Effectively treating infectious diseases often requires a multi-step approach to target different components involved in disease pathogenesis. Similarly, the COVID-19 pandemic has become a global health crisis that requires a comprehensive understanding of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection to develop effective therapeutics. One potential strategy to instill greater immune protection against COVID-19 is boosting the innate immune system. This boosting, termed trained immunity, employs immune system modulators to train innate immune cells to produce an enhanced, non-specific immune response upon reactivation following exposure to pathogens, a process that has been studied in the context of and clinical studies prior to the COVID-19 pandemic. Evaluation of the underlying pathways that are essential to inducing protective trained immunity will provide insight into identifying potential therapeutic targets that may alleviate the COVID-19 crisis. Here we review multiple immune training agents, including Bacillus Calmette-Guérin (BCG), β-glucan, and lipopolysaccharide (LPS), and the two most popular cell types involved in trained immunity, monocytes and natural killer (NK) cells, and compare the signaling pathways involved in innate immunity. Additionally, we discuss COVID-19 trained immunity clinical trials, emphasizing the potential of trained immunity to fight SARS-CoV-2 infection. Understanding the mechanisms by which training agents activate innate immune cells to reprogram immune responses may prove beneficial in developing preventive and therapeutic targets against COVID-19.

Background: Post COVID-19 Condition (PCC, also known as long COVID and post-acute sequelae of COVID-19) is a major public health concern with severe and pervasive impacts on physical and mental health. PCC is highly heterogeneous and may manifest as different clusters of symptoms of varying intensity and duration. The etiology of PCC remains uncertain, though several underlying pathophysiological mechanisms, such as cellular damage, inflammatory cytokines, and a hypercoagulable state, are thought to contribute to PCC inception and trajectory. Examination of potential serological markers of PCC, accounting for clinical covariates, may yield emergent pathophysiological insights. Objectives: Primary objectives of this thesis are to 1) Identify key clinical and potential serological predictors of PCC; 2) Acquire clinical and serological data in a large-scale prospective observational study; 3) Assess relationships between PCC and serological markers, accounting for clinical covariates; 4) Systematically review evidence to date on primary observational studies comparing serological response between people with and without persistent symptoms post COVID-19 recovery; 5) Discuss persisting gaps in knowledge and data quality, and propose strategies for resolve. Methods: This thesis is framed around three core efforts: 1) The design of survey questions and study materials, recruitment of participants, and data collection in a large-scale prospective cohort study launched in 2020; 2) The assessment of relationships between pre-defined serological predictors and PCC, accounting for clinical covariates; and 3) A robust rapid review of PCC onset and phenotype as functions of serological markers. Expert opinion was sought to define serological predictors. Clinical predictors were defined a priori based on systematic reviews meeting AMSTAR 2 guidelines. Conclusions: To address objectives, we described efforts to collect clinical and serological data from a large-scale prospective cohort study; identify PCC-cases and infected-controls; assess associations between pre-defined serological predictors (IgG titres targeting SARS-CoV-2 spike (S), nucleocapsid (N), and receiver binding domain (RBD) antigens, and efficient neutralization) and PCC; and synthesized findings from an extensive rapid review on PCC as a function of serological markers. Our multivariate analysis using Stop the Spread Ottawa data is, to our knowledge, the first Canadian study to report the direction and magnitude of association between selected serological predictors (anti-IgG response to S, N, and RBD SARS-CoV-2 antigens, and neutralizing efficiency) and PCC status and impact on quality of life. Finally, we described five potential strategies which may improve the accessibility, quality, and amalgamation of data pertaining to PCC: 1) Fostering comparability between studies to enable synthesis of multiple datasets; 2) Advancing the characterization and consensus on PCC phenotypes; 3) Employing innovative modelling strategies that could potentially yield novel insights; 4) Promoting robust collaboration and knowledge sharing among research teams; and 5) Engaging people with lived experience at all stages of research.