The scientific case for delaying the second dose of the COVID-19 vaccine

Share on:

Original author: Fahad Razak, Gerald Evans & Arthur Slutsky

Published: March 17, 2021


The development of highly effective vaccines against COVID-19 within one year of the start of the pandemic is a towering scientific achievement. Three of the four vaccines currently approved in Canada use two-dose regimens. Randomized control trials studying the Pfizer-BioNTech and Moderna vaccines administered the second dose three to four weeks after the first dose, and for the AstraZeneca vaccine this interval was four two 12 weeks after first dose.

Under ideal conditions these vaccines would be administered using exactly the same protocol as the trials that tested them. In fact, regulatory agencies like Health Canada approve vaccines within the constraints of clinical trial evidence, with little to no consideration about vaccine availability. But Canada’s current reality is far from ideal, with substantially less vaccine available at present than hoped for, and new variants of concern rapidly spreading through our population.

To address this reality, the National Advisory Committee on Vaccination (NACI) has recommended that delays in the second dose of up to four months be considered. This recommendation has led to marked discord in the scientific community.

The major argument against delaying a second dose to four months is that this recommendation is not “evidence-based.” We know from clinical trials that a second dose of the Pfizer or Moderna vaccine, when given between three and four weeks after the first dose is about 95 per cent effective versus placebo; but we don’t know from the trials how effective it would be when given at four months.

Therefore, the argument goes, that the second dose should be given exactly as in the trials, i.e., follow the evidence.

We believe that this criticism of a delayed second vaccine dose strategy is overly narrow. A broader consideration of the totality of scientific evidence and real-world constraints supports a Canadian strategy of delaying the second dose. Rather than just a question of applying evidence, the problem we face is one of optimizing benefit.

First let’s be clear about what the trials tell us: The effectiveness of the first dose in the Pfizer and Moderna trials was about 85 per cent, even before the second dose was given. So, the thought experiment we need to consider is as follows: Does it makes sense to provide a second dose of vaccine to increase protection from 85 per cent to 95 per cent, while leaving an equal number of people with zero protection?

The question becomes, is it better to have one Canadian with 95 per cent protection and a second Canadian with zero protection, or is it better to have two Canadians, each with 85 per cent protection?

But the delay strategy is not without some risk. The most important assumption on which a delayed second dose strategy operates is the durability of immune response; this has not been shown in clinical trials against COVID-19. However, immunological evidence from numerous other vaccines suggests that longer intervals (up to many months) between vaccine doses often enhances the degree of protection derived.

There is also emerging real-world evidence demonstrating the durability of the immune response for the Pfizer and Moderna vaccines lasts for at least for two months. Though possible, it seems unlikely that this immunity would drop substantially between two and four months; it would have to drop by more than about 50 per cent to make this strategy less effective. But it’s important to note that these extrapolations may not apply to specific subgroups — for example, immunocompromised individuals or the elderly.

A final critical consideration is the urgency to protect as many Canadians as possible as new variants become ascendant. Already representing more than 50 per cent of all cases in Ontario, these variants are more infectious than the original strain and may be more lethal as well. A delayed second dose that would initially double the number of Canadians protected is an important strategy in response to this next variant-driven phase of the pandemic.

Canada will eventually receive enough vaccine to ensure our entire population has access to a second dose. But it will still be many months before enough of our population is immunized to reach the point where herd immunity will allow us to get back to normal life: Open schools, economic recovery and a meaningful reduction on health system burden. A delayed second dose strategy will accelerate us towards the outcome we all want, while protecting as many Canadians as possible along the way.

Fahad Razak is a general internist at St Michael’s Hospital. He is an assistant professor at the University of Toronto and a member of Ontario’s COVID-19 Science Advisory Table. Gerald Evans is an infectious disease specialist, director of infection prevention and control at Kingston Health Sciences Centre and professor at Queen’s University. Arthur Slutsky is a clinician-scientist at St. Michael’s Hospital and professor at the University of Toronto. Drs. Razak, Evans and Slutsky are members of Ontario’s COVID-19 Science Advisory Table.