European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) SARS-CoV-2 Antibody Study Protocol. Covid-19

The study will be conducted within existing cohorts of children, adolescents and young adults living with HIV being followed up in several European countries and South Africa: the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) Paediatric Study and the Cape Town Adolescent Antiretroviral Cohort (CTAAC). In CTAAC, adolescents without HIV are also enrolled and will be included in this study. For all participants, two blood samples will be taken at routine clinic visits approximately six months apart and tested for antibodies to SARS-CoV-2; clinical data and data on potential COVID-19 exposures will also be collected. MAIN AIM OF THE STUDY The overall aim of this study is to describe the prevalence and distribution of antibodies to SARS-CoV-2 in children and adolescents living with HIV in Europe and South Africa. Primary objective: •To estimate prevalence of SARS-CoV-2 antibodies in the paediatric and adolescent HIV population and how this changes over time, overall and by key age groups and regions Secondary objectives: * To assess factors associated with presence of SARS-CoV-2 antibodies (including demographic factors, antiretroviral treatment, HIV-associated factors or co-morbidities and exposure to household members with COVID-19) * To estimate the incidence of changes in antibody status to SARS-CoV-2 and associated factors ENROLMENT Where feasible, all children and adolescents meeting the inclusion criteria and attending the participating clinics during the study period will be invited to take part; where this is not possible, a convenience sample of children and adolescents (e.g. those attending clinic on a specified day of the week) should be invited. The invitation to participate should be independent of the patient's probability of having been exposed to COVID-19. Participants enrolled in the EPPICC Paediatric Study or CTAAC will continue to be followed up as part of the ongoing study. DATA COLLECTION The study will use data collected in the main EPPICC Paediatric study for participants attending clinics which participate in that study. This includes demographic data and clinical, therapeutic, laboratory and outcome information relating to HIV, COVID-19 and multi-system inflammatory syndrome in children (MIS-C). These data are extracted from clinic records and submitted as part of the main EPPICC study, and will be linked to data collected through the serology study. Sites which are not members of the EPPICC network will submit equivalent data relating to the time of the two study visits for CLWHIV and HIV-uninfected adolescents. Additionally, a short questionnaire will be completed by the participant (or their parent / carer) about potential exposures to COVID-19, including diagnoses in household members and known contacts. For any participant with a record of a suspected or confirmed COVID-19 or MIS-C diagnosis, the cohort will be asked to complete an additional case record form providing details of the diagnosis (e.g. clinical features, hospital admissions, treatments and outcomes). Cohorts will send pseudonymised electronic datasets to the MRC CTU at UCL. Transfer of data to the MRC CTU at UCL takes place using Galaxkey or an equivalent secure method such as UCL's REDCap server. Data will then be uploaded into a customised database. LABORATORY TESTING Where sites are conducting serological testing as part of standard care, venous blood samples taken at each site will be transported to the laboratory(ies) routinely carrying out antibody testing for that site. Samples will be analysed with the tests used by each site in routine practice according to manufacturers' instructions or, if in-house tests are used, local SOPs/protocols. At sites not offering routine serological testing, arrangements should be made with local laboratories for testing. There is strong preference for tests for IgG against the viral spike protein; however, it is recognised that there may be local considerations influencing the range of tests available across settings and results from other tests will be considered. DISCONTINUATION OR EARLY WITHDRAWAL OF PARTICIPANTS Participants (or their parents/carers) may withdraw from the study at any time without providing a reason. Participants wishing to withdraw from the study will be offered two options: 1. Participants may withdraw from active follow-up (i.e. future study procedures) within this study but allow the retention and use of data already collected, and further linkage with other data sources as described in the Participant Information Sheet. 2. Participants may withdraw completely from the study, in which case all data and samples collected (if not already tested) would be destroyed and no further follow-up or linkage would take place as part of this study. Should a participant (or their parent / carer) lose the capacity to consent, they will be withdrawn from active follow-up and their data / samples retained and included in data linkages. Participants who withdraw for any reason will not be replaced. All withdrawals will be recorded in the study database. ANALYSIS PLAN Proportions with SARS-CoV-2 antibody at baseline and follow-up and the number/incidence of changes in antibody status between baseline and subsequent test will be estimated overall and by key patient characteristics, region, history of symptomatic COVID-19, contact with COVID-19 cases. Factors associated with the presence of SARS-CoV-2 antibody, changes in antibody status and any subsequent COVID-19 diagnosis (if numbers allow), will be explored using univariable and multivariable logistic and Poisson regression. Exposures of interest include age, sex, ART class and regimen (e.g. protease inhibitor- or tenofovir-based versus other), CD4 count, viral load, ethnicity, BMI-for-age z-score, co-infections (e.g. tuberculosis), co-morbidities and household size. The association between HIV status and SARS-CoV-2 seropositivity, changes in antibody status and subsequent COVID-19 diagnosis will be assessed in the South African cohort (which includes HIV-uninfected children as well as CLWHIV) using similar methods. If there is substantial variation in the type of antibody test used (anti-S versus anti-N), analyses will be stratified by type of test. For participants with positive results at both baseline and follow-up and if data allow, quantitative antibody results will be explored to qualitatively describe the possible contribution of re-exposure boosting antibody responses (versus persistence of an existing response). In sensitivity analyses, we will investigate the implications of misclassification of results due to imperfect sensitivity / specificity of the serological tests used. COMPLIANCE The study will be conducted in compliance with the approved protocol, the Declaration of Helsinki 1996, the principles of Good Clinical Practice as laid down by the ICH topic E6 (R2), General Data Protection Regulation and the UK Data Protection Act 2018 (DPA number: Z6364106), and the UK Policy Framework for Health and Social Care Research. Each cohort is responsible for ensuring compliance with local and national regulatory and ethical processes, and data protection.