Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

The GENCOV study aims to identify patient factors which affect COVID-19 severity and outcomes. Here, we aimed to evaluate patient characteristics, acute symptoms and their persistence, and associations with hospitalization. Participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada. Patient-reported demographics, medical history, and COVID-19 symptoms and complications were collected through an intake survey. Regression analyses were performed to identify associations with outcomes including hospitalization and COVID-19 symptoms. In total, 966 responses were obtained from 1106 eligible participants (87% response rate) between November 2020 and May 2022. Increasing continuous age (aOR: 1.05 [95%CI: 1.01–1.08]) and BMI (aOR: 1.17 [95%CI: 1.10–1.24]), non-White/European ethnicity (aOR: 2.72 [95%CI: 1.22–6.05]), hypertension (aOR: 2.78 [95%CI: 1.22–6.34]), and infection by viral variants (aOR: 5.43 [95%CI: 1.45–20.34]) were identified as risk factors for hospitalization. Several symptoms including shortness of breath and fever were found to be more common among inpatients and tended to persist for longer durations following acute illness. Sex, age, ethnicity, BMI, vaccination status, viral strain, and underlying health conditions were associated with developing and having persistent symptoms. By improving our understanding of risk factors for severe COVID-19, our findings may guide COVID-19 patient management strategies by enabling more efficient clinical decision making.

The GENCOV study sought to evaluate serological differences between individuals with differing COVID-19 severity and outcomes. We assessed the SARS-CoV-2 antibody response of GENCOV participants cross-sectionally 1-, 6-, and 12-months following COVID-19 diagnosis to identify patient factors associated with more robust and durable humoral immune responses. COVID-19 patients and a control cohort of vaccinated infection-naïve participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada. Commercially available and laboratory-developed serological assays were used to characterize features of participants' antibody responses, including both binding and neutralizing antibodies. Regression analyses were performed to identify associations between participant characteristics and features of the SARS-CoV-2 antibody response. Samples were obtained from participants 1- (n = 938), 6- (n = 842), and 12-months (n = 662) post-infection or vaccination. At all time points, vaccinees, and to a greater extent those who were both infected and vaccinated, had significantly elevated anti-spike antibody levels compared to unvaccinated participants. Increasing age and/or illness severity were associated with significantly higher antibody levels among unvaccinated participants. Among vaccines, those who were vaccinated after infection (i.e., hybrid immunity) had consistently higher antibody levels compared to participants who were infection-naïve or vaccinated before their infection (i.e., breakthrough infections). Additionally, receiving more vaccine doses and having a more recent vaccination were strongly associated with higher antibody levels across all time points. Our findings highlight various patient factors, including vaccination, which contribute to robust, durable SARS-CoV-2 antibody responses. Overall, the findings presented here may inform future vaccine development and rollout plans.

The integration of copy number variant (CNV) workflows into genome sequencing (GS) analysis pipelines allows for the identification of CNVs implicated in disease. Here, we generated a novel resource of CNVs identified in the HostSeq population cohort from Canada, identified the prevalence of recurrent CNVs associated with neurodevelopmental disorders, and determined CNVs of potential clinical relevance for reproductive planning and personal disease risk. GS data and CNV calls were generated for 10,488 participants from across Canada as part of the HostSeq initiative. The CNV calls were filtered to generate a rare dataset, which was further filtered into the OMIM morbid, ClinGen dosage, and DECIPHER datasets. CNV deletions were stratified into either Tier 1, 2, or 3 based on the inheritance pattern of the genes involved. A putatively pathogenic dataset was generated by identifying CNVs in the ClinGen dosage and DECIPHER datasets with at least 80% overlap with previously identified pathogenic CNVs. A total of 8,543,334 CNV calls were generated. Filtering for rare variants yielded 36,631 CNVs, of which 9,922 (27.08%) encompassed at least one OMIM gene, 728 (1.99%) had at least 10% overlap with a DECIPHER region, and 1,136 (3.10%) encompassed at least one ClinGen dosage-sensitive gene. CNV deletions were stratified into 1,833 Tier 1 deletions, 32 Tier 2 deletions, and 184 Tier 3 deletions. There were 82 CNVs identified in regions associated with neurodevelopmental disorders. Of the genes with either a ClinGen dosage sensitivity score or overlap with a DECIPHER region, 206 CNVs were deemed as putatively pathogenic. We were able to detect a wide range of CNVs, highlighting the use of integrating CNV workflows into the analysis pipeline, and generated a data resource for medical genomics for the Canadian population encompassing the full spectrum of CNVs.