Janssen Jcovden® Post-Authorisation Safety Study

Background

The European Commission authorized the Ad26.COV2.S vaccine for individuals aged 18 and older on 11 March 2021 and requested a post-authorization safety study to evaluate the vaccine's safety profile in real-world settings.

Objectives

To assess the association between the Ad26.COV2.S vaccine and 36 prespecified adverse events of special interest (AESIs) within the VAC4EU framework and to compare the risk with mRNA COVID-19 vaccines and unvaccinated individuals. The secondary objective was to assess the association in specific sub-populations, such as immunocompromised individuals.

Methods

This retrospective observational study used data from three European electronic healthcare data sources: PHARMO Data Network (Netherlands), SIDIAP and VID (Spain). The study period spanned from 21 April 2021 to 31 Dec 2022. Self-controlled risk interval (SCRI), and matched cohort (mRNA and unvaccinated) analyses were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) using Poisson regression models for each AESI. Where appropriate, results were meta-analysed. Sensitivity analyses, and age/sex-stratified analyses were conducted.

Results

The study population included 510,073 recipients of a first dose of Ad26.COV2.S, matched 1:1 to mRNA vaccinees, and to unvaccinated individuals. Event rates varied across data sources. For frequently occurring events (>50 events), primary analyses did not suggest a strongly (IRR>2) increased risk for any AESIs. SCRI analysis results suggested increased pooled risks after Ad26.COV2.S vaccination for thrombocytopenia (IRR=1.60; 95% CI: 1.38-1.84), peripheral thrombosis (IRR=1.56; 95% CI: 1.21-2.00), and arrhythmia (IRR=1.27; 95% CI: 1.10-1.47). Among less frequent AESIs (<50 events), the results for anaphylaxis, Guillain-Barré syndrome (GBS), and immune thrombocytopenia suggested strongly increased risks but with low precision. Age- and sex-stratified analyses showed differences in risk for conditions such as Bell’s palsy and pulmonary embolism.

Conclusions

This study confirmed the risks outlined by the JCOVDEN prescribing information for events like thrombocytopenia. However, the robustness of the study was limited by the heterogeneity across data sources, due to differences in coding systems, and/or availability of hospital data.

Background:

Adverse events of special interest (AESI) are assessed in post-authorization safety studies (PASS) using real-world data (RWD), but the accuracy of codes and algorithms to identify them require validation according to the regulatory guidance for RWD studies.

Objectives:

To estimate the positive predictive value (PPV) of diagnostic algorithms for 11 prespecified AESIs across neurological, hematological/thrombotic, and cardiovascular disorders in a retrospective PASS of JCOVDEN in the European Union.

Methods:

Case validation was conducted using the VAC4EU framework for defining, ascertaining, and validating AESIs. This was carried out across two data sources (VID, SIDIAP) by trained abstractors using electronic medical records and REDCap questionnaires. We validated up to 50 cases for JCOVDEN and 30 for comparators for each AESI. Cases were assigned a level of diagnostic certainty (LOC) ranging from 1 (definite case) to 5 (definite alternative diagnosis) using adapted Brighton Collaboration case definitions. For each AESI, the PPVs with 95% confidence intervals (CIs) were calculated by dividing the number of confirmed cases (those with a LOC 1-3) by the total number of validated cases (LOC 1, 2, 3, 4a, or 5).

Results:

Among JCOVDEN vaccinees, 324 events were validated. The PPV (95%CI) for thrombosis with thrombocytopenia syndrome was 55.2% (35.7–73.6%) in SIDIAP and 100% (2.5–100%) in VID . The PPV of cerebral venous sinus thrombosis was 100% in both data sources. The other AESIs were validated only in VID. High PPVs (above 80%) were observed for cardiac inflammatory disorder (PPV = 83.3% (62.6–95.3%); pulmonary embolism (PPV = 83.3% (67.2–93.6%); hemorrhagic stroke, (PPV = 85.7% (67.3–96.0%). Moderate PPVs (60-75%) were observed for immune thrombocytopenia, PPV = 75.0% (34.9-96.8%); non-hemorrhagic stroke, PPV = 72.4% (52.8–87.3%); transverse myelitis, PPV = 66.7% (9.4-99.1%); Guillain-Barré syndrome, PPV = 62.5% (24.5–91.5%); and deep vein thrombosis, PPV = 60.0% (42.1-76.1%). The PPV for encephalitis was low, PPV = 26.7% (7.8-55.1%).

Conclusion:

Levels of diagnostic certainty and PPVs varied across AESIs. The validation approach was effective but limited by available clinical data, highlighting the need for robust data in vaccine safety monitoring.

As part of the lifecycle benefit-risk assessment of vaccines, we are conducting a post-authorisation safety study (PASS) utilizing real-world data to characterize and assess the safety profile of JCOVDEN.

Objectives: As part of the JCOVDEN PASS, this second feasibility study aimed to i) describe JCOVDEN patterns of use compared to other COVID-19 vaccine brands, ii) characterise vaccinated individuals, iii) describe follow–up time and reasons for censoring, and iv) conduct time-to-onset analyses for 36 pre-specified adverse events of special interest (AESIs).

Methods: This retrospective observational study used electronic healthcare data from two European countries (the Netherlands [PHARMO Data Network] and Spain [VID, SIDIAP]) collaborating in the VAC4EU consortium. Data were harmonised across data sources using the ConcePTION common data model. Analytical steps included syntactic and semantic harmonisation of data, implementation of the epidemiological study design, and statistical analysis.

Descriptive statistics were used. Unadjusted incident rates (IRs) of AESIs (per 10.000 person-years) were compared to 1st feasibility assessment and to the 2018 background rates published in the ACCESS study.

Results: A total of 510,145 individuals received the first dose of the JCOVDEN vaccine in line with ECDC Vaccine Tracker data for the Netherlands and Spain. The first dose was predominantly administered to those aged 40-49 in SIDIAP and VID and 20-29 in PHARMO; female vaccinated individuals were 36.9% in PHARMO, 44.1% in SIDIAP, and 46.2% in VID. Between 0.4 and 1.2% of vaccinated individuals were pregnant across data sources. Most individuals (>65%) received a COVID-19 mRNA vaccine as a second dose approximately six months after initial vaccination with JCOVDEN.

The AESIs were identified using disease codes (ICD10CM, ICD9CM, ICPC) and free texts and our feasibility analyses identified clinically relevant AESIs. Compared to the 1st feasibility assessment, this assessment exhibits improved specificity in centralised code lists, programming enhancements, and refined study population selection. IRs of AESIs were also consistent with 2018 ACCESS background rates.

Conclusions: This feasibility study identified over half a million individuals vaccinated with JCOVDEN. While the data from the three data sources are suitable for the planned final analysis, statistical power may be limited for very rare AESIs for the final comparative analysis.

As part of the lifecycle benefit-risk assessment of vaccines, a post-authorisation safety study (PASS) using real-world data was required by EMA-PRAC to characterise and evaluate the safety of the JCOVDEN.

Objectives: The first phase of the study was a feasibility assessment i) to describe JCOVDEN patterns of use compared to other COVID-19 vaccine brands, ii) to characterise vaccinated individuals, iii) to describe follow–up time and reasons for censoring, and iv) to conduct time-to-onset analyses for 17 selected adverse events of special interest (AESIs).

Methods: This retrospective observational study used electronic healthcare data from two European countries (the Netherlands [PHARMO Data Network] and Spain [VID, SIDIAP]).

A common protocol and the ConcePTION common data model pipeline were used to perform the data management and analyses. The pipeline encompassed the syntactic and semantic harmonisation of data, the implementation of the epidemiological study design, and the statistical analysis.

We report frequencies and percentages, means and standard deviations (SD), medians and interquartile ranges (IQR). The unadjusted incident rates (IRs) per 10,000 person-years of the selected AESIs were calculated and benchmarked to the 2018 background rates published in the ACCESS study.

Results: A total of 527,513 individuals received the first dose of the JCOVDEN. Almost all administration of JCOVDEN occurred in Q2-Q3 2021 (98%). More than 80% of the COVID-19 vaccines administered in 2021 were mRNA vaccines. The relative use of the different COVID-19 vaccine brands was consistent with that reported by the European Centre for Disease Prevention and Control (ECDC). In VID and SIDIAP, JCOVDEN was administered more frequently in individuals aged 40-49 years. Around 55% of JCOVDEN vaccinees were females. Most individuals with a first dose of JCOVDEN received a booster dose with one of the mRNA vaccines about 6 months later. For PHARMO, only vaccine uptake and follow-up data were available for this first feasibility assessment.

In SIDIAP and VID, the unadjusted IRs for most assessed AESIs were consistent with those expected from the background IRs reported in the ACCESS study.

Conclusions: This feasibility analysis showed that the planned PASS is feasible but faces limitations (e.g., the number of persons who received JCOVDEN, channelling of COVID-vaccines over time to different age groups and heterologous schemes) that will be considered by design during the full implementation of the safety study.

Incomplete capture of COVID-19 vaccination in claims data can lead to misclassification of vaccination status in studies using real world data. As COVID-19 vaccine administration may occur without reimbursement from payers, the capture in claims data of vaccine exposure information needed for vaccine safety studies is not currently well understood.

Objective: To assess capacity for identifying health insurance plan enrollees with Janssen Ad26.COV2.S COVID-19 vaccination within 4 US health insurance databases in preparation for an observational post-authorization safety study (PASS).

Methods: Research partners provided A26.COV2.S counts of vaccinees in May 2021, which included demographic characteristics of vaccinees and source of exposure information as recorded in claims. Partners also provided monthly counts from October 2021 through January 2022 and responded to surveys in May 2021 and November 2021. The surveys included information regarding COVID-19 vaccine capture and timeliness in claims data, and potential linkages to states’ Immunization Information Systems (IISs).

Results: In May 2021, we identified 350,532 enrollees with Ad26.COV2.S vaccination in claims data; of these 51% were female, 47% were 18-49 years, 36% were 50-64 years, and 17% were ≥65 years. Vaccine administrations were most commonly recorded in claims with national drug codes (58%) followed by vaccine administration codes (30%); 11% of enrollees had multiple sources of information. The majority of vaccination claims (approximately 77%) were recorded in outpatient settings; 17% had no setting identified, 5% occurred in other settings, and only 1% were captured in mass vaccination settings. Pharmacy claims had the shortest lag time (~1 month) and inpatient claims the longest (~6 months). As of the November 2021 survey, 2 of 4 partners were conducting linkage with IISs in 9 states and negotiating with 14 others. Timing and frequency of IIS linkage varied by partner and IIS, but typically occurred either monthly or weekly. The ability to incorporate IIS records into databases is still being determined. By January 2022, we identified 566,891 enrollees with Ad26.COV2.S vaccination.

Conclusions: As the extent of missing COVID-19 vaccine information in claims is still unknown, the potential for exposure misclassification should be considered in the design of vaccine safety studies. An active comparator design and a self-controlled risk interval design are planned to be used in this US PASS to overcome potential misclassification of unexposed vaccination status. Ongoing work includes assessment of Ad26.COV2.S vaccine uptake in the insurers’ databases and the ability to incorporate IIS records.