COVID-19 VACCINE JANSSEN suspension for injection medication leaflet

JCOVDEN suspension for injection

COVID-19 vaccine (Ad26.COV2-S [recombinant])

This is a multi-dose vial which contains 5 doses of 0.5 mL.

One dose (0.5 mL) contains:

Adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein* (Ad26.COV2-S), not less than8.92 log10 infectious units (Inf.U).

* Produced in the PER.C6 TetR Cell Line and by recombinant DNA technology.

The product contains genetically modified organisms (GMOs).

Each dose (0.5 mL) contains approximately 2 mg of ethanol.

For the full list of excipients, see section 6.1.

Suspension for injection (injection).

Colourless to slightly yellow, clear to very opalescent suspension (pH 6-6.4).

JCOVDEN is indicated for active immunisation to prevent COVID-19 caused by SARS-CoV-2 inindividuals 18 years of age and older.

The use of this vaccine should be in accordance with official recommendations.

JCOVDEN is administered as a single-dose of 0.5 mL by intramuscular injection only.

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A booster dose (second dose) of 0.5 mL of JCOVDEN may be administered intramuscularly at least2 months after the primary vaccination in individuals 18 years of age and older (see also sections 4.4,4.8 and 5.1).

A booster dose of JCOVDEN (0.5 mL) may be administered in individuals 18 years of age and olderas a heterologous booster dose following completion of primary vaccination with an mRNA COVID-19 vaccine or an adenoviral vector-based COVID-19 vaccine. The dosing interval for the heterologousbooster dose is the same as that authorised for a booster dose of the vaccine used for primaryvaccination (see also sections 4.4, pct. 4.8 and 5.1).

The safety and efficacy of JCOVDEN in children and adolescents (less than 18 years of age) have notyet been established. No data are available.

No dose adjustment is required in elderly individuals ≥ 65 years of age. See also sections 4.8 and 5.1.

JCOVDEN is for intramuscular injection only, preferably in the deltoid muscle of the upper arm.

Do not inject the vaccine intravascularly, intravenously, subcutaneously or intradermally.

The vaccine should not be mixed in the same syringe with any other vaccines or medicinal products.

For precautions to be taken before administering the vaccine, see section 4.4.

For instructions on handling and disposal of the vaccine, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

A history of confirmed thrombosis with thrombocytopenia syndrome (TTS) following vaccinationwith any COVID-19 vaccine (see also section 4.4).

Individuals who have previously experienced episodes of capillary leak syndrome (CLS) (see alsosection 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Events of anaphylaxis have been reported. Appropriate medical treatment and supervision shouldalways be readily available in case of an anaphylactic reaction following the administration of thevaccine. Close observation for at least 15 minutes is recommended following vaccination.

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Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐relatedreactions may occur in association with vaccination as a psychogenic response to the needle injection.

It is important that precautions are in place to avoid injury from fainting.

Vaccination should be postponed in individuals suffering from an acute severe febrile illness or acuteinfection. However, the presence of a minor infection and/or low-grade fever should not delayvaccination.

- Thrombosis with thrombocytopenia syndrome: A combination of thrombosis andthrombocytopenia, in some cases accompanied by bleeding, has been observed very rarelyfollowing vaccination with JCOVDEN. This includes severe cases of venous thrombosis atunusual sites such as cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis aswell as arterial thrombosis concomitant with thrombocytopenia. Fatal outcome has beenreported. These cases occurred within the first three weeks following vaccination, and mostly inindividuals under 60 years of age.

Thrombosis in combination with thrombocytopenia requires specialised clinical management.

Healthcare professionals should consult applicable guidance and/or consult specialists (e.g.,haematologists, specialists in coagulation) to diagnose and treat this condition.

Individuals who have experienced thrombosis with thrombocytopenia syndrome followingvaccination with any COVID-19 vaccine should not receive JCOVDEN (See also section 4.3).

- Venous thromboembolism: Venous thromboembolism (VTE) has been observed rarelyfollowing vaccination with JCOVDEN (see section 4.8). This should be considered forindividuals at increased risk for VTE.

- Immune thrombocytopenia: Cases of immune thrombocytopenia with very low platelet levels(<20000 per μL) have been reported very rarely after vaccination with JCOVDEN, usuallywithin the first four weeks after receiving JCOVDEN. This included cases with bleeding andcases with fatal outcome. Some of these cases occurred in individuals with a history of immunethrombocytopenia (ITP). If an individual has a history of ITP, the risks of developing lowplatelet levels should be considered before vaccination, and platelet monitoring is recommendedafter vaccination.

Healthcare professionals should be alert to the signs and symptoms of thromboembolism and/orthrombocytopenia. Those vaccinated should be instructed to seek immediate medical attention if theydevelop symptoms such as shortness of breath, chest pain, leg pain, leg swelling, or persistentabdominal pain following vaccination. Additionally, anyone with neurological symptoms includingsevere or persistent headaches, seizures, mental status changes or blurred vision after vaccination, orwho experiences spontaneous bleeding, skin bruising (petechia) beyond the site of vaccination after afew days, should seek prompt medical attention.

Individuals diagnosed with thrombocytopenia within 3 weeks after vaccination with JCOVDENshould be actively investigated for signs of thrombosis. Similarly, individuals who present withthrombosis within 3 weeks of vaccination should be evaluated for thrombocytopenia.

As with other intramuscular injections, the vaccine should be given with caution in individualsreceiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such ashaemophilia) because bleeding or bruising may occur following an intramuscular administration inthese individuals.

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Very rare cases of capillary leak syndrome (CLS) have been reported in the first days after vaccinationwith JCOVDEN, in some cases with a fatal outcome. A history of CLS has been reported. CLS is arare disorder characterised by acute episodes of oedema mainly affecting the limbs, hypotension,haemoconcentration and hypoalbuminaemia. Patients with an acute episode of CLS followingvaccination require prompt recognition and treatment. Intensive supportive therapy is usuallywarranted. Individuals with a known history of CLS should not be vaccinated with this vaccine. Seealso section 4.3.

Guillain-Barré syndrome (GBS) and transverse myelitis (TM) have been reported very rarelyfollowing vaccination with JCOVDEN. Healthcare professionals should be alert to GBS and TM signsand symptoms to ensure correct diagnosis, in order to initiate adequate supportive care and treatmentand to rule out other causes.

There is an increased risk of myocarditis and pericarditis following vaccination with JCOVDEN(section 4.8). These conditions can develop within just a few days after vaccination and have primarilyoccurred within 14 days. They have been observed more often in males younger than 40 years of age.

Healthcare professionals should be alert to the signs and symptoms of myocarditis and pericarditis.

Vaccinees should be instructed to seek immediate medical attention if they develop symptomsindicative of myocarditis or pericarditis such as (acute and persisting) chest pain, shortness of breath,or palpitations following vaccination. Healthcare professionals should consult guidance and/orspecialists to diagnose and treat these conditions.

Risk of severe adverse events after a booster dose

The risk of severe adverse events (such as coagulation disorders including thrombosis withthrombocytopenia syndrome, CLS, GBS, myocarditis and pericarditis) after a booster dose of

JCOVDEN has not yet been characterised.

The efficacy, safety and immunogenicity of the vaccine have not been assessed inimmunocompromised individuals, including those receiving immunosuppressant therapy.

The efficacy of JCOVDEN may be lower in immunosuppressed individuals.

The duration of protection afforded by the vaccine is unknown as it is still being determined byongoing clinical trials.

Protection starts around 14 days after vaccination. As with all vaccines, vaccination with JCOVDENmay not protect all vaccine recipients (see section 5.1).

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 mL dose, that is to sayessentially ‘sodium-free’.

Medicinal pr duct no l nge autho ised

This medicinal product contains 2 mg of alcohol (ethanol) per 0.5 mL dose. The small amount ofalcohol in this medicinal product will not have any noticeable effects.

JCOVDEN can be administered concomitantly with seasonal standard dose inactivated influenzavaccine. The reactogenicity following concomitant administration was higher than when the vaccineswere administered alone.

Injection should be done at different injection sites.

Concomitant administration of JCOVDEN with other vaccines has not been studied.

There is limited experience with the use of JCOVDEN in pregnant women. Animal studies with

JCOVDEN do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetaldevelopment, parturition or postnatal development (see section 5.3).

Administration of JCOVDEN in pregnancy should only be considered when the potential benefitsoutweigh any potential risks to the mother and foetus.

It is unknown whether JCOVDEN is excreted in human milk.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

JCOVDEN has no or negligible influence on the ability to drive and use machines. However, some ofthe adverse reactions mentioned under section 4.8 may temporarily affect the ability to drive or usemachines.

The safety of JCOVDEN was evaluated in the primary pooled analysis from the double-blind phase ofthe randomised, placebo-controlled studies COV1001, COV1002, COV2001, COV3001 and

COV3009. A total of 38,538 adults aged 18 years and older received at least a single-dose primaryvaccination of JCOVDEN. The median age of individuals was 52 years (range 18-100 years). For theprimary pooled analysis, the median follow-up for individuals who received JCOVDEN wasapproximately 4 months after completion of primary vaccination. Longer safety follow-up of≥ 6 months is available for 6,136 adults who received JCOVDEN.

In the primary pooled analysis, the most common local adverse reactions reported was injection sitepain (54.3%). The most common systemic adverse reactions were fatigue (44.0%), headache (43.0%),myalgia (38.1%) and nausea (16.9%). Pyrexia (defined as body temperature ≥ 38.0°C) was observed

Medicinal product no longer authorisedin 7.2% of participants. Most adverse reactions were mild to moderate in severity. Across the studies,most adverse reactions occurred within 1-2 days following vaccination and were of short duration (1-2 days).

Reactogenicity was generally milder and reported less frequently in older adults .

The safety profile was generally consistent across participants with or without prior evidence of

SARS-CoV-2 infection at baseline. A total of 10.6% of individuals that received JCOVDEN were

SARS-CoV-2 positive at baseline (based on serology or RT-PCR assessment).

The safety of a booster dose (second dose) with JCOVDEN administered approximately 2 monthsafter the primary vaccination was evaluated in an ongoing randomised, double-blind, placebo-controlled Phase 3 Study (COV3009). In the FAS (full analysis set), from the 15708 adults aged18 years and older who received 1 dose of JCOVDEN, a total of 8646 individuals received a seconddose during the double-blind phase.

The safety of a booster dose (second dose) with JCOVDEN administered at least 6 months after theprimary vaccination was evaluated in a randomised, double-blind Phase 2 Study (COV2008 Cohort 1

N=330).

Overall, the solicited adverse reaction profile for the homologous booster dose was similar to that afterthe first dose. There were no new safety signals identified.

Overall, in 3 clinical studies (including 2 independent studies) approximately 500 adults have receivedprimary vaccination with 2 doses of an mRNA COVID-19 vaccine and received a single booster doseof JCOVDEN, at least 3 months after primary vaccination (COV2008, COV-BOOST and DMID 21-0012 studies). There were no new safety concerns identified. However, a trend towards an increase infrequency and severity of solicited local and systemic adverse events after the heterologous boosterdose was observed when compared with the homologous booster dose of JCOVDEN.

The safety of a heterologous booster dose of JCOVDEN was evaluated in the COV-BOOST studyfollowing primary vaccination with an adenoviral vector-based COVID-19 vaccine. Participantsreceived 2 doses of Vaxzevria (N=108) followed by a booster dose of JCOVDEN 77 days post seconddose (median; IQR: 72-83 days). There were no new safety concerns identified.

Adverse drug reactions observed in the primary pooled analysis or from post marketing sources areorganised by MedDRA System Organ Class (SOC). Frequency categories are defined as follows:

Very common (≥ 1/10);

Common (≥ 1/100 to < 1/10);

Uncommon (≥ 1/1000 to < 1/100);

Rare (≥ 1/10000 to < 1/1000);

Very rare (< 1/10000);

Not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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Table 1: Adverse reactions reported following vaccination with JCOVDEN

Not known(cannot be

Very Common Uncommon Rare estimated from

System Organ common (≥ 1/100 to (≥ 1/1000 to (≥ 1/10000 to Very Rare the available

Class (≥ 1/10) < 1/10) < 1/100) < 1/1000) (< 1/10000) data)

Blood and Lymph- Immunelymphatic system adenopathy thrombo-disorders cytopenia

Immune system Urticaria; Anaphylaxisbdisorders hypersensitivitya

Nervous system Headache Dizziness; Paraesthesia; Guillain- Transversedisorders tremor; hypoaesthesia, Barré myelitis

Facial paralysis syndrome(including Bell’spalsy)

Ear and labyrinth Tinnitusdisorders

Cardiac disorders Myocarditis,pericarditis

Vascular Venous Thrombosis Capillary leakdisorders thromboembolism in syndrome;combination cutaneouswith small vesselthrombo- vasculitiscytopenia

Respiratory, Cough;thoracic and oropharyngealmediastinal pain;disorders Sneezing

Gastrointestinal Nausea Diarrhoea;disorders vomiting

Skin and Rash Hyperhidrosissubcutaneoustissue disorders

Musculoskeletal Myalgia Arthralgia;and connective musculartissue disorders weakness; backpain; pain inextremity

General disorders Injection Pyrexia; Malaise;and site pain; injection astheniaadministration fatigue sitesite conditions erythema;injectionsiteswelling;chillsa Hypersensitivity refers to allergic reactions of the skin and subcutaneous tissue.b Cases received from an ongoing open-label study in South Africa.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V and include batch/Lot number if available.

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No case of overdose has been reported. In Phase 1/2 studies where a higher dose (up to 2-fold) wasadministered JCOVDEN remained well-tolerated, however vaccinated individuals reported an increasein reactogenicity (increased vaccination site pain, fatigue, headache, myalgia, nausea and pyrexia).

In the event of overdose, monitoring of vital functions and possible symptomatic treatment isrecommended.

Pharmacotherapeutic group: COVID-19, viral vector, non-replicating, ATC code: J07BN02

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

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 primaryvaccination of JCOVDEN for the prevention of COVID-19 in adults aged 18 years and older. Thestudy excluded individuals with abnormal function of the immune system resulting from a clinicalcondition, individuals who are under immunosuppressive therapies within 6 months, as well aspregnant women. Participants with stable HIV infection under treatment were not excluded. Licensedvaccines, excluding live vaccines, could be administered more than 14 days before or more than14 days after the vaccination in the study. Licensed live attenuated vaccines could be administeredmore than 28 days before or more than 28 days after the vaccination in the study.

A total of 44325 individuals were randomised in parallel in a 1:1 ratio to receive an intramuscularinjection of JCOVDEN or placebo. A total of 21895 adults received JCOVDEN and 21888 adultsreceived placebo. Participants were followed for a median follow-up of approximately 2 months aftervaccination.

The primary efficacy analysis population of 39321 individuals included 38059 SARS-CoV-2seronegative individuals at baseline and 1262 individuals with an unknown serostatus.

Demographic and baseline characteristics were similar among individuals who received JCOVDENand those who received placebo. In the primary efficacy analysis population, among the individualswho received JCOVDEN, the median age was 52.0 years (range: 18 to 100 years); 79.7% (N=15646)of individuals were 18 to 64 years old [with 20.3% (N=3984) 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 totalof 7830 (39.9%) individuals had at least one pre-existing comorbidity associated with increased risk ofprogression to severe COVID-19 at baseline. Comorbidities included: obesity defined as BMI

Medicinal produt no longer authorised≥ 30 kg/m2 (27.5%), hypertension (10.3%), type 2 diabetes (7.2%), stable/well-controlled HIVinfection (2.5%), serious heart conditions (2.4%) and asthma (1.3%). Other comorbidities were presentin ≤ 1% of the individuals.

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

Table 2: Analysis of vaccine efficacy against COVID-19b in SARS-CoV-2 seronegativeadults - primary efficacy analysis population after a single-dose

JCOVDEN Placebo

N=19630 N=19691 % Vaccine

COVID-19 Person- COVID-19 Person- Efficacy

Subgroup Cases (n) Years Cases (n) Years (95% CI)c14 days post-vaccination

All subjectsa 116 3116.6 348 3096.1 66.9(59.0; 73.4)18 to 64 years of age 107 2530.3 297 2511.2 64.2(55.3; 71.6)65 years and older 9 586.3 51 584.9 82.4(63.9; 92.4)75 years and older 0 107.4 8 99.2 100(45.9; 100.0)28 days post-vaccination

All subjectsa 66 3102.0 193 3070.7 66.1(55.0; 74.8)18 to 64 years of age 60 2518.7 170 2490.1 65.1(52.9; 74.5)65 years and older 6 583.3 23 580.5 74.0(34.4; 91.4)75 years and older 0 106.4 3 98.1 -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 othersystemic 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-2seronegative adults - primary efficacy analysis population after a single-dose

JCOVDEN Placebo

N=19630 N=19691 % Vaccine

COVID-19 Person- COVID-19 Person- Efficacy

Subgroup Cases (n) Years Cases (n) Years (95% CI)b14 days post-vaccination

Severe 76.714 3125.1 60 3122.0 (54.6; 89.1)28 days post-vaccination

Severe 85.45 3106.2 34 3082.6 (54.2; 96.9)a Final determination of severe COVID-19 cases was made by an independent adjudication committee, who alsoassigned 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

Medicinal product no longer authorisedmajority of the remaining severe cases fulfilled only the oxygen saturation (SpO2) criterion for severedisease (≤ 93% on room air).

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

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

JCOVDEN Placebo

Efficacyc N=19577d N=19608d (95% CI)

Endpoint

COVID-19 COVID-

Person- Person-

Cases 19 Cases

Years Years(n) (n)14 days post-vaccination56.3

Symptomatic COVID-19 484 6685.6 1067 6440.2(51.3; 60.9)55.318 to 64 years of age 438 5572.0 944 5363.6(49.9; 60.2)63.865 years and older 46 1113.6 123 1076.6(48.9; 74.8)48.375 years and older 9 198.2 15 170.9(-26.1; 80.1)73.3

Severe COVID-19 56 6774.6 205 6625.2(63.9; 80.5)74.318 to 64 years of age 46 5653.8 175 5531.4(64.2; 81.8)67.565 years and older 10 1120.8 30 1093.8(31.6; 85.8)71.275 years and older 2 199.4 6 172.4(-61.2; 97.2)28 days post-vaccination52.9

Symptomatic COVID-19 433 6658.4 883 6400.4(47.1; 58.1)52.218 to 64 years of age 393 5549.9 790 5330.5(46.0; 57.8)58.565 years and older 40 1108.5 93 1069.9(39.3; 72.1)22.375 years and older 9 196.0 10 169.3(-112.8; 72.1)74.6

Severe COVID-19 46 6733.8 176 6542.1(64.7; 82.1)75.418 to 64 years of age 38 5619.2 150 5460.5(64.7; 83.2)70.165 years and older 8 1114.6 26 1081.6(32.1; 88.3)65.575 years and older 2 197.2 5 170.1(-110.7; 96.7)a Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 othersystemic signs or symptoms, as defined in the protocol.b Final determination of severe COVID-19 cases was made by an independent adjudication committee, who alsoassigned disease severity according to the definition per FDA guidance.c Co-primary endpoint as defined in the protocol.d Per-protocol efficacy population

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Beyond 14 days after vaccination, 18 vs. 74 cases of molecularly confirmed COVID-19 werehospitalised, 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 placebogroup required Intensive Care Unit (ICU) admission and 4 vs. 8 cases in the JCOVDEN and placebogroup 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 maleand female participants, as well as for participants with and without medical comorbidities associatedwith 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 byvariant strain following a single-dose

Severity

Symptomatic

COVID-19 Severe COVID-19% Vaccine Efficacy % Vaccine Efficacy

Variant Onset (95% CI) (95% CI)67.5% 88.5%

At least 14 days after vaccination (56.1; 76.2) (67.7; 97.0)58.9% 89.6%

Reference At least 28 days after vaccination (43.4; 70.5) (66.3; 98.0)70.1% 51.1%

At least 14 days after vaccination (35.1; 87.6) (-241.2; 95.6)70.2% 51.4%

Alpha (B.1.1.7) At least 28 days after vaccination (35.3; 87.6) (-239.0; 95.6)38.1% 70.2%

At least 14 days after vaccination (4.2; 60.4) (28.4; 89.2)51.9% 78.4%

Beta (B.1.351) At least 28 days after vaccination (19.1; 72.2) (34.5; 94.7)37.2% 62.4%

Gamma At least 14 days after vaccination (15.2; 53.7) (19.4; 83.8)(P.1/P.1.x/P.1.x 37.3% 62.6%.x) At least 28 days after vaccination (15.4; 53.8) (19.9; 83.9)64.6% 91.1%

At least 14 days after vaccination (47.7; 76.6) (38.8; 99.8)64.0% 87.9%

Zeta (P.2) At least 28 days after vaccination (43.2; 77.7) (9.4; 99.7)31.9% 80.4%

Mu At least 14 days after vaccination (-3.3; 55.5) (41.6; 95.1)(B.1.621/B.1.6 32.0% 80.6%21.1) At least 28 days after vaccination (-3.1; 55.6) (42.0; 95.2)11.2% 60.9%

At least 14 days after vaccination (-34.6; 41.6) (-35.6; 91.0)

Lambda 11.4% 61.1%(C.37/C.37.1) At least 28 days after vaccination (-34.3; 41.7) (-34.7; 91.1)3.7% NE*

Delta At least 14 days after vaccination (-145.0; 62.1) NE*(B.1.617.2/AY. 3.9% NE*x) At least 28 days after vaccination (-144.5; 62.2) NE*73.0% 81.4%

Other At least 14 days after vaccination (65.4; 79.2) (59.8; 92.5)

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At least 28 days after vaccination (59.3; 76.6) (46.2; 90.3)a Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 othersystemic signs or symptoms, as defined in the protocol.

b Final determination of severe COVID-19 cases was made by an independent adjudication committee, who alsoassigned 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.

A final analysis (cut-off date 25 June 2021) of a multicenter, randomised, double-blind, placebo-controlled 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 a56-day interval. The study excluded individuals with abnormal function of the immune systemresulting from a clinical condition, individuals who were under immunosuppressive therapies within6 months, as well as pregnant women. Participants with stable HIV infection under treatment were notexcluded. Licensed vaccines, excluding live vaccines, could be administered more than 14 days beforeor more than 14 days after the vaccination in the study. Licensed live attenuated vaccines could beadministered 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 of36 days (range: 0-172 days) after vaccination.

Demographic and baseline characteristics were similar among individuals who received at least twodoses of 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: 18to 99 years); 87.0% (N=6512) of individuals were 18 to 64 years old [with 13.0% (N=972) aged 65 orolder 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 leastone pre-existing comorbidity associated with increased risk of progression to severe COVID-19 atbaseline. 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%) andstable/well-controlled HIV infection (1.3%). Other comorbidities were present in ≤ 1% of theindividuals.

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

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

JCOVDEN Placebo

N=7484c N=7008c % Vaccine

COVID-19 Person- COVID-19 Person- Efficacy

Endpoint Cases (n) Years Cases (n) Years (95% CI)d

Symptomatic 75.214 1730.0 52 1595.0

COVID-19 (54.6; 87.3)

Severe COVID-19 0 1730.7 8e 1598.9(32.6; 100.0)a Symptomatic COVID-19 requiring positive RT-PCR result and at least 1 respiratory sign or symptom or 2 othersystemic signs or symptoms, as defined in the protocol.

b Final determination of severe COVID-19 cases was made by an independent adjudication committee, who alsoassigned 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.

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Final analysis results of variants with sufficient cases available for meaningful interpretations (Alpha[B.1.1.7] and Mu [B.1.621/B.1.621.1]) show that, after the first dose of JCOVDEN, efficacy 14 dayspost-dose 1 (Day 15-Day 56) for these 2 variants was 73.8% [95% CI: 49.7; 87.4] and 38.6% [95% CI:

- 43.9; 75.1], respectively. After the second dose (≥71 days), efficacy for Alpha and Mu was 83.7%[95% CI: 43.8; 97.0] and 53.9% [95% CI: -48.0; 87.6], respectively. There were only 7 Delta cases (4and 3 Delta cases in the JCOVDEN group and placebo group, respectively). There were no referencestrain 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).

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

JCOVDEN approximately 2 months after the primary vaccination. Immunogenicity was assessed bymeasuring neutralising antibodies to SARS-CoV-2 Victoria/1/2020 strain using a qualified wild-typevirus neutralisation assay (wtVNA). Immunogenicity data are available from 39 individuals, of whom15 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**28 Days 14 Days 28 Days

Post- Post- Post-

Primary Pre-Booster Booster Booster

Baseline Vaccination Dose Dose Dose(Day 1) (Day 29) (Day 57) (Day 71) (Day 85)

N 38 39 39 39 38

Geometric mean <LLOQ260 (196; 212 (142; 514 (357; 424 (301;titre (95% CI) (<LLOQ,346) 314) 740) 597)<LLOQ)

Geometric meanfold increase (95% 2.3 1.8n/a n/a n/a

CI) from pre- (1.7; 3.0) (1.4; 2.4)booster

LLOQ = lower limit of quantification

* Victoria/1/2020 strain is considered as reference strain

** PPI set: The per-protocol immunogenicity population includes all randomised and vaccinated individuals for whomimmunogenicity data are available excluding individuals with major protocol deviations expected to impact theimmunogenicity outcomes. In addition, samples obtained after missed vaccinations or individuals with natural SARS-

CoV-2 infection occurring after screening (if applicable) were excluded from the analysis.

Neutralising antibody (wtVNA) and S-binding antibody (enzyme-linked immunosorbentassay) 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 and6 months, when compared to pre-boost values. Overall, the increases of geometric mean titres (GMTs)pre-boost to 1 month post-boost ranged from 1.5 to 4.4 fold for neutralising antibodies, and from 2.5to 5.8 fold for binding antibodies. A 2-fold decrease in antibody levels was observed 4 monthsfollowing 2-month booster dose, compared to 1 month following 2-month booster dose. Antibodylevels were still higher than antibody levels following a single-dose at a similar timepoint. These datasupport the administration of a booster dose when administered at an interval of 2 months or longerafter primary vaccination.

COV-BOOST study is a multicentre, randomised Phase 2 investigator-initiated study (NCT73765130)conducted in the United Kingdom, to evaluate a booster vaccination against COVID-19. Participants

Medicinal p oduct no longer authorisedwere adults aged 30 years or older. A cohort of participants received two doses of Comirnaty (N=89),followed by a booster dose of JCOVDEN. The median interval (IQR) was 106 (91-144) days betweenthe second and booster dose. JCOVDEN boosted binding (N=88), pseudovirus neutralising (N=77)and wild type neutralising antibody responses (N=21) against the reference strain, as observed at Day28. At Day 84 post-boost, GMTs were still higher than pre-boost values. Furthermore, JCOVDENboosted pseudovirus neutralising antibody responses against the Delta variant assessed at Day 28(N=89).

DMID 21-0012, an independent Phase 1/2 open-label clinical study (NCT04889209) conducted in the

United States evaluated a heterologous booster dose of JCOVDEN. Due to the limited sample size,differences observed are only descriptive. A booster dose of JCOVDEN was administered to adultswho had completed primary vaccination with a Spikevax 2-dose series or a Comirnaty 2-dose series atleast 12 weeks prior to enrolment (mean interval [range] of 20 [13-26] and 21 [12-41] weeks for

Spikevax and Comirnaty, respectively) and who reported no history of SARS-CoV-2 infection.

JCOVDEN boosted binding and pseudovirus neutralising antibody responses against the referencestrain and the Delta variant in individuals primed with Spikevax 2-dose series (N=49) or Comirnaty 2-dose series (N=50), as observed at Day 15 post-boost. JCOVDEN boosted pseudovirus neutralisingantibody responses against the Omicron BA.1 variant in individuals primed with Comirnaty 2-doseseries (N=50), as observed at Day 29.

Immunogenicity of a booster dose following primary vaccination with an adenoviral vector-based

COVID-19 vaccine

COV-BOOST study (see study design above) also evaluated a booster dose of JCOVDEN inparticipants who had received 2 doses of Vaxzevria (N=101). The median interval (IQR) was 77 (72-83) days between the second and booster dose. JCOVDEN boosted binding (N=94), pseudovirusneutralising (N=94) and wild type neutralising antibody responses (N=21) against the reference strain.

At Day 84 post-boost, GMTs were still higher than pre-boost values. Furthermore, JCOVDEN boostedpseudovirus neutralising antibody responses against the Delta variant assessed at Day 28 (N=90).

Descriptive data from the COV-BOOST study and DMID 21-0012 study indicate that boosting with

JCOVDEN after primary vaccination with an adenoviral vector-based vaccine induces lower antibodyresponses compared to heterologous boosting with a licensed mRNA vaccine after primaryvaccination with an adenoviral vector-based vaccine. The studies also indicate that neutralisingantibody titres reached at 1 month post-boost with JCOVDEN after primary vaccination with anmRNA vaccine are comparable to after a homologous boost with an mRNA vaccine.

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

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 (seesection 4.2 for information on paediatric use).

Not applicable.

Non-clinical data reveal no special hazards for humans based on conventional studies of repeat-dosetoxicity and local tolerance, and reproductive and developmental toxicity.

Medicinal product o longer authorised

JCOVDEN has not been evaluated for its genotoxic or carcinogenic potential. The components of thevaccine are not expected to have genotoxic or carcinogenic potential.

Female reproductive toxicity and fertility were assessed in a combined embryo-foetal and pre- andpost-natal development study in the rabbit. In this study a first vaccination of JCOVDEN wasadministered intramuscularly to female rabbits 7 days prior to mating, at a dose equivalent to 2-foldabove the recommended human dose, followed by two vaccinations at the same dose during thegestation period (i.e., at gestational days 6 and 20). There were no vaccine-related effects on femalefertility, pregnancy, or embryo-foetal or offspring development. The parental females as well as theirfoetuses and offspring exhibited SARS-CoV-2 S protein-specific antibody titres, indicating thatmaternal antibodies were transferred to the foetuses during gestation. No JCOVDEN data are availableon vaccine excretion in milk.

In addition, a conventional (repeat-dose) toxicity study in rabbits with JCOVDEN did not reveal anyeffects on male sex organs that would impair male fertility.

10 vial pack2-hydroxypropyl-β-cyclodextrin (HBCD)

Citric acid monohydrate

Hydrochloric acid (for pH-adjustment)

Polysorbate-80

Sodium chloride

Sodium hydroxide (for pH-adjustment)

Trisodium citrate dihydrate

Water for injections20 vial pack2-hydroxypropyl-β-cyclodextrin (HBCD)

Citric acid monohydrate

Hydrochloric acid (for pH-adjustment)

Polysorbate-80

Sodium chloride

Sodium hydroxide (for pH-adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products or diluted.

Unopened vial2 years when stored at -25°C to -15°C.

Medicinal product no longer authorised

Once removed from the freezer, the unopened vaccine may be stored refrigerated at 2°C to 8°C,protected from light, for a single period of up to 11 months, not exceeding the printed expiry date(EXP).

Once thawed, the vaccine should not be re-frozen.

For special precautions for storage, see section 6.4.

Chemical and physical in-use stability, including during transportation, of the vaccine has beendemonstrated for 6 hours at 2°C to 25°C. From a microbiological point of view, the product shouldpreferably be used immediately after first puncture of the vial; however, the product can be storedbetween 2°C to 8°C for a maximum of 6 hours or remain at room temperature (maximally 25°C) up to3 hours after first puncture of the vial. Beyond these times, in-use storage is the responsibility of theuser.

Store and transport frozen at -25°C to -15°C. The expiry date for storage at -25°C to -15°C is printedon the vial and outer carton after “EXP”.

When stored frozen at -25°C to -15°C, the vaccine can be thawed either at 2°C to 8°C or at roomtemperature:

- at 2°C to 8°C: a carton of 10 or 20 vials will take approximately 13 hours to thaw, and a singlevial will take approximately 2 hours to thaw.

- at room temperature (maximally 25°C): a carton of 10 or 20 vials will take approximately4 hours to thaw, and a single vial will take approximately 1 hour to thaw.

The vaccine can also be stored in a refrigerator or transported at 2°C to 8°C for a single period of up to11 months, not exceeding the original expiry date (EXP). Upon moving the product to 2°C to 8°Cstorage, the updated expiry date must be written on the outer carton and the vaccine should be used ordiscarded by the updated expiry date. The original expiry date should be crossed out. The vaccine canalso be transported at 2°C to 8°C as long as the appropriate storage conditions (temperature, time) areapplied.

Once thawed, the vaccine cannot be re-frozen.

Keep the vials in the original carton in order to protect from light.

Unopened JCOVDEN is stable for a total of 12 hours at 9°C to 25°C. It is not a recommended storageor shipping condition but may guide decisions for use in case of temporary temperature excursionsduring the 11 month storage at 2°C to 8°C.

For storage conditions after first opening of the medicinal product, see section 6.3.

A 2.5 mL suspension in a multi-dose vial (type I glass) with a rubber stopper (chlorobutyl withfluoropolymer coated surface), aluminium crimp and blue plastic cap. Each vial contains 5 doses of0.5 mL.

Pack sizes of 10 or 20 multi-dose vials.

Not all pack sizes may be marketed.

Medici al product no longer authorised

This vaccine should be handled by a healthcare professional using aseptic technique to ensure thesterility of each dose.

- The vaccine comes ready to use once thawed.

- The vaccine may be supplied frozen at -25°C to -15°C or thawed at 2°C to 8°C.

- Do not re-freeze vaccine once thawed.

- Keep the vials in the original carton in order to protect from light and to record the expiry forthe different storage conditions, if applicable.

- 25°C to -15°C 2°C to 8°C

OR

Store in a freezer Store in a refrigerator

- The vaccine can be stored and transported - The vaccine can also be stored andfrozen at -25°C to -15°C. transported at 2°C to 8°C for a single period

- The expiry date for storage is printed on the of up to 11 months, not exceeding thevial and outer carton after “EXP” (see original expiry date (EXP).section 6.4). - Upon moving the product to a refrigeratorat 2°C to 8°C, the updated expiry date mustbe written on the outer carton and the vaccineshould be used or discarded by the updatedexpiry date. The original expiry dateshould be crossed out (see section 6.4).

IF YOU RECEIVE YOUR VACCINE THAWED AT 2°C to 8°C you should store in arefrigerator:

2°C to 8°C

Do not re-freeze if the product is received already thawed at 2°C to 8°C.

Note: If the vaccine is received refrigerated at 2°C to 8°C, check that the expiry date has beenupdated by the local supplier upon receipt. If you cannot find the new EXP date, contact the localsupplier to confirm the refrigerated EXP date. Write the new expiry date on the outer carton before

Medicinal product no longer authorisedthe vaccine is stored in the refrigerator. The original expiry date should be crossed out (seesection 6.4).

b. If stored frozen, thaw vial(s) either in a refrigerator or at room temperature beforeadministration2°C to 8°C Maximally 25°C

OR Thaw for Thaw for

Thaw for 4 hours 1 hour13 hours

Thaw in refrigerator Thaw at room temperature

- When stored frozen at -25°C to -15°C, a - When stored frozen at -25°C to -15°C, acarton of 10 or 20 vials will take carton of 10 or 20 vials or individual vialsapproximately 13 hours to thaw or individual should be thawed at room temperaturevials will take approximately 2 hours to thaw maximally 25°C.at 2°C to 8°C. - A carton of 10 or 20 vials will take

- If the vaccine is not used immediately, refer approximately 4 hours to thaw.to the instructions in section ‘Store in a - Individual vials will take approximatelyrefrigerator’. 1 hour to thaw.

- The vial must be kept in the original carton in - The vaccine is stable for a total of 12 hoursorder to protect from light and to record the at 9°C to 25°C. It is not a recommendedexpiry for the different storage conditions, if storage or shipping condition but may guideapplicable. decisions for use in case of temporary

Do not re-freeze once thawed. temperature excursions.

- If the vaccine is not used immediately, referto the instructions in section Store in arefrigerator.

Do not re-freeze once thawed.

- JCOVDEN is a colorless to slightly yellow, clear to very opalescent suspension (pH 6-6.4).

- The vaccine should be inspected visually for particulate matter and discoloration prior toadministration.

- The vial should be inspected visually for cracks or any abnormalities, such as evidence oftampering prior to administration.

If any of these should exist, do not administer the vaccine.

Medicinal product no longer authorised

SEC

Swirl the vial gently Withdraw 0.5 mL Inject 0.5 mL

- Before administering a dose - Use a sterile needle and - Administer byof vaccine, swirl the vial sterile syringe to extract a intramuscular injectiongently in an upright single-dose of 0.5 mL from only into the deltoid muscleposition for 10 seconds. the multi-dose vial (see of the upper arm (see

- Do not shake. section 4.2). section 4.2).

A maximum of 5 dosescan be withdrawn from themulti-dose vial. Discard anyremaining vaccine in the vialafter 5 doses have beenextracted.

e. Storage after first puncture2°C to 8°C Maximally 25°C

Store up to 6 hours

Store up to 3 hours

OR

Record date and time the - After the first puncture of - After the first puncture ofvial should be discarded the vial, the vaccine can the vial, the vaccine can

- After first puncture of the be held at 2°C to 8°C for be held at roomvial record the date and up to 6 hours. temperature (maximallytime the vial should be - Discard if vaccine is not 25°C) for a single perioddiscarded on each vial used within this time. of up to 3 hours. (seelabel. section 6.3).

Preferably, use - Discard if vaccine is notimmediately after first used within this time.

puncture.

Any unused vaccine or waste material should be disposed of in compliance with local guidance forpharmaceutical waste. Potential spills should be disinfected with agents with viricidal activityagainst adenovirus.

Medicinl product no longer authorised

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/20/1525/001

EU/1/20/1525/002

Date of first authorisation: 11 March 2021

Date of latest renewal: 03 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Medicinal product no longer authorised