Summary Basis of Decision for Jcovden (previously the Janssen COVID-19 Vaccine)

The clinical data provided in the application for authorization of the Janssen COVID-19 Vaccine (Ad26.COV2.S, recombinant) under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) included results based on the interim efficacy analysis data from the ongoing Phase III efficacy, safety, and immunogenicity study (Study COV3001 or the ENSEMBLE Study), in which the two co‑primary efficacy endpoints were met. Data from the first-in-human study (COV1001), Phase I and II studies (COV1002 and COV2001), and a Phase III study (COV3009) have also been submitted in support of the vaccine, dosage regimen, and the safety and immunogenicity of the vaccine. The clinical data reviewed in this application were submitted on a rolling basis, as is permitted under the Interim Order. Correspondence between the sponsor and the European Medicines Agency and the Food and Drug Administration was also consulted. Information presented by the sponsor to the Vaccines and Related Biological Products Advisory Committee was used as an added reference.

Initial immunogenicity and safety data (28 days post Dose 1 data from Cohort 1a and available data from Cohort 3) from the COV1001 study demonstrated that a single‑dose of Ad26.COV2.S, (recombinant), the medicinal ingredient in the Janssen COVID‑19 Vaccine, at dose levels of 5 x 10¹⁰ virus particles induced a sufficient immune response and is safe. The sponsor therefore chose to proceed with the single‑dose regimen at a dose level of 5 x 10¹⁰ virus particles in the ENSEMBLE Study.

Following review, terms and conditions were imposed upon the authorization of the Janssen COVID-19 Vaccine to ascertain the continued quality, safety, and efficacy of the product.

Clinical Pharmacology

The Janssen COVID‑19 Vaccine is a monovalent vaccine composed of a recombinant, replication‑incompetent human adenovirus type 26 (Ad26) vector, constructed to encode the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein in a stabilized conformation. The S protein on the surface of the coronavirus binds to the angiotensin‑converting enzyme 2 (ACE2) receptor of a host cell, allowing the virus to infect the cell. Vaccination with the Janssen COVID-19 Vaccine leads to humoral and cellular immune responses directed against the S protein and in particular the production of neutralizing and other functional anti‑S antibodies which can block the binding of the S protein to the ACE2 receptor, contributing to protection against COVID‑19.

Immunogenicity was assessed as part of the clinical efficacy evaluation of the Janssen COVID‑19 Vaccine.

For further details, please refer to the Janssen COVID‑19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

Clinical Efficacy

Evidence of the clinical efficacy of the Janssen COVID‑19 Vaccine (Ad26.COV2.S, recombinant) is based primarily on the available data from the pivotal ENSEMBLE Study (Study COV3001) which assessed the efficacy, safety, and immunogenicity of the Janssen COVID‑19 Vaccine. The interim analysis results are based on a cut-off date of January 22, 2021.

The ENSEMBLE Study is an ongoing Phase III randomized, double‑blind, placebo‑controlled study that evaluated a single intramuscular injection of the Janssen COVID‑19 Vaccine (5 x 10¹⁰ virus particles/0.5 mL) for the prevention of COVID-19 in adults aged 18 years and older. The study is currently being conducted in the United States, South Africa, Brazil, Chile, Argentina, Columbia, Peru, and Mexico.

The ENSEMBLE Study has enrolled 44,325 participants 18 years of age and older, of whom 43,783 were vaccinated (21,895 in the Janssen COVID‑19 Vaccine group and 21,888 in the placebo group). A total of 39,321 participants were included in the per‑protocol set with 19,630 in the Janssen COVID‑19 Vaccine group and 19,691 in the placebo group.

The median age in the per‑protocol set was 53.0 years. In total, 66.4% of participants were ≥18 to <60 years of age and 34.6% of the participants were ≥60 years of age, and 20.4% and 3.6% of the participants were ≥65 and ≥75 years of age, respectively. The majority of participants were Caucasian (62.1%), Black/African American (17.2%), Native American (8.4%), or Asian (3.7%). Lastly, 39.9% of the participants had one or more comorbidities, consisting of stable pre-existing medical conditions, defined as disease not requiring significant change in therapy during the 3 months preceding vaccination, as well as individuals with stable human immunodeficiency virus (HIV) infection. The most common pre-existing medical conditions were obesity, hypertension, type 2 diabetes mellitus, serious heart conditions, and asthma. Other comorbidities were present in ≤1% of the participants. Human immunodeficiency virus infection was reported at baseline in 2.5% of the participants. Participants with comorbidities were phased into the ENSEMBLE Study only after the safety review of 2,000 participants without comorbidities (for participants ≥18 to <60 years of age in stage 1, and for participants ≥60 years of age in stage 2).

Participants who had previously received a coronavirus vaccine, pregnant women, and participants with abnormal function of the immune system were ineligible to participate in the ENSEMBLE Study. Participants were also excluded if they had known or suspected allergy or a history of anaphylaxis or serious adverse reactions to vaccines or their excipients.

The study design included stratification of the participants by age (18 to 59 years, 60 years and older) in addition to the presence or absence of comorbidities associated with an increased risk of progression to severe COVID‑19. Participants were then randomized in a 1:1 ratio to receive either an intramuscular injection of the Janssen COVID‑19 Vaccine (at a dose level of 5 x 10¹⁰ virus particles; number of participants [n] = 21,895) or a placebo (0.9% sodium chloride; n = 21,888). The study included a median follow‑up of 2 months after vaccination. It is planned that participants will be followed for up to 2 years for assessment of safety and efficacy against COVID‑19.

The primary efficacy endpoint of the ENSEMBLE Study was defined as a symptomatic moderate to severe/critical COVID‑19 case, confirmed by positive SARS COV-2 viral ribonucleic acid (RNA) results using a polymerase chain reaction (PCR)‑based test in a central laboratory. To conduct the evaluation, the ENSEMBLE Study contained two co‑primary endpoints as follows:

• first occurrence of molecularly confirmed moderate to severe/critical COVID‑19, with onset at least 14 days post vaccination (Day 15);
• first occurrence of molecularly confirmed moderate to severe/critical COVID‑19, with onset at least 28 days post vaccination (Day 29).

Moderate COVID‑19 was defined based on the following criteria:

• the participant must have experienced any one of the following new or worsening signs or symptoms: respiratory rate ≥20 breaths/minute, abnormal saturation of oxygen (SpO2) but still >93% on room air at sea level, clinical or radiologic evidence of pneumonia, radiologic evidence of deep vein thrombosis (DVT), shortness of breath or difficulty breathing; or
• any two of the following new or worsening signs or symptoms: fever (≥38.0 °C or ≥100.4 °F), heart rate ≥90 beats/minute, shaking chills or rigors, sore throat, cough, malaise, headache, muscle pain (myalgia), gastrointestinal symptoms, new or changing olfactory or taste disorders, red or bruised appearing feet or toes.

Severe/critical COVID‑19 was defined based on the following criteria:

• the participant must have experienced any one of the following at any time during the course of observation: clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths/minute, heart rate ≥125 beats/minute, oxygen saturation [SpO2] ≤93% on room air at sea level, or partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] <300 mmHg), respiratory failure (defined as needing high-flow oxygen, non‑invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]), evidence of shock (defined as systolic blood pressure <90 mmHg, diastolic blood pressure <60 mmHg, or requiring vasopressors), significant acute renal, hepatic, or neurologic dysfunction, admission to intensive care unit (ICU), death.

Final determination of severe/critical COVID‑19 cases was made by an independent adjudication committee.

At the time of the interim efficacy analysis cut-off date January 22, 2021, participants had been followed for symptomatic COVID‑19 for a median of 2 months, corresponding to 3,143.7 person‑years in the Janssen COVID‑19 Vaccine group and 3,146.7 person‑years in the placebo group.

Results from the ENSEMBLE Study demonstrated that both co‑primary efficacy endpoints were met. For the first co‑primary endpoint with onset as of 14 days after vaccination, there were 116 cases of moderate to severe/critical COVID-19 in the vaccine group and 348 in the placebo group. For the second co‑primary endpoint with onset as of 28 days after vaccination, there were 66 cases of moderate to severe/critical COVID‑19 in the vaccine group and 193 in the placebo group. Vaccine efficacy for the co‑primary endpoints against moderate to severe/critical COVID‑19 in individuals who were seronegative (or of unknown serostatus) at baseline was 66.9% (95% confidence interval [CI]: 59.0; 73.4) as of 14 days after vaccination and 66.1% (95% CI: 55.0; 74.8) as of 28 days after vaccination. Higher vaccine efficacy was observed against severe/critical COVID‑19. The vaccine efficacy as of 14 days after vaccination was 76.7%, and was 85.4% as of 28 days after vaccination. Efficacy against COVID‑19 was consistent across age, gender, race, and ethnicity demographics.

Vaccine efficacy against moderate to severe/critical COVID‑19 as of 14 days after vaccination was 67.6% (95% CI: 59.38; 74.30) in participants without comorbidities and 64.2% (95% CI: 52.68; 73.14) in participants with comorbidities. Vaccine efficacy against moderate to severe/critical COVID‑19 as of 28 days after vaccination was 68.8% (95% CI: 58.98; 76.58) in participants without comorbidities and 58.6% (95% CI: 40.57; 71.55) in participants with comorbidities. The slightly lower vaccine efficacy observed in participants with comorbidities could be due to differences in length of follow‑up, since participants with comorbidities were included in the later stages of the study by design.

Janssen COVID‑19 Vaccine was observed to have a positive impact on COVID‑19‑related hospitalization and COVID‑19‑associated death. As of 14 days after vaccination, 2 versus 29 cases of COVID‑19‑related hospitalizations were observed in the vaccine group compared to placebo. As of 28 days after vaccination, 0 versus 16 cases of COVID‑19‑related hospitalizations were observed in the vaccine group compared to placebo. There were no COVID‑19‑related deaths reported in vaccine recipients, compared to 5 COVID‑19‑related deaths reported in placebo recipients (all from South Africa), who were SARS‑CoV‑2 PCR‑negative at baseline.

Among the 39,321 participants in the ENSEMBLE Study, a total of 20.4% (8,021) and 3.7% (1,455) of the participants were ≥65 and ≥75 years of age, respectively. When the Janssen COVID‑19 Vaccine was assessed in this subpopulation, vaccine efficacy against moderate to severe/critical COVID‑19 as of 14 and as of 28 days after vaccination in participants ≥65 years of age was 76.5% (95% Confidence Interval [CI]: 59.12; 87.30) and 68.6% (95% CI: 38.60; 85.06), respectively. For participants ≥75 years vaccine efficacy was 89.7% (95% CI: 25.95; 99.77) as of 14 days after vaccination. In regard to COVID‑19 cases reported with onset at least 28 days after vaccination, there were 0 cases in the Janssen COVID‑19 Vaccine and 4 cases in the placebo group.

A difference in the point estimates of vaccine efficacy against moderate to severe/critical COVID‑19 was observed in participants ≥60 years of age with and without comorbidities. As of 28 days after vaccination, the point estimate for vaccine efficacy against moderate to severe/critical COVID‑19 in participants ≥60 years of age without comorbidities was 72.4% (95% CI: 45.04; 87.25), while the point estimate for participants ≥60 years with comorbidities was 42.3% (95% CI: ‑13.14; 71.57). The observed differences in vaccine efficacy are partially driven by the relatively low number of cases, which explains the relatively wide confidence intervals around the point estimates of the vaccine efficacy in these subgroup analyses. This could also be due to differences in the length of follow‑up, since older participants and participants with comorbidities were included in the later stages of the study. For participants ≥60 years of age without comorbidities, approximately 50% and 25% of participants were followed for at least 56 days and 72 days after vaccination, respectively. In contrast, only 25% of participants ≥60 years of age with comorbidities were followed for approximately 56 days after vaccination, and none were followed at least 72 days after vaccination.

Exploratory subgroup analyses of vaccine efficacy against moderate to severe/critical COVID‑19 in different regions (Brazil, South Africa, and the United States) were conducted in parallel with strain sequencing. For these subgroup analyses, all COVID‑19 cases (PCR‑positive cases confirmed and pending confirmation by the central laboratory) accrued up to the primary efficacy analysis data cut-off date of January 22, 2021 were included.

Strain sequencing was conducted on available samples with sufficient viral load from centrally confirmed COVID‑19 cases (one sequence per case). A total of 71.7% of central laboratory confirmed primary analysis cases have been sequenced (United States [73.5%], South Africa [66.9%] and Brazil [69.3%]). In the United States, 96.4% of strains were identified as the Wuhan‑H1 variant D614G; in South Africa, 94.5% were identified as the 20H/501Y.V2 variant (B.1.351 lineage); in Brazil, 69.4% were identified to be a variant of the P.2 lineage and 30.6% as the Wuhan‑H1 variant D614G. As of February 12, 2021, SARS‑CoV‑2 variants from the B1.1.7 or P.1 lineages were not found in any of the sequenced samples.

In the United States specifically, the vaccine efficacy against all moderate to severe/critical cases of COVID‑19 was 74.4% (95% CI: 65.00; 81.57) as of Day 14, and 72.0% (95% CI: 58.19; 81.71) as of Day 28. In South Africa the corresponding vaccine efficacy rates were 52.0% (95% CI: 30.26; 67.44) and 64.0% (95% CI: 41.19; 78.66), respectively. In Brazil the corresponding vaccine efficacy rates were 66.2% (95% CI: 51.01; 77.14) and 68.1% (95% CI: 48.81; 80.74), respectively. Vaccine efficacy against all severe/critical cases of COVID‑19 in the United States was 78.0% (95% CI: 33.13; 94.58) 14 days after vaccination, and 85.9% (95% CI: 99.38; 99.69) 28 days after vaccination. In South Africa the corresponding vaccine efficacy rates were 73.1% (95% CI: 40.03; 89.36) and 81.7% (95% CI: 46.18; 95.42), respectively. In Brazil the corresponding vaccine efficacy rates were 81.9% (95% CI: 17.01; 98.05) and 87.6% (95% CI: 7.84; 99.72), respectively.

Collectively, the results of the efficacy analysis demonstrated that the Janssen COVID-19 Vaccine met the vaccine efficacy success criteria as specified in Health Canada's Guidance Document, Guidance for Market Authorization Requirements for COVID-19 Vaccines. The Phase III ENSEMBLE Study is ongoing and data will be submitted to assess longer-term safety. In addition, the study will continue to provide additional information on the safety and efficacy of the Janssen COVID‑19 vaccine over a period of 2 years.

Immunogenicity

The immunogenicity of the Janssen COVID-19 Vaccine was evaluated in four studies, one Phase I, two Phase I/II, and one Phase III.

• Study COV1001 is a randomized, double‑blind, placebo‑controlled, Phase I/IIa study, conducted in adults ≥18 to ≤55 years of age (Cohort 1 and Cohort 2) and adults ≥65 years of age (Cohort 3).
• Study COV1002 is a randomized, double‑blind, placebo‑controlled, Phase I study, conducted in adults ≥20 to ≤55 years of age and ≥65 years of age.
• Study COV2001 is a randomized, double‑blind, placebo‑controlled, Phase IIa study, conducted in adults ≥18 to ≤55 years of age and adults ≥65 years of age.
• Study COV3001 (ENSEMBLE Study) is a randomized, double‑blind, placebo‑controlled, Phase III study, conducted in adults ≥18 years of age.

The immunogenicity of the Janssen COVID‑19 Vaccine was evaluated using the following methods: neutralizing antibodies were measured with a wild type SARS‑CoV‑2 neutralization assay (wtVNA), spike protein‑binding antibody responses were measured using a spike‑enzyme‑linked immunosorbent assay (S-ELISA), and cellular immunogenicity was measured using S‑specific CD4+ and CD8+ T‑cell responses.

For both the wtVNA and S‑ELISA assays, a participant was considered to have responded to vaccination if one of the following criteria were met:

• If the baseline sample value was negative (i.e., below the lower limit of quantification) and the post‑vaccination sample value was positive; or
• If the baseline sample value was positive (i.e., above the lower limit of quantification) and the post‑vaccination sample value was ≥4‑fold over the baseline sample.

The immunogenicity data should be interpreted with caution, because there is no immune correlate of protection. These analyses were exploratory, and the results are based on small groups of subjects.

Humoral Immunogenicity

Across the Phase I and II studies (COV1001, COV1002, and COV2001), a SARS‑CoV‑2 neutralizing antibody response was observed at Day 29 in at least 88% of participants ≥18 to ≤55 years of age and at least 93% of participants ≥65 years of age.

In study COV1001, neutralizing antibody responses were 96% at Day 29, and 100% at Day 57, Day 71 and Day 85, in individuals ≥18 to ≤55 years of age. In individuals ≥65 years of age, neutralizing antibody responses were 100% at Day 15, 96% at Day 29, and 90% at Day 87.

In the Phase III ENSEMBLE Study (COV3001), S‑specific binding antibody concentrations increased from baseline (geometric mean concentration [GMC] <lower limit of quantification [LLOQ]) to Day 29 with a GMC of 462 (95% CI: 381; 560) in participants ≥18 to 59 years of age, and a GMC of 347 (95% CI: 278; 434) in participants ≥60 years of age. No major difference was observed in S‑specific binding antibody levels induced by the Janssen COVID‑19 Vaccine between participants from Brazil, South Africa, and the United States.

In the placebo groups, no overall humoral response was observed at any of the time points.

Cellular Immunogenicity

In COV1001, a single dose of the Janssen COVID‑19 vaccine elicited CD4 and CD8 T‑cell responses in participants ≥18 to ≤55 years of age and individuals ≥65 years of age, at Day 28. The CD4 T‑cell responses were skewed towards a Th1 phenotype.

Immunogenicity Against the B1.1.7 SARS‑CoV‑2 Variant

Sera obtained 28 days after vaccination with the Janssen COVID‑19 vaccine in the COV1001 study (in participants aged ≥18 to ≤55 years) showed an almost 9‑fold reduction in the ability to neutralize the B1.1.7 SARS‑CoV‑2 variant relative to the SARS‑CoV‑2 Victoria strain, which has high homology to the WuhanHu‑1 S sequence used to construct the vector‑based vaccine. With a more mature antibody response in sera obtained 70 days after vaccination, the reduction in neutralizing activity against the B1.1.7 variant was 3.3‑fold.

Indication

The sponsor filed the application for authorization of the Janssen COVID‑19 Vaccine under the Interim Order with the following indication:

• Janssen COVID‑19 Vaccine (Ad26.COV2.S, recombinant) is indicated for active immunization against coronavirus disease 2019 (COVID‑19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in persons 18 years of age and older.

Health Canada approved the following indication:

• Janssen COVID‑19 Vaccine (SARS‑CoV‑2 Vaccine [Ad26.COV2.S, recombinant]) is indicated for active immunization for the prevention of coronavirus disease 2019 (COVID‑19) caused by SARS‑CoV‑2 virus in individuals 18 years of age and older.

For more information, refer to the Janssen COVID-19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.

 

Clinical Safety

The evidence of safety for the Janssen COVID-19 Vaccine is largely based on data from the ongoing pivotal Phase III COV3001 study (ENSEMBLE Study) with a cut-off date of January 22, 2021.

The full analysis set included 43,783 participants aged 18 years and older, of whom 21,895 received the Janssen COVID-19 Vaccine (dose 5 x 10¹⁰ virus particles) and 21,888 received a saline placebo. At the time of the analysis, the median follow‑up was 58 days from vaccination. Enrollment was stratified by age (18 to 59 and ≥60 years of age) and 7,331 (33%) of participants in the Janssen COVID‑19 Vaccine group were ≥60 years old.The median age of individuals was 53 years. The safety analysis was performed once the median follow‑up duration of 2 months after vaccination was reached. The participants were monitored for solicited local and systemic reactions, unsolicited adverse events and serious adverse events.

Solicited adverse reactions and unsolicited adverse events were collected in a subset of participants called the safety subset. This set included 6,376 participants from 45 sites in the United States, Brazil, and South Africa. Of the 6,376 participants, 2,651 (39.4%) participants were ≥60 years of age. A total of 3,356 participants received the Janssen COVID-19 Vaccine and 3,380 received the placebo.

Solicited Adverse Reactions

Solicited local and systemic adverse reactions were collected in the safety subset for the first 7 days after vaccination. Assessments included local reactions (pain, erythema, and swelling) and systemic reactions (fatigue, headache, myalgia, nausea, and fever). Both solicited local and systemic adverse reactions were more common in participants who received the Janssen COVID‑19 Vaccine compared with placebo (66.0% vs. 41.9% respectively). Solicited events were more commonly reported by younger adults (18 to 59 years of age) than by older adults (≥60 years of age). The majority of these events were mild to moderate in severity, with slightly lower rates of Grade ≥3 events in the older age group. No Grade 4 adverse reactions were reported. Time to onset and duration of both local and systemic adverse reactions were similar in younger and older adults and in participants with and without comorbidities.

Solicited local adverse reactions were more common in participants who received the Janssen COVID‑19 Vaccine than in those who received placebo (50.3 and 41.9% respectively). The most common solicited local adverse reaction was vaccination site pain, which occurred in 48.7% of participants in the Janssen COVID‑19 Vaccine group and 16.7% in the placebo group. The majority of local adverse reactions occurred within the first 2 to 3 days post vaccination, with a median duration of 2 to 3 days.

Solicited systemic adverse reactions were more common in participants who received the Janssen COVID‑19 Vaccine than in those who received placebo (55.2% vs. 35.1%). The most common solicited systemic adverse reactions were headache and fatigue which occurred in almost 40% of participants, and myalgia which occurred in a third of participants. The most common systemic events of Grade ≥3 severity were fatigue and myalgia which each occurred at rates of 1.0%. The majority of local adverse reactions began within the first 2 to 3 days post vaccination and the median duration was 1 to 2 days.

Unsolicited Adverse Events

Within the first 28 days after vaccination, the incidence of unsolicited adverse events was similar for the Janssen COVID‑19 Vaccine group and the placebo group (13.1% and 12.0% respectively). Most unsolicited adverse events were Grade 1 or Grade 2 in severity, with 0.6% in both the vaccine and placebo groups reporting an adverse event of ≥ Grade 3 severity. Related unsolicited adverse events in the first 28 days were higher in the Janssen COVID‑19 Vaccine group than in the placebo group (7.2% vs. 4.6% respectively).The imbalance was primarily due to an imbalance in related adverse events in the General Disorders and Administration Site Conditions category (5.2% vs. 2.6%) which were related to reactogenicity.

Serious Adverse Events

Overall, serious adverse event rates were lower in the Janssen COVID‑19 Vaccine group than in the placebo group (0.4% [n = 90] and 0.6% [n = 137] respectively). When serious adverse events related to COVID-19 were excluded, serious adverse events were reported by 0.4% of participants in both the vaccine and placebo groups (83 and 95 participants, respectively).

A total of 7 participants in the Janssen COVID‑19 Vaccine group compared to 3 participants in the control group experienced serious adverse events that were considered possibly related to the Janssen COVID‑19 Vaccine by the investigator. Three of these serious adverse events in the Janssen COVID‑19 Vaccine group were:

• one case of fever, headache and asthenia in a 35‑year‑old male that occurred less than a day after vaccination;
• one case of severe injection site pain in a 30‑year‑old male that occurred immediately after vaccination and was ongoing 10 weeks later; and
• one case of type IV hypersensitivity in a 42‑year‑old male that occurred 3 days after vaccination.

For the remaining four serious adverse events considered possibly related by the investigator, a contributing role of the Janssen COVID‑19 Vaccine could not be ruled out:

• one case of Guillain-Barré Syndrome in a 60‑year‑old female that occurred 16 days after vaccination;
• two cases of facial paralysis, one in a 62‑year‑old male that occurred 3 days after vaccination, and one in a 43‑year‑old male that occurred 16 days after vaccination; and
• one case of pericarditis in a 68‑year‑old male that occurred 17 days after vaccination.

A contributory effect of the vaccine also could not be excluded for two additional serious adverse events: a case of transverse sinus thrombosis in a 25‑year‑old male that occurred 21 days after vaccination, and a case of hemiparesis in a 49‑year‑old female that occurred 26 days after vaccination.

No participants withdrew from the ENSEMBLE Study due to an adverse event. There were 3 fatal adverse events in the vaccine group and 16 in the placebo group. None of the deaths were considered related to the Janssen COVID‑19 Vaccine.

Other Adverse Events of Interest

Hypersensitivity events, including both serious and non‑serious reactions, occurred more frequently in the Janssen COVID‑19 Vaccine group than in the placebo group (0.4% and 0.3% respectively). Hypersensitivity events in the vaccine group which were considered likely related to vaccination included rash and urticaria, two cases of facial swelling, a case of lip swelling, a case of eyelid swelling and a serious adverse event of type IV hypersensitivity.

An imbalance of thromboembolic events was noted with 15 cases in the Janssen COVID‑19 Vaccine group and 10 in the placebo group. Deep vein thrombosis and pulmonary embolism were more frequent in the Janssen COVID‑19 Vaccine group than in the placebo group (10 vs. 3); receipt of the vaccine was considered a possible contributing factor for two cases of deep vein thrombosis and one case of pulmonary embolism. Receipt of the vaccine could also not be excluded as a contributing factor in the serious adverse events of transverse sinus thrombosis and hemiparesis. The sponsor has undertaken a coagulopathy work up of a subset of participants in Study COV2001, and thromboembolic events will be monitored post authorization.

Imbalance in neurological events was noted for tinnitus, vertigo and seizures. Six cases of tinnitus were reported in the Janssen COVID‑19 Vaccine group and none in the placebo group. Two cases of tinnitus were considered related to the vaccine. Thirteen cases of vertigo occurred in the vaccine group as compared to 7 in the placebo group, of which 5 cases occurred in the vaccine group of the safety subset in the first 28 days. In the full analysis set, four cases of vertigo were considered related to the vaccine by the investigator. Four cases of seizures were reported in the vaccine group and none were reported in the placebo group; none were considered related to the vaccine. One case of Guillain‑Barré syndrome occurred in both groups. Facial paralysis (Bell's palsy) occurred in 3 participants in the vaccine group and in 2 participants in the control group.

Fewer cases of COVID‑19 were reported in the Janssen COVID‑19 Vaccine group compared to the control group. There was no evidence of vaccine‑associated enhanced disease (VAED) at this time. Vaccine‑associated enhanced disease will continue to be assessed as additional data becomes available.

Special Populations

Pregnant and Breastfeeding Women

The safety and efficacy of the Janssen COVID‑19 Vaccine in pregnant women have not yet been established.

To date, women who were pregnant were excluded from the Janssen COVID‑19 clinical studies. Up to the cut-off date of January 22, 2021, a total of 8 pregnancies were reported in the ENSEMBLE Study: 4 in the Janssen COVID‑19 Vaccine group and 4 in the placebo group. Of the pregnancies in the vaccine group, 2 are ongoing, one ended in spontaneous abortion, and one was an ectopic pregnancy. These participants continue to be followed for pregnancy outcomes. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to the Janssen COVID‑19 Vaccine during pregnancy. Women who are vaccinated with the Janssen COVID‑19 Vaccine during pregnancy are encouraged to enroll in the registry.

It is not known whether the components of the Janssen COVID-19 Vaccine or antibodies induced by the Janssen COVID-19 Vaccine are excreted in human breast milk. Human data are not available to assess the impact of the Janssen COVID-19 Vaccine on milk production or its effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for immunization against COVID‑19.

Immunocompromised Individuals

Adults with stable/well-controlled human immunodeficiency virus (HIV) infection or adults receiving chronic low‑dose immunosuppressive therapy (less than 20 mg of prednisone or equivalent) were included in Janssen COVID‑19 Vaccine Phase III clinical studies. Immunocompromised individuals including those receiving substantial immunosuppressive therapy may have a diminished immune response to Janssen COVID‑19 Vaccine.

Vaccine Safety from Other Studies

Up to the data cut‑off of January 22, 2021, across studies COV1001, COV1002, COV2001, and COV3009, a total of 26 participants reported one or more serious adverse event. One serious adverse event considered to be vaccine‑related was reported in study COV1001: a case of Grade 3 pyrexia beginning 6 hours post vaccination in a participant who received a high dose of Janssen COVID‑19 Vaccine (1 x 10¹¹ virus particles). No safety concerns were identified in any of these studies.

In COV3012, an ongoing Phase IIIb open‑label single‑arm effectiveness study conducted in South Africa, two additional serious hypersensitivity adverse events (including one confirmed anaphylaxis) were reported. Additional information is pending.

Risk Management Plan

A Core Risk Management Plan (RMP) for the Janssen COVID-19 Vaccine was submitted by Janssen Inc. to Health Canada as part of the application for interim authorization. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and to describe measures that will be put in place to minimize risks associated with the product, when needed.

The following information relates to the RMP submitted by Janssen Inc., as part of the initial application for interim authorization. It is the sponsor's responsibility to monitor the safety profile of the drug and to submit an update to the RMP if there is a significant change to the benefits, harms or uncertainties associated with the drug. Updates to the RMP will be reflected in the Post-Authorization Activity Table for the Janssen COVID‑19 Vaccine.

Based on results from non-clinical and clinical studies, the RMP included no important identified risks and one important potential risk (vaccine‑associated enhanced disease, including vaccine‑associated enhanced respiratory disease). There were seven areas of missing information identified: "use during pregnancy", "use in breastfeeding women", "use in immunocompromised patients", "use in patients with autoimmune or inflammatory disorders", "use in frail patients with comorbidities" (e.g., Chronic obstructive pulmonary disease, diabetes, chronic neurological disease, and cardiovascular disorders), "interaction with other vaccines", and "long-term safety". The proposed routine and additional pharmacovigilance activities for the above safety concerns are considered to be acceptable and the sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include seven planned post-authorization studies, including two effectiveness studies, a safety and immunogenicity study in immunocompromised patients, two safety studies, a pregnancy registry, and a coadministration study of the Janssen COVID-19 Vaccine with seasonal influenza vaccine. Routine risk minimization measures (i.e., Product Monograph and labelling) are also considered to be appropriate.

Following review of the RMP, Health Canada determined that "anaphylaxis" and "venous thromboembolism" should be included as important potential risks. With respect to missing information, Janssen Inc. was requested to include "use in the pediatric (younger than 18 years of age) population" and "long-term effectiveness". As per the terms and conditions imposed on the interim authorization, the sponsor has agreed to reflect the aforementioned in an updated Canadian Addendum to the RMP, which will also include a description of the planned pharmacovigilance activities for monitoring of use in pregnant and breastfeeding women in Canada (e.g., inclusion of Canadian women in the pregnancy registry). Furthermore, the sponsor will submit an updated Core RMP and Canadian Addendum in a timely manner if a signal of safety issue is observed in post-authorization surveillance.

In addition, the sponsor will provide the following information in the post-market period:

• Older adults: Older adults were included in the clinical development program. The sponsor will submit monthly safety reports to Health Canada, which will include analyses of subpopulations by age and gender.
• Children: Children were not included in the clinical development program. This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.
• Pregnant women: More information is needed about the use of the vaccine for pregnant women. This subpopulation was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation through a pregnancy registry.
• Breastfeeding women: This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation through a pregnancy registry.
• Immunocompromised individuals and patients with chronic or debilitating conditions: A small number of these subpopulations were included in the clinical development program. This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.
• Anaphylaxis: This was identified as an important potential risk in the RMP. This will be assessed via routine pharmacovigilance activities, and reported in monthly summary safety reports.
• Indigenous populations in Canada: Adverse drug reactions (ADRs) from all subpopulations, including indigenous, will be reported as expeditiously as applicable, and will be assessed in the monthly reports. Other government departments as well as the sponsor will continue to be engaged in the assessment of ADRs in the indigenous subpopulation.

The sponsor is required to promptly report adverse reactions and provide monthly safety summary reports. In addition, the sponsor will provide, prior to distribution, patient information cards to support traceability, where required, which will include elements such as manufacturer name, name of vaccinee, space for recording date of administration, associated batch/lot numbers, and information on how to report any adverse events.

Results related to safety and effectiveness from ongoing and planned studies will be submitted for review as they become available. The results from these studies and the monthly safety summary reports are expected to address the data gaps related to the long‑term safety and effectiveness of the vaccine, interactions with other vaccines, and specific subpopulations (e.g., pregnant and breastfeeding women, pediatric [i.e., younger than 18 years of age] population, patients with autoimmune or inflammatory disorders, immunocompromised patients and frail patients with comorbidities).

For more information, refer to the complete list of terms and conditions available on the Health Canada COVID‑19 vaccines and treatments portal.

Collectively, the results of the clinical safety evaluation demonstrated that the Janssen COVID‑19 Vaccine met the vaccine safety requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID-19 Vaccines. The vaccine was determined to be safe and well tolerated in participants 18 years of age and older when administered according to the recommended dosage regimen. The Phase III ENSEMBLE Study is ongoing and will continue to collect information on the long‑term safety and efficacy of the Janssen COVID‑19 vaccine.

For more information, refer to the Janssen COVID‑19 Vaccine Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.