Canada's National Advisory Committee on Immunization (NACI) issued a bold recommendation to delay second doses well beyond manufacturing guidelines to a maximum of four months. The move sparked criticism that Canada was engaged in a "population level experiment," with concerns ranging from a lack of data, to a growing body of research suggesting it's not the safest approach for immunocompromised and older adults. Layered on that controversial move are more recent shifts toward mixing doses — including offering up an mRNA-based option, from Pfizer-BioNTech or Moderna, to some Canadians who have already gotten a first shot of AstraZeneca-Oxford. According to multiple vaccine experts, these moves may seem unorthodox on the surface, but are rooted in decades of science, backed up by emerging research, and could be preventing COVID-19 deaths at a time when Canada has been struggling to bring in enough vaccines from abroad. "I think having the single dose strategy, which was put forth by our Canadian public health agencies, has really saved a lot of lives and has been really instrumental and will be important for us getting back to a more normal life," said Alyson Kelvin, a vaccinologist with VIDO-InterVac, a vaccine development company in Saskatoon. Mixing doses could also wind up being a useful approach in the months ahead, according to Dr. Christopher Labos, a Montreal-based cardiologist and epidemiologist. "Especially because we want people to get their second doses," he said. "And if supply issues continue to be a problem, we don't want to be pushing second doses back waiting for vaccine supply to come our way." Healthcare workers with Humber River Hospital administer doses of the Moderna COVID-19 vaccine at a temporary clinic for member’s of Toronto’s Spanish-speaking community at the Glen Long Community Centre on May 14, 2021.(Evan Mitsui/CBC) Delaying doses can lead to 'better' immune response When it comes to Canada's unique approach to delaying doses, vaccine experts stressed that while it strayed significantly from the shorter schedule of the clinical trials, it falls in line with the broader body of vaccine science. Typically giving a bit more time between a first vaccine dose and the second vaccine dose "really leads to a better overall immune response, and protection from whatever pathogen the vaccine was made against," noted Kelvin. The exact guidelines for various COVID-19 vaccines vary, but one thing is common: the manufacturers' dosing schedules specify tight timelines, including two shots just 28 days apart for Moderna, two shots 21 days apart for Pfizer, and two shots a minimum of four weeks apart and no longer than 12 weeks for AstraZeneca. While the manufacturers recommend sticking with the dosing intervals from clinical trials, those schedules were based on quickly developing safe and effective vaccines during a global health crisis, not to figure out the best-possible time frame between doses, Kelvin said. WATCH | Clinical trials focused on 'shortest path to results' for COVID-19 vaccines, explains vaccinologist: On Friday, news broke that a U.K. study showed the Pfizer vaccine generates antibody responses 3.5 times larger in older people when a second dose was delayed to 12 weeks after the first — offering an early hint that a delay may actually offer more protection. More research is still needed. Dr. Danuta Skowronski of the BC Centre for Disease Control, whose research helped guide Canada's decision to extend the interval between COVID-19 vaccine shots, told CBC News the findings weren't a "surprise"; they underscored scientists' understanding that a longer time frame between doses could be beneficial. The move is also helping Canada rapidly vaccinate more residents, with more than half of all eligible adults getting at least one dose so far. Still, Labos is hoping most Canadians do get their second doses sooner than NACI's four-month maximum timeframe to ensure they develop solid protection, particularly for vulnerable and older populations who could experience waning immunity. "Four months is probably the outside limit; I don't think anybody's going to suggest that we push it much beyond that," he said. "The sweet spot probably is somewhere between that three week to three month interval." A woman walks by a sign advertising for COVID-19 vaccines in Montreal on May 14. (CBC / Radio-Canada) Different vaccines for different doses not 'unprecedented' For Canadians already wary of a potential months-long delay between doses, the notion of mixing brands — again, an approach not studied in the initial clinical trials — might also raise questions. Even so, various provinces are already going that route, or exploring mixed dosing strategies for the future, given the varying levels of supply coming from different manufacturers and ongoing concern over rare-but-serious blood clot risks tied to the AstraZeneca vaccine. The condition, known as vaccine-induced immune thrombotic thrombocytopenia (VITT), has been reported 28 times across Canada out of more than 2.3 million AstraZeneca doses administered, according to federal public health data, including four deaths. Several experts stressed a mixing-doses approach could be helpful given Canada's situation, and isn't that unusual for other vaccines. "Certainly mixing and matching vaccine types is not unprecedented," noted Matthew Miller, an associate professor of infectious diseases and immunology at McMaster University in Hamilton, who is also affiliated with NACI but not speaking on the advisory body's behalf. "It's just that the nature of the situation here is that we're having to make these decisions based on evolving evidence in the context of an unprecedented public health emergency." WATCH | Dr. Tam discusses second doses, mixing vaccines: Annual flu shots, for instance, can come from a variety of sources, meaning people could be getting a different brand or form of vaccine technology each year. Same with the shingles vaccine, Miller said, which had one formulation in its first generation while a different formulation was used for a later, more effective dose. "Prior to this, nobody would actually ask, 'who made my vaccine,' you would just go for a flu vaccine," said Labos. "And nobody seemed to realize that there were multiple companies making different types of flu vaccines, and they were being used in different segments of the population — people were relatively oblivious to this entire issue." He also noted that preliminary results from a U.K. study suggest using different vaccines for different doses could even offer a "better immune response." The early findings, based on a trial using Pfizer and AstraZeneca vaccines, showed swapping in one of each for the two doses hiked the chance of someone having mild or moderate reactions like fatigue, headache or a fever. These reactions may bode well for immunity, though further research is needed before drawing any firm conclusions. Deaths, hospitalizations among older adults dropping In recent weeks, despite the questions over Canada's approaches, it's becoming clear that country-wide vaccination efforts are starting to bear fruit. COVID-19 cases, hospitalizations and deaths among the oldest Canadians recently began dropping at a faster rate than in younger adults who are less likely to be vaccinated yet, according to a CBC News analysis released in late April. That finding suggests this country is now moving along the same path as the U.S., the U.K. and Israel, where mass vaccination campaigns are further along and deaths are dropping dramatically. Overall, Kelvin said Canada's strategies may raise questions but they're nonetheless in line with a body of vaccine research that existed long before COVID-19. "I think it was definitely a valid concern that all of the evidence we had for COVID-19 vaccines were based on the phase three clinical trials," she said. "Of course, that didn't take into consideration what we understand about vaccines and vaccine immune responses."