Recruitment and screening
Participants will be recruited from up to 20 academic affiliated, IDCRC sites throughout the U.S. Study staff will inform potential participants/legally authorized representatives of the study, obtain informed consent, and determine study eligibility.
Screening and enrollment visits will occur sequentially or on the same day. Study staff will collect baseline information on participants (e.g., demographics, medical history, obstetric history, history of respiratory illnesses) (Tables 1 and 2). Pregnant individuals who meet all eligibility criteria will be enrolled. Infants born to pregnant individuals will become study participants upon delivery and maternal consent. Postpartum individuals who meet all eligibility criteria will be enrolled along with their infants. Once enrolled, each individual will be registered in a study database. Enrollment will continue until number of participants is reached for a particular vaccine type/study group. If new vaccines receive EUA or licensure, vaccine types will be added.
For women enrolled during pregnancy, a pre- and post-vaccination serology will be obtained if the subject had not received a vaccine prior to screening/enrollment, and post-vaccination serology will be obtained at any time after receipt of vaccine at the time of screening/enrollment if the subject had previously completed their full vaccination series. Routine follow-up visits for the women and infants include hospital delivery date, 2 weeks, 2, 6, and 12 months postpartum. Routine visits for postpartum women and their infants include visits at 2 weeks postpartum (or earliest enrolled date), 28 days (+/− 14) after last vaccination/ ≤3 months postpartum, 6 and 12 months postpartum. All routine visits will consist of obtaining updated clinical data, concomitant medications, collection of venous blood for antibody assays, obtaining date(s)/type of COVID-19 vaccine, date and severity of confirmed COVID-19 illness, and optional collection of breast milk samples (Tables 1 and 2). Unscheduled visits may be needed to complete study procedures that could not be conducted at the routine visits.
Outcomes of pregnancy, both maternal and fetal/infant, will be collected. Since this is an observational protocol, no serious adverse events (SAEs) or adverse events of special interest (AESIs) will be collected during this study. Potential non-serious adverse events that could occur in association with study procedures such as blood sample collection will be reported to the IRB. Maternal outcomes that will be recorded include death of mother or fetus, maternal hospitalization or prolonging of existing hospitalization, or important medical events reported after vaccination requiring treatment. Infant outcomes that will be recorded include neonatal or infant death through 12 months post-delivery, infant hospitalization, a congenital defect or genetic anomaly, preterm delivery/prematurity (defined as live birth prior to 37 weeks gestation). The assessment of these maternal and infant events will be harmonized by using existing Brighton Collaboration case definitions .
Pregnancy outcome data include the type of delivery (e.g., vaginal vs. Cesarean section), and any complications during labor and delivery for both the mother as well as the neonate. Neonatal assessments include but are not limited to gestational age, birth weight, Apgar scores, congenital and genetic abnormalities, infection, hematological and metabolic complications, admission to nursery or NICU and the need for respiratory support or other life sustaining interventions.
All information on COVID-19 cases during the study will be collected via medical records including polymerase chain reaction (PCR) or antigen testing results and severity of illness.
Primary and secondary endpoint assays to determine serum levels of total and SARS-CoV-2 antigen-specific immunoglobulin G (IgG)  and live  and pseudovirus [ 18] neutralizing antibodies will be performed at central IDCRC laboratories utilizing qualified assays (Table 4). Reagents will include vaccine-matched and emerging variants to evaluate the ability of variants to escape antibody generated by vaccine in this cohort. Additional exploratory endpoint analyses may include Ig subclass, and SARS-CoV-2 IgG Fc glycosylation (Table 4) .
Measurement of total and SARS-CoV-2 antigen-specific immunoglobulin IgA (IgA) and IgG and live and pseudovirus neutralizing antibodies will be performed at the same central laboratories as with serum (see above and Table 4). These assays are being qualified using breast milk samples from vaccinated and/or COVID-19 infected women.
The collection of whole blood and its processing for peripheral blood mononuclear cells (PBMC) in a subset of participants and/or subset of clinical sites are under discussion in order to conduct additional ancillary studies (Table 4).
Data collection, quality and management
Data collection is the responsibility of the study personnel at the participating clinical study site under the supervision of the site PI. During the study, the site PI must maintain complete and accurate documentation for the study.
The site PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data reported. All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.
Copies of the electronic Case Report Form (eCRF) will be provided for use as source CRFs, as needed, and maintained for recording data for each subject enrolled in the study. Data reported in the eCRF derived from source CRFs should be consistent or the discrepancies should be explained.
The data coordinating center for this study will be responsible for data management, quality review, analysis, and reporting of the study data.
Clinical (including, but not limited to, AEs, concomitant medications, medical history, physical assessments) and immunogenicity data will be entered into a 21 CFR 11-compliant Clinical Data Management System provided by the data coordinating center. The data system includes password protection and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the CRFs completed by the study personnel.
This study will generate descriptive data that is supportive of the hypothesis that COVID-19 vaccines elicit adequate immune responses among pregnant and postpartum individuals and will describe the transplacental antibody transfer for SARS-CoV-2 and serum SARS-CoV-2 antibodies in mother and infants of vaccinated mothers.
Approximately 200 pregnant individuals and their infants and up to 65 postpartum individuals and their infants per SARS-CoV-2 vaccine type (Groups 1–4) will be enrolled in this protocol. Two additional groups (Groups 5 and 6) have been added since beginning enrollment following approval of administration of a booster dose in late 2021. It is important to generate data on kinetics and durability of maternal and infant antibodies for all vaccine regimens, including those with additional doses beyond the primary series administered during pregnancy. Figure 1 illustrates the study precision of estimation of GMT of Neut antibodies the study with various sample sizes using Phase 1 data from the Pfizer, Moderna, and Janssen COVID-19 vaccines [26,27,28]. In addition, there will be good precision for estimation of transplacental transfer ratios.
The analysis groups are:
Group 1: Individuals who receive a COVID-19 vaccine during pregnancy (up to 200 individuals per vaccine type).
Group 2: Individuals who receive a COVID-19 vaccine postpartum (up to 65 individuals per vaccine type).
Group 3: Infants of individuals who receive COVID-19 vaccine during pregnancy (approximately 200 infants per vaccine type).
Group 4: Infants of individuals who receive COVID-19 vaccine postpartum (approximately 65 infants per vaccine type).
Group 5: Individuals who receive additional COVID-19 vaccine(s) (booster) during pregnancy (up to 200 individuals).
Group 6: Infants of individuals who received additional COVID-19 vaccine(s) (booster) during pregnancy (approximately 200 infants).
The study will not randomize participants between vaccines, and statistical analyses will seek to adjust for covariates when deemed appropriate to account for potential confounders. All analyses will be done by vaccine type and/or platform or vaccination regimen on all available data, and analyses for each endpoint are outlined in Table 5. Multiple imputation may be used if there is substantial missingness. Additional analysis details will be included in a statistical analysis plan.
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