Paediatric Meningitis in the Conjugate Vaccine Era and Development of a Novel Clinical Decision Model to Predict Bacterial Aetiology in 3,002 Children with Suspected Meningitis (preprint)

Background: Implementation of bacterial conjugate vaccines have resulted in dramatic reductions in bacterial meningitis globally. The aetiology of childhood meningitis in the conjugate vaccine era is not well-defined, and differentiating bacterial meningitis from other similar childhood illnesses is a major challenge. The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.Methods: Children aged <16 years hospitalised with suspected meningitis/encephalitis were included. Meningitis was defined as identification of bacteria/viruses from CSF and/or a CSF WBC>5/μL. Aetiology and clinical and laboratory features were analysed. Two new clinical decision rules were developed to distinguish bacterial meningitis from aseptic or suspected meningitis.Findings: 3,002 children (median age 2·4 months, IQR: 1·0-12·7) were prospectively recruited at 31 UK hospitals. Overall 1,101/3,002 (36·7%) had meningitis, including 203 with a bacterial aetiology, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged < six months and 10-16 years, with N. meningitidis and/or S. pneumoniae commonest at age six months–nine years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after LP (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis.Interpretation: Bacterial meningitis comprised only 6% of children presenting to hospital with suspected meningitis/encephalitis. Our clinical decision rules provide important novel approaches to identify the children with bacterial meningitis.Funding: This independent research was supported by the UK Meningitis Research Foundation, Pfizer, and the National Institute for Health Research Programme Grants for Applied Research Programme (Understanding and improving the outcome of viral encephalitis, RP-PG-0108- 10048). MS is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC. TS is supported by the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections (Grant Nos. IS-HPU- 1112-10117 and NIHR200907).Declaration of Interest: MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. AJP was a member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization until January 2022 and remains chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI). AJP also reports providing advice to Shionogi on COVID-19, and funding from the National Institute for Health Research (NIHR), AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, and the Coalition for Epidemic Preparedness Innovations (CEPI). Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. TS is Director of The Pandemic Institute, which has received funding from Innova, CSL Seqirus, Aviva and DAM Health; was an advisor to the GSK Ebola Vaccine programme and the Siemens Diagnostic Programme; Co-Chaired the WHO Neuro-COVID task force and sat on the UK Government’s Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on Covid-19 vaccines. PH has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi- Pasteur, Novavax, Valneva, Minervax and AZ. All funds have been paid to his institute, and he has not received any personal payments. He is a member of the UK JCVI. All other authors have no COI to disclose.Ethical Approval: The study was approved by NRES Committee East Midlands - Nottingham 1 (Ref: 11/EM/0442).

Higher Perceived Stress during the COVID-19 pandemic increased Menstrual Dysregulation and Menopause Symptoms (preprint)

Purpose The increased stress the globe has experienced with the COVID-19 pandemic has affected mental health, disproportionately affecting women. However, how perceived stress in the first year affected menstrual and menopausal symptoms has not yet been investigated. Methods Residents in British Columbia, Canada, were surveyed online as part of the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE). A subgroup (n=4171) who were assigned female sex at birth (age 25-69) and were surveyed within the first 6-12 months of the pandemic (August 2020-February 2021), prior to the widespread rollout of vaccines, were retrospectively asked if they noticed changes in their menstrual or menopausal symptoms, as well as completing validated measures of stress, depression, and anxiety. Results We found that 27.8% reported menstrual cycle disturbances and 6.7% reported increased menopause symptoms. Those who scored higher on perceived stress, depression, and anxiety scales were more likely to have reproductive cycle disturbances. Free text responses revealed that reasons for disturbances were perceived to be related to the pandemic. Conclusions The COVID-19 pandemic has highlighted the need to research womens health issues, such as menstruation. Our data indicates that in the first year of the pandemic, almost a third of the menstruating population reported disturbances in their cycle, which is approximately two times higher than in non-pandemic situations and four times higher than any reported changes in menopausal symptoms across that first year of the pandemic.

Transition to Endemic: Acceptance of Additional COVID-19 Vaccine Doses Among Canadian Adults in A National Cross-Sectional Survey (preprint)

Background: Additional doses of COVID-19 vaccine have been proposed as solutions to waning immunity and decreased effectiveness of primary doses against infection with new SARS-CoV-2 variants. However, the effectiveness of additional vaccine doses relies on widespread population acceptance. We aimed to assess the acceptance of additional COVID-19 vaccine doses (third and annual doses) among Canadian adults and determine associated factors. Methods: We conducted a national, cross-sectional online survey among Canadian adults from October 14 to November 12, 2021. Weighted multinomial logistic regression analyses were used to identify sociodemographic and health-related factors associated with third and annual dose acceptance and indecision, compared to refusal. We also assessed influences on vaccine decision-making, and preferences for future vaccine delivery. Results: Of 6010 respondents, 70% reported they would accept a third dose, while 15.2% were undecided. For annual doses, 64% reported acceptance, while 17.5% were undecided. Factors associated with third dose acceptance and indecision were similar to those associated with annual dose acceptance and indecision. Previous COVID-19 vaccine receipt, no history of COVID-19 disease, intention to receive an influenza vaccine, and increasing age were strongly associated with both acceptance and indecision. Chronic illness was associated with higher odds of acceptance, while self-reported disability was associated with higher odds of being undecided. Higher education attainment and higher income were associated with higher odds of accepting additional doses. Minority first language was associated with being undecided about additional doses, while visible minority identity was associated with being undecided about a third dose and refusing an annual dose. All respondents reported government recommendations were an important influence on their decision-making and identified pharmacy-based delivery and drop-in appointments as desirable. Co-administration of COVID-19 and influenza vaccines was viewed positively by 75.5% of the dose 3 acceptance group, 12.3% of the undecided group, and 8.4% of the refusal group. Conclusions: To increase acceptance, targeted interventions among visible minority and minority language populations, and those with a disability, are required. Offering vaccination at pharmacies and through drop-in appointments are important to facilitate uptake, while offering COVID-19/influenza vaccine co-administration may have little benefit among those undecided about additional doses.

Epidemiology and role of SARS-CoV-2 Linkage in Paediatric Inflammatory Multisystem Syndrome (PIMS): A Canadian Paediatric Surveillance Program National Prospective Study (preprint)

Background: Paediatric inflammatory multisystem syndrome (PIMS) is a rare but serious condition temporally associated with SARS CoV2 infection. Using the Canadian Paediatric Surveillance Program (CPSP), a national surveillance system, we aimed to 1) study the impact of SARS CoV2 linkage on clinical and laboratory characteristics, and outcomes in hospitalized children with PIMS across Canada 2) identify risk factors for ICU admission, and 3) establish the minimum national incidence of hospitalizations due to PIMS and compare it to acute COVID 19. Methods: Weekly online case reporting was distributed to the CPSP network of more than 2800 pediatricians, from March 2020 to May 2021. Comparisons were made between cases with respect to SARS CoV2 linkage. Multivariable modified Poisson regression was used to identify risk factors for ICU admission and Minimum incidence proportions were calculated. Findings: In total, 406 PIMS cases were analyzed, of whom 202 (49.8%) had a positive SARS CoV2 linkage, 106 (26.1%) had a negative linkage, and 98 (24.1%) had an unknown linkage. The median age was 5.4 years (IQR 2.5 to 9.8), 60% were male, and 83% had no identified comorbidities. Compared to cases with a negative SARS CoV2 linkage, children with a positive SARS CoV2 linkage were older (8.1 years [IQR 4.2 to 11.9] vs 4.1 years [IQR 1.7 to 7.7]; p<0.001), had more cardiac involvement (58.8% vs 37.4%; p<0.001), gastrointestinal symptoms (88.6% vs 63.2%; p<0.001), and shock (60.9% vs 16.0%; p<0.001). At risk groups for ICU admission include children >=6 years and those with a positive SARS CoV2 linkage. No deaths were reported. The minimum incidence of PIMS hospitalizations during the study period was 5.6 hospitalizations per 100,000 population <18 years. Interpretation: While PIMS is rare, almost 1 in 3 hospitalized children required ICU admission and respiratory/hemodynamic support, particularly those >=6 years and with a positive SARS CoV2 linkage. Funding: Financial support for the CPSP was received from the Public Health Agency of Canada.

Risk factors for severe COVID-19 in hospitalized children in Canada: A national prospective study from March 2020--May 2021 (preprint)

Background: Children living with chronic comorbid conditions are at increased risk for severe COVID-19, though there is limited evidence regarding the risks associated with specific conditions and which children may benefit from targeted COVID-19 therapies. The objective of this study was to identify factors associated with severe disease among hospitalized children with COVID-19 in Canada. Methods: We conducted a national prospective study on hospitalized children with microbiologically confirmed SARS-CoV-2 infection via the Canadian Paediatric Surveillance Program from April 2020--May 2021. Cases were reported voluntarily by a network of >2800 paediatricians. Hospitalizations were classified as COVID-19-related, incidental infection, or infection control/social admissions. Severe disease (among COVID-19-related hospitalizations only) was defined as disease requiring intensive care, ventilatory or hemodynamic support, select organ system complications, or death. Risk factors for severe disease were identified using multivariable Poisson regression, adjusting for age, sex, concomitant infections, and timing of hospitalization. Findings: We identified 544 children hospitalized with SARS-CoV-2 infection, including 60{middle dot}7% with COVID-19-related disease and 39{middle dot}3% with incidental infection or infection control/social admissions. Among COVID-19-related hospitalizations (n=330), the median age was 1{middle dot}9 years (IQR 0{middle dot}1--13{middle dot}3) and 43{middle dot}0% had chronic comorbid conditions. Severe disease occurred in 29{middle dot}7% of COVID-19-related hospitalizations (n=98/330), most frequently among children aged 2-4 years (48{middle dot}7%) and 12-17 years (41{middle dot}3%). Comorbid conditions associated with severe disease included technology dependence (adjusted risk ratio [aRR] 2{middle dot}01, 95% confidence interval [CI] 1{middle dot}37-2{middle dot}95), neurologic conditions (e.g. epilepsy and select chromosomal/genetic conditions) (aRR 1{middle dot}84, 95% CI 1{middle dot}32-2{middle dot}57), and pulmonary conditions (e.g. bronchopulmonary dysplasia and uncontrolled asthma) (aRR 1{middle dot}63, 95% CI 1{middle dot}12-2{middle dot}39). Interpretation: While severe outcomes were detected at all ages and among patients with and without comorbidities, neurologic and pulmonary conditions as well as technology dependence were associated with increased risk of severe COVID-19. These findings may help guide vaccination programs and prioritize targeted COVID-19 therapies for children. Funding: Financial support for the CPSP was received from the Public Health Agency of Canada.

Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) Network study (preprint)

BackgroundPregnant individuals have been receiving COVID-19 vaccines following pre-authorization clinical trials in non-pregnant people. This study aimed to determine significant health events amongst pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. MethodsStudy participants were pregnant and non-pregnant females aged 15-49 years who had received any COVID-19 vaccine, and pregnant unvaccinated controls. Participants reported significant health events occurring within seven days of vaccination. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines. FindingsOverall 226/5,597(4.0%) vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227/3,108(7.3%) after dose two, compared with 11/339(3.2%) pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event after dose two of mRNA-1273 (aOR 4.4,95%CI 2.4-8.3) compared to pregnant unvaccinated controls, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant females had decreased odds of a significant health event compared to non-pregnant females after both dose one (aOR 0.63,95%CI 0.55-0.72) and dose two (aOR 0.62,95%CI 0.54-0.71) of mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention. InterpretationCOVID-19 mRNA vaccines have a good safety profile in pregnancy. Rates of significant health events were higher after dose two of mRNA-1273 compared with unvaccinated controls, with no difference when considering events leading to medical consultation. Rates of significant health events were lower in pregnant females than similarly aged non-pregnant individuals. FundingThis work was supported by the COVID-19 Vaccine Readiness funding from the Canadian Institutes of Health Research and the Public Health Agency of Canada CANVAS grant number CVV-450980 and by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force.

Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review (preprint)

Background: A correlate of protection (CoP) is an immunological marker associated with protection against infection. A CoP can be used to determine whether an individual is protected from infection, evaluate candidate vaccines, guide vaccination dosing intervals and policy, and understand population-level immunity against a pathogen. Despite an urgent need, a CoP for SARS-CoV-2 is currently undefined, leaving an evidence gap for informing public health policy and adapting it appropriately as new variants of concern emerge. The objective of this study was to systematically review and assess the evidence for a humoral SARS-CoV-2 CoP. Methods and Findings: We searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews and Scopus from inception to January 4, 2022 and pre-prints (using NIH iSearch COVID-19 portfolio) from inception to December 31, 2021, for studies describing SARS-CoV-2 re-infection or breakthrough infection with associated antibody measures. Two reviewers independently extracted study data and performed quality assessment. Twenty-five studies were included in our systematic review. Several studies reported re-infection or breakthrough cases that occurred in the presence of robust antibody levels. Studies that compared aggregate antibody concentrations from individuals who experienced re-infection or breakthrough compared to those who remained protected did not always find differences that were statistically significant. However, several studies found an inverse relationship between antibody levels and infection incidence, risk, or viral load, and a correlation between antibody levels and vaccine efficacy (VE). Estimates of the contribution of antibody levels to VE varied from 48.5% to 94.2%, suggesting that both humoral immunity and other immune components contribute to protection. Only two studies estimated a quantitative CoP. For Ancestral SARS-CoV-2, these included 154 (95% confidence interval (CI) 42, 559) anti-S binding antibody units/mL (BAU/mL), and 28.6% (95% CI 19.2, 29.2%) of the mean convalescent antibody level following infection. One study reported a CoP for the Alpha (B.1.1.7) variant of concern of 171 (95% CI 57, 519) BAU/mL. As of our search date, no studies reported an Omicron-specific CoP. Conclusions: The reviewed literature was limited by a wide variation in assay methodology and antibody targets. Few studies reported SARS-CoV-2 lineage. The studies included in our review suggest that if it exists, a SARS-CoV-2 CoP is likely relative, where higher antibody levels decrease the risk of infection, but do not eliminate it completely. More work is urgently needed in this area to establish a SARS-CoV-2 CoP and guide policy as the pandemic continues.

Hematologic manifestations of SARS-CoV-2 infection and MIS-C in hospitalized children. Results of the PICNIC registry. (preprint)

Introduction: Hematologic complications of SARS-CoV-2 infection are well described in hospitalized adults with correlation to adverse outcomes. Information published in children has been limited. Methods: An international multi-centered retrospective registry was established to collect data on the clinical manifestations of SARS-CoV-2 or multisystem inflammatory syndrome (MIS-C) in hospitalized children between February 1, 2020 – May 31, 2021. This sub-study focused on hematologic manifestations. Study variables included patient demographics, comorbidities, clinical presentation, course, laboratory parameters, management, and outcomes. Results: Nine hundred and eighty-five children were enrolled and 915 (93%) had clinical information available; 385 (42%) had symptomatic SARS-CoV-2 infection upon admission, 288 had MIS-C (31.4%) and 242 (26.4%) had alternate diagnosis with SARS-CoV-2 identified incidentally. During hospitalization, 10 children (1%) experienced a thrombotic event, 16 (1.7%) had hemorrhage and 2 (0.2%) had both thrombotic and hemorrhagic episodes. Significant prothrombotic comorbidities included congenital heart disease (p-value = 0.007), central venous catheter (p = 0.04) in children with primary SARS-CoV-2 infection; and obesity (p-value= 0.002), cytokine storm (p= 0.012) in those with MIS-C. Significant pro- hemorrhagic conditions included age > 10 years (p = 0.04), CVC (p= 0.03) in children with primary SARS-CoV-2infection; and thrombocytopenia (0.001), cytokine storm (0.02) in those with MIS-C. Eleven patients died (1.2 %) with no deaths attributed to thrombosis or hemorrhage Conclusion: Thrombotic and hemorrhagic complications are uncommon in children with SARS-CoV-2 infection and observed with underlying co-morbid conditions. Understanding the complete spectrum of hematologic complications in children with SARS-CoV-2 infection or MIS-C requires ongoing multi-center studies.

Infants Hospitalized for Acute COVID-19: Disease Severity in a Multicenter Cohort Study (preprint)

Age is the most important determinant of COVID-19 severity. Infectious disease severity by age is typically J-shaped, with infants and the elderly carrying a high burden of disease. We report on the comparative disease severity between infants and older children in a multicenter retrospective cohort study of children 0 to 17 year old admitted for acute COVID-19 February 2020 through May 2021 in 17 pediatric hospitals. We compare clinical and laboratory characteristics and estimate the association between age group and disease severity using ordinal logistic regression. We found that infants comprised one third of cases, but were admitted for a shorter period (median 3 days IQR 2-5 versus 4 days IQR 2-7), had a lower likelihood to have an increased C-reactive protein and had half the odds of older children of having severe or critical disease (OR 0.50 (95% Confidence Interval 0.32-0.78)). Conclusion: When compared to older children, there appeared to be a lower threshold to admit infants but their length of stay is shorter and they have a lower odds than older children of progressing to severe or critical disease.

Risk factors for severe PCR-positive SARS-CoV-2 infection in hospitalized children: a multicenter cohort study (preprint)

Importance: Children are less likely than adults to have severe outcomes from SARS-CoV-2 infection and the corresponding risk factors are not well established. Objective: To identify risk factors for severe disease in symptomatic children hospitalized for PCR-positive SARS-CoV-2 infection. Design: Cohort study, enrollment from February 1, 2020 until May 31, 2021 Setting 15 children's hospitals in Canada, Iran, and Costa Rica Participants: Patients <18 years of age hospitalized with symptomatic SARS-CoV-2 infection, including PCR-positive multisystem inflammatory syndrome in children (MIS-C) Exposures: Variables assessed for their association with disease severity included patient demographics, presence of comorbidities, clinical manifestations, laboratory parameters and chest imaging findings. Main Outcomes and Measures: The primary outcome was severe disease defined as a WHO COVID-19 clinical progression scale of [≥]6, i.e., requirement of non-invasive ventilation, high flow nasal cannula, mechanical ventilation, vasopressors, or death. Multivariable logistic regression was used to evaluate factors associated with severe disease. Results: We identified 403 hospitalizations. Median age was 3.78 years (IQR 0.53-10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Severe disease occurred in 33.8% (102/403). In multivariable analyses, presence of multiple comorbidities (adjusted odds ratio 2.24, 95% confidence interval 1.04-4.81), obesity (2.87, 1.19-6.93), neurological disorder (3.22, 1.37-7.56), anemia, and/or hemoglobinopathy (5.88, 1.30-26.46), shortness of breath (4.37, 2.08-9.16), bacterial and/or viral coinfections (2.26, 1.08-4.73), chest imaging compatible with COVID-19 (2.99, 1.51-5.92), neutrophilia (2.60, 1.35-5.02), and MIS-C diagnosis (3.86, 1.56-9.51) were independent risk factors for severity. Comorbidities, especially obesity (40.9% vs 3.9%, p<0.001), were more frequently present in adolescents [≥]12 years of age. Neurological disorder (3.16, 1.19-8.43) in children <12 years of age and obesity (3.21, 1.15-8.93) in adolescents were the specific comorbidities associated with disease severity in age-stratified adjusted analyses. Sensitivity analyses excluding the 81 cases with MIS-C did not substantially change the identified risk factors. Conclusions and Relevance: Pediatric risk factors for severe SARS-CoV-2 infection vary according to age and can potentially guide vaccination programs and treatment approaches in children.

Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec, Canada (preprint)

Background The Canadian COVID-19 immunization strategy deferred second doses and allowed mixed schedules. We compared two-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in two of Canada's larger provinces. Methods Two-dose VE against infections and hospitalizations due to SARS-CoV-2, including variants of concern, was assessed between May 30 and October 2, 2021 using test-negative designs separately conducted among community-dwelling adults [≥]18-years-old in British Columbia (BC) and Quebec, Canada. Findings In both provinces, two doses of homologous or heterologous SARS-CoV-2 vaccines were associated with ~95% reduction in the risk of hospitalization. VE exceeded 90% against SARS-CoV-2 infection when at least one dose was an mRNA vaccine, but was lower at ~70% when both doses were ChAdOx1. Estimates were similar by age group (including adults [≥]70-years-old) and for Delta-variant outcomes. VE was significantly higher against both infection and hospitalization with longer 7-8-week vs. manufacturer-specified 3-4-week interval between doses. Two-dose mRNA VE was maintained against hospitalization for the 5-7-month monitoring period and while showing some decline against infection, remained [≥]80%. Interpretation Two doses of mRNA and/or ChAdOx1 vaccines gave excellent protection against hospitalization, with no sign of decline by 5-7 months post-vaccination. A 7-8-week interval between doses improved VE and may be optimal in most circumstances. Findings indicate prolonged two-dose protection and support the use of mixed schedules and longer intervals between doses, with global health, equity and access implications in the context of recent third-dose proposals.

Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, including early variants of concern: a test-negative design, British Columbia, Canada (preprint)

IntroductionIn randomized controlled trials, single-dose efficacy against SARS-CoV-2 illness exceeded 90% for mRNA vaccines (BNT162b2 and mRNA-1273), and 75% for ChAdOx1. In British Columbia (BC), Canada second doses were deferred up to 16 weeks and ChAdOx1 was only initially recommended for adults 55 years of age and older. We compared single-dose vaccine effectiveness (VE) during the spring 2021 wave in BC when Alpha and Gamma variants of concern (VOC) predominated. MethodsVE was estimated against infection and hospitalization by test-negative design: cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Adults 50-69 years old with specimen collection between April 4 and May 22 (weeks 14-20) were included. Variant-specific VE was estimated between weeks 17-20 when genetic characterization of all case viruses was performed, primarily through whole genome sequencing. ResultsVE analyses included 7,116 (10%) cases and 60,958 controls. Three-quarters of vaccinated participants received mRNA vaccine (60% BNT162b2, 15% mRNA-1273) and 25% received ChAdOx1. Half of genetically characterized viruses were Alpha, with 38% Gamma, 4% Delta and 8% non-VOCs. Single-dose VE against any infection was 75% (95%CI: 72-78) for BNT162b2, 82% (95%CI: 76-87) for mRNA-1273 and 61% (95%CI: 54-66) for ChAdOx1. VE against hospitalization was 83% (95%CI: 76-89), 85% (95%CI: 63-94) and 96% (95%CI: 86-99), respectively. VE against Alpha vs. Gamma infections did not differ among mRNA (78%;95%CI: 73-82 and 80%;95%CI: 74-85) or ChAdOx1 (66%;95%CI: 57-74 and 60%;95%CI: 48-69) recipients. ConclusionsA single dose of mRNA vaccine reduced the SARS-CoV-2 infection risk by at least 75%, including infections due to early VOC. Although effectiveness of a single dose of ChAdOx1 was lower at 60% against infection, just one dose of any vaccine reduced the hospitalization risk by more than 80%. In the context of constrained vaccine supplies, these findings have implications for global vaccine deployment to reduce the overall burden of infections and hospitalizations due to SARS-CoV-2.

Intention to receive a COVID-19 vaccine by HIV status among a population-based sample of women and gender diverse individuals in British Columbia, Canada (preprint)

IntroductionCOVID-19 vaccination is recommended for people living with HIV (PLWH), among whom social inequities and co-morbidities may drive risks of COVID-19 infection and outcome severity. Among a provincial (British Columbia) sample, we determined the prevalence of COVID-19 vaccine intention by HIV status and assessed socio-demographic, vaccine hesitancy, and psychological predictors of vaccine intention. MethodsIndividuals (25-69y) recruited from province-wide research cohorts completed an online survey examining COVID-19 impacts (August/2020-March/2021). Among women and gender diverse participants, we compared intention to receive a recommended COVID-19 vaccine (Very likely/Likely vs Neutral/Unlikely/Very Unlikely) by self-reported HIV status. Logistic regression models assessed the independent effect of HIV status and other factors on vaccine intention. ResultsOf 5,588 participants, 69 (1.2%) were PLWH, of whom 79.7% were on antiretroviral therapy. Intention to vaccinate was significantly lower among PLWH compared to participants not living with HIV (65.2% vs 79.6%; OR: 0.44; 95%CI: 0.32-0.60). However, this association was attenuated after adjustment for social disparities (aOR:0.85; 95%CI: 0.48-1.55). Among PLWH, those with greater vaccine confidence, positive attitudes towards the COVID-19 vaccine, and more strongly influenced by direct and indirect social norms to vaccinate had significantly higher odds of vaccine intention. DiscussionTailored messaging is needed to build vaccine confidence, address questions about vaccine benefits, and support informed vaccination decision-making to promote COVID-19 vaccine uptake among women and gender diverse PLWH.

Performance of Immunoglobulin G Serology on Finger Prick Capillary Dried Blood Spot Samples to Measure SARS-CoV-2 Humoral Immunogenicity (preprint)

Abstract: Importance: Measuring humoral immunogenicity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines and finding population-level correlates of protection against coronavirus disease (COVID-19) presents an immediate challenge to public health practitioners. Objective: To study the diagnostic accuracy and predictive value of finger prick capillary dried blood spot (DBS) samples tested using an anti-immunoglobulin G (IgG) serology assay to measure SARS-CoV-2 seropositivity and the humoral immunogenicity of COVID-19 vaccination. Design, Setting and Participants: This cross-sectional study enrolled participants (n= 644) who had paired DBS and serum samples collected by finger prick and venipuncture, respectively, in British Columbia, Canada between January 12th, 2020 and May 21st, 2021. Samples were tested by a multiplex electrochemiluminescence assay for SARS-CoV-2 anti-Spike (S), -Nucleocapsid (N) and -receptor binding domain (RBD) IgG reactivity using a Meso Scale Discovery (MSD) platform. Additionally, unpaired DBS samples (n= 6,706) that were collected in the province during the same time period were included for analysis of SARS-CoV-2 anti-N IgG reactivity. Exposure: Collection of a capillary DBS by finger prick alone or paired with serum by venipuncture. Outcome: Humoral immune response to SARS-CoV-2 measured by detection of anti-S, -N or -RBD IgG. Results: In comparison to a paired-serum reference, DBS samples possessed a sensitivity of 80% (95% CI: 61%-91%) and specificity of 97% (95% CI: 95%-98%). Receiver operator characteristic curve analysis (ROC) found that participant DBS samples tested for anti-SARS-CoV-2 IgG by MSD V-PLEX COVID-19 Coronavirus Panel 2 assay accurately classify SARS-CoV-2 seroconversion at an 88% percent rate, AUC= 88% (95% CI: 81%-96%). Modelling found that a DBS-based testing approach has a high positive predictive value (PPV) (98% [95% CI: 98%-99%]) in a theoretical population with seventy-five percent COVID-19 vaccine coverage. At lower vaccine coverages of fifteen and forty-five percent, the test's PPV decreased and the negative predictive value increased. Conclusion: We demonstrate that DBS samples, when tested using an electrochemiluminescence assay, provide a valid alternative to traditional venipuncture and should be considered to reliably detect SARS-CoV-2 seropositivity.

SARS-CoV-2 seroprevalence among Vancouver public school staff in British Columbia, Canada (preprint)

Importance Contact-tracing studies suggest minimal secondary transmission in schools. However, there are limited school data accounting for asymptomatic cases, particularly late in the 2020/21 school year, and in the context of uninterrupted in-person schooling and widespread community transmission. Objectives To determine the SARS-CoV-2 seroprevalence in a sample of school staff, compared to the community, and to COVID-19 rates among all students and staff within the same school population. Design Incident COVID-19 cases among students and school staff using public health data, with an embedded cross-sectional serosurvey among school staff sampled from February 10 to May 15, 2021, comparing to age, sex and geographic location-matched blood donors sampled in January 2021. Setting Vancouver School District (British Columbia, Canada) from kindergarten to grade 12. Participants Active s chool staff enrolled from February 3 to April 23, 2021. Main outcome measures SARS-CoV-2 antibodies in a sample of school staff using spike (S)-based testing (unvaccinated staff) or N-based serology testing (vaccinated staff). Results The incidence of COVID-19 cases among students attending in-person was 9.8 per 1,000 students during the 2020/21 school year (N = 47,280 students), and among staff was 13 per 1,000 since the beginning of the pandemic (N = 7,071 active school staff). In total, 1,689 school staff (64% elementary, 28% secondary, 8.3% school board staff or multiple grades) completed the questionnaire, 78.2% had classroom responsibilities, and spent a median of 17.6 hours in class per week [IQR: 5.0 – 25 hours]. Although 21.5% (363/1,686) reported close contact with a COVID-19 case, only 1.4% (24/1688) of the school staff reported having had a positive viral nucleic acid test. Of this group, five believed they acquired the infection at school. The adjusted seroprevalence in staff who gave blood (1,556/1,689, 92.1%) was 2.3% [95%CI: 1.6 – 3.2%] compared to 2.3% [95%CI: 1.7 – 3.0%] in blood donors. Conclusion and relevance Despite high reported COVID-19 cases among students and staff, and frequent within-school exposures, we found no detectable increase in seroprevalence among school staff above the community seroprevalence. These findings corroborate claims that, with appropriate mitigation strategies, in-person schooling is not associated with significantly increased risk for school staff. Key Points Question What was the prevalence of COVID-19 infections in school staff who maintained in-person schooling during the 2020/21 school year in Vancouver, British Columbia, and how does it compare to the risk of COVID-19 infection in the community. Findings As of March 4, 2021, the incidence of COVID-19 cases among school staff was 13 per 1,000 (N = 7,071 school staff) since the beginning of the pandemic. In a cross-sectional seroprevalence analysis from February 10 to May 15, 2021, the adjusted seroprevalence among a sample of school staff (N = 1,556) was 2.3% [95%CI: 1.6 – 3.2%], compared to 2.3% [95%CI: 1.7 – 3.0%] in 1:2 age, sex and geographical location (by postal code)-matched reference group of blood donors. Meaning We found no detectable increase in seroprevalence among school staff above the community seroprevalence. These findings corroborate claims that, with appropriate mitigation strategies in place, in-person schooling is not associated with significantly higher risk for school staff.

The influence of sex, gender, age, and ethnicity on psychosocial factors and substance use throughout phases of the COVID-19 pandemic (preprint)

The SARS-CoV-2 (COVID-19) pandemic has had profound physical and mental health effects on populations around the world. Limited empirical research has used a gender-based lens to evaluate the mental health impacts of the pandemic, overlooking the impact of public health measures on marginalized groups, such as women, and the gender diverse community. This study used a gender-based analysis to determine the prevalence of psychosocial symptoms and substance use by age, ethnicity, income, rurality, education level, Indigenous status, and sexual orientation. Participants in the study were recruited from previously established cohorts as a part of the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE) study. Those who agreed to participate were asked to self-report symptoms of depression, anxiety, pandemic stress, loneliness, alcohol use, and cannabis use across five phases of the pandemic as well as retrospectively before the pandemic. For all psychosocial outcomes, there was a significant effect of time with all five phases of the pandemic being associated with more psychosocial symptoms relative to pre-COVID levels (p < .0001). Gender was significantly associated with all outcomes (p < .0001) with men exhibiting lower scores (i.e., less symptoms) than women and gender diverse participants, and women exhibiting lower scores than the gender diverse group. Other significant predictors were age (younger populations experiencing more symptoms, p < .0001), ethnicity (Chinese/Taiwanese individuals experiencing less symptoms, p = .005), and Indigenous status (Indigenous individuals experiencing more symptoms, p < .0001). Alcohol use and cannabis use increased relative to pre-pandemic levels, and women reported a greater increase in cannabis use than men (p < .0001). Our findings highlight the need for policy makers and leaders to proactively consider gender when tailoring public health measures for future pandemics.

Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada (preprint)

Introduction: Randomized-controlled trials of mRNA vaccine protection against SARS-CoV-2 included relatively few elderly participants. We assess singe-dose mRNA vaccine effectiveness (VE) in adults [≥]70-years-old in British Columbia (BC), Canada where the second dose was deferred by up to 16 weeks and where a spring 2021 wave uniquely included co-dominant circulation of B.1.1.7 and P.1 variants of concern (VOC). Methods: Analyses included community-dwelling adults [≥]70-years-old with specimen collection between April 4 (epidemiological week 14) and May 1 (week 17). Adjusted VE was estimated by test-negative design through provincial laboratory and immunization data linkage. Cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Vaccine status was defined by receipt of a single-dose [≥]21 days before specimen collection, but a range of intervals was assessed. In variant-specific analyses, test-positive cases were restricted to those genetically-characterized as B.1.1.7, P.1 or non-VOC. Results: VE analyses included 16,993 specimens: 1,226 (7.2%) test-positive cases and 15,767 test-negative controls. Of 1,131 (92%) viruses genetically categorized, 509 (45%), 314 (28%) and 276 (24%) were B.1.1.7, P.1 and non-VOC lineages, respectively. VE was negligible at 14% (95% CI 0-26) during the period 0-13 days post-vaccination but increased from 43% (95% CI 30-53) at 14-20 days to 75% (95% CI 63-83) at 35-41 days post-vaccination. VE at [≥]21 days was 65% (95% CI 58-71) overall: 72% (95% CI 58-81), 67% (95% CI 57-75) and 61% (95% CI 45-72) for non-VOC, B.1.1.7 and P.1, respectively. Conclusions: A single dose of mRNA vaccine reduced the risk of SARS-CoV-2 in adults [≥]70-years-old by about two-thirds, with protection only minimally reduced against B.1.1.7 and P.1 variants. Substantial single-dose protection in older adults reinforces the option to defer the second dose when vaccine supply is scarce and broader first-dose coverage is needed.

Multicenter cohort study of multisystem inflammatory syndrome in children (MIS-C) (preprint)

BACKGROUND SARS-CoV-2 infection can lead to multisystem inflammatory syndrome in children (MIS-C). We investigated risk factors for severe disease and explored changes in severity over time. METHODS Children up to 17 years of age admitted March 1, 2020 through March 7 th , 2021 to 15 hospitals in Canada, Iran and Costa Rica with confirmed or probable MIS-C were included. Descriptive analysis and comparison by diagnostic criteria, country, and admission date was performed. Adjusted absolute average risks (AR) and risk differences (RD) were estimated for characteristics associated with ICU admission or cardiac involvement. RESULTS Of 232 cases (106 confirmed) with median age 5.8 years, 56% were male, and 22% had comorbidities. ICU admission occurred in 73 (31%) but none died. Median length of stay was 6 days (inter-quartile range 4-9). Children 6 to 12 years old had the highest AR for ICU admission (44%; 95% confidence interval [CI] 34-53). Initial ferritin greater than 500 mcg/L was associated with ICU admission. When comparing cases admitted up to October 31, 2020 to those admitted later, the AR for ICU admission increased from 25% (CI 17-33) to 37% (CI 29-46) and for cardiac involvement from 44% (CI 35-53) to 75% (CI 66-84). Risk estimates for ICU admission in the Canadian cohort demonstrated a higher risk in December 2020-March 2021 compared to March-May 2020 (RD 25%; 95%CI 7-44). INTERPRETATION MIS-C occurred primarily in previously well children. Illness severity appeared to increase over time. Despite a high ICU admission incidence, most children were discharged within one week.

Neurological Manifestations of SARS-CoV-2 in Hospitalized Children: A Multi-National Cohort Study (preprint)

Background: Knowledge about neurological manifestations of SARS-CoV-2 in children is limited. We describe neurological manifestations in an international cohort of hospitalized pediatric patients.Methods: This is a multi-national observational study involving tertiary healthcare institutions in Canada, Costa Rica and Iran. We included patients 1 day-18 years admitted for any medical reason February 1, 2020-January 31, 2021 with laboratory evidence of SARS-CoV-2 infection by RT-PCR or serological testing. Descriptive analyses and logistic regression were performed where appropriate using JASP version 0⋅13.Findings: 298 hospitalized children with confirmed SARS-CoV-2 infection (median age 3⋅9 years [IQR 0⋅6-10⋅1]) from Canada (n=152), Costa Rica (n=115) and Iran (n=31) were included. Fifty-one (17%) had neurological manifestations, of which headache (73%), seizures (23%) and altered mental status (6%) were most frequently seen. Children with neurological symptoms had equivalent rates of comorbidities overall but were more likely to have underlying chronic neurological conditions. Additionally, those with neurological symptoms were more likely to be admitted to the ICU (15/51 [29%] vs. 32/247 [13%]; p =0⋅0033) and had longer length of hospital stay (6 days [IQR 3-8] vs. 4 days [IQR 2-7]; p =0⋅0060). Abnormalities were found in all children with neurological manifestations who received neuroimaging (n=6). Neurological manifestations were seen in 19% of the Iranian cohort, 23% of the Costa Rican cohort, and 12% of the Canadian cohort. Country of residence Costa Rica (adjusted OR: 2⋅520, 95% CI: 1⋅325-4⋅791, p =0⋅005), ICU admission (adjusted OR: 2⋅678, 95% CI: 1⋅307-5⋅486, p =0⋅007) and number of acute SARS-CoV-2 infection symptoms (adjusted OR: 1⋅355, 95% CI: 1⋅232-1⋅491, p <0⋅0001) were independently associated with neurological manifestations using multivariate analysis.Interpretation: We show that children with underlying comorbidities, especially underlying neurological diagnoses, are more likely to develop neurological complications of SARS CoV-2, and that sociodemographic factors, such as country of residence associate with varying rates of neurological manifestations. Future studies should focus on long-term outcomes in these children.Funding Statement: There was no funding source for this study.Declaration of Interests: Unrelated to this work, E.A. Yeh has received research funding from NMSS, CMSC, CIHR, NIH, OIRM, SCN, CBMH Chase an Idea, SickKids Foundation, Rare Diseases Foundation, MS Scientific Foundation (Canada), McLaughlin Centre, Mario Battaglia Foundation. Investigator initiated research funding from Biogen. Scientific advisory: Biogen, Hoffman-LaRoche, Vielabio. Speaker honoraria: Saudi Epilepsy Society, NYU, MS-ATL; ACRS, PRIME. J. Papenburg holds a “Chercheur-boursier clinicien” career award from the Fonds de recherche du Québec – Santé (FRQS) and reports grants from MedImmune, grants from Sanofi Pasteur, personal fees from Seegene, grants and personal fees from AbbVie, outside the submitted work. All other authors declare no conflict of interest.Ethics Approval Statement: All clinical and laboratory investigations were performed according to institutional protocols. Informed consent and ethics approval were obtained following requirements of the research ethics board of each participating institution.