JCOVDEN Suspension for injection Ref.[11085] Active ingredients: SARS-CoV-2 Spike glycoprotein (Ad26.COV2-S)

Pharmacotherapeutic group: Vaccines, other viral vaccines
ATC code: J07BX03

Mechanism of action

JCOVDEN is a monovalent vaccine composed of a recombinant, replication-incompetent human adenovirus type 26 vector that encodes a SARS-CoV-2 full-length spike (S) glycoprotein in a stabilised conformation. Following administration, the S glycoprotein of SARSCoV-2 is transiently expressed, stimulating both neutralising and other functional S-specific antibodies, as well as cellular immune responses directed against the S antigen, which may contribute to protection against COVID-19.

Clinical efficacy

Efficacy from a single-dose primary vaccination

Primary analysis

A primary analysis (cut-off date 22 January 2021) of a multicentre, randomised, double-blind, placebo-controlled Phase 3 study (COV3001) was conducted in the United States, South Africa and Latin American countries to assess the efficacy, safety, and immunogenicity of a single-dose primary vaccination of JCOVDEN for the prevention of COVID-19 in adults aged 18 years and older. The study excluded individuals with abnormal function of the immune system resulting from a clinical condition, individuals who are under immunosuppressive therapies within 6 months, as well as pregnant women. Participants with stable HIV infection under treatment were not excluded. Licensed vaccines, excluding live vaccines, could be administered more than 14 days before or more than 14 days after the vaccination in the study. Licensed live attenuated vaccines could be administered more than 28 days before or more than 28 days after the vaccination in the study.

A total of 44 325 individuals were randomised in parallel in a 1:1 ratio to receive an intramuscular injection of JCOVDEN or placebo. A total of 21 895 adults received JCOVDEN and 21 888 adults received placebo. Participants were followed for a median of 58 days (range: 1-124 days) after vaccination.

The primary efficacy analysis population of 39 321 individuals included 38 059 SARS-CoV-2 seronegative individuals at baseline and 1 262 individuals with an unknown serostatus.

Demographic and baseline characteristics were similar among individuals who received the JCOVDEN and those who received placebo. In the primary efficacy analysis population, among the individuals who received JCOVDEN, the median age was 52.0 years (range: 18 to 100 years); 79.7% (N=15 646) of individuals were 18 to 64 years old [with 20.3% (N=3 984) aged 65 or older and 3.8% (N=755) aged 75 or older]; 44.3% of individuals were female; 46.8% were from Northern America (United States), 40.6% were from Latin America and 12.6% were from Southern Africa (South Africa). A total of 7 830 (39.9%) individuals had at least one pre-existing comorbidity associated with increased risk of progression to severe COVID-19 at baseline (comorbidities included: obesity defined as BMI ≥30 kg/m² (27.5%), hypertension (10.3%), type 2 diabetes (7.2%), stable/well-controlled HIV infection (2.5%), serious heart conditions (2.4%) and asthma (1.3%)). Other comorbidities were present in ≤1% of the individuals.

COVID-19 cases were confirmed by a central laboratory based on a positive SARS-CoV-2 viral RNA result using a polymerase chain reaction (PCR)-based test. Vaccine efficacy overall and by key age groups are presented in Table 2.

Table 2. Analysis of vaccine efficacy against COVID-19^b in SARS-CoV-2 seronegative adults – primary efficacy analysis population:

^a Co-primary endpoint as defined in the protocol.
^b Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 other systemic signs or symptoms, as defined in the protocol.
^c Confidence intervals for ‘All Subjects’ were adjusted to implement type I error control for multiple testing. Confidence intervals for age groups are presented unadjusted.

Vaccine efficacy against severe COVID-19 is presented in Table 3 below.

Table 3. Analyses of vaccine efficacy against severe COVID-19a in SARS-CoV-2 seronegative adults – primary efficacy analysis population:

^a Final determination of severe COVID-19 cases was made by an independent adjudication committee, who also assigned disease severity according to the definition per FDA guidance. ^b Confidence intervals were adjusted to implement type I error control for multiple testing.

Of the 14 vs. 60 severe cases with onset at least 14 days after vaccination in the JCOVDEN group vs. placebo group, 2 vs. 6 were hospitalised. Three individuals died (all in the placebo group). The majority of the remaining severe cases fulfilled only the oxygen saturation (SpO2) criterion for severe disease (≤93% on room air).

Updated analyses

The updated efficacy analyses at the end of the double-blind phase (cut-off date 09 July 2021) were performed with additional confirmed COVID-19 cases accrued during blinded, placebo-controlled follow-up, with a median follow-up of 4 months after a single-dose of the JCOVDEN.

Table 4. Analysis of vaccine efficacy against symptomatica and severeb COVID-19 – 14 days and 28 days after a single-dose:

^a Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 other systemic signs or symptoms, as defined in the protocol.
^b Final determination of severe COVID-19 cases was made by an independent adjudication committee, who also assigned disease severity according to the definition per FDA guidance.
^c Co-primary endpoint as defined in the protocol.
^d Per-protocol efficacy population.

Beyond 14 days after vaccination, 18 vs. 74 cases of molecularly confirmed COVID-19 were hospitalised, respectively in the JCOVDEN vs. placebo group, resulting in 76.1% (adjusted 95% CI: 56.9; 87.7) vaccine efficacy. A total of 5 cases in the JCOVDEN group vs. 17 cases in the placebo group required Intensive Care Unit (ICU) admission and 4 vs. 8 cases in the JCOVDEN and placebo group respectively required mechanical ventilation.

Vaccine efficacy against asymptomatic infections at least 28 days after vaccination was 28.9% (95% CI: 20.0; 36.8) and against all SARS-CoV-2 infections was 41.7% (95% CI: 36.3; 46.7).

Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates for male and female participants, as well as for participants with and without medical comorbidities associated with high risk of severe COVID-19.

A summary of vaccine efficacy by variant strain is presented in Table 5 below:

Table 5. Summary of vaccine efficacy against symptomatica and severeb COVID-19 by variant strain following a single-dose:

^a Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 other systemic signs or symptoms, as defined in the protocol.
^b Final determination of severe COVID-19 cases was made by an independent adjudication committee, who also assigned disease severity according to the definition per FDA guidance.
^* If less than 6 cases are observed for an endpoint then the VE will not be shown. NE = not estimable.

Efficacy of two-doses of JCOVDEN administered 2 months apart

A final analysis (cut-off date 25 June 2021) of a multicenter, randomised, double-blind, placebocontrolled Phase 3 study (COV3009) was conducted in North and Latin America, Africa, Europe and Asia to assess the efficacy, safety, and immunogenicity of 2 doses of JCOVDEN administered with a 56-day interval. The study excluded individuals with abnormal function of the immune system resulting from a clinical condition, individuals who were under immunosuppressive therapies within 6 months, as well as pregnant women. Participants with stable HIV infection under treatment were not excluded. Licensed vaccines, excluding live vaccines, could be administered more than 14 days before or more than 14 days after the vaccination in the study. Licensed live attenuated vaccines could be administered more than 28 days before or more than 28 days after the vaccination in the study.

A total of 31300 individuals were randomised in the double-blind phase of the study. In total, 14492 (46.3%) individuals were included in the per-protocol efficacy population (7484 individuals received JCOVDEN and 7008 individuals received placebo). Participants were followed for a median of 36 days (range: 0-172 days) after vaccination.

Demographic and baseline characteristics were similar among individuals who received at least two doses of the JCOVDEN and those who received placebo. In the primary efficacy analysis population, among the individuals who received 2 doses of JCOVDEN, the median age was 50.0 years (range: 18 to 99 years); 87.0% (N=6512) of individuals were 18 to 64 years old [with 13.0% (N=972) aged 65 or older and 1.9% (N=144) aged 75 or older]; 45.4% of individuals were female; 37.5% were from North America (United States), 51.0% were from Europe (including UK), 5.4% were from South Africa, 1.9% from Philippines and 4.2% from Latin America. A total of 2747 (36.7%) individuals had at least one pre-existing comorbidity associated with increased risk of progression to severe COVID-19 at baseline. Comorbidities included: obesity defined as BMI ≥ 30 kg/m² (24.6%), hypertension (8.9%), sleep apnea (6.7%), type 2 diabetes (5.2%), serious heart conditions (3.6%), asthma (1.7%) and stable/well-controlled HIV infection (1.3%). Other comorbidities were present in ≤ 1% of the individuals.

Vaccine efficacy against symptomatic COVID-19 and severe COVID-19 is presented in Table 6 below:

Table 6. Analysis of vaccine efficacy against symptomatica and severeb COVID-19 – 14 days post-booster dose (second dose):

^a Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 other systemic signs or symptoms, as defined in the protocol.
^b Final determination of severe COVID-19 cases was made by an independent adjudication committee, who also assigned disease severity according to the definition per FDA guidance.
^c Per-protocol efficacy population.
^d Confidence intervals were adjusted to implement type I error control for multiple testing. e Of the 8 participants with severe disease, 1 was admitted to an intensive care unit.

Approximately 68% of centrally confirmed strains have been sequenced as of this analysis (July 2021). Preliminary analysis results of variants with sufficient cases available for meaningful interpretations (Alpha [B.1.1.7] and Mu [B.1.621]) show that, after the first dose of JCOVDEN, efficacy 14 days post-dose 1 (Day 15-Day 56) for these 2 variants was 71.6% [95% CI: 43.2; 86.9] and 43.9% [95% CI: -43.4; 79.6], respectively. After the second dose (≥71 days), efficacy for Alpha and Mu was 94.2% [95% CI: 62.9; 99.9] and 63.1% [95% CI: -27.9; 91.6], respectively. Therefore, statistically significant efficacy for Mu was not demonstrated. There were only few Delta cases (2 and 1 in the JCOVDEN group and placebo group, respectively) and no reference strain cases in either the JCOVDEN or placebo group in the follow-up 14 days after the booster dose (≥71 days).

Vaccine efficacy against asymptomatic infections at least 14 days after second vaccination was 34.2% (95% CI: -6.4; 59.8).

Immunogenicity of a booster dose (second dose) following primary vaccination with JCOVDEN

It should be noted that there is no established immune correlate of protection. In a Phase 2 Study (COV2001), individuals 18 through 55 years of age and 65 years and older received a booster dose of the JCOVDEN approximately 2 months after the primary vaccination. Immunogenicity was assessed by measuring neutralising antibodies to SARS-CoV-2 Victoria/1/2020 strain using a qualified wild-type virus neutralisation assay (wtVNA). Immunogenicity data are available from 39 individuals, of whom 15 were 65 years of age and older, and are summarised in Table 7.

Table 7. SARS-CoV-2 Neutralisation Wild Type VNA-VICTORIA/1/2020 (IC50), Study COV2001 Group 1, Per-Protocol Immunogenicity Set*:

LLOQ = lower limit of quantification
^* PPI set: The per-protocol immunogenicity population includes all randomised and vaccinated individuals for whom immunogenicity data are available excludingindividuals with major protocol deviations expected to impact the immunogenicity outcomes. In addition, samples obtained after missed vaccinations or individuals with natural SARSCoV-2 infection occurring after screening (if applicable) were excluded from the analysis.

Neutralising antibody and binding antibody increases against the reference SARS-CoV-2 strain were also observed in studies COV1001, COV1002 and COV2001 in a limited number of study participants after a boost given at 2, 3 and 6 months, when compared to pre-boost values. Overall, the increases of GMTs pre-boost to 1 month post-boost ranged from 1.5 to 4.4 fold for neutralising antibodies, and from 2.5 to 5.8 fold for binding antibodies. A 2-fold decrease in antibody levels was observed 4 months following 2-month booster dose, compared to 1 month following 2-month booster dose. Ab levels were still higher than antibody levels following a single-dose at a similar timepoint. These data support the administration of a booster dose when administered at an interval of 2 months or longer after primary vaccination.

Immunogenicity of a booster dose following primary vaccination with an approved mRNA COVID-19 vaccine

An independent Phase ½ open-label clinical trial (NCT04889209) conducted in the United States that evaluated a heterologous booster dose of the JCOVDEN. Immunogenicity was assessed by using a psVNA based on a lentivirus expressing the SARS-CoV-2 Spike protein with D614G mutation. Due to the limited sample size, differences observed are only descriptive. In this study, adults who had completed primary vaccination with a Spikevax 2-dose series (N=151), a JCOVDEN single-dose (N=156), or a Comirnaty 2-dose series (N=151) at least 12 weeks prior to enrollment and who reported no history of SARS-CoV-2 infection were randomised 1:1:1 to receive a booster dose of one of three vaccines: Spikevax, JCOVDEN, or Comirnaty. Neutralising antibody titres were assessed on Day 1 prior to administration of the booster dose and on Day 15 and Day 29 after the booster dose. A booster response to the JCOVDEN was demonstrated regardless of primary vaccination. The antibody level on Day 15 after a heterologous boost by JCOVDEN is lower than after a homologous boost by a licensed mRNA vaccine while on Day 29, neutralising antibody titers are roughly similar between both regimens. Data indicate the homologous regimen with JCOVDEN induces lower antibody responses compared to heterologous boosting with a licensed mRNA vaccine. The clinical relevance of this is unknown. Only short-term immunogenicity data are available, long-term protection and immunological memory are currently unknown.

Elderly population

JCOVDEN was assessed in individuals 18 years of age and older. The efficacy of JCOVDEN was consistent between elderly (≥65 years) and younger individuals (18-64 years).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with JCOVDEN in one or more subsets of the paediatric population in prevention of COVID-19 (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.