REVISED SOW Seattle.pdf

Section C - Statement of Work

Title: Longitudinal study of COVID-19 antibody response in children in Seattle WA

C.1 Background and Need

Proposal: We propose to expand an existing IRB-approved study examining immune responses of children to SARS-CoV-2, influenza and respiratory syncytial virus (RSV) infections in our submission, Longitudinal study of SARS-CoV-2 antibody response in children in Seattle, WA.

This project addresses CDC’s BAA 75D301-20-R-67897 issued on March 11, 2020, Topic Area

1.2: Natural history of SARS-CoV-2 infections among special populations.

Background: Limited data on immune responses following SARS-CoV-2 infection is available, and data on immune responses in children is even more limited. There are currently no data regarding the kinetics and duration of antibody responses following infection in children of various age groups, or diverse underlying health conditions and descriptions of quantitative IgG and IgM levels and neutralizing antibody are lacking. Preliminary data on antibody kinetics will be available soon for critically ill adults, but data in children will likely not be generated given the low hospitalization rates. This is a serious shortcoming, as children are likely to be a major target population for any future SARS-CoV-2 vaccines. We are uniquely positioned to characterize the immune responses in healthy and immunocompromised or high-risk children of all ages infected with SARS-CoV-2 and conduct longitudinal serosurveillance using a variety of methodologies. We will leverage our laboratory expertise in assessing immune responses to viruses to assess qualitative and quantitative IgG, IgM, and neutralizing antibody responses to

SARS-CoV-2 infection and vaccine.

This study contains four substudies: 1) Prospective study of SARS-CoV-2+ children, some of whom may be vaccinated during the course of the study, to assess clinical outcomes and to assess infection- and vaccine-acquired immune responses; 2) Prospective study of pediatric solid organ transplant recipients, some of whom may be vaccinated during the course of the study, to assess SARS-CoV-2 incidence and to assess vaccine-acquired immune responses; 3) Prospective study of vaccinated immunocompetent children to assess immune response to vaccination; and 4)

Evaluation of residual sera monthly to assess seroprevalence. Processes for biospecimen collection and analysis are already established under our existing IRB-approved protocol. At least 50 children between the ages of 0 and 18 years with known or suspected SARS-CoV-2 infection based on PCR testing, serological testing, or clinical history will be recruited for participation in the base year. In this study, up to 3 venous blood samples will be collected per patient in the first year of the study, starting at ~2, 6, and 12 months after infection or illness onset. In addition to these SARS-CoV-2+ children, 100 immunocompromised (IC) solid organ transplant recipients will be screened serologically every 6 months for antibody to SARS-CoV-2.

These IC children will be invited to enroll in the longitudinal serological study if antibody (Ab) to SARS-CoV-2 is detected. In addition, 400 residual clinical sera are to be collected and analyzed monthly in the base year to assess IgG antibody to SARS-CoV-2. Residual sera will be obtained from children seeking healthcare at Seattle Children’s Hospital and Clinics. Electronic data collection tools are already in use to collect demographics, hospitalization data, laboratory results, vaccine history, clinical information including respiratory support, ICU admission, length of stay, and laboratory studies including viral testing, and medical history including chronic underlying medical conditions, as well as to assess clinical status during the one-year followup period.

BAA Option 1 (period of performance: 3/1/2021-5/31/2022) will support three substudies

(longitudinal followup of at least 50 SARS-CoV-2+ patients, longitudinal followup of 100 solid organ transplant (SOT) recipients, and evaluation of residual sera) for an additional year. The

Government must exercise each option period prior to the Contractor beginning work.

BAA Option 2 (period of performance: Date of award-7/31/2023) will support further longitudinal followup of SARS-CoV-2+ patients and select solid organ transplant (SOT) recipients. Additionally, we will evaluate long-term immune effects of vaccination among 1) children in the longitudinal arm and SOT arm who have become vaccinated since enrollment, and 2) newly enrolled pediatric patients, who have been recently vaccinated, are immunocompetent, and have no known history of SARS-CoV-2 infection prior to vaccination. If possible we will continue the population arm of the initial study, testing up to 200 residual samples per month. The government must exercise each option period prior to the Contractor beginning work.

Our proposals are appropriate for a study conducted in a targeted population during a pandemic, particularly when both personnel and protective equipment are limited and collecting blood samples is crucial. Our project is proposed by a group with experience in respiratory viral surveillance, longitudinal clinical studies, care of special high risk pediatric populations, and serological studies in children.

C.2. Project Objectives

1. Examine the quantity and quality of SARS-CoV-2 specific IgG and neutralizing antibody levels and kinetics over time in children enrolled in a longitudinal clinical study. Blood samples will be obtained at approximately 2, 6, 12, 18, 24, and 28-36 M following infection as these timepoints fall within the contract period of performance

2. Describe the longitudinal long-term symptoms and signs of COVID-19 disease in children 0-18 years of age, beginning at 1-2 months (M) following diagnosis, including an assessment of respiratory symptoms, activity, and impact on overall functioning.

3. Investigate seroprevalence, antibody responses and secondary clinical outcomes relevant to high-risk pediatric populations, including solid organ (renal, intestine, heart, and liver) transplant recipients.

4. Examine the seroprevalence of SARS-CoV-2 specific IgG antibody levels by chemiluminescence immunoassay and validation of this antibody by a different laboratory method (such as ELISA or pseudoneutralization assay) in residual laboratory samples from children seeking medical care.

5. Evaluate the long-term vaccine induced antibody response up to approximately 12 months post vaccination in immunocompetent children with and without a history of prior SARS-CoV-2 infection as well as in immunocompromised children.

The goal of BAA Option 1 is the longitudinal study of SARS-CoV-2 antibody response in children in Seattle WA. During this period the contractor will: 1) Characterize antibody longivity in children previously infected with SARS-CoV-2, 2) Estimate the incidence of SARS-

CoV-2 infection in pediatric solid organ transplant patients, and 3) Assess the prevalence of

SARS-CoV-2 specific antibody in a pediatric population seeking healthcare as both outpatients and inpatients.

The goal of BAA Option 2 is to continue to characterize SARS-CoV-2 antibody response in children, and to assess the prevalence of SARS-CoV-2 specific antibody in a pediatric population seeking healthcare as both inpatients and outpatients if possible. During Option 2, the contract will also evaluate long-term vaccine-induced antibody response at approximately 6 and 12 months post vaccination in immunocompetent children with and without a history of prior infection as well as immunocompromised children.

C.3 Scope of Work

The objective of this project is rapid extension of an IRB- approved protocol and currently working infrastructure (screening, specimen collection, and testing capacity) to quickly establish a unique and underrepresented cohort of at least 50 children infected with SARS-CoV-2, to quantify pediatric immunity over time (including after vaccination), to identify seroprevelance in hospitalized children, and to describe the characteristics, demographics and clinical outcome of children with various underlying conditions and varying severities of SARS-CoV-2 infection

(COVID-19 disease).

BAA Option 1 (period of performance: 3/1/2021—5/31/2022) will serve to:

1. Follow the original cohort of at least 50 COVID-19 infected children over a second year, assuming an 80% continuation rate.

2. Enroll up to 15 additional children with a positive SARS-CoV-2 PCR test or possibly children from the SOT and population (residual sera) arms who test positive for antibody

(using CMIA) and consent to participate in the longitudinal arm. Children will be followed until the end of BAA Option 1. The number of additional enrollees will be dependent on the rate of drop out, aiming for a target of 55 evaluable enrollees who participate for at least 6 months.

3. Follow the original 100 solid organ transplant (SOT) recipients (renal, intestine, liver, heart) for an additional 6 months.

4. Conduct serosurveillance for SARS-CoV-2 antibody on residual sera from 200 children per month (2400 additional samples). Residual sera samples will be from children seeking inpatient or outpatient medical care at a Seattle Children’s facility.

BAA Option 2 (period of performance: date of award--5/31/2023) will serve to:

1. Follow the original cohort of COVID-19 infected children for a third year. Timing of blood sample collection, and testing performed will depend on enrollee’s vaccination status

2. Follow all children from the SOT arm who become vaccinated while enrolled in the study, and assess pre-vaccination immune responses and vaccine-induced immune responses at multiple time points up to 12 months post-vaccination.

3. Follow 50 recently vaccinated, immunocompetent children without prior history of

SARS-COV-2 infection for approximately12 months after vaccination.

4. Test a subset of participants to explore variant specific antibodies if possible.

5. If possible, conduct serosurveillance for SARS-CoV-2 antibody on residual sera from up to 200 children 11 years of age or younger per month (up to 2400 additional samples).

C.4 Technical Requirements

Our deliverables are categorized and described below.

Organizational and Scheduled Meetings: A phase ongoing throughout the study from initiation to completion

• Investigator/Kickoff Meeting—The investigator meeting will be a onetime occurrence for sponsor-site communication prior to protocol implementation.

• CDC Update Calls—Monthly conference calls will be used to maintain open communication with the CDC and to discuss results, challenges and/or successes. During

BAA Option 2, update calls will be held bi-monthly until enrollment is complete or as the

CDC and Offerer agree.

• Protocol Implementation Meeting (PIM)—This is a meeting hosted by the site to train study staff and research laboratory team.

• Research Laboratory Services (PIM)—This meeting is to confirm logistics of biospecimen collection, processing, storage, and shipment in accordance with the protocol and Bloom Laboratory requirements.

• Monthly Dashboard Reports—This report will be emailed to the CDC monthly for the duration of the study.

• Interim Dataset – These datasets will be securely transmitted to the CDC every six months for the duration of the study.

• Final Dataset —This dataset will be the final dataset securely transmitted to the CDC upon completion of the study.

• Annual Report—This report will summarize the past year’s activities, accomplishements, and challenges. It will be emailed to the CDC within two months following the completion of each year of the study.

Enrollment of SARS-CoV-2 positive children, immunocompromised (SOT) children, and immunocompetent children without history of SARS-CoV-2 infection:

Population Screening—Hospitalized patients will be screened by research staff on weekdays using admission diagnosis code(s) or laboratory testing results. Potential community participants will be screened through community based pediatric clinics that this team has previously established working relationships with and self-referral. These data will be shared with the CDC via dashboard on a monthly basis for the duration of the study.

• Demographic Dashboard and Dataset Reports—Demographic data will be collected from all enrolled participants and reported in monthly dashboard and biannual interim dataset reports. This includes age, sex, ethnicity, race, and other demographic variables including underlying conditions or diseases, as mutually agreed upon by the Offeror and the CDC. The dashboard reports will be shared with the CDC via email on a monthly basis for the duration of the study. The interim dataset reports will be securely transmitted to CDC every six months for the duration of the study. For BAA Option 2:

the dashboard for children enrolled in the vaccine arms will be created in conjunction with CDC and the Offeror.

• Participant Informed Consent—Informed consent, and assent as appropriate by age, will be obtained from all participants in the longitudinal serological followup study via a phone or video conversation with parent/guardian of a potential participant. In addition, informed consent will also be obtained from patients with underlying immunosuppression due to solid organ transplant (SOT) for serosurveillance without presumed evidence of prior infection with SARS-CoV-2, and from recently vaccinated immunocompetent children without history of SARS-CoV-2 infection. This report will be shared with the CDC via dashboard on a monthly basis for the duration of the study.

• Enrollment of SARS-CoV-2 positive children, immunocompromised children, and recently vaccinated immunocompetent children without history of SARS-CoV-2 infection—Enrollment of at least 50 SARS-CoV-2 positive children over 6 M in the base year, and ~ 15 new children in BAA Option 1 for participation in longitudinal serological followup. The number enrolled in BAA Option 1 (period of performance: 3/1/2021—

5/31/2022) will, in part, be dependent on the number of base year enrollees who drop out, with a target of at least 55 evaluable children who participate for at least six months.

Enrollment of 100 pediatric recipients of solid organ transplants in the base year for the prospective study of immunocompromised children. In BAA Option 2, 50 vaccinated immunocompetent children with no self/caregiver-reported history of SARS-CoV-2 infection will be enrolled ideally within 3 months, but no later than 6 months post vaccination. Data will be shared with the CDC via dashboard on a monthly basis for the duration of the study. This dashboard will minimally include number of children enrolled in each study arm by age group.

• Symptom & Clinical Dashboard and Datasets —Data related to SARS-CoV-2 will be collected from enrolled participants in the longitudinal study arm, and will be reported in monthly dashboard and biannual interim dataset reports. Data will include hospitalization data, lab results, vaccine history, acute illness history, symptoms, clinical information including respiratory support, ICU admission, length of stay, laboratory studies including viral testing, vital status, and medical history including chronic underlying medical conditions. This information will be recorded in REDCap, the electronic data capture system for this study. High level data will be shared with the CDC via dashboard on a monthly basis for the duration of the study. The interim dataset will be securely transmitted to CDC every six months for the duration of the study. During

BAA Option 2, the datasets submitted every six months will also include vaccine-induced immune responses.

• Monthly Contact—Parents of enrolled participants with SARS-CoV-2 infection and/or participants themselves, as possible, will be contacted monthly for the first 3 months following diagnosis and then every 6 months thereafter via their preferred contact method

(phone, email, text, etc.) to complete a survey to assess duration of ongoing symptoms and return of normal activity, respiratory status, and sleep patterns. Questions regarding healthcare-seeking behavior, absenteeism from school, respiratory symptoms, and energy levels will in particular be included. Data will be recorded in REDCap and shared during conference calls with the CDC quarterly for the duration of the study.

Obtain Blood Samples:

• Collect baseline blood samples —Baseline blood samples will be collected from all participants enrolled in the longitudinal study arm. This sample time point will occur at approximately 4-8 weeks post SARS-CoV-2 infection when antibody is likely present and PPE usage may be decreased or not necessary. Baseline blood samples will be collected during routine Transplant Clinic followup for the participants enrolled in the

SOT study arm. During BAA Option 2, baseline blood samples will be collected from the newly enrolled immunocompetent participants if needed to confirm infection status.

Data regarding number of baseline samples collected will be shared with the CDC via dashboard on a monthly basis for the duration of the study.

• Collect follow up blood samples—In the longitudinal arm, blood samples will be collected at 1-2 M, 6 M, 12 M, 18 M, 24 M, and 28-36 M following infection as these timepoints fall within the contract period of performance. During BAA Option 2, for longitudinal arm enrollees who are vaccinated, this schedule will be adjusted so that blood samples will be collected approximately 6 and 12 months after vaccination. For participants enrolled in the SOT study arm, blood samples will be collected every 6 months during routine Transplant Clinic follow up at 6 M and 12 M (in base year) and 18

M (in BAA Option 1). During BAA Option 2, SOT arm enrollees who have been vaccinated will continue to have blood samples collected at routine Transplant Clinic follow up visits. DData regarding number of follow up samples collected will be shared with the CDC via dashboard on a monthly basis for the duration of the study.

• Collect residual clinical sera samples—This phase will begin in month 1. Clinical blood sample residuals will be salvaged from the clinical lab weekly for the population arm. 400 samples per month per year for base year and 200 samples per month during

BAA Option 1 of the study as previously described. During BAA Option 2, up to 200 samples per month will be collected from children 11 years of age or younger if possible.

All residual sera from the Seattle Children’s Hospital Laboratory will be collected approximately 3-5 days after blood has been drawn, de-identified, cataloged and aliquoted for screening of SARS-CoV-2 antibody at the Seattle Children’s Hospital

Laboratory. Data regarding number of residual sera samples collected will be shared with the CDC via dashboard on a monthly basis for the duration of the study.

Evaluate residual sera for SARS-CoV-2 specific IgG antibodies: This effort is aligned with screening through enrollment and study completion.

• Sera evaluation using nucleocapasid-specific IgG assay—During the Base and BAA

Option 1 periods, all serum aliquots will be rapidly screened for IgG at Seattle Children’s

Clinical Laboratory using the Abbott ARCHITECT platform with the CMIA method

(chemiluminescent microparticle immunoassay). Children from the SOT study arm whose samples test positive for IgG by CMIA will be invited to participate in the longitudinal portion of the study. Children in the population study arm whose samples test positive for IgG by CMIA, and who have supporting information to indicate timing of SARS-CoV-2 infection, will be invited to participate in the longitudinal portion of the study. During BAA Option 2, samples from children who remainin the longitudinal arm will continue to be screened for IgG by CMIA. Results will be shared with the CDC via dashboard on a monthly basis, and via an interim dataset report every 6 months for the duration of the study.

• Test for binding and neutralizing antibodies: During BAA Option 2, blood from vaccinated children in all arms will be evaluated using FDA approved/EUA authorized quantitative or semi-quantitative anti-nucleocapsid-specific and spike-specific IgG assay(s) and (pseudo)neutralization assay(s) selected in consultation with CDC. For enrollees from the longitudinal and SOT arms, ideally a sample from pre-vaccination as well as approximately 6 and 12 months post vaccination samples also will be tested. If possible, during BAA Option 2, an assessment of variant-specific neutralizing anti-body levels or variant-specific quantitative binding antibody levels will be conducted on a subset of enrollees. Also if possible during BAA Option 2, further analyses will occur on blood collected from both vaccinated and unvaccinated enrollees in the longitudinal arm who have had at least 2 blood samples collected during the Base and BAA Option 1 periods. This will include a retrospective analysis of previously collected blood as well as any additional samples collected from unvaccinated enrollees during BAA Option 2.

This analysis will use EUA authorized or FDA approved anti-S quantitative/semi-quantitative and anti-N specific assay (s) selected in consultation with CDC. Results will be shared with the CDC via dashboard on a monthly basis, and via an interim dataset report every 6 months for the duration of the study.

Validate Sera with Confirmatory Antibody Assay: A phase aligned with screening through enrollment and study completion.

• Sera validation using spike/RBD-specific IgG and/or pseudoneutralization—In the base period (6/1/2020 to 5/31/2022), sera with evidence of IgG by CMIA on the Abbott

ARCHITECT platform will be validated with a spike/RBD ELISA and pseudoneutralization assay using the methodology of the Bloom laboratory. In BAA

Option 1, samples from the longitudinal study arm with evidence of IgG by CMIA on the

Abbott ARCHITECT platform will be validated with pseudoneutralization assay, but not with spike/RBD ELISA. (See Table 1 below). In BAA Option 1, samples from the SOT study arm and the population arm will not undergo any sera validation with either the the spike/RBD ELISA or the psueneutralization assays (see Table 1 below). Further assays, such as additional ELISA assays may be performed on select samples.

All testing results with be shared with the CDC during conference calls and via dashboard on a monthly basis and via interim dataset reports every 6 months beginning at one year, for the duration of the study. Because of the need to assess samples for pseudoneutralization from the same patient with the same reagents at the same time, samples from the longitudinal and SOT study arms will likely be evaluated once per subject per year. Note that pseudoneutralization assays for residual sera will be run on a quarterly basis starting approximately 15 months into this study . These pseudovirus assay results will be shared with the CDC via dashboard on a quarterly basis starting at 6 months for the duration of the study.

Follow-up clinical data at 1-2 M, 6 M, 12 M, 18 M, 24 M, 28-36 M as these timepoints fall within the contract period of performance: This phase is aligned from enrollment through study completion.

• Follow-up Clinical Data—Participants enrolled in the longitudinal arm will be contacted at 1-2 M, 6 M, 12 M, 18 M, 24 M, and 28-36 M following disease onset as these timepoints fall within the contract period of performance via their preferred contact method (phone, email, text, etc.) and will complete a brief survey to assess duration of ongoing symptoms and return of normal activity and sleep patterns. During BAA Option

2, the timing of this data collection will be adjusted to correspond to time of blood sample collection for vaccinated participants in the longitudinal arm. During BAA

Option 2, vaccinated participants in the SOT arm and newly enrolled immunocompetent children will complete a survey at enrollment and at the time of their blood draws. Data will be recorded in REDCap and will be shared via dashboards, during conference calls with the CDC quarterly and via interim dataset reports every 6 months for the duration of the study.

Table 1: Blood Testing Algorithm by Study Arm and Time of Specimen Collection

Longitudinal arm Solid Organ Transplant arm Population (residual) arm Immunocompetent arm; no Hx of infection (BAA Option 2)

Specimens collected in Months 1-

Specimens collected in BAA Option 1

Specimens collected in BAA Option

Specimens collected in Months 1-

Specimens collected in BAA Option 1

Specimens collected BAA Option

Specimens collected in Months 1-

Specimens collected in BAA Option

Specimens collected in BAA Option

Specimens collected in BAA Option 2

Abbott CMIA

(evaluation)

X x X x x x X (X)

Semi Quantitative/

Quantitative anti- S assay

(X) (X) X if vaccinated

(X) if un-vaccinated

X (X) X

S/RBD ELISA

(validation)

X x x

Anti-N specific assay (not Abbott

CMIA)

(X) (X) X if vaccinated

(X) if un-vaccinated

X (X) X

(Pseudo) neutralization x x X x

X x

X

(X) = testing performed if possible