March 8, 2021

We acknowledge that there are rapidly evolving social pressures and emerging situations around the
COVID-19 pandemic, including the newly arising variants. It is clear that difficult decisions are made with
the best outcomes in mind for Canadians, with a priority given to saving lives given the recent evidence
that a single dose is showing efficacy. However, we would like to take this opportunity to outline some
issues related to the decision to extend the second dose of the vaccine to 4 months.

As we all appreciate, the RNA-based vaccines have never been used as a platform for controlling virus
spread, so prior knowledge and experience cannot be used. Therefore, we are relying only on the
knowledge gained from the clinical trials that evaluated these vaccines and /or directly related studies.
Analysis has shown that both T cell and antibody responses can be induced with the RNA vaccines, and
efficacy is achieved when the second dose is given 21-28 days later. This booster dose is important for
improving the T cell and antibody responses (T and B cell memory), as well as improving the quality and
duration of the immune response. Furthermore, this timing is scientifically predicted to be a reasonable
time point to stimulate the T cell response. To shift this timing out to 4 months, when there are no data
available, raises concern. The partial protection afforded by a single dose extends vulnerability to
infection - specifically the variants of concern - by 13 weeks when the 2nd dose is delayed to 4 months.

Scientifically, we can predict many scenarios, one being that a limited T cell response, together with the
lack of a neutralizing antibody response, could lead to protection of the individual from severe disease,
while permitting this individual to continue to spread the virus, therefore creating a situation where the
individual is somewhat protected but not allowing herd immunity. Will this really benefit Canadians, given
that a proportion will not take a vaccine? This situation could arise with the B.1.351 variant (South
African), since it is known that 1 dose of the vaccine does not neutralize the B.1.351 variant, but 2 doses
partially neutralize this variant. In principle, a sub-optimal immune response due to delaying the second
dose could create a situation that will impair viral clearance and foster the development of new variant
strains.
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Although reports have shown that a single dose may partially protect from severe disease and death,
industry will continue to gather knowledge based on their initial dosing scheme. To deviate from the
protocol followed by the most advanced cohort (i.e. those in the phase 3 trials) means that what is learned
from that cohort as time goes by will not be relevant for everyone treated off protocol. Is it worth setting
Canadians off down a path where there will be no way to make future decisions based on the findings of
these trials? When will booster doses be given? What will the impact be on the variants of concern and
potential others? This will remain a guessing game without being able to transfer knowledge from
properly performed trials.

Does the decision to offer partial protection for a larger number of Canadians, versus full protection for a
smaller number, by delaying the 2nd dose of vaccine, outweigh the risk of infection rates increasing,
especially with variants of concern such as B.1.351, for which the first dose of vaccine offers more limited
protection? At a minimum, there should be stratification for the second dose, where the elderly,
immunocompromised and individuals in high-risk groups are given the second dose according to the
recommended schedule (21-28 days after 1st dose). Importantly, planning for dose 2 needs to be made
now and communicated to the public.

We would be happy to engage in discussion and provide further details or suggestions.

Sincerely,

Pamela Ohashi, Ph.D., F.R.S.C.

Director, Tumor Immunotherapy Program
Princess Margaret Cancer Centre
Professor, Department of Immunology, University of Toronto
University of
610 University Avenue, Toronto, Ontario M5G 2M9 CANADA Toronto
T: (416) 946-4501 X3689, Email: pam.ohashi@uhnresearch.ca

David Brooks, Ph.D. Eleanor N. Fish, Ph.D.

Senior Scientist, Princess Margaret Cancer Center Emerita Scientist
Professor, Department of Immunology, University of Toronto General Hospital Research Institute
Toronto Associate Chair, International Initiatives &Collaborations
Toronto, ON Dept. of Immunology, University of Toronto
Toronto, ON
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Jen Gommerman, PhD Naoto Hirano, MD, PhD

Professor & Associate Chair, Graduate Studies Associate Director for Research, Tumor Immunotherapy
Canada Research Chair in Tissue Specific Immunity Program
Department of Immunology, Temerty Faculty of Princess Margaret Cancer Centre
Medicine Professor, Department of Immunology
Toronto, ON University of Toronto
Toronto, ON

Tak Mak, Ph.D. Mario Ostrowski, MD

Senior Staff Scientist Professor, Infectious Diseases, Immunology
Princess Margaret Cancer Centre, University Health University of Toronto,
Network Toronto, ON
Professor, University of Toronto and University of
Hong Kong
Toronto, ON

Christopher Paige, Ph.D. André Veillette, MD

Senior Scientist Professor
University Health Network Montreal Clinical Research Institute (IRCM)
Toronto, ON Montreal, QC

Tania Watts, Ph.D. J.C. Zúñiga-Pflücker, Ph.D.

Professor Professor & Chair
Department of Immunology Department of Immunology, University of Toronto
Temerty Faculty of Medicine Senior Scientist
University of Toronto Biological Sciences, Sunnybrook Research Institute
Toronto, ON Toronto, ON