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Abstract
Introduction Although SARS-CoV-2 vaccines were first approved under Emergency Use Authorization by the Food and Drug Administration in late 2020 for adults, authorisation for young children 6 months to <5 years of age did not occur until 2022. These authorisations were based on clinical trials, understanding real-world vaccine effectiveness (VE) in the setting of emerging variants is critical. The primary goal of this study is to evaluate SARS-CoV-2 VE against infection among children aged >6 months and adults aged <50 years.
Methods CASCADIA is a 4-year community-based prospective study of SARS-CoV-2 VE among 3500 adults and paediatric populations aged 6 months to 49 years in Oregon and Washington, USA. At enrolment and regular intervals, participants complete a sociodemographic questionnaire. Individuals provide a blood sample at enrolment and annually thereafter, with optional blood draws every 6 months and after infection and vaccination. Participants complete weekly self-collection of anterior nasal swabs and symptom questionnaires. Swabs are tested for SARS-CoV-2 and other respiratory pathogens by reverse transcription-PCR, with results of selected pathogens returned to participants; nasal swabs with SARS-CoV-2 detected will undergo whole genome sequencing. Participants who test positive for SARS-CoV-2 undergo serial swab collection every 3 days for 21 days. Serum samples are tested for SARS-CoV-2 antibody by binding and neutralisation assays.
Analysis The primary outcome is SARS-CoV-2 infection. Cox regression models will be used to estimate the incidence rate ratio associated with SARS-CoV-2 vaccination among the paediatric and adult population, controlling for demographic factors and other potential confounders.
Ethics and dissemination All study materials including the protocol, consent forms, data collection instruments, participant communication and recruitment materials, were approved by the Kaiser Permanente Interregional Institutional Review Board, the IRB of record for the study. Results will be disseminated through peer-reviewed publications, presentations, participant newsletters and appropriate general news media.
- COVID-19
- epidemiology
- paediatric infectious disease & immunisation
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Strengths and limitations of this study
CASCADIA will include a large sample of children and adults that will contribute to estimation of vaccine effectiveness.
The study will generate a data repository that can be used to address many research questions, such as duration of SARS-CoV-2 serological results, post-acute sequelae of COVID-19 and re-infection rates.
Retention and compliance may be challenging given the 4-year duration of the study.
Annual blood collection for assessment of humoral immunity may be a potential deterrent for participation, particularly among younger children.
Introduction
SARS-CoV-2, the virus that causes COVID-19 rapidly disseminated across the world and was declared a pandemic by the WHO on 11 March 2020.1 Up until 10 March 2023, COVID-19 resulted in over 676 000 000 cases and 6 800 000 deaths worldwide.2 Currently, in the USA over 103 000 000 cases of COVID-19 have been reported, resulting in over 1.1 million deaths.2
As of 11 May 2023, approximately 15.6 million children in the USA have tested positive for SARS-CoV-2, accounting for 17.9% of all COVID-19 cases in reporting states, New York City, the District of Columbia, Puerto Rico and Guam.3 Throughout the pandemic, paediatric infections have been milder than infections among adults, and have resulted in a lower frequency of hospitalisations, deaths and post-COVID conditions.4–6 However, disease burden has varied by variant strain. For instance, the emergence of the B.1.1.529 (Omicron) variant in the USA from September 2021 to January 2022 resulted in a 2.3 times higher peak hospitalisation rate among children aged 5–11 years than the peak rate during the B.1.617.2 (Delta) variant surge.7 With emerging variants of concern (VOCs), understanding infection and reinfection rates, and variant specific outcomes, will be important for future prevention planning.8–15
During the COVID-19 pandemic, a worldwide collaborative effort resulted in the development of COVID-19 vaccines shown to decrease mortality and severe morbidity from SARS-CoV-2 infection.16–19 Due to emerging VOCs, waning antibody levels, and increased neutralising antibody response following booster vaccines, booster vaccines have been implemented as a strategy for prevention of COVID-19 disease in several countries including the USA.20 21 Vaccine effectiveness (VE) estimates in the setting of novel VOCs may guide future vaccination strategies.
From November 2021 to June 2022, only the Pfizer-BioNTech vaccine had received authorisation for use among children aged ≥5 years for a primary vaccine series.22 In May 2022, a booster vaccine was approved under Emergency Use Authorization (EUA) for 5 years and older.2 On 17 June 2022, both BNT162b2 (Pfizer-BioNTech) and mRNA-1273 vaccine (Moderna) received approval under EUA for children 6 months and older.23 According to the CDC, 73.5% of the US population 5 years and older have received a COVID-19 primary vaccine series.24 Rates of vaccine uptake vary by age strata, as of 3 May 2023, 13% of 6 months to 4 years old, 39% 5–11 years old and 68% 12–17 years old have received at least one dose of a COVID-19 vaccine.25 Additionally, parental/guardian vaccine hesitancy may continue to delay paediatric vaccine uptake. As the landscape evolves with vaccine uptake, new emerging variants with potential for immune escape, and the introduction of novel vaccines, this longitudinal surveillance study will inform our understanding of VE.
In the CASCADIA study, active surveillance and testing protocols will systematically identify both asymptomatic and symptomatic SARS-CoV-2 infection. Enrolling a cohort of children as soon as possible after the recent EUA of bivalent paediatric vaccines enables us to estimate the real-world COVID-19 VE in a paediatric population. The serology components of the protocol will allow for the evaluation of humoral immune responses to SARS-CoV-2 infection and vaccination and will allow for comparisons of symptomatic and asymptomatic infections and for primary infection versus reinfection over time. The study data will aid in informing public health measures and vaccine strategies.
Aims
The primary study objective is to estimate the effectiveness of authorised COVID-19 vaccines against laboratory-confirmed symptomatic and asymptomatic SARS-CoV-2 virus infection among children aged 5 to <18 years. A secondary objective is to estimate VE among children 6 months to 4 years and adults 18 years of age. Additional primary and secondary objectives include evaluating humoral immune response following vaccination and infection, estimating secondary attack rates within households, and monitoring evolution of the SARS-CoV-2 virus by genomic sequencing (box 1). Exploratory objectives include evaluating the incidence and outcomes of other respiratory viruses including respiratory syncytial virus (RSV) and influenza (online supplemental table 1).
Supplemental material
CASCADIA study objectives
Primary objectives
Estimate vaccine effectiveness (VE) of authorised COVID-19 vaccines against laboratory-confirmed symptomatic and asymptomatic SARS-CoV-2 virus infection among children aged 5 to <18 years.
Estimate the incidence of laboratory-confirmed SARS-CoV-2 infection, including asymptomatic and symptomatic infections, among those 6 months to <50 years of age, and describe differences by age and other sociodemographic characteristics, health status or other risk factors.
Secondary objectives
Estimate VE of future authorised COVID-19 vaccines against laboratory-confirmed symptomatic and asymptomatic SARS-CoV-2 virus infection among children aged 6 months to 4 years.
Estimate VE of authorised COVID-19 vaccines against laboratory-confirmed symptomatic and asymptomatic SARS-CoV-2 virus infection among adults aged 18 to <50 years.
Identify demographic and clinical factors that modify the effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among children and adults.
Examine illness severity, duration of illness, and viral shedding (defined by detectable RNA and RNA levels) among vaccinated and unvaccinated children and adults with SARS-CoV-2 infection.
Estimate the incidence and characteristics of SARS-CoV-2 asymptomatic and symptomatic re-infections in children and adults and identify associated risk factors.
Describe transmission patterns and epidemiological characteristics of SARS-CoV-2 infection within households.
Genetically characterise SARS-CoV-2 viruses causing infection in unvaccinated as compared to breakthrough infection in vaccinated persons as compared to the overall genetic population in the region.
Describe the incidence of post-COVID conditions among vaccinated and unvaccinated persons.
Estimate VE of authorised COVID-19 booster doses for adults or children and describe the characteristics of adults and children receiving booster doses compared to those who do not.
Immunological objectives
Primary
Evaluate the effect of SARS-CoV-2 binding and neutralising antibody titres prior to infection on risk of infection with SARS-CoV-2 and evaluate factors including vaccination status (primary or booster), symptom status, age and virological risk factors for infection.
Secondary
Estimate VE of authorised COVID-19 vaccines in children and adults against serological infection.
Estimate the incidence of serological infection in children and adults and identify associated risk factors for seroconversion.
Evaluate the kinetics and half-life of SARS-CoV-2 spike, receptor-binding domain (RBD) and nucleocapsid binding and neutralising antibody in children and adults, and identify factors associated with increased half-life.
Evaluate the effect of additional doses of SARS-CoV-2 vaccine on SARS-CoV-2 spike, RBD and nucleocapsid binding and neutralising antibody titres.
VE, vaccine effectiveness.
Methods and analysis
Setting
The CASCADIA study is being conducted in Washington (WA) and Oregon (OR) through a collaboration between Kaiser Permanente Northwest (KPNW), University of Washington (UW) Medicine and Seattle Children’s Hospital (SCH).
Study design
CASCADIA is a prospective longitudinal cohort study of children and adults designed to evaluate VE against laboratory-confirmed SARS-CoV-2 infection, and to estimate the incidence of asymptomatic and symptomatic SARS-CoV-2 infection. Approximately 2400 children aged 6 months to 17 years and 1100 adults aged 18–49 years will be enrolled and followed for up to 4 years; the study population will be split equally between KPNW and UW/SCH. Households with multiple participants residing together will be prioritised for enrolment. The CASCADIA study is funded by the US Centres for Disease Control and Prevention (CDC). Investigators from KPNW, UW and SCH, in consultation with CDC, provided input on the study design, data collection instruments, laboratory testing procedures, data analysis and implementation of this study.
Recruitment
In the preceding months to study launch, preparation included reinitiating and building new relationships with community partners. Prior to the official study launch, a soft launch was conducted targeting 3–5 families per site (KPNW and UW) and feedback was collected prior to beginning general study enrolment. The soft launch led to improvements in participant facing materials and contributed to the broader recruitment strategy (figure 1). Recruitment strategies involve outreach to KPNW health plan members and local school districts and daycares; press releases and social media campaigns; and outreach to community-based organisations and other healthcare partners, prioritising those with strong ties to racial and ethnic minorities and low-income individuals, where possible. Recruitment activities will continue during the study to replace participants who withdraw and adapted to meet demographic and vaccination enrolment targets.
Tiered recruitment strategy. KPNW, Kaiser Permanente Northwest; UW, University of Washington.
Data collection
Data collection and survey implementation is performed through Research Electronic Data Capture (REDCap), a metadata-driven EDC software and database methodology designed at Vanderbilt University.26 Web-based surveys are completed by participants and are entered directly into the study REDCap database.
Screening
A central study website (www.cascadiastudy.org) enables potential participants to review information about the study and eligibility criteria (box 2) and watch a video that provides an overview of the study and explains what is involved in participating in the study. The website links to an eligibility screener that collects sociodemographic data, contact information, enrolment site and number of COVID-19 vaccines received. The website is available in English and will be available in Spanish. Study staff monitor data from the eligibility screener and eligible participants are contacted and scheduled for consent/assent and enrolment visits. Eligible participants are offered the opportunity to self-schedule their consent call or enrolment visit. Once enrolled in the study, participants are granted access to a secure household home page through REDCap and are assigned a unique participant identification number for the duration of the study.
Eligibility criteria
Inclusion criteria
Age 6 months to 49 years on the date of enrolment.
Access to the internet and telephone.
Willingness and ability to complete periodic data collection activities online.
Willingness to collect nasal swabs (either self-collected or collected by the child’s parent/guardian) and arrange pick-up time and location at least once per week for pick up and delivery of swabs.
Willingness to participate in an enrolment blood collection and a subsequent minimum of one blood collection per year.
Willing and able to provide consent or assent to participate.
Live within the Kaiser Permanente Northwest catchment area of Oregon and southern Washington, or within the University of Washington catchment area of King, Snohomish and Pierce Counties in Washington State.
Exclusion criteria
Participation in a clinical trial of investigational prevention therapies for SARS-CoV-2 infections, such as prophylactic antiviral medications or other immune system modifying interventions in the 3 months prior to enrolment.
Unwilling or unable to provide consent or assent to participate.
Registered in Kaiser Permanente Northwest exclusion database.
Unable to comply with study procedures, as determined by the investigators.
Enrolment and surveillance
Following the informed consent/assent process, participants are required to have or attempt a baseline blood draw and asked to complete an online enrolment survey (online supplemental table 2). Web-based surveys are used to collect data throughout the duration of the study with varying content by survey (online supplemental table 3). Study procedures are demonstrated in figure 2A,B (also see online supplemental table 4).
(A) CASCADIA annual study procedures; (B) Participant flow for COVID-19 like symptoms or positive SARS-CoV-2 testing.
Weekly surveys
Participants or their parent/guardian complete a weekly Symptom and Swabbing survey which asks if they have experienced >1 of the following symptoms for over 24 hours: fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhoea, persistent pain or pressure in the chest, pale, grey, or blue-coloured skin, lips, or nail beds.27–29 Each participant is then prompted to collect a weekly nasal swab. As part of the weekly Symptom and Swabbing survey, participants are asked whether they were tested for SARS-CoV-2 outside of the study and if they had a known exposure to COVID-19. Additionally, participants can report new symptoms when they occur outside their weekly Symptom and Swabbing survey reporting day.
Weekly illness update and recovery from illness
Once an acute illness or positive test for SARS-CoV-2 is identified (day 0), participants are asked to answer an Infection/Illness Onset Survey that captures specific symptoms, date of symptom onset, overall health status and potential COVID-19 exposures. Following this survey, participants or their parent/guardian complete a postinfection/illness follow-up survey on day 7 and day 14 after they reported symptom onset. These surveys assess symptoms, recovery, overall health status, additional effects of their infection/illness (eg, healthcare usage and work and school absenteeism) and COVID-19 prevention behaviours. A survey at day 30 following a positive SARS-CoV-2 test is completed to capture the continuation or resolution of symptoms, including illness/infection conditions, overall health status, and paediatric asthma/wheezing. Participants who test positive for influenza and RSV will also complete a 30-day postillness survey.
Additionally, positive SARS-CoV-2 study results trigger the serial collection of nasal swabs every 3 days for 21 days for both asymptomatic and symptomatic participants. If a participant reports a positive test for SARS-CoV-2 outside the study, they will be prompted to collect a study swab within 72 hours. If the study swab is positive for SARS-CoV-2, serial swabbing will be triggered.
Monthly survey and semi-annual survey
Following enrolment, updated job information, absenteeism, vaccination status, respiratory virus testing outside of the study and overall health status are collected on a monthly basis. The monthly survey involves rotating questions which may change during the study but could assess the receipt of influenza or other routine immunisations, participation in extracurricular activities, social and emotional burdens related to the pandemic, mitigation measures, and knowledge, attitudes, and perceptions about COVID-19 vaccines and therapeutics. The semi-annual survey will include additional post-COVID-19 conditions and lifestyle questions (online supplemental table 3).
Immunisation information systems
Sites will use data from state immunisation information registries to obtain vaccination information for participants, including the Washington State Immunization Information System and Oregon Health Authority ALERT Immunization Information System. For participants enrolled in the KPNW health plan, vaccination history will also be obtained from medical records. Participants are consented prior to accessing these databases.
Use of electronic medical record data
Medical records data from participants regarding COVID-19 hospitalisations, clinical respiratory virus testing, respiratory illness visits, and associated diagnostic tests and treatments will be used to supplement participant self-reported history of illness. Participants are consented at enrolment for medical release of information.
Respiratory specimens
Materials
Swab kits include instructions, a sealed nasal swab, a dry tube with a barcode sticker linked to the individual participant, a biohazard bag, and a preaddressed return polymailer bag (International Air Transport Association-compliant Category B; figure 3A–C). All specimen collection materials are Food and Drug Administration (FDA)-approved or authorised for SARS-CoV-2 reverse transcription (RT)-PCR testing. Direct shipments of kits are sent on a regular basis to ensure a continuous supply of swabs available to participants. For households with multiple participants, the collection kits for each household member are divided into separate boxes with labels used to designate each household member. At enrolment, each participant is asked to choose an animal, which is printed on a sticker that is used to label their swab kits and serve as a personal identifier throughout the study (figure 3D).
(A) Participant swab kit. (B) Participant swab kit contents. (C) TINY RHINOstic swab. (D) Participant animal stickers.
Collection and processing
TINY RHINOstic (anterior nares) (Rhinostics, Boston, MA) nasal swabs are being used for nasal specimen collection for all participants. For children aged 6 months to 12 years, a parent/guardian collects the nasal swab; swabs can be collected by a parent/guardian or self-collected under supervision of their parent/guardian for children aged 13–17.
All nasal swabs are dry and transported via courier service at ambient temperatures from participant households to the UW laboratory for processing. Specimens from the Portland, OR and Vancouver, WA area are transported to Seattle two times a day by courier. The limit of detection at 2–4 molecules/µL, includes 100% sensitivity and 99.4% specificity for SARS-CoV-2.30 Swabs are processed at the lab within 48 hours of receipt. A participant communications team is available by phone 7 days a week to assist participants.
Nasal swab testing
Nasal swab specimens are tested using a laboratory-developed RT-quantitative PCR (qPCR) assay for SARS-CoV-2. All swabs are stored dry without media and eluted with 300 µL Tris-EDTA for RHINOsticTM. 50 µL of eluate is treated with proteinase K and heat for direct RT-qPCR (Swab-Express RT-qPCR).31 The RT-qPCR assay uses probe sets for SARS-CoV-2 Orf1b and S gene (Life Technologies) against ancestral virus and are multiplexed with probe against RNaseP and set on a QuantStudio 6 instrument (Applied Biosystems).31 The laboratory is clinically certified to test for SARS-CoV-2 by the Washington State Department of Health. As funding permits, specimens will undergo multiplex RT-qPCR testing for SARS-CoV-2, influenza A/B and RSV A/B as well as other respiratory pathogens.
Viral genome sequencing will be attempted on all SARS-CoV-2-positive samples with an appropriate viral concentration. Genomes will be assembled according to standard bioinformatics methods. Genomes that meet quality metrics will be made publicly available in the Global Initiative on Sharing All Influenza Data and National Center for Biotechnology Information databases and categorised according to lineage.
Return of results
The UW laboratory will provide RT-PCR results for SARS-CoV-2. Testing results will be loaded into a REDCap module and linked to participant records that correspond to the barcoded specimen kits. In parallel, the testing results will be loaded into an online return of results portal. If a participant’s specimen tests positive for SARS-CoV-2, participants and or parents/guardians of participants will be contacted via text, email and/or phone for guidance on further study procedures. Positive SARS-CoV-2 results will be reported to local and state public health authorities to be compliant with notifiable disease reporting guidelines.
Serum and blood specimens
Collection and processing
All participants are asked to provide blood samples prior to enrolment and annually. Participants who consent for substudies may undergo additional blood draws and mucosal sampling every 6 months and following immunisations and/or illness.
We collect approximately 5 mL from children <13 years of age, and 20 mL from participants 13 years of age and older. For participants unable to provide a venous blood draw, a Tasso+ (Tasso, Inc) home blood collection device is being used.32
All samples are logged into REDCap using a blood sample collection form. Serum specimens are divided into aliquots labelled with the participant ID and an aliquot ID unique to each tube. At KPNW serum samples are temporarily stored at 4°C for up to 72 hours and subsequently stored in a −20°C or colder freezer prior to being shipped to UW laboratory. At UW or SCH, specimens are kept in a 4°C refrigerator for up to 96 hours at the clinical collection site and subsequently transported to the UW laboratory on wet ice by a courier service or by study staff. These samples are then aliquoted and stored at –20°C or colder in a temperature-monitored freezer until serological testing is performed. After testing, residual specimens are stored at −20°C or colder for long-term storage, and possible additional future testing in individuals in whom consent was obtained for additional testing. Aliquots may be sent to the CDC or to a CDC-designated laboratory for additional immunological testing or long-term storage.
Serological and cellular assays
ELISA or a quantitative electrochemiluminescence test (Mesoscale Diagnostics (MSD), Rockville, MD) for IgG, IgA, and potentially other antibodies for SARS-CoV-2, influenza, RSV and other respiratory pathogens may be used. The quantitative IgG assay will allow for assessing SARS-COV-2 infection risk by relative antibody levels following infection or vaccination. Briefly, a multiplexed MSD immunoassay will be used to measure the response to SARS-CoV-2 and other respiratory pathogens. 96-well plates coated with SARS-CoV-2 antigens (spike, receptor binding domain, nucleocapsid) or other respiratory pathogen antigens will be tested. Plates will be blocked, followed by addition of reference standards, controls, and samples in diluent buffer. After incubation, detection antibody will be added, followed by an additional buffer, and the plate will be read using a plate reader. Standards (eg, a WHO standard reference panel) for the different respiratory pathogens, will be included as part of assays for standardisation against an international standard and to ensure interlaboratory agreement. Standards and positive and negative controls will also be included as per the manufacturer’s instructions. Data will be analysed using the MSD software, followed by importation into R for further analysis and visualisation.
Additional assays that may be performed in a subset of samples include influenza serological assays, RSV neutralisation assays and ELISAs, cytokine assays, flow cytometry and cytokine multiplex assays for characterisation of the B and T-cell repertoire, as well as SARS-CoV-2 pseudovirus neutralisation assays for VOCs and wild-type neutralisation assays.
Participant retention
Participants are allowed to pause weekly study activities for reasons such as family event or vacations, by notifying study staff. Text messages, emails and phone calls that encourage participation are implemented at determined time intervals if participants do not complete weekly swabbing and symptom surveys for more than two consecutive weeks without notifying study staff. After 5 weeks of non-compliance with weekly swabbing and subsequent lack of response to study retention outreach, participants will be withdrawn from the study. Participants may be re-enrolled if a future response is received.
Patient and public involvement
Participants can provide feedback throughout the study. The study team reviews this feedback and study changes are made when possible. Study results are currently planned to be shared via interim newsletters and publications.
Remuneration
Participants are compensated for completion of weekly swab collection and surveys on a monthly basis. Participants receive further compensation for completing illness swab series and for visits for blood collection.
Data analysis
Vaccine effectiveness
For the VE objectives, Cox regression models will be used to estimate the incidence rate ratio (IRR) comparing individuals with different SARS-CoV-2 vaccination status, controlling for important demographic factors and other potential confounders. COVID-19 VE will be calculated as:
Cox regression models are well suited to account for censored person-time (as subjects disenrol) and time-varying exposures (as subjects become vaccinated or infected). Robust SEs will be used to account for clustering by household. VE will be estimated separately for the effectiveness in preventing all SARS-CoV-2 infection and then against symptomatic SARS-CoV-2 infection (defined by presence of symptoms and detection of SARS-CoV-2 by RT-PCR). VE will also be estimated for preventing medically attended SARS-CoV-2 infection; however, it is anticipated that power will not be adequate to calculate VE to prevent severe infection resulting in hospitalisation, intensive care unit admission or death.
The effect of the following covariates on VE estimates will be considered for all outcomes: sociodemographic characteristics (eg, age, sex, race and ethnicity), exposures (school, day care, extracurriculars, social), study site, percent of other household members vaccinated and community-level circulation of the virus. Stratified analyses will be conducted to estimate VE by age group, prior infection at enrolment (using seropositivity and self-reported infections), vaccine product, vaccine doses (primary series and boosters), and other factors, including time since last vaccination and prior infection. We acknowledge that this study is underpowered for paediatric VE and we will be exploring combining data with other CDC VE studies.
Incidence objectives
The crude incidence rate will be calculated as the ratio of the number of SARS-CoV-2 infections divided by the total person-time contributed by all study participants during the follow-up period. Participants’ person-time will be censored at the time of first infection during the follow-up period or loss from cohort. The 95% CI will be constructed based on a Poisson model of assumption. Incidence will be presented overall, and separately, for symptomatic and asymptomatic laboratory confirmed SARS-CoV-2. Incidence will also be stratified by vaccination status, age, sex, race and ethnicity, history of prior infection and other important risk factors. Funding permitted; the crude incidence rate will be calculated for other respiratory viruses.
Ethics and dissemination
All study materials including the protocol, informed consent forms, participant communications and recruitment materials, data collection instruments and other documents associated with the protocol were approved prior to study implementation. The Kaiser Permanente Interregional Institutional Review Board (KPiIRB) serves as the IRB of record for the study, with UW, SCH and CDC ceding to the KPiIRB. Results will be disseminated through peer-reviewed publications, presentations, participant newsletters and appropriate general news media.
Assessment of harm and adverse events
Breaches of confidentiality, protocol deviations and adverse events are tracked by the study team. Events determined by the principal investigators to meet reporting criteria are submitted to the IRB.
Study status
The study enrolment period began in June 2022 and enrolment is ongoing. Data collection is planned to end in September 2026.
Discussion
The CASCADIA study is enrolling participants in order to estimate the incidence of asymptomatic and symptomatic SARS-CoV-2 infection and real-world COVID-19 VE in children and adults. Additionally, our study allows for the evaluation of humoral immune response following vaccination and infection, estimation of household transmission of SARS-CoV-2 in children and adults, and monitoring of the evolution of the SARS-CoV-2 virus by genomic sequencing.
This study design has several strengths. The CASCADIA study uses a remote web-based survey model which allows for access to a larger population and captures sociodemographic, clinical and behavioural characteristics of persons before, during and after a respiratory illness from SARS-CoV-2. The surveys are designed to collect comprehensive data but are not time consuming for participants. The 4-year study design and collection of weekly respiratory samples will allow us a standardised methodology for capturing VE, including both symptomatic and asymptomatic infection. This study allows for the collection of data regarding community-based transmission among children and adults in persons who might not have otherwise sought medical care or testing. Weekly nasal swab collection captures presymptomatic, symptomatic and asymptomatic SARS-CoV-2 infection. Additionally, the inclusion of blood specimens will allow us to assess the kinetics and durability of immune response following infection and vaccination. By using multiplex molecular testing, immunity to variants of SARS-CoV-2 will be assessed. This assay was used previously to recognise community transmission in the beginning of the SARS-CoV-2 pandemic in the USA.33 34 Genomic sequencing of SARS-CoV-2 will provide information about circulating variants strains, intrapatient virus evolution, and changes in household or community transmission patterns. The rotating design of the monthly surveys allows for flexibility in data collection which may change as the study progresses.
In studies evaluating VE in the paediatric population, medical care and symptomatic infection are typical endpoints.35–39 The CASCADIA study will collect longitudinal information in a paediatric and adult cohort using a weekly swabbing study design to evaluate the clinical spectrum SARS-CoV-2 infection, spanning asymptomatic viral shedding to severe disease. The prospective design and active surveillance within the study allows for the identification of risk factors leading to symptomatic and asymptomatic infection.
This study has limitations. Given the study design, a selection bias of pro-medical and vaccinated persons will likely occur. Enrolment of persons with distrust of the medical community may be difficult and under-enrolment of unvaccinated persons is expected. The web-based survey design may introduce selection bias and limit generalisability. Recruitment efforts will be adapted throughout the enrolment period to ensure a diversity of study participants. Given the longitudinal nature of the study, retention and consistency will need to be monitored and carefully maintained. Annual blood collection may be a limitation for child participants and if a hindrance to enrolment, this mandatory requirement may require re-consideration. Additional methods such as a Tasso+ (Tasso, Inc) may improve blood collection participation.32
In conclusion, this study design allows for large population surveillance of SARS-CoV-2 and other respiratory viruses with a predominantly remote, web-based structure to inform on real-world VE in children and adults.
Ethics statements
Patient consent for publication
Acknowledgments
Deralyn Almaguer, Britt Ash, Kristi Bays, Tara Beatty, Trevor Bedford, Kristin Bialobok, Allison Bianchi, Cathleen Bourdoin, Stacy Bunnell, Joseph Cerizo, Evelin Coto, Phil Crawford, Lantoria Davis, Lisa Fox, Kenni Graham, Tarika Holness, Madison Hollcroft, Matt Hornbrook, Keelee Kloer, Dorothy Kurdyla, Max Lin, Natalie Lo, Kyle Lutein, Richard Martin, Melissa P MacMillan, Ariana Magedson, Denise McCulloch, John Ogden, Aaron Piepert, Joanne Price, Angela Reyes-Ochoa, Jennifer Rivelli, Sperry Robinson, Katrina Schell, Emily Schield, Jay Shendure, Anna Shivinsky, Valencia Smith, Jeremy Stone, Alexandra Varga, Mica Werner.
References
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 TMB, LRF, SS, ZA, CLB, MB-H, AC, SNC, BE, JAE, SPF, CJF, MC, HG, PDH, JLK, TL, CMM, RAM, TO, SLR, MAS, NS, LS, JS, MV, AAW, CRW, HYC, ALN provided substantial contributions to the conception and design of the work, approved the final version of the manuscript, and are in agreement to be accountable for the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding This study was supported by the Centers for Disease Control and Prevention contract 75D30121C12297 to Kaiser Foundation Hospitals.
Disclaimer This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Competing interests HYC reports consulting with Ellume, Pfizer, The Bill and Melinda Gates Foundation, Glaxo Smith Kline, and Merck. HYC received research funding from Gates Ventures, Sanofi Pasteur, and support and reagents from Ellume and Cepheid outside of the submitted work. JAE reports research support from Gates Ventures, AstraZeneca, GlaxoSmithKline, Merck, and Pfizer, and consulting with Sanofi Pasteur, AstraZeneca, Teva Pharmaceuticals, and Meissa Vaccines, outside of the submitted work. ALN reports research funding from Pfizer and Vir Biotechnology, outside of the submitted work. JLK reports research funding from Vir Biotechnology, outside of the submitted work.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods and analysis section for further details.
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.