Janssen COVID-19 vaccine

Extended version of the vaccine

Janssen COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure
Listed for emergency use
Status of assessment: finalized March 12, 2021 [WHO, 2021 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Individuals aged 18 years and above [WHO, 2021 ]

European Commission (based upon the recommendation of the European Medicines Agency)
Conditional Marketing Authorization
March 11, 2021
Conditional Marketing Authorization in individuals 18 years of age and older [EMA, 2021 ]

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Not authorized

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Authorized for emergency use: 31 March, 2021 [Agência Nacional de Vigilância Sanitária (Anvisa), 2021 ]

Health Canada
Authorized for emergency use: 5 March, 2021 [Health Canada, 2021 ]

Public Health Institute (ISP, Chile)
Authorized for emergency use : 10 June 2021 [Instituto de Salud Pública de Chile, 2021 ]

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use: 25 March, 2021 [Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA), 2021 ]

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized

U.S. Food and Drug Administration
Authorized for emergency use (Emergency Use Authorization)
February 27, 2021
Emergency Use Authorization (EUA) in individuals 18 years of age and older. [FDA, 2021 ],[Johnson & Johnson, 2021 ]

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use: 27 May, 2021 [Gobierno de México, 2021 ]

Authorization in jurisdictions in Latin America and the Caribbean
Bahamas
Maldives
Saint Vincent and the Grenadines

Authorization in other jurisdictions
Andorra
Austria
Bahrain
Bangladesh
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
European Union
Faroe Islands
Finland
France
Germany
Greece
Hungary
Ireland
Italy
Kuwait
Latvia
Libya
Liechtenstein
Lithuania
Luxembourg
Malaysia
Malta
Netherlands
New Zealand
Nigeria
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
South Africa
South Korea
Spain
Sweden
Switzerland
Thailand
Tunisia
Ukraine
United States
Vietnam

Manufacturing

Manufacturer
Janssen-Cilag International NV, is a Belgian pharmaceutical company currently developing and manufacturing Janssen COVID-19 vaccine [WHO, 2021 ].

Other manufacturers
Drug substance [WHO, 2021 ]
Janssen Biologics B.V.; The Netherlands. Manufacturer of Janssen COVID-19 vaccine [WHO, 2021 ].
Janssen Vaccines & Prevention B.V.; The Netherlands [WHO, 2021 ]
Emergent Manufacturing Operations Baltimore LLC.; United States (USA). Site currently under investigation by USFDA due to non GMP compliance* [WHO, 2021 ].
Drug product [WHO, 2021 ]
Janssen Biologics B.V.; The Netherlands. Manufacturer of Janssen COVID-19 vaccine [WHO, 2021 ].
Janssen Pharmaceutica NV.; Belgium [WHO, 2021 ]
Aspen SVP.; South Africa [WHO, 2021 ]
Catalent Inc.; USA. Manufacturing partner with Johnson & Johnson for the Janssen COVID-19 vaccine [Catalent, 2020 ].
Catalent Inc.; Italy. Sterile manufacturings and packaging of the vaccine in Italy [Catalent, 2021 ]
Grand River Aseptic Manufacturing, Michigan; USA. Vaccine manufacturing, including technology transfer, fill and finish process [Grand River Aseptic Manufacturing, 2020 ].

General characteristics

Janssen COVID-19 vaccine is a colorless to slightly yellow, clear to very opalescent sterile suspension for intramuscular injection. The vaccine consists of a replication-incompetent recombinant adenovirus type 26 (Ad26) vector expressing the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein in a stabilized conformation [WHO, 2021 ].

The Ad26 vector expressing the SARS-CoV-2 S protein is grown in PER.C6® TetR Cell Line, in media containing amino acids and no animal-derived proteins. After propagation, the vaccine is processed through several purification steps, formulated with inactive ingredients and filled into vials [FDA, 2021 ].

Dosage form and ingredients
The pharmaceutical form is a suspension for intramuscular injection that is provided in a multidose vial (5 doses of 0.5 mL per vial) [WHO, 2021 ].


The vaccine contains the following ingredients:
Active ingredient
The active substance is Adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2-S) no less than 2.5 x 10^10 virus particles or no less than 8.92 log10 infectious units (IU) in each 0.5 mL.
Excipients
Citric acid monohydrate
Trisodium citrate dihydrate
Ethanol
2-hydroxypropyl-β-cyclodextrin (HBCD)
Polysorbate 80
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections

Risk considerations

The vaccine is based on the Ad26 vector platform. Clinical experience with this platform consists of the Ad26.ZEBOV/MVA-BN-Filo Ebola vaccine regimen, and vaccines against Zika, filovirus, HIV, HPV, malaria and respiratory syncytial virus. Almost 200,000 participants have used Ad26-based vaccines in clinical studies and vaccination programs with an acceptable clinical safety profile [WHO, 2021 ].

Dosification and schedule

Dose-finding studies
COV1001 trial evaluated 805 healthy adults participants 18 years of age or older that received the vaccine at a dose of 5 × 10^10 viral particles (low dose) or 1 × 10^11 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule.
The vaccine had an acceptable safety and reactogenicity profile and was immunogenic after a single vaccination with either the low or high dose.
The single dose of Ad26.COV2.S elicited a strong humoral response with the presence of S-binding and neutralizing antibodies in more than 90% of the participants, regardless of dose. Antibody titers further increased and stabilized after the first dose (follow-up: 71 days) [Sadoff J, 2021 ].

Janssen COVID-19 vaccine was as a single dose of 0.5 mL (which is a preferred characteristic according to the WHO Target Product Profiles for COVID-19 Vaccines). If, however, clinical data would show that a second dose is needed to provide long-term protection, the company is considering minimum 2 weeks interval between doses [WHO, 2021 ].
The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose of Janssen COVID-19 vaccine.

No case of overdose has been reported. In phase 1/2 studies, where a higher dose was administered, the vaccine remained well-tolerated, however, vaccinated individuals reported an increase in reactogenicity. In the event of overdose, monitoring of vital functions and possible symptomatic treatment is recommended [WHO, 2021 ]

There is no data available on the interchangeability of the Janssen COVID-19 vaccine with other COVID-19 vaccines to complete the vaccination series.
There is no evidence yet about the effects of the coadministration of Janssen COVID-19 vaccine with other vaccines included in routine vaccination programs

Indications and contraindications

Indications
Janssen COVID-19 vaccine is indicated in adult individuals 18 years and older [WHO, 2021 ].
No dose adjustment is required in individuals 65 years of age or more

Contraindications
Janssen COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the Janssen COVID-19 vaccine [WHO, 2021 ].

Precautions
To improve traceability, the name and batch number of the administered product should be clearly recorded [WHO, 2021 ].
Severe allergic reaction (e.g. anaphylaxis) to a previous dose of any vaccine (not including Janssen COVID-19 vaccine). Appropriate medical treatment should be provided [WHO, 2021 ].
Anxiety-related, or stress-related reactions may occur in association with vaccination. It is important that precautions are in place to avoid injury from fainting [WHO, 2021 ].
A very rare syndrome of blood clotting combined with low platelet counts has been reported about 3 to 15 days following vaccination with Ad26.COV2.S, described as Thrombosis with Thrombocytopenia Syndrome (TTS). TTS typically involves thrombosis in unusual locations, including cerebral venous sinuses, portal vein, splenic vein and other rare venous and arterial thrombosis, but can also occur in more common locations, causing deep vein thrombosis and pulmonary embolism. Early identification of TTS is important in order to initiate appropriate treatment. Patients who are diagnosed with thrombocytopenia (low blood platelets) within 30 days of vaccination should be actively investigated for signs of thrombosis (formation of blood clots in the vessels); and patients who present with thrombosis within 30 days of vaccination should be evaluated for thrombocytopenia. Clinicians should also be aware that although heparin is used to treat blood clots in general, administration of heparin in TTS may exacerbate the syndrome due to the presence of PF4 antibodies, and alternative treatments such as immunoglobulins and non-heparin anticoagulants should be considered [WHO, 2021 ].
Healthcare professionals should be alert to the signs and symptoms of thromboembolism and thrombocytopenia, as well as coagulopathies. Vaccinated individuals should be instructed to seek immediate medical attention if they develop the following symptoms; severe or persistent headaches, blurred vision, confusion, seizures, shortness of breath, chest pain, leg swelling, leg pain, persistent abdominal pain or unusual skin bruising and or petechia a few days after vaccination [WHO, 2021 ].

EMA recommends that Individuals who have previously had capillary leak syndrome must not be vaccinated with Janssen COVID-19 vaccine. Healthcare professionals should be aware of the signs and symptoms of capillary leak syndrome and of its risk of recurrence in people who have previously been diagnosed with the condition. Vaccinated individuals should be instructed to seek immediate medical attention if they experience rapid swelling of the arms and legs or sudden weight gain in the days following vaccination. These symptoms are often associated with feeling faint (due to low blood pressure) [EMA, 2021 ].
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection. However, the presence of a minor infection, such as cold, and/or low-grade fever should not delay vaccination [WHO, 2021 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [WHO, 2021 ].
The interaction of concomitant administration of Janssen COVID-19 vaccine with other vaccines has not been studied. [WHO, 2021 ].
WHO recommends the use of Ad26.COV2.S in pregnant women only if the benefits of vaccination to the pregnant woman outweigh the potential risks. To help pregnant women make this assessment, they should be provided with information about the risks of COVID-19 in pregnancy (including, for example, that some pregnant women are at increased risk of infection or have co-morbidities that add to their risk of severe disease), the likely benefits of vaccination in the local epidemiologic context, and the current limitations of the safety data in pregnant women. WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2021 ].
Data are not available on the potential benefits or risks of the vaccine to breastfed children. However, as Ad26.COV2.S is not a live virus vaccine, it is biologically and clinically unlikely to pose a risk to the breastfeeding child. On the basis of these considerations, WHO recommends the use of Ad26.COV2.S in lactating women as in other adults. WHO does not recommend discontinuing breastfeeding because of vaccination [WHO, 2021 ].
The safety and efficacy of Janssen COVID-19 vaccine in children and adolescents (less than 18 years of age) has not yet been established. No data are available [WHO, 2021 ].

Age is not a precaution. Vaccination is generally recommended for older people without an upper age limit since the benefits outweigh the potential risks [WHO, 2021 ].
Benefit-risk assessments for subgroups (e.g. younger vs. older individuals) may differ from country to country, and countries should consider their epidemiological situation, individual and population-level risks, availability of other vaccines, and alternate options for risk mitigation. The benefit risk ratio is greatest in older age groups as the risk of severe COVID-19 disease outcomes increases with age [WHO, 2021 ].
Efficacy and safety of Janssen COVID-19 vaccine have not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. The efficacy of the vaccine can be lower on immunosuppressed individuals. In the interim, given that the vaccine is nonreplicating, immunocompromised persons who are part of a group recommended for vaccination may be vaccinated. Information and, where possible, counselling about vaccine safety and efficacy profiles in immunocompromised persons should be provided to inform individual benefit-risk assessment. [WHO, 2021 ].
The available data on Janssen COVID-19 vaccine in immunocompromised persons, including persons living with HIV, are insufficient to assess the efficacy of the vaccine. In the interim, given that the vaccine is nonreplicating, persons living with HIV who are part of a group recommended for vaccination may be vaccinated. Information and, where possible, counselling should be provided to inform individual benefit-risk assessment. It is not necessary to test for HIV infection prior to vaccine administration. [WHO, 2021 ]
There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule, until data on co-administration with other vaccines are available [World Health Organization, 2021 ].
Vaccination may be offered regardless of a person‘s history of symptomatic or asymptomatic SARS-CoV-2 infection [World Health Organization, 2021 ].
Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].
Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].

Close observation for at least 30 minutes is recommended following vaccination.

Storage and logistics

Storage
Two years stored frozen at -25°C to -15°C (-13°F to 5°F), or
The shelf life of Janssen COVID-19 vaccine of up to 4.5 months stored between 2 ° C and 8 ° C (36 ° F to 46 ° F) [WHO, 2021 ]
FDA/USA authorized the extension of the shelf-life of Janssen COVID-19 Vaccine stored at 2-8°C for up to 6 months [FDA, 2021 ]
Upon moving the product to 2°C to 8°C (36°F to 46°F) storage, the updated expiry date must be written on the outer carton and the vaccine should be used or discarded by the updated expiry date [WHO, 2021 ].
Do not refreeze once thawed.
Store in the original carton to protect from light.
If you receive your vaccine thawed at 2°C to 8°C (36°F to 46°F) you should store in a refrigerator [WHO, 2021 ]

Logistic at the time of administration
Thaw in refrigerator: When stored frozen at -25°C to -15°C (-13°F to 5°F), a carton of 10 vials will take approximately 12 hours to thaw or, individual vials will take approximately 2 hours to thaw at 2°C to 8°C (36°F to 46°F).
Thaw at room temperature: When stored frozen at -25°C to -15°C (-13°F to 5°F), a carton of 10 vials or individual vials should be thawed at room temperature maximally 25°C (77°F). A carton of 10 vials will take approximately 2 hours to thaw. Individual vials will take approximately 1 hour to thaw.
The vaccine should be inspected visually for particulate matter and discoloration prior to administration.
The vial should be inspected visually for cracks or any abnormalities, such as evidence of tampering prior to administration. If any of these should exist, do not administer the vaccine.
Before administering a dose of vaccine, swirl the vaccine in an upright position for 10 seconds. Do not shake [WHO, 2021 ].
Use a sterile needle and syringe to extract a single dose of 0.5 mL from the multidose vial. A maximum of 5 doses can be withdrawn from the multidose vial.
After, administered by intramuscular injection.
Discard any remaining vaccine in the vial after the extraction of 5 doses.

Storage after first puncture
After the first puncture of the vial, preferably use immediately [WHO, 2021 ].
After the first puncture of the vial, the vaccine can be held at 2°C to 8°C (36°F to 46°F) for up to 6 hours [WHO, 2021 ], or at room temperature (maximally 25°C [77°F]) for a single period of up to 3 hours [EMA, 2021 ].
Record the date and time the vial should be discarded.
To improve traceability, the name and batch number of the administered product should be clearly recorded [WHO, 2021 ].
Administration [WHO, 2021 ]
1. Before administering a dose of vaccine, swirl the vial gently in an upright position for 10 seconds. Do not shake
2. Use a sterile needle and sterile syringe to extract a single dose of 0.5 mL from the multi-dose vial
3. Administer by intramuscular injection only (0.5 mL) into the deltoid muscle of the upper arm.
A maximum of 5 doses can be withdrawn from the multi-dose vial. Discard any remaining vaccine in the vial after 5 doses have been extracted
Disposal
Any unused vaccine or waste material should be disposed of in compliance with the local guidance for pharmaceutical waste. Potential spills should be disinfected with agents with viricidal activity against adenovirus [WHO, 2021 ].
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

Randomized trials
ENSEMBLE, also known as VAC31518COV3001 or Study 3001, is a randomized phase 3 trial (registered with the numbers NCT04505722 [Janssen Vaccines & Prevention B.V., 2020 ] and PER-048-20 [Janssen Vaccines & Prevention B.V.,, 2020 ]) sponsored by Janssen Research and Development, which is an affiliate of Janssen Vaccines and Prevention and part of the Janssen pharmaceutical companies of Johnson & Johnson, in collaboration with the Operation Warp Speed Covid-19 Rapid Response Team (which includes the Biomedical Advanced Research and Development Authority, the National Institutes of Health, the Covid-19 Prevention Trials Network, and the Department of Defense) that is being conducted in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States [Sadoff J, 2021 ]. It was first registered in August 2020 and enrolled 44325 adults, 18 years of age or older, that received a single dose of Ad26.COV2.S supplied in single-use vials at a concentration of 1 × 10^11 viral particles per milliliter administered at a dose of 5 × 10^10 viral particles as a single intramuscular injection (0.5 ml). It is expected to run until January 2023. Data was submitted to the United States Food and Drug Administration agency in February 2021 [Stephenson KE, 2021 ], and was published in a peer reviewed journal in April 2021.

COV1001 is a randomized phase 1/2a trial (registered with the numbers NCT04436276 [Janssen Vaccines & Prevention B.V., 2020 ] and 2020-001483-28 [Janssen Vaccines & Prevention B.V., 2020 ]) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in the United States and Belgium. The aim of this trial is to assess the safety, reactogenicity, and immunogenicity of 2 doses of the vaccine. It was first registered in June 2020 and plans to enroll 1085 healthy adults, aged 18 years and older that will receive the vaccine at 2 dose levels (5 × 10^10 viral particles or 1 × 10^11 viral particles), administered intramuscularly as a single-dose or 2-dose schedule, with a single booster vaccination administered in one cohort. It is expected for this study to run until February 2024. Results after the administration of the first vaccine dose in 805 participants and after the second dose in participants 65 years of age or older were published in January 2021 [Sadoff J, 2021 ]. Immunogenicity data on 25 participants followed until day 71 were published in March 2021 [Stephenson KE, 2021 ].

Ongoing randomized trials:
ENSEMBLE 2 is an ongoing randomized phase 3 trial (registered with the numbers NCT04614948 [Janssen Vaccines & Prevention B.V., 2020 ], 2020-003643-29 [Janssen Vaccines & Prevention B.V., 2020 ] and ISRCTN14722499 [Janssen (Netherlands), 2020 ]), sponsored by Janssen Vaccines & Prevention B.V., that is being conducted in the United States. This trial aims to assess the efficacy of the vaccine in the prevention of molecularly confirmed moderate to severe/critical COVID-19, as compared to placebo, in adult participants in the double-blind phase. Also, it aims to evaluate the efficacy of two doses of the vaccine in the prevention of molecularly confirmed, moderate to severe/critical COVID-19, as compared to one dose of the vaccine, in SARS CoV-2 seronegative adults in the open-label phase. It was first registered in November 2020 and plans to enroll 30000 adults aged 18 years and older that will receive an intramuscular injection of the vaccine on day 1 and day 57. It is expected to run until May 2023.

COV3003 is an ongoing randomized phase 3 trial (registered with the number 2020-005801-14 [Janssen Vaccines & Prevention B.V., 2021 ]), sponsored by Janssen Vaccines & Prevention B.V., that is being conducted in Poland, Germany and the United States. It was first registered in December 2020 and plans to enroll 1450 healthy participants 18 to 55 years of age that will receive 3 dose levels of the vaccine administered as single-dose and two-dose schedules. The expected end date has not been reported.

COV1002 (also known as CR108871 and VAC31518COV1002) is an ongoing randomized phase 1 trial (registered with the number NCT04509947 [Janssen Pharmaceutical K.K., 2020 ]) sponsored by Janssen Pharmaceutical K.K., that is being conducted in Japan. The purpose of this study is to assess the safety and reactogenicity of the vaccine administered intramuscularly at 2-dose levels, as 2-dose schedule in healthy adults. It was first registered in August 2020 and plans to enroll 250 healthy adults between 20 to 55 years (cohort 1) and 65 years or older (cohort 2) that will receive high dose and low dose of an intramuscular injection of the vaccine as 2-dose schedule on day 1 and day 57. It is expected to run until December 2021.

COV2001(also known as CR108854 and VAC31518COV2001) is an ongoing randomized phase 2 trial (registered with the number NCT04535453 [Janssen Vaccines & Prevention B.V., 2020 ]) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in Spain, United Kingdom, Germany, Brazil, Canada, the United States and the Netherlands. The purpose of this study is to assess humoral immune responses of 3 dose levels of the vaccine. It was first registered in September 2020 and plans to enroll 1210 adolescents (12-17 years) and adults (18 years or older) that will receive different dose levels of the vaccine, as a one or two-dose schedule (56 days apart) and as compressed and expanded 2-dose schedules (28 and 84 days apart). It is expected to run until August 2023.

HORIZON 1 (also known as CR108962 and VAC31518COV2004) is an ongoing open-label, phase 2 study (registered with the number NCT04765384 [Janssen Vaccines & Prevention B.V., 2021 ]) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in South Africa, Brazil and the United States. It was first registered in February 2021 and plans to enroll 400 adult participants during the second and/or third trimester of pregnancy and post-partum that will receive standard dose of the vaccine as intramuscular injection (first dose on day 1 and second dose on day 57). It is expected to run for until June 2023.

SWITCH is an ongoing multicenter, randomized, single-blind, controlled trial (registered with the number NCT04927936 [Erasmus Medical Center, 2021 ]) sponsored by Erasmus Medical Center that is being conducted in the Netherlands. It was first registered in June 2021 and plans to enroll 432 health care workers aged 18 to 65 years that were once vaccinated with Janssen vaccine and that will receive Janssen vaccine (homologous boosting); Moderna vaccine (heterologous boosting); or Pfizer vaccine (heterologous boosting). It is expected to run until September 2022.

DAIT ACV01 is an ongoing randomized, multi-site, adaptive, open-label clinical trial (registered with the number NCT05000216 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in The United States. It was first registered in August 2021 and plans to enroll 600 participants with autoimmune diseases requiring immunosuppressive medications that will receive different COVID-19 vaccine (Moderna, Pfizer-BioNTech or Janssen COVID-19 vaccine) booster doses to compare the immune response in participants with autoimmune disease. It is expected to run until December 2022.

CR109060 is an ongoing randomized, double-blind, phase 2 study (registered with the number NCT04999111 [Janssen Vaccines & Prevention B.V., 2021 ]) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in United States. It was first registered in August 2021 and plans to enroll 660 adults 18 years of age and older who have previously received primary vaccination with Ad26.COV2.S or BNT162b2 that will receive booster vaccination with Janssen (Ad26.COV2.S) or Pfizer (BNT162b2) vaccine. It is expected to run until March 2022.

Boost-TX is an ongoing phase 2, randomized, single-blinded study (registered with the number 2021-002927-39 [Medical University of Vienna, 2021 ]) sponsored by Medical University of Vienna that is being conducted in Austria. It was first registered in May 2021 and plans to enroll 200 kidney transplant recipients that will receive BNT162b2 or mRNA-1273 (mRNA) vaccines. End of study: Date not available

HORIZON 2 (also known as VAC31518COV3006) is an ongoing randomized, double-blind, placebo-controlled, phase 2/3 study (registered with the number 2020-005720-11 [Janssen Vaccines & Prevention B.V., 2021 ]) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in Netherlands. It was first registered in April 2021 and plans to enroll 3675 healthy children from birth to 17 years and healthy adults aged 18 to 55 years that will receive different dose levels of Janssen COVID-19 vaccine in healthy children to evaluate the safety, reactogenicity, and immunogenicity of the vaccine compared to the administration of the vaccine in healthy adults. It is expected to run until not reported.

Other ongoing registered studies
Covid-19-Abs is an ongoing non-randomized study (registered with the number NCT04944095 [Dr. Sidney J. Stohs, 2021 ]) sponsored by Dr. Sidney J. Stohs that is being conducted in United States. It was first registered in June 2021 and plans to enroll 10000 residents and staff associated with nursing homes, extended care facilities, and over-55 communities following vaccination with one of the authorized SARS-CoV-2 vaccines (Pfizer, Moderna, or J &J). It is expected to run until December 2022.

ImmunoHaema-COVID-VAX-21 is an ongoing prospective, cohort, non-interventional, single-center clinical study (registered with the number NCT04878822 [Ospedale di Circolo - Fondazione Macchi, 2021 ]) sponsored by Ospedale di Circolo - Fondazione Macchi that is being conducted in Italy. It was first registered in May 2021 and plans to enroll 300 patients with haematological malignancies 18 years of age and older, who will received BNT162b2, ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine. It is expected to run until April 2023.

21-0012 is an ongoing phase 1/2, non-randomized (registered with the number NCT04889209 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases that is being conducted in United States. It was first registered in May 2021 and plans to enroll 550 healthy individuals 18 years of age and older, who received Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. Participants will receive a single intramuscular injection of the designated booster vaccine (Ad26.COV2.S or mRNA-1273). It is expected to run until May 2025.

IROC is an ongoing non-randomized study (registered with the number NCT04930055 [Indiana University, 2021 ]) sponsored by Indiana University that is being conducted in United States. It was first registered in June 2021 and plans to enroll 240 cancer patients 18 years of age and older receiving either BTN162b2, mRNA-1273, or Ad26.COV2.S. It is expected to run until August 2023.

Sisonke (Together) is an ongoing single group assignment study (registered with the number NCT04838795 [Wits Health Consortium (Pty) Ltd, 2021 ]) sponsored by Wits Health Consortium (Pty) Ltd that is being conducted in South Africa. The purpose of this study is to monitor the effectiveness of a single-dose of the vaccine among health care workers (HCW). It was first registered in April 2021 and plans to enroll 500000 health care workers. Its objective is to monitor the effectiveness of a single dose of the vaccine. It is expected to run until March 2022.

Methods used to assess efficacy and effectiveness

The following methods are in use to assess efficacy in the phase 3 trials evaluating the vaccine:
ENSEMBLE trial [Janssen Vaccines & Prevention B.V., 2020 ]
Primary efficacy endpoints
Number of participants with a first occurrence of confirmed, moderate to severe/critical, COVID-19 occurring at least 14 days post-vaccination. Confirmed with a positive SARS-CoV-2 RT-PCR test or positive serology against SARS-CoV-2 nucleocapsid on Day 1.
Inclusion of a co-primary endpoint was reported in the trial: COVID-19 cases from 28 days post-vaccination among participants who received a dose of the vaccine or placebo and were seronegative or their serostatus was unknown at administration, and had no protocol deviations
Moderate COVID-19 was defined as one sign or symptom from a list of signs and symptoms, such as respiratory rate greater than or equal to 20 breaths per minute, symptoms such as shortness of breath, or two signs or symptoms from a list of signs and symptoms or severe COVID-19 defined in FDA guidance.
Severe COVID-19 was defined as one sign or symptom from a list of signs and symptoms, such as respiratory rate greater than or equal to 30 breaths per minute and symptoms such as shortness of breath or two signs or symptoms from a list of sign and symptoms or severe COVID-19 defined in FDA guidance.

COV3003 trial [Janssen Vaccines & Prevention B.V., 2021 ]
Primary efficacy endpoint
Binding antibody concentrations to SARS CoV-2 S protein as measured by ELISA 28 days after first dose of the vaccine.
Binding antibody concentrations to SARS CoV-2 S protein as measured by ELISA 28 days after second dose of the vaccine.
Non-inferiority will be demonstrated in terms of humoral immune response expressed by the geometric mean concentrations of S-ELISA, 28 days post-dose, using a non-inferiority margin of 2/3 for the geometric mean concentration ratio (GMC 2.5 x 10^10 [or 1.25 x 10^10 viral particles]/GMC 5 x 10^10 viral particles)

Methods used to assess safety

The following methods are in use to assess safety in the phase 3 trials evaluating the vaccine:
ENSEMBLE trial [Janssen Vaccines & Prevention B.V., 2020 ]
Primary safety endpoints
Number of participants with adverse events or serious adverse events leading to study discontinuation of the study, for the duration of the trial.
Number of participants with medically attended adverse events during the 6 months following vaccination.
Number of participants with solicited local and systemic adverse reactions during the 7 days following vaccination.
Number of participants with unsolicited adverse events during the 28 days following vaccination.


COV3003 trial [Janssen Vaccines & Prevention B.V., 2021 ]
Primary safety endpoints
Solicited local and systemic adverse events for 7 days after each vaccination
Unsolicited adverse events for 28 days after each vaccination
Solicited adverse events throughout the study (from first vaccination until end of the study)
Medically attended adverse events (until 6 months post vaccination)
Medically attended adverse events leading to study discontinuation (during the entire study) for all participants following vaccination

Efficacy and effectiveness of the vaccine

Efficacy of the vaccine in preclinical studies

Mercado et al [Mercado NB, 2020 ] conducted a study assessing the immunogenicity and protective efficacy of a single dose of the vaccine in 52 rhesus macaques. The animals were challenged with SARS-CoV-2 by the intranasal and intratracheal routes and the vaccine induced neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs. The vaccine elicited neutralizing antibody titers correlated with protective efficacy.
Tostanoski et al [Tostanoski LH, 2020 ] conducted a study in hamsters with severe clinical disease. A single immunization with the vaccine elicited binding and neutralizing antibody responses, and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality.

Efficacy of the vaccine in clinical trials


Main immunogenicity outcomes

Immunogenicity was evaluated in the phase 1/2a randomized trial COV1001 [Sadoff J, 2021 ]. The trial included healthy adults older than 18 years, that received the vaccine at a dose of 5×10^10 viral particles (low dose) or 1×10^11 viral particles (high dose) per milliliter, or placebo, in a single-dose or two-dose schedule. Neutralizing-antibody titers were detected in 90% or more of all participants on day 29 after the first vaccine dose, and reached 100% by day 57, with a further increase in titers, regardless of vaccine dose or age group. A second dose provided an increase in the titer. Spike-binding antibody responses were similar to neutralizing-antibody responses. CD4+ T-cell responses were detected in 60 to 83% of the participants in different age groups with different cell response profiles in each group.

Main efficacy outcomes of Janssen COVID-19 vaccine

Key messages

Janssen COVID-19 vaccine reduces the risk of contracting any symptomatic COVID-19

Janssen COVID-19 vaccine reduces the risk of contracting moderate to severe COVID-19

The efficacy of Janssen COVID-19 vaccine presented here was estimated from the different reports of the ENSEMBLE trial, the only phase 3, randomized trial with available data at this moment [Sadoff J, 2021 ]. It is based on data from 39,321 participants.

Contracting COVID-19

The risk of contracting any COVID-19 infection has not yet been reported, so it was not possible to estimate the effect for this outcome.

Contracting any symptomatic COVID-19 (measured at least 14 days after the injection)

The relative risk of contracting any symptomatic COVID-19 in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.33 (95% CI 0.27 to 0.41). This means Janssen COVID-19 vaccine reduced the risk of contracting any symptomatic COVID-19 in 67%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting any symptomatic COVID-19. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the available trial 351 people not receiving Janssen COVID-19 vaccine out of 19544 presented this outcome (18 per 1000) versus 117 out of 19514 in the group that did receive it (6 per 1000). In other words, 12 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.2%, or that the intervention reduced the risk of contracting any symptomatic COVID-19 by 1.2 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 83.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting moderate to severe COVID-19 (measured at least 14 days after the injection)

The relative risk of contracting moderate to severe COVID-19 in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.33 (95% CI 0.27 to 0.41). This means Janssen COVID-19 vaccine reduced the risk of contracting moderate to severe COVID-19 in 67%, compared with the placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting moderate to severe COVID-19. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 348 people not receiving Janssen COVID-19 vaccine out of 19544 presented this outcome (18 per 1000) versus 116 out of 19514 in the group that did receive it (6 per 1000). In other words, 12 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.2%, or that the intervention reduced the risk of contracting moderate to severe COVID-19 by 1.2 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 83.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting severe/critical COVID-19 (measured at least 14 days after the injection)

The relative risk of contracting severe/critical COVID-19 in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.24 (95% CI 0.14 to 0.39). This means Janssen COVID-19 vaccine reduced the risk of contracting severe/critical COVID-19 by 76%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe/critical COVID-19. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 80 people not receiving Janssen COVID-19 vaccine out of 19544 presented this outcome (4 per 1000) versus 19 out of 19514 in the group that did receive it (1 per 1000). In other words, 3 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.3% of contracting severe/critical COVID-19. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H). In this case, the NNTB is 333, which means that 333 people need to receive the vaccine for one of them to not contract severe/ critical COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.


Mortality

The existing evidence does not allow to assess the impact of Janssen COVID-19 vaccine on the risk of mortality. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to Janssen COVID-19 vaccine would require trials with a higher statistical power.


Summary of findings (iSoF)


Efficacy and effectiveness of the vaccine on subgroups

Subgroup analyses of the primary efficacy endpoint in the ENSEMBLE trial, the only phase 3 randomized trial available, showed similar efficacy point estimates across different age groups, sex, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19 [Sadoff J, 2021 ].

Sex

Randomized trials
The proportion of females in the ENSEMBLE trial was 45% (19722 out of 43783 participants) [Sadoff J, 2021 ].
Among females, the relative risk of contracting moderate to severe COVID-19 with onset at least 14 days or 28 days after vaccination, when comparing with the group that received placebo vaccine, was 0.37 (95% CI 0.29 to 0.47). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 63%, compared with the placebo vaccine. This estimate is not importantly different from the one in males and in the overall population of the trial, for this outcome.
Race and ethnic group

Randomized trials
The proportion of white participants in the ENSEMBLE trial was 62% (24416 out of 39321 participants) [Sadoff J, 2021 ].
The relative risk of contracting COVID-19 in white participants that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.33 (95% CI 0.26 to 0.41). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in white participants in 67%, compared with the placebo vaccine. This estimate is not statistically different from the estimate for this outcome in the overall population of the trial.
Age

Randomized trials
The proportion of participants 65 years of age and more in the ENSEMBLE trial was 19.6% (8561 out of 43783 participants) [Sadoff J, 2021 ].
Among participants 65 years or older, the relative risk of contracting moderate to severe COVID-19, with onset at least 14 or 28 days after vaccination, when comparing the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine, was 0.24 (95% CI 0.14 to 0.41). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 76%, compared with the placebo vaccine. This number is not importantly different from the estimate for this outcome in younger patients, and in the overall population of the trial

Children and adolescents

Randomized trials
Children were excluded from the ENSEMBLE trial, so no efficacy data are available from participants aged 17 years and younger [Sadoff J, 2021 ].
The randomized phase 2 ongoing trial COV2001 (also known as CR108854 and VAC31518COV2001) is currently evaluating the efficacy/safety of the vaccine in adolescents (12-17 years) and adults (18 years or older) [Janssen Vaccines & Prevention B.V., 2020 ].
The randomized, double-blind, placebo-controlled, phase 2/3 ongoing trial HORIZON 2 (also known as VAC31518COV3006) is currently evaluating the efficacy/safety of the vaccine in healthy children from birth to 17 years [Janssen Vaccines & Prevention B.V., 2021 ].
Pregnancy

Randomized trials
Pregnant females were excluded from the ENSEMBLE trial, so no efficacy data are available [Sadoff J, 2021 ].
The open-label, phase 2 ongoing trial HORIZON 1 (also known as CR108962 and VAC31518COV2004) is currently evaluating the efficacy/safety of the vaccine in adult participants during the second and/or third trimester of pregnancy and post-partum [Janssen Vaccines & Prevention B.V., 2021 ].

Other studies
Evidence suggests that pregnant women with COVID-19 (second and third trimester) are at higher risk of developing severe disease compared to non-pregnant women of reproductive age. COVID-19 in pregnancy has also been associated with an increased risk of preterm birth and of neonates requiring neonatal intensive care. Pregnant women who are older (age 35 years and above), or have a high body mass index, or have existing comorbidities such as diabetes or hypertension are at particular risk of serious outcomes from COVID-19 [WHO, 2021 ].
Completed developmental and reproductive toxicology (DART) studies in animals have not shown harmful effects of the vaccine in pregnancy. Ad26.COV2.S is a replication-defective vaccine. While available data on Ad26.COV2.S vaccination of pregnant women are insufficient to assess vaccine efficacy or vaccine-associated risks in pregnancy, studies in pregnant women are planned in the coming months. [WHO, 2021 ].
Breast-feeding

Randomized trials
Females who were breast-feeding were excluded from the ENSEMBLE trial, so no efficacy data are available [Sadoff J, 2021 ].
Other studies
This group is being studied in the HORIZON 1 study (see 'ongoing registered studies') [Janssen Vaccines & Prevention B.V., 2021 ].
Medical comorbidities associated with high risk of severe COVID-19

Obesity

Randomized trials
The proportion of participants with obesity in the ENSEMBLE trial was 28.5% (12492 out of 43783 participants) [Sadoff J, 2021 ].
The relative risk of contracting severe COVID-19 in participants with obesity that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.34 (95% CI 0.25 to 0.46). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 66%, compared with the placebo vaccine. This number is not importantly different from the estimate for this outcome in the overall population of the trial.

Immunocompromised persons

Randomized trials
The ongoing phase 2, randomized, single-blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].
Other studies
The prospective, cohort, non-interventional, single-center clinical ongoing study ImmunoHaema-COVID-VAX-21 is currently evaluating the efficacy/safety of the vaccine in patients with haematological malignancies 18 years of age and older, who will received BNT162b2 vaccine, ChAdOx1 nCoV-19 vaccine, or Ad26.COV2.S vaccine [Ospedale di Circolo - Fondazione Macchi, 2021 ].
The non-randomized study IROC is currently evaluating the efficacy/safety of the vaccine in cancer patients receiving either BTN162b2, mRNA-1273, or Ad26.COV2.S [Indiana University, 2021 ]

Persons living with HIV

Randomized trials
The proportion of individuals living with HIV in the ENSEMBLE trial was 2.8% (1218 out of 43783 participants) [Sadoff J, 2021 ].
The relative risk of contracting COVID-19 in participants with HIV that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 1.07 (95% CI 0.31 to 3.66). This number is not importantly different from the estimate for this outcome in the overall population of the trial.

COPD

Randomized trials
The proportion of participants with chronic lung disease in the ENSEMBLE trial was 1% (437 out of 43783 participants) [Sadoff J, 2021 ].
The relative risk of contracting severe COVID-19 in the participants with chronic lung disease that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.18 (95% CI 0.02 to 1.55). There were no sufficient participants with COPD enrolled in this trial to estimate the effect of the vaccine in this subgroup reliably.

Cardiac disease

Randomized trials
The proportion of participants with cardiac disease in the ENSEMBLE trial was 2.3% (1008 out of 43783 participants) [Sadoff J, 2021 ].
The relative risk of contracting severe COVID-19 in the participants with cardiac disease that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.24 (95% CI 0.07 to 0.85). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 76%, compared with the placebo vaccine. This estimate is not importantly different from the estimate for this outcome in the overall population of the trial.
Diabetes

Randomized trials
The proportion of participants with diabetes in the ENSEMBLE trial was 7.3% (3194 out of 43783 participants) [Sadoff J, 2021 ].
The relative risk of contracting severe COVID-19 in the participants with diabetes type 2 that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.47 (95% CI 0.26 to 0.87). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 53%, compared with the placebo vaccine. This number is not importantly different from the estimate for this outcome in the overall population of the trial.

Other data from vaccine efficacy and effectiveness

Duration of protection

The exact duration of protection afforded by the vaccine is unknown as it is still being determined by ongoing clinical trials.
Because participants in the trial were followed up for a short period of time, it is not possible to assess sustained efficacy over a period longer than 2 months [FDA, 2021 ].

Limitations of vaccine effectiveness

Individuals may not be fully protected until 14 days after receiving the vaccine. As with all vaccines, inoculation with the Janssen COVID-19 vaccine may not protect all recipients.
SARS-CoV-2 variants

Randomized trials
While ENSEMBLE trial was being conducted, new SARS-CoV-2 variants emerged in geographical regions where the study took place. A subgroup analysis of vaccine efficacy against moderate to severe/critical COVID-19 showed lower relative efficacy in South Africa (52%) than in Brazil (66%) or the United States (74%) [FDA, 2021 ].
Vaccine efficacy against specific SARS-CoV-2 variants in the context of ENSEMBLE trial is ongoing but has not been yet reported [FDA, 2021 ].
In the US, where newly emerging variants of concern were not predominant at the time of the vaccine trial, vaccine efficacy for moderate to severe COVID-19 was 72.0% (58.2, 81.7), and efficacy for severe COVID-19 was 85.9% (-9.4, 99.7) [FDA, 2021 ]. In South Africa, despite the fact that the 20H/501Y.V2 variant (B.1.351 lineage) was the predominant strain, similar efficacies were observed as in the US: efficacy for moderate to severe COVID-19 was 64.0% (95% CI: 41.2, 78.7) and efficacy for severe COVID-19 was 81.7% (95% CI: 46.2, 95.4). In Brazil, where a variant from the P.2 lineage was the predominant strain, vaccine efficacy for moderate to severe COVID-19 was 68.1% (95% CI: 7.8, 99.7) and for severe COVID-19 87.6% (95% CI: 48.8, 80.7). There are no data as yet with regards to the newly emerged B1.617 [WHO, 2021 ].

Safety of the vaccine

Safety of the vaccine in preclinical studies

Genotoxicity and carcinogenicity
Janssen COVID-19 vaccine has not been evaluated for its genotoxic or carcinogenic potential but, according to the manufacturers, the components of the vaccine are not expected to have genotoxic or carcinogenic potential [EMA, 2021 ].

Risk of thrombosis
The causal relation between the Janssen COVID-19 vaccine or other adenoviral vector vaccines and thrombosis is not yet established. One hypothesis that would explain the rare occurrence of thrombotic events related to adenoviral vector vaccines is the generation of antibodies against platelet factor 4 (PF4). IgG antibodies would recognize PF4 and activate platelets through their Fcγ receptors. This condition would resemble autoimmune heparin-induced thrombocytopenia [Muir KL, 2021 ],[Warkentin TE., 2019 ].

Reproductive toxicity and fertility
Female reproductive toxicity and fertility were assessed in a developmental study with rabbits. The vaccine was administered to female rabbits 7 days prior to mating, at a dose equivalent to 2-fold above the recommended human dose, followed by two vaccinations at the same dose during the gestation period. There were no vaccine-related effects on female fertility, pregnancy, or embryo-fetal or offspring development. Female rabbits as well as their offspring exhibited SARS-CoV-2 S protein-specific antibody titers, indicating that maternal antibodies were transferred to the fetuses during gestation.
Additionally, a toxicity study was performed with repeated conventional doses in male rabbits. The vaccine did not show any effects on male sex organs that would impair male fertility [EMA, 2021 ].

Thrombocytopenia
Thrombocytopenia has been reported following the administration of adenoviral gene transfer vectors. The mechanism underlying this phenomenon is currently unknown. A study in mice showed thrombocytopenia occurred between 5 to 24 hours following adenovirus administration. Some changes induced by the virus were endothelial cell activation, platelet activation and accelerated platelet clearance [Othman M, 2007 ].

Safety of the vaccine in clinical trials

Key messages

Janssen COVID-19 vaccine increases the risk of local adverse events following vaccination

Janssen COVID-19 vaccine reduces the risk of serious adverse events

Main safety outcomes of Janssen COVID-19 vaccine

Local adverse events following vaccination (7 days following vaccination)

The relative risk of local adverse events following vaccination in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 2.58 (95% CI 2.39 to 2.79). This means that, in relative terms, Janssen COVID-19 vaccine increased the risk of local adverse events following vaccination by 158%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events following vaccination. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 657 people not receiving Janssen COVID-19 vaccine out of 3380 presented this outcome (194 per 1000) versus 1685 out of 3356 in the group that did receive it (501 per 1000). In other words, the intervention led to an absolute risk increase of 30.7% of local adverse events following vaccination. Another way of presenting the same information about the absolute effects is the number of people needed to treat for an additional beneficial/harmful outcome (NNTB/H). In this case, the NNTH is 3, which means that 3 people need to receive the vaccine for one of them to experience an unsolicited adverse event.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Systemic adverse events following vaccination (7 days following vaccination)

The relative risk of systemic adverse events following vaccination in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 1.57 (95% CI 1.49 to 1.66). This means that, in relative terms, Janssen COVID-19 vaccine increased the risk of systemic adverse events following vaccination by 57%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events following vaccination. Comparison: versus placebo vaccine

In the trial identified in this review, 1185 people not receiving Janssen COVID-19 vaccine out of 3380 presented this outcome (351 per 1000) versus 1850 out of 3356 in the group that did receive it (552 per 1000). In other words, 201 more people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 20.1%. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H). In this case, the NNTH is 5, which means that 5 people need to receive the vaccine for one of them to experience an unsolicited adverse event.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.


Any unsolicited adverse event (during 28 days post-vaccination)

The relative risk of any unsolicited adverse event in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 1.09 (95% CI 0.96 to 1.24). This means Janssen COVID-19 vaccine increased the risk of any unsolicited adverse event by 9%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any unsolicited adverse event. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 407 people not receiving Janssen COVID-19 vaccine out of 3380 presented this outcome (120 per 1000) versus 440 out of 3356 in the group that did receive it (131 per 1000). In other words, 11 more people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 1.1%. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H). In this case, the NNTH is 91, which means that 91 people need to receive the vaccine for one of them to experience an unsolicited adverse event.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Serious adverse events (median follow-up 56 days)

The relative risk of serious adverse events in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.86 (95% CI 0.64 to 1.16). This means Janssen COVID-19 vaccine reduced the risk of serious adverse events by 14%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 96 people not receiving Janssen COVID-19 vaccine out of 21888 presented this outcome (4 per 1000) versus 83 out of 21895 in the group that did receive it (3 per 1000). In other words, 1 less people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.1%, or that the intervention reduced the risk of serious adverse events by 0.1 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H). In this case, the NNTB is 1000, which means that 1000 people need to receive the vaccine for one of them to not experience a severe adverse event

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: Low number of events; Publication bias: no concerns.

Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Subgroup analyses of the primary efficacy endpoint in the ENSEMBLE trial, the only phase 3 randomized trial available, showed similar efficacy point estimates across different age groups, sex, racial and ethnic groups [Sadoff J, 2021 ].

Sex

Randomized trials
The proportion of females in the ENSEMBLE trial was 45% (19722 out of 43783 participants) [Sadoff J, 2021 ].
The proportion of women that experienced adverse effects with Janssen COVID-19 vaccine versus the group that received placebo vaccine was not reported in detail. However, it was reported that no specific safety concerns were identified in this subgroup.

Age

Randomized trials
The frequency of adverse effects in the vaccinated/not vaccinated population according to age was the following:
Solicited local adverse reactions
· 59.8 vs 20.2 (RR 2.96; difference: 39.6 percentage points) in the group 18-59 years.
· 35.4 vs 18.3 (RR 1.93; difference: 17.1 percentage points) in the group ≥60 years.
Solicited systemic adverse reactions
· 61.5 vs 36.4 (RR 1.69; difference: 25.1 percentage points) in the group 18-59 years.
· 45.3 vs 33.1 (RR 1.37; difference: 12.2 percentage points) in the group ≥60 years.
Serious adverse events
· 0.3 vs 0.4 (RR 0.75; difference: -0.1 percentage points) in the group 18-59 years.
· 0.5 vs 0.5 (RR 1; difference: 0 percentage points) in the group ≥60 years.
Children and adolescents

Randomized trials
Children were excluded from the ENSEMBLE trial, so no safety data are available from participants ages 17 years and younger [Sadoff J, 2021 ].
The randomized phase 2 ongoing trial COV2001 (also known as CR108854 and VAC31518COV2001) is currently evaluating the efficacy/safety of the vaccine in adolescents (12-17 years) and adults (18 years or older) [Janssen Vaccines & Prevention B.V., 2020 ].
The randomized, double-blind, placebo-controlled, phase 2/3 ongoing trial HORIZON 2 (also known as VAC31518COV3006) is currently evaluating the efficacy/safety of the vaccine in healthy children from birth to 17 years [Janssen Vaccines & Prevention B.V., 2021 ].

Pregnancy

Randomized trials
Pregnant females were excluded from the ENSEMBLE trial, so no safety data are available [Sadoff J, 2021 ].
Other studies
Breast-feeding

Randomized trials
Females who were breast-feeding were excluded from the ENSEMBLE trial, so no safety data are available [Sadoff J, 2021 ].
Other studies
This group is being studied in the HORIZON 1 study (see 'ongoing registered studies') [Janssen Vaccines & Prevention B.V., 2021 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative studies
None available
Non-comparative studies
Based on previous experience with other vaccine use during pregnancy, the effectiveness of Ad26.COV2.S in pregnant women is expected to be comparable to that observed for non-pregnant women in similar age groups. Of note, compared to non-pregnant women, pregnancy is associated with higher rates of thrombosis, thrombocytopenia, and hemorrhage; however, it is currently not known whether pregnancy is associated with a higher risk of TTS [WHO, 2021 ].

According to a study on pharmacovigilance analysis on cerebrovascular accidents (CVA) and Coronavirus disease 2019 Vaccines a total of 6,751 adverse events with Janssen‘s vaccine were reported in the VAERS database. Of these, 17 had a CVA event (0.25% of reported events) with 0 of the 17 reports resulting in death [Pushkar Aggarwal, 2021 ].
Case reports and case series
Muir et al [Muir KL, 2021 ] reported a single case of extensive thrombosis associated with severe thrombocytopenia and disseminated intravascular coagulation on a 48-year-old white woman with, according to the authors, an unremarkable medical history, who had received the vaccine 14 days before symptom onset.

Spontaneous report data
Disclaimer: Reporting suspected adverse reactions after authorization of the medicinal product is important because it allows continuous monitoring of the benefit/risk balance of the vaccines. However, they do not indicate a causal association between the vaccine and the observed effects. Furthermore, this information should not be used to estimate the frequency of adverse events in people receiving the vaccine or to make comparisons between different vaccines. The information emerging about possible adverse effects needs to be carefully evaluated in order to first establish if the adverse effect might have been caused by the vaccine.

In a news release distributed via the CDC Health Alert Network in April 13, 2021, it was informed that The Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) were reviewing data involving six U.S. cases of cerebral venous sinus thrombosis after receiving the Janssen COVID-19 vaccine that were reported to the Vaccine Adverse Event Reporting System (VAERS). All cases occurred among females aged 18-48 years. The interval from vaccine receipt to symptom onset ranged from 6-13 days. One patient died [CDC, 2021 ].
A review of all the cases of cerebral venous sinus thrombosis (CVST) and all known cases of thrombosis with thrombocytopenia was presented in a meeting of the Advisory Committee on Immunization Practices of the United States Centers for Disease Control and Prevention held on 14 April 2021 [ACIP, 2021 ]. The review included information from multiple sources, including study 3001 [Stephenson KE, 2021 ], study 3009 [Janssen Vaccines & Prevention B.V., 2020 ] and Sisonke Open Label Study [Wits Health Consortium (Pty) Ltd, 2021 ]. The review identified 8 cases of CVST associated to the Janssen COVID-19 vaccine.

Monitoring

WHO recommends the following research and post-authorization monitoring activities:
-Safety surveillance and monitoring:
• Serious adverse events such as myocarditis, thrombosis with thrombocytopenia syndrome (TTS), anaphylaxis, and other serious allergic reactions,
•Cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death,
• Background rates of AESIs (including thromboembolic events, cerebral venous sinus thrombosis, and thrombosis with thrombocytopenia syndrome), maternal and neonatal outcomes, and mortality in groups prioritized for vaccination.
•Incidence of TTS by WHO region, age, and sex,
− Vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− Studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding.
− Assessment and reporting of vaccination failures and virus sequence information.
- Prospective studies on the safety of Janssen COVID-19 vaccine in pregnant and lactating females.
− Randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− Safety data on vaccination in immunocompromised individuals, including people living with HIV and autoimmune disease.
− Immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older people.
− Safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− Stability of the vaccine under alternative cold-chain distribution and storage conditions.
− Effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− Interchangeability studies within and across COVID-19 vaccine platforms.

References

[WHO, 2021] WHO. WHO adds Janssen vaccine to list of safe and effective emergency tools against COVID-19. Press release - World Health Organization - 12 March 2021. 2021; WHO. WHO adds Janssen vaccine to list of safe and effective emergency tools against COVID-19. Press release - World Health Organization - 12 March 2021. 2021;
[WHO, 2021] WHO. WHO recommendation Janssen–Cilag International NV (Belgium) COVID-19 Vaccine (Ad26.COV2-S [recombinant]). WHO Product Information. 2021; WHO. WHO recommendation Janssen–Cilag International NV (Belgium) COVID-19 Vaccine (Ad26.COV2-S [recombinant]). WHO Product Information. 2021;
[WHO, 2021] WHO. Interim recommendations for the use of the Janssen Ad26.COV2.S (COVID-19) vaccine. 15 June 2021. 2021; WHO. Interim recommendations for the use of the Janssen Ad26.COV2.S (COVID-19) vaccine. 15 June 2021. 2021;
[EMA, 2021] EMA. EMA recommends COVID-19 Vaccine Janssen. SUMMARY OF PRODUCT CHARACTERISTICS JANSSEN VACCINE. 2021; EMA. EMA recommends COVID-19 Vaccine Janssen. SUMMARY OF PRODUCT CHARACTERISTICS JANSSEN VACCINE. 2021;
[Agência Nacional de Vigilância Sanitária (Anvisa), 2021] Agência Nacional de Vigilância Sanitária (Anvisa). Anvisa aprueba el uso de emergencia de la vacuna Janssen. 2021; Agência Nacional de Vigilância Sanitária (Anvisa). Anvisa aprueba el uso de emergencia de la vacuna Janssen. 2021;
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