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Abstract
Background Predictors of COVID-19 vaccine immunogenicity and the influence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require elucidation.
Methods Stop the Spread Ottawa is a prospective cohort of individuals at-risk for or who have been infected with SARS-CoV-2, initially enrolled for 10 months beginning October 2020. This cohort was enriched for public-facing workers. This analysis focuses on safety and immunogenicity of the initial two doses of COVID-19 vaccine.
Results Post-vaccination data with blood specimens were available for 930 participants. 22.8% were SARS-CoV2 infected prior to the first vaccine dose. Cohort characteristics include: median age 44 (IQR: 22–56), 66.6% women, 89.0% white, 83.2% employed. 38.1% reported two or more comorbidities and 30.8% reported immune compromising condition(s). Over 95% had detectable IgG levels against the spike and receptor binding domain (RBD) 3 months post second vaccine dose. By multivariable analysis, increasing age and high-level immune compromise predicted diminishing IgG spike and RBD titres at month 3 post second dose. IgG spike and RBD titres were higher immediately post vaccination in those with SARS-CoV-2 infection prior to first vaccination and spike titres were higher at 6 months in those with wider time intervals between dose 1 and 2. IgG spike and RBD titres and neutralisation were generally similar by sex, weight and whether receiving homogeneous or heterogeneous combinations of vaccines. Common symptoms post dose 1 vaccine included fatigue (64.7%), injection site pain (47.5%), headache (27.2%), fever/chills (26.2%) and body aches (25.3%). These symptoms were similar with subsequent doses.
Conclusion The initial two COVID-19 vaccine doses are safe, well-tolerated and highly immunogenic across a broad spectrum of vaccine recipients including those working in public facing environments.
- COVID-19
- immunology
- safety
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The Stop the Spread Ottawa (SSO) cohorts is representative of males and female adults as well as a broad range of ages.
A large proportion of SSO participants is employed in public facing occupations or is subject to frequent exposures to other individuals.
A large proportion of SSO participants is immune compromised.
A small proportion of the SSO cohort is non-white, limiting our ability for evaluation of racialised populations.
Background
COVID-19 vaccines have proven to be a key tool for combating the pandemic and have lowered infection rates and risk of severe disease.1 2 Pragmatic vaccine roll-out in Canada resulted in extended dosing schedules beyond the time periods used in clinical trials, the mixing of vaccine types and the widespread administration of vaccines primarily based on messenger RNA (mRNA) technology.3 4 As new viral variants have evolved over time, additional booster doses have been employed and bivalent vaccines have been introduced.
Clinical trials and observational population studies indicate that multiple vaccine technologies induce robust IgG levels against SARS-CoV-2.5 An analysis involving 30 individuals from two randomised controlled trials (RCTs) for the ChAdOx1 vaccine in the UK (COV001 and COV002) found that longer intervals between the first and second doses (up to 44–45 weeks) resulted in higher antibody titres 28 days after the second dose. Heightened humoral response and slower antibody decay up to 6 months were observed in the Com-COV2 RCT following mixed vaccination with ChAdOx1 and then Pfizer-BioNTech or Moderna vaccines compared with homologous vaccination. However, immunogenicity varies in different populations6 and the generalisability of the phase I–III randomised clinical trials for COVID-19 vaccines was limited due to restricted eligibility criteria that excluded older, younger and at-risk populations.2 7 Therefore, prospective observational evaluation of COVID-19 vaccine immunogenicity in diverse populations and in real-world settings is needed to fully elucidate the role of vaccine type, time between doses, number of doses and patient characteristics (such as sex, race, age and comorbidities). The long-term durability of vaccine-mediated immunity and risk for breakthrough infections are not fully characterised. Longitudinal research is required to determine how long vaccine response persists, the level of protection provided against emerging variants of concern, and the immunogenicity of bivalent COVID-19 vaccines.
The Stop the Spread Ottawa (SSO) cohort was established in September of 2020 to address these knowledge gaps. SSO employed less restrictive eligibility criteria than clinical trials and multiple subgroups are represented in the cohort such as those working in public-facing occupations such as healthcare, childcare and the transportation sector. Additionally, older age groups, immune compromised individuals, those with multimorbidities and people with post-COVID condition (PCC) were also specifically sought.8 In this paper we report on a multiparameter humoral response to COVID-19 vaccination and identify factors that influence vaccine immunogenicity in a complex, real-world population.
Methods
SSO is a prospective, longitudinal, cohort study investigating immune response to SARS-CoV-2 natural infection and vaccination.8 Recruitment began 14 September 2020 and was completed 28 September 2021. Enrolled participants were followed for 10 months with the option to extend for an additional 24 months. Those with a documented history of SARS-CoV-2 infection at baseline based on quantitative reverse transcription PCR (RT-PCR) or serology testing were allocated to the convalescent cohort for longitudinal sampling and participants without prior SARS-CoV-2 infection were included in the surveillance cohort. During follow-up, participants who tested positive for SARS-CoV-2 by RT-PCR or rapid antigen test (RAT) or received SARS-CoV-2 vaccine(s) were asked to cross-over from the surveillance cohort to follow the study protocol for the convalescent cohort.
Individuals 18 years or older, residing in the Ottawa-region and at-risk for SARS-CoV-2 exposure/infection due to occupation or health condition or having a documented history of COVID-19 natural infection confirmed by PCR and/or serology testing were eligible.8 Recruitment efforts prioritised inclusion of individuals at-risk of SARS-CoV-2 infection based on occupation (healthcare, long-term care facilities, air travel cabin crew, dental care, teachers, daycare) or a pre-existing health condition. Participants were classified as having a compromised immune system if they had a primary or secondary immunodeficiency, rheumatological condition, autoimmune disease, inflammatory condition, cancer, diabetes, asthma or chronic obstructive pulmonary disease requiring medication, organ/bone marrow transplant and/or received immunosuppressive treatment. Those reporting excessive alcohol consumption (men: 15 or more standard drinks a week; women: 8 or more standard drinks) were also considered immune compromised.9
Participants completed electronic questionnaires at baseline; at months 3, 10, 16, 22, 28 and 34; and following documented SARS-CoV-2 infection(s).8 Information on demographics, medical history, socioeconomic and psychosocial status, exposure risk factors, acute and persistent COVID-19 symptoms and vaccine reactogenicity was collected. Self-reported COVID-19 vaccinations and positive SARS-CoV-2 diagnostic results were tracked by the study coordinator and COVID-19 infection and vaccination histories were confirmed through medical records, where available. At baseline, participants provided blood samples for serum and peripheral blood mononuclear cell (PBMC) isolation.8 Convalescent participants completed monthly serum and bimonthly PBMC draws for 10 months. During months 11–34, extension participants provided blood specimens every other month. All biological specimens are stored in the Coronavirus Variants Rapid Response Network biobank, following the highest standards of biobanking practices in sample collection, processing, storage, access and distribution (on application).
IgG titres (BAU/mL) against SARS-CoV-2 spike (S), receptor-binding domain (RBD) and nucleocapsid (N) proteins in participant serum samples were quantified using a high-throughput chemiluminescent direct ELISA as previously described.8 10 11 A surrogate neutralisation ELISA assay using the full-trimeric S protein from the Wuhan Hu-1 strain was performed to determine neutralisation efficiency in sera. This surrogate protein-based assay enables the quantification of spike-ACE2 interaction in a high-throughput fashion. This approach has been validated with WHO reference serum and internal control.10 Incident COVID-19 infections were identified through self-report of positive PCR and RAT results to the study coordinator and through serology testing. Anti-N IgG titres were used to distinguish between vaccine-acquired immunity and infection-acquired immunity from a prior SARS-CoV-2 infection. Participants were classified as having vaccine-based immunity if they were positive (signal-to-cut-off (SCO)>1) for anti-S and anti-RBD IgG and infection-acquired immunity if they were positive for anti-N IgG and either anti-S or anti-RBD IgG. In the case of one-off or intermittent positive serum sample results for infection-acquired immunity for individuals with no self-reported positive test results, natural immunity was determined by examining the signal strength (the magnitude of SCO) and the preceding and subsequent serum results. The date of the first positive serum sample was taken as the best available estimate of date of infection for participants with COVID-19 infections identified through serum testing.
Participant characteristics and titres were compared according to study cohort at baseline, vaccine type and immune status. Student’s t-test and χ2 statistical tests were employed for continuous and categorical variables when assumptions were met. Fisher’s exact test as well as non-parametric Mann-Whitney U and Kruskal-Wallis tests were used in the case of low cell values or non-normal distribution. Monte Carlo simulation (n=1 000 000 samples) was employed to estimate p values for large contingency tables with high computational loads. Univariate and multivariable quantile regression analyses were conducted to compare log-adjusted anti-S and anti-RBD levels due to non-normal distribution of the log transformed data. Time points included week 6 post first vaccine dose (data from specimens collected from 4 to 8 weeks post first dose included in analysis), 3 months post second dose (2−4 months data included) and 6 months post second dose (4−6 months data included). Statistical tests and regression analyses were conducted using Statistical Analysis System (SAS) V.9.4 (copyright 2016 by SAS Institute, Cary, North Carolina, USA). Nested models which included or excluded the main term and interaction term were compared through a joint Wald test of the overall models using the R package ‘quantreg’ to obtain joint p values. Plots were constructed using RStudio (ggplot2 package).
Patient and public involvement
Consultation with members of the public at risk for exposure to SARS-CoV-2 was conducted during the design and implementation of this cohort study. This resulted in the creation of several ‘participant friendly’ pathways for providing serial blood specimens. A web-based, user-friendly study portal was designed which enabled participation and direct access to personal study data was created based on patient and public input. Feedback was sought and implemented throughout the conduct of this study to facilitate patient participation and retention. Consented participants assisted in recruitment as they were provided the opportunity to direct interested individuals to our study team and/or study website to explore enrolling in the SSO cohort study. Patient-focused webinars led by Dr Cooper and his study team were held during the course of the study conduct to provide SSO updates and the opportunity to ask questions related to the study and COVID-19 in general. Study updates were also provided on the SSO website. Our study coordinators and Dr Cooper also provided individualise SSO updates to participants on request. We remain deeply grateful for the considerable time, commitment, data and biological specimens provided by our SSO participants.
Results
Participant characteristics
A total of 1112 participants were consented and enrolled in SSO (online supplemental figure 1). Participant retention was high with 67% of participants completing the initial 10 months of follow-up despite the challenges of public health measures and an arduous study protocol. Participant protocol compliance was high and the number of missing samples was low. Baseline questionnaire and serum draws were completed by 730 surveillance and 257 convalescent participants. Of participants in the surveillance cohort, 20.9% had at least one incident COVID-19 infection after enrolment, identified through self-report of a positive test result and/or serum IgG antibodies. At least one COVID-19 infection was identified in 10% of all convalescent SSO participants during the study period. Of note, assay failure rates were low (0.6%, 0.6% and 0.1% for anti-N, anti-RBD and anti-S IgG).
Supplemental material
During the initial 10-month follow-up period, 195 individuals transitioned from the surveillance cohort into the convalescent cohort following COVID-19 infection (n=22) or vaccination (n=173). Thirty-three per cent of participants were lost to follow-up (13%) or withdrew (20%).
A high proportion of participants were women (67.1%), white (89.0%) and Canada-born (87.1%) (table 1). A high proportion of participants (63.0%) were engaged in public facing occupations. Nearly two-thirds (64.2%) had obtained an undergraduate or advanced degree, 83.3% were employed at baseline and 65% earned at least $C90 000 annually. Those with a history of a prior COVID-19 infection at baseline were older (mean age 46.8 vs 44.4 years) and more likely to be obese (19.1% obese vs 12.6%) than those without prior infection. The most prevalent comorbidities at baseline included allergy (42.7%), obesity (14.1%), hypertension (10.4%), dyslipidaemia (9.0%), endocrine disorder (10.1%), heart disease (4.0%) and chronic neurological condition (3.0%). Current or past smoking was reported in 27.3% of participants. Just over 30% of participants were classified as immune compromised.
Characteristics of study participants (n=1034) at baseline in the surveillance cohort (no history of COVID-19 infection at baseline) and convalescent cohort (history of a COVID-19 infection at baseline)
Vaccination and infection summary
At the time of data analysis, 98.5% and 97.7% of participants had received at least one or two vaccine doses, respectively, and 70.9% had received one or more booster shot(s) (table 2). The majority of participants (87.4%) were vaccinated with mRNA vaccines (Pfizer-BioNTech (Pfizer) (77.6% first dose and 73.7%second dose); Moderna (10.1% for dose 1 and 25.0% dose 2). Adenovirus-based ChAdOx1 vaccine (AstraZeneca) was administered to 12.3% of dose 1 and 1.2% of dose 2 recipients. The median days between the first and second COVID-19 vaccine doses was 58 (IQR: 35–76) and ranged from 11 to 344 days. The length of time in days between second and third vaccine doses was 185 IQR (IQR: 174–212). Post COVID-19 condition symptoms were reported in 224 (21.7%) participants.
Participant COVID-19 vaccination information as of analysis cut-off date (September 2022) according to cohort allocation at the time of initial cohort entry
Humoral immune response following first and second vaccine doses
After excluding those with history of COVID-19 infection, 95.9% tested positive for humoral antibody evidence of vaccine-based immunity 6 weeks after dose 1. This proportion increased after full vaccination (97.7% 3 months after dose 2 and 100% 6 months after dose 2). These proportions were similar by vaccine type. Participants who tested negative for vaccine-based immunity 6 weeks after dose 1 were older (median age 59.0 (IQR: 44.0–72.5) vs 54.0 (41.0–60.0), p=0.03) and were more likely to be immune compromised (87.5% vs 29.1%, p<0.01) to a severe degree (85.7% vs 38.2%, p=0.04) than those who tested positive.
An increase in log-adjusted anti-S and anti-RBD IgG titres were observed following vaccination across the cohort (table 3, online supplemental figure 2). Median anti-S and anti-RBD IgG titres (log10 BAU/mL) 6 weeks post dose 1 were higher with mRNA vaccination (Moderna (S: 3.348 (IQR: 3.189–3.776), RBD: 2.950 (2.645–3.461))) and Pfizer doses (S: 3.101 (IQR: 2.564–3.634), RBD: 2.643 (2.252–3.767)) compared with adenovirus vector vaccine (AstraZeneca (S: 1.893 (1.737–2.582), RBD: 1.939 (1.751–2.550))) (S: p<0.0001, RBD: p<0.001). Median anti-S and anti-RBD IgG titres were comparable regardless of vaccine type 3 months following dose 1.
Median log-adjusted IgG titres (log10 BAU/mL) against the SARS-CoV-2 spike (S) and receptor-binding domain (RBD) proteins at time points prior to and following COVID-19 vaccination, according to COVID-19 infection history*
Maximum median log-adjusted anti-S and anti-RBD titres were observed following completion of the second dose schedule after which median titres declined over time until the next vaccination or natural infection (table 3, online supplemental figure 2). Median anti-S and anti-RBD IgG titres were comparable regardless of vaccine type 6 months following dose 2. Receiving two mRNA vaccines resulted in a higher humoral response compared with receiving first adenovirus vector vaccine and then an mRNA vaccine 6 weeks post dose 1 (anti-S: 3.118 (IQR: 2.573–3.637) vs 1.893 (IQR: 1.737–2.582); p<0.0001) but not 6 weeks post dose 2 (anti-S: 3.539 (IQR: 3.286–3.706) vs 3.680 (IQR: 3.512–4.053); p<0.01). The humoral response was comparable by vaccine type 3 months following dose 2 as well.
At all time points, those with a history of COVID-19 infection prior to first vaccination had higher median log-adjusted anti-S and anti-RBD IgG titres (table 3).
Predictors of humoral immune responses by regression analysis
Univariate analysis was used to identify variables potentially influencing vaccine immunogenicity following the initial two doses in those without a history of SARS-CoV2 infection (data not shown). After adjusting for immune compromised status, sex, obesity, vaccine type(s) administered for dose 1 and 2, and days between first and second doses by multivariable quantile regression, older age was identified as a predictor of lower median anti-S and anti-RBD IgG titres 3 months after dose 2 for participants with no history of infection (table 4). By 6 months following vaccine dose 2, age no longer was associated with anti-S and anti-RBD IgG titres. Immune compromised status also predicted lower median log-adjusted anti-S IgG and anti-RBD titres 3 months post dose 2. Increased time between first and second doses predicted higher anti-RBD IgG titres at month 3 and anti-S IgG titres at 6 months after dose 2.
Difference in median log-adjusted IgG titres (log10 BAU/mL) against the SARS-CoV-2 spike and RBD proteins following the initial two COVID-19 vaccine doses by multivariable quantile regression, stratified by SARS-CoV-2 infection history: (A) No history of SARS-CoV-2 infection*; (B) history of SARS-CoV-2 infection prior to vaccination‡§
Shorter duration of time from SARS-CoV-2 infection to dose 1 of vaccine predicted higher IgG S and RBD titre at month 6 post second dose of vaccine. No other covariates consistently predicted higher or lower anti-S or anti-RBD IgG titres for participants with COVID-19 infection history prior to vaccination (table 4).
Consistent with IgG antibody titre findings, older age and longer time between first and second vaccine dose predicted higher neutralisation at 3 months after vaccine dose 2 in those without SARS-CoV-2 infection prior to vaccination (table 5, online supplemental figure 3). Immune compromised state also predicted diminished vaccine neutralisation at months 3 and 6 post second vaccine dose. Similar to IgG antibody titre findings, duration of time from SARS-CoV-2 infection to dose 1 of vaccine predicted higher IgG neutralisation at month 6 post second dose of vaccine.
Difference in median IgG neutralisation percentage (%) against the Wuhan-Hu-1 SARS-CoV-2 spike protein following two COVID-19 vaccine doses in those without a history of SARS-CoV-2 infection* (A) and those with a history of one SARS-CoV-2 infection prior to vaccination† (B) by multivariable quantile regression‡
Vaccine tolerability and reactogenicity
Results are reported for the initial two doses plus the first booster dose. No serious adverse events (SAEs) related to vaccination were reported by SSO participants. One participant died due to malignancy deemed unrelated to vaccination. Commonly reported vaccination symptoms following dose 1 included fatigue (64.7%), pain at the injection site or arm soreness (47.5%), headache (27.2%), fever or chills (26.2%) and body aches (25.3%) (online supplemental table 1). The type and proportion of symptoms was similar with subsequent vaccinations. Symptoms lasted the longest after dose 1 (median of 2.0 days (IQR: 1.0–3.0)) compared with subsequent vaccinations.
Supplemental material
Discussion
Large scale administration of novel COVID-19 vaccines was deployed to combat the SARS-CoV-2 pandemic. In Canada, supply constraints during initial roll-out lead to staged administration in which high-risk groups were prioritised (eg, healthcare workers, older adults, adults in Indigenous communities), an increase in the length of time between priming and boosting doses beyond the recommended 21 days (for Pfizer) or 28 days (for Moderna) up to 4 months, and the mixing of different vaccine types.3 4 12 Our analysis suggest that these strategies all ultimately achieved a potent induction of humoral immunity. In fact, a longer interval than recommended by the manufacturer between dose 1 and 2 increased durability of humoral responses.
Most SSO participants had received two mRNA vaccines at the time of analysis. mRNA and adenovirus vector COVID-19 vaccines elicited robust humoral responses that were sustained 3 months after dose 2. Crude median anti-S and anti-RBD titres (log10 BAU/mL) peaked 6 weeks after the second dose and then generally decreased over time. All vaccine types demonstrated acceptable safety and tolerability profiles with no reported vaccine-specific SAEs. Mild reactogenicity symptoms were commonly reported but generally lasted a few days. Our results are consistent with prior studies which have found the mRNA COVID-19 vaccine to be overall safe and effective.13
In our analysis, vaccine-elicited antibody responses persisted 6 months post vaccination. Of note, all participants without a history of infection at baseline were found to possess evidence of humoral immunity at 6 months following the second vaccine dose. However, to date the correlates of protection for COVID-19 infection remains poorly defined and it is unclear if the titres reported in this study 6 months post vaccination are sufficient to protect individuals from infection, especially variants of concern, or how long this protection will last beyond 6 months.14 15 Other studies have observed a gradual decline in titres following initial two dose vaccination which is consistent with our findings.6 14 There is evidence that humoral responses decline at the 4–6 months point after vaccination, especially in immune compromised individuals.16 17 Podrazil et al observed a sharp decline in humoral and cellular immune responses 6 months after vaccination with the mRNA Pfizer vaccine in asthma patients receiving biological therapy.16 Breakthrough COVID-19 infections further raise concerns regarding the durability of protection following two doses.18
Vaccine immunogenicity was robust in young and middle age participants; many of which worked in public-facing occupations including as healthcare providers, teachers, daycare and in the transport sector. Achieving protective immunity with these occupation groups is a critical public health piece in minimising community transmission of SARS-CoV-2. Older age predicted lower anti-S and anti-RBD IgG titres and neutralisation at 3 months following vaccination in those without prior SARS-CoV-2 infection. Immune senescence is a phenomenon that leads to chronic inflammation as well as suboptimal T cell, B cell, neutrophil and dendritic cell activity and counts.19 These changes increase the risk of acquiring infections and reduce vaccine immunogenicity (eg, as shown for influenza and herpes zoster vaccines) in the elderly.19 20 Immune senescence is likely a contributing factor to the decrease in SARS-CoV-2 immunogenicity with older age, although the specific mechanism as it relates to COVID-19 remain to be characterised. The elderly are at higher risk of severe outcomes from COVID-19.21 These findings, in combination with the observed accelerated decline in anti-S and anti-RBD IgG titres over time, support current recommendations to receive a booster dose 4–6 months after full vaccination.15
High level immune compromised status was associated with diminished COVID-19 vaccine humoral responses in those without prior SARS-CoV-2 infection. Adjusted median anti-S and anti-RBD titres 3 months after the second vaccine dose as well as anti-RBD and neutralisation at month 6 were lower for immune compromised participants. Our cohort includes a heterogeneous collection of immune compromising conditions including cancer, chronic inflammatory, autoimmune or rheumatological disease, HIV and those receiving immune suppressants medications (eg, transplant recipients). Our results are consistent with other COVID-19 vaccination studies focused on immune compromised populations.6 16 22 23
There is emerging evidence that extending the time interval between the first and second COVID-19 vaccine doses improves immune responses.15 24 Due to the variation in the number of days between vaccine doses received by SSO participants, we were able to prospectively investigate the impact of the time interval on vaccine immunogenicity. In those without pre-vaccine SARS-CoV-2 infection, increasing the number of days between vaccine doses was associated with higher anti-S and RBD IgG titres in the 6-month period vaccination and higher anti-S IgG neutralisation at month 3 following vaccine dosing. These results show that concerns regarding decreased efficacy from extending the interval between doses are unwarranted and suggest a potential benefit.25 Extending the vaccine schedule may improve long-term durability of COVID-19 vaccine immunogenicity and prolong protection from SARS-CoV-2 infection and severe symptoms.
SARS-CoV-2 infection prior to initial vaccination was a consistent predictor of anti-S and anti-RBD IgG antibody titres and neutralisation identified in this study. At all time points, having a history of infection increased humoral response to the vaccine. The time interval between SARS-CoV-2 infection and first vaccine predicted anti-S and anti-RBD titres as well as neutralisation in the 6-month period following the second vaccine dose. The crude difference in IgG titres compared with those with no prior infection gradually increased over time following the initial two doses of vaccine suggesting that the slope of antibody decay may be less marked in those with hybrid immunity. Recent research has found that breakthrough infections increase humoral response and neutralisation of SARS-CoV-2 variants.26 27 Our results warrant further investigation into the joint effect of vaccine-mediated and infection-acquired immunity compared with either independently.
The findings in this study are subject to several strengths and limitations. The SSO cohort has a large sample size of over 1000 participants at baseline with high retention. Prospective, longitudinal data collection commenced prior to widespread vaccine roll-out enabling the collection of pre-vaccination baseline data.8 Information on many different variables was collected allowing for many key covariates to be included in multivariable analyses. Self-reported infection and vaccination histories were validated using medical records. Multiple testing methods (rapid antigen tests, PCR and serology testing) were used to confirm present and past COVID-19 infections.
SSO participants are primarily white, characterised by a high level of employment and many reported high-income status. The study was conducted in a developed nation with a robust public health infrastructure. With this in mind, our results may not be fully generalisable to all settings. Adults over 80 years of age are not well represented.8 Because non-white individuals comprised only 11% of our cohort, we could not explore this important variable in our evaluation of vaccine safety and immunogenicity. Blood draws occurred based on time of enrolment and were not fixed to vaccination dates. Therefore, blood samples for humoral immune assessment were not always available for each post-vaccination time point evaluated. The high-throughput chemiluminescent direct ELISA antibody assay used is subject to a range of uncertainty in the quantification method (3% false discovery rate). Natural infection histories of participants with intermittent or one-off positive results for infection-acquired immunity were manually adjusted but misclassification is possible. There is also a risk of misclassification when relying on self-reported data. Selection bias may have been introduced by the 33% of participants who were lost to follow-up or withdrew. However, we believe that the potential for selection bias is minimal as those who provided serum data and those who were lost to follow-up were similar in terms of baseline data. Our sample size was not of sufficient size to identify rare side effects of vaccination.
Despite these limitations, our analysis of a large, heterogeneous cohort followed for a prolonged duration during the SARs-CoV-2 pandemic demonstrates that the initially administered COVID-19 vaccinations were safe, well-tolerated and highly immunogenic across a broad spectrum of recipients including those employed in public-facing occupations. Our analysis continues to assess durability of vaccine immunogenicity as well as the influence of additional vaccine boosters and natural infection.
Supplemental material
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
All participants provided informed consent. Stop the Spread Ottawa is approved by the Ottawa Health Science Network Research Ethics Board (#2020-0481-01H).
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors AK: data analysis, manuscript preparation. YG: laboratory analysis, data analysis, manuscript preparation. AH: data analysis, manuscript preparation. EC: study design, study recruitment, manuscript preparation. PSM: laboratory analysis, data analysis. CA: laboratory analysis, data analysis. RS: study design, manuscript preparation. RB: laboratory analysis, manuscript preparation. JL: study design, data analysis, manuscript preparation. MM: study design, manuscript preparation. CAB: study design, manuscript preparation. AC: study design, laboratory analysis, data analysis, manuscript preparation. M-AL: study design, laboratory analysis, data analysis, manuscript preparation. CLC: study design, study recruitment, data analysis, manuscript preparation. CC: guarantor.
Funding This study is funded by the Canadian Institutes of Health Research - Instituts de recherche en santé du Canada (CIHR) (424425), the COVID-19 Immunity Task Force (CITF) and the University of Ottawa. The study extension is funded by the Coronavirus Variants Rapid Response Network (CoVaRR-Net) (156941) (https://covarrnet.ca/investigating-long-term-variables-to-sars-cov-2-infection-and-vaccine-immunity/). CoVaRR-Net is funded by an operating grant from CIHR (FRN# 175622). Production of COVID-19 reagents was financially supported by the National Research Council of Canada's Pandemic Response Challenge Program. YG is supported by a Charles Best and Frederick Banting (CGS-Doctoral award) from CIHR (476885). M-AL holds a Faculty of Medicine Chair of Excellence in Pandemic Viruses and Preparedness Research. The authors thank the uOttawa High Throughput Serology and Diagnostics facility staff: Danielle Dewar-Darch, Gwendoline Ward, Justino Hernandez Soto, Klaudia Baumann, Nicholas Bradette, Yuchu Dou, Abishek Xavier and Lynda Rocheleau
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.