Background:

People living with immunocompromising conditions (PLIC) are more susceptible to
complications related to respiratory infections. According to Statistics Canada data, in
2020 approximately 14% of Canadians aged 15 years or older suffered from a compromised
immune system. PLIC (e.g., solid organ transplant (SOT) recipients, people living with
human immunodeficiency viruses (PLWH), inflammatory bowel disease (IBD), or systemic
autoimmune rheumatic diseases (RD) are at risk for experiencing a wide range of
respiratory infections. A recent North American study assessed the socioeconomic burden
associated with immunocompromising conditions. MarketScan datasets from 2017-2021 showed
that PLIC accounted for 32% of hospitalizations for acute respiratory infections
(representing a 5-8-fold higher risk than in non-immunocompromised hosts).

PLIC are at elevated risk of severe infection and death from COVID-19 increasing burden
to patients and healthcare systems. Often including members of diverse ethnocultural
origin, PLIC have also been among the most significantly affected by the COVID-19
pandemic. Vaccination is the most effective way to reduce the severity respiratory
disease and infection-associated complications in the general population. Yet, suboptimal
immune status results in a higher risk for COVID-19-related hospitalization (up to
13-fold) and death (up to 19-fold) compared with the general population in many PLIC,
with substantial implications for healthcare burden and costs, despite PLIC comprising
but a minority of the overall population.

Immunogenicity and protection from severe disease can be improved in PLIC with COVID-19
booster doses. A systematic review by the COVID-19 evidence network found that PLIC were
more susceptible to severe infections and hospitalizations with emerging variants when
compared with the general public. This was attributed to immunomodulatory agents (e.g.,
calcineurin inhibitors, antimetabolites, steroids, cytotoxic therapy, biological response
modifiers) impairing the formation of memory T cells, decreasing cellular-mediated immune
responses, and limiting capacity to seroconvert and sustain protective immune memory
responses. For example, a meta-analysis in SOT found seroconversion and cellular response
rates of 39.2% (95% confidence interval [CI], 33.3%-45.3%) and 41.6% (95% CI,
30.0%-53.6%), respectively, after the primary series in solid organ transplant (SOT).

As the pandemic progressed, it was observed that three or four doses of COVID-19 vaccines
increased immunogenicity and protected against severe disease requiring hospitalization,
with antibody response being most pronounced in the presence of hybrid immunity, arising
when SARS-CoV-2 infection was paired with multiple vaccinations. Importantly, decreased
immunogenicity has been observed in PLIC in relation to other vaccines, such as the
Inactivated Influenza Vaccine (IIV), warranting high-dose (HD) IIV administration to
accomplish seroconversion.

Rationale:

The increased risk of COVID-19 and influenza, alongside adverse outcomes of respiratory
infections in PLIC and the variability in vaccine responses highlight the need for
optimizing immunogenicity and elucidating the mechanisms underlying blunted and/or less
durable vaccine responses in PLIC.

Correlates of protective humoral immunity and COVID-19 disease severity. Antigen-binding
antibodies, as well as neutralizing antibodies, have been proposed as independent
correlates of protection from SARS-CoV-2 infections. The WHO expert committee consensus
defined anti-SARS-CoV-2-S1-Receptor-Binding Domain IgG of BAU/mL as low concentrations,
200-300 BAU/mL as mid-range concentrations, and 700-800 BAU/mL as high concentrations.
PLIC demonstrated a reduced capacity to mount protective antibody responses. Yet,
additional doses resulted in higher antibody concentrations. A recent analysis by De
Serres and team demonstrated antibody levels in the range of 700-1200 BAU/ml conferred
protection as measured by a surrogate virus neutralization test (sVNT) threshold of 30%
against Omicron. Taken together, this body of evidence suggests that neutralizing or
binding anti-S could serve as correlates for protection. Importantly, humoral correlates
of protection need to also be evaluated for emerging viral variants especially those
which have acquired immune-evasion properties. Moreover, in addition to humoral immunity,
spike-specific CD4+ and CD8+ T cells are also critical for vaccine-induced protection and
are active contributors to global correlates of protection in many individuals.

Correlates of protective cellular immunity. The identification of correlates of cellular
immunity capable of informing clinical care has been hampered by a paucity of rapid
antigen-specific cellular immunity assays alongside increased costs and time demands.
Activation-induced marker (AIM) assays, wherein antigen-specific T cell subsets are
enumerated in peripheral blood mononuclear cells (PBMC) identified by their upregulation
of AIM (e.g., CD40L, 4-1BB, CD69), are effective at quantifying virus antigen-reactive T
cells. However, the rarity of these cells seldom conveys the quality and functional fate
of antigen-specific T cell subsets contributing to the global cellular response. Whether
AIM phenotypes could be implemented as rapid assays of cellular immunity and exploited
towards clinical decision-making, warrants further study.

The trial will provide evidence to guide health policy in a highly diverse and vulnerable
subpopulations of PLIC. More specifically, the trial will inform the preferred vaccine
schedule for COVID-19 and IIV in these patients, potentially improving upon vaccine
acceptance, adherence, and protection, eventually improving burden to patients,
caretakers, and the health care system.

Primary Objective(s):

1. To assess whether co-administration of seasonal inactivated influenza vaccine (IIV)
with the most up-to-date recommended COVID-19 booster dose is non-inferior in
inducing a 1-month peak protective humoral response against COVID-19, compared to a
strategy of sequential administration of COVID-19 booster dose followed by seasonal
IIV given one month later

It is hypothesized that the co-administration strategy will be non-inferior to the
sequential strategy in inducing a peak 1-month SARS-CoV-2-specific neutralizing
antibody response in PLIC. It will also be less costly, with no increase in adverse
effects, and no detrimental effect on response to seasonal IIV as measured by
hemagglutination inhibition.

2. To assess whether the administration of the most up-to-date recommended COVID-19
booster doses at 3-month intervals is superior at maintaining a longer term
protective humoral immune response, compared to booster doses administered at
6-month intervals

It is hypothesized that the 3-month booster strategy will be superior to the 6-month
strategy in inducing a SARS-CoV-2--specific neutralizing antibody response that is
sustained for 12 months without increasing adverse effects or disease-specific
complications.