Importance of second dose of COVID-19 vaccine remains constant despite changing recommendations

Retrieving one dose out of a vaccine vial

One of the most challenging aspects of the COVID-19 vaccine rollout has been the controversy and confusion over the timing and type of vaccine required for second doses. Compounding the situation has been the emergence of COVID-19 variants that respond differently to different vaccines.

The science is clear on the requirement for two doses of vaccine for the three products currently being used in Canada in order to provide maximum efficacy. However, changing government policies based on evolving science has left the public uncertain about the best course of action. This in turn has led to some people postponing their second dose or vaccine shopping to find the vaccine of their choice.

This blog has been created to summarize the information to date and to resolve any current confusion.

How the Vaccines Work

With the Pfizer-BioNTech and Moderna mRNA vaccines, the vaccine contains the genetic instructions for making the SARS-CoV-2 spike (S) protein, found on the surface of the SARS-CoV-2. The vaccines encode for the pre-fusion stabilized Spike protein of SARS-CoV-2 and after intramuscular injection, cells take up the lipid nanoparticle, effectively delivering the mRNA sequence into cells for expression of the SARS-CoV-2 S antigen. The vaccine induces both neutralizing antibody and cellular immune responses to the spike (S) antigen. The first dose of vaccine primes the immune system and allows it to generate a small immune response prior to the second dose which provides more immunity.

The AstraZeneca vaccine is a viral vector-based vaccine which uses replication-deficient chimpanzee adenovirus as a delivery system. The vector virus produces the SARS-CoV-2 spike protein found on the surface of the SARS-CoV-2 virus. Following administration, the S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralizing antibody and cellular immune responses. As with the mRNA vaccines, two doses of the AstraZeneca vaccine has been shown to produce a much stronger immune response than one dose alone.

Initial clinical data showed even one dose of the three vaccines provided a significant degree of protection against hospitalization or death due to COVID-19, but that two doses provided stronger protection against the virus.

Frequently cited analyses include:

  • Real world data from Public Health England showing two doses of Astra Zeneca were 66% effective in preventing mild, moderate, or severe COVID-19 infection whereas two doses of the Moderna or Pfizer vaccines were 93% effective.
  • Data from the U.S. Centers of Disease Control (CDC) showing people who received one dose of either Pfizer or Moderna were 64% less likely to be hospitalized than people who were unvaccinated. Those who received both doses were 94% less likely than unvaccinated people to need hospitalization.
  • A UK study of 150,000 people over age 70 showing one dose of AstraZeneca or Pfizer vaccine was 80% effective in preventing hospitalization.

(The Johnson and Johnson vaccine has also been approved for use in Canada as a single injection, but this vaccine has not been distributed due to quality control issues with the original shipment).

is a 2-dose vaccine schedule new?

The requirement for multiple doses to complete a vaccine schedule was not uncommon before the COVID19 vaccines. The measle/mumps/rubella (MMR) vaccine and vaccines against hepatitis and shingles are examples of vaccines that require multiple doses to obtain maximum benefit.

When is the right time for the 2nd dose?

According to the product monographs submitted to Health Canada by the companies producing the vaccines, the original intended scheduling for the vaccines were as follows:

  • The Pfizer-BioNTech COVID-19 vaccine is administered intramuscularly after dilution as a series of two doses (0.3 mL each) 21 days apart. It may take until 7 days after the second dose of Pfizer-BioNTech COVID-19 vaccine to develop protection against COVID-19.
  • The Moderna COVID-19 vaccine is a two-dose regimen. The second dose should be administered 4 weeks after the first dose.
  • The AstraZeneca COVID-19 vaccination course consists of two separate doses of 0.5 mL each. The second dose should be administered between 4 and 12 weeks after the first dose.

(The Janssen Johnson and Johnson vaccine has also been approved for use in Canada has a single injection, but this vaccine has not been distributed due to production issues with the original shipment)

However, due to issues with vaccine supply early in 2021, the decision was made to extend the time between the two doses of vaccine to 12 weeks. In March, the National Advisory Committee on Immunization (NACI) recommended delaying second doses by up to four months for all Canadians. At the time, this was the longest recommended interval between vaccine doses made by any country in the world. This followed an earlier recommendation in January to extend the interval for the mRNA vaccines to six weeks.

The committee stated it was making this recommendation in the context of a limited supply of COVID-19 vaccines in order “maximize the number of individuals benefiting from the first dose of vaccine.”  The advisory body noted that while at the time the recommendation was made “studies have not yet collected four months of data on vaccine effectiveness after the first dose, the first two months of real-world effectiveness are showing sustained high levels of protection.”

The recommendation was controversial but was eventually adopted by all Canadian provinces during the initial phase of the vaccine rollout to the general population. It was not until the end of May 2021 that NACI changed its recommendation to urge everyone to receive their second doses of vaccine as soon as possible. This was in response to growing vaccine supply in Canada.

In the period between March and June 2021, discussions in Canada also focused on the AstraZeneca vaccine due to reports of Vaccine Induced Thrombotic Thrombocytopenia (VITT) associated with the vaccine. The risk of developing VITT is extremely low and in Canada was estimated to be 1 in 55,000 after the first dose of the AstraZeneca vaccine. UK data showed the risk of developing VITT after the second dose was 1 in 600,000. This initially led to use of the vaccine being restricted, limited to use for first doses only or being halted altogether in some countries and some Canadian jurisdictions. It also resulted in those who had received Astra Zeneca as their first vaccine dose wondering what they should do about the second dose especially after NACI recommended they receive either the Pfizer or Moderna vaccines as their second dose.

More recent recommendations issued by NACI call in mid-June call for mRNA vaccines to be given as both first and second doses and that the AstraZeneca vaccine only be used if these vaccines are unavailable or contraindicated due to a potential allergic reaction.

An article and decision-guide published by a group of Canadian clinicians, scientists and patients provided a comprehensive overview of the situation in mid-June. Among the main conclusions of this group was that real world evidence to date shows there is no greater risk from having a second vaccine dose that is different from the first dose received and potentially improved benefits. The group also noted: “The important thing to remember is that a second dose with AstraZeneca, Pfizer or Moderna is better than no second dose at all.”

What about the Delta Variant?

The spread and growing predominance of the Delta variant of COVID-19 is the latest development to raise to questions about the appropriate approach to vaccination and reinforce the importance of being fully vaccinated. A pre-print article from the UK suggests one dose of AstraZeneca is 33% effective against symptomatic infection from the Delta variant and two doses are 60% effective. The same study showed the same efficacy from one dose of the Pfizer vaccine but 88% effectiveness after two doses. An analysis from Public Health England showed two doses of either the AstraZeneca and Pfizer vaccines were highly effective (92% and 96% respectively) in preventing hospitalizations as a result of the Delta variant.

Experience with COVID-19 to date suggests Canadian policies and recommendations about doses will continue to evolve. However there is strong evidence that everyone should get two doses of available vaccines as soon as they are available to have the best possible protection and help return us to a normal life. It is also important that everyone continue to follow public health recommendations to prevent further spread of COVID-19.

About the authors

Alan Kaplan is a Family Physician working in York Region, Ontario, Canada and the Chairperson of the Family Physician Airways Group of Canada (www.fpagc.com), the Past-Chairperson of the Respiratory Section of the College of Family Physicians of Canada, and Senate member of the International Primary Care Respiratory Group. He co-chaired the Community Standards of COPD program for Health Quality Ontario. In addition, Dr. Kaplan provides his expertise to a number of medical journals across the world.

Dr. Alan Kaplan

MD, CCFP(EM), FCFP

Dr. Mohit Bhutani is currently a Professor of Medicine in the Faculty of Medicine & Dentistry at the University of Alberta. He is the director of the Asthma and COPD clinics and a member of the executive of the Alberta Research Center. He has been involved with the Alberta Health Services Respiratory Health Strategic Clinical Network since 2011 and, was co-chair of the Airways Working Group of the Respiratory Health Strategic Clinical Network (RHSCN) from 2014-2020. Nationally, he chairs the Royal College of Physicians and Surgeons of Canada Adult Respiratory Examination Board and is the past chair of the Canadian Thoracic Society COPD Clinical Assembly. He is a member of the CTS Executive Committee.

Dr. Mohit Bhutani

MD, FRCPC, FCCP

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