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 on 12 March 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency in individuals 18 years of age and older [WHO, 2022 ].

European Commission (based upon the recommendation of the European Medicines Agency)
Authorized for emergency use on 11 March 2021.
Conditional Marketing authorization for individuals 18 years of age and older [EMA, 2022 ].

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Authorized for emergency use on 1 October 2021 [ANMAT, 2022 ].

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Authorized for emergency use on 5 April 2022 [Anvisa, 2022 ].

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

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

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use on 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 (FDA)
Authorized for emergency use on 27 February 2021.
Emergency Use Authorization (EUA) for 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 on 27 May 2021 [Gobierno de México, 2021 ].

Authorization in jurisdictions in Latin America and the Caribbean
Antigua and Barbuda
Bahamas
Barbados
Belize
Bolivia
Jamaica
Peru
Puerto Rico
Saint Lucia
Saint Vincent and the Grenadines
Trinidad and Tobago

Authorization in other jurisdictions
Afghanistan
Australia
Austria
Bahrain
Bangladesh
Belgium
Benin
Botswana
Bulgaria
Burkina Faso
Burundi
Cambodia
Cameroon
Central African Republic
Côte d'Ivoire
Croatia
Cyprus
Czechia
Democratic Republic of the Congo
Denmark
Djibouti
Egypt
Estonia
Eswatini
Ethiopia
European Union
Faroe Islands
Finland
France
Gabon
Gambia
Germany
Ghana
Greece
Guinea
Guinea-Bissau
Hungary
Iceland
India
Indonesia
Iran
Ireland
Italy
Kenya
Kuwait
Laos
Latvia
Lesotho
Liberia
Libya
Liechtenstein
Lithuania
Luxembourg
Madagascar
Malaysia
Malawi
Maldives
Mali
Malta
Mauritania
Mauritius
Micronesia
Moldova
Morocco
Mozambique
Namibia
Nepal
Netherlands
New Zealand
Nigeria
Norway
Papua New Guinea
Philippines
Poland
Portugal
Romania
Rwanda
Saudi Arabia
Senegal
Slovakia
Slovenia
South Africa
South Korea
South Sudan
Spain
Sudan
Sweden
Switzerland
Tanzania
Thailand
Togo
Tunisia
Ukraine
United Kingdom
United States
Vietnam
Zambia
Zimbabwe

The Emergency Use Authorization does not constitute marketing authorization in the country.

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.
Janssen Vaccines & Prevention B.V., The Netherlands.
*Emergent Manufacturing Operations Baltimore LLC., United States (USA). Site currently under investigation by USFDA due to non GMP compliance (Refer to WHO website fot the lastest update status).

Drug product [WHO, 2021 ]
Janssen Biologics B.V., Leiden, The Netherlands.
Janssen Pharmaceutica NV. Beerse, Belgium.
Aspen SVP. Gqeberha, South Africa.
Catalent Indiana., USA. Manufacturing partner with Johnson & Johnson [Catalent, 2020 ].
Catalent Inc. Anagni, Italy.
Grand River Aseptic Manufacturing, Michigan, USA. Vaccine manufacturing, including technology transfer, fill and finish process [Grand River Aseptic Manufacturing, 2020 ].
Merck Sharp & Dohme. West Point, United States.
Biological E Ltd. Telengana, India.

General characteristics

The 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 ].

 

Ingredients
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 1010 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 ].

Dosing and schedule

Dose-finding studies

COV1001 trial evaluated 805 healthy adults participants 18 years of age or over that received the vaccine at a dose of 5 × 10¹⁰ viral particles (low dose) or 1 × 10¹¹ 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 ].

Indications and contraindications

Indications

The Janssen COVID-19 vaccine is indicated for individuals18 years and over [WHO, 2022 ].

Contraindications

The Janssen COVID-19 vaccine is contraindicated for individuals with a known history of a severe allergic reaction to any component of the Janssen COVID-19 vaccine [WHO, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).

The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose.

People who have had thrombosis with thrombocytopenia syndrome (TTS) following the first dose of the Janssen COVID-19 vaccine should not receive a second dose of the same vaccine [WHO, 2022 ].

Precautions
Allergic reactions [WHO, 2022 ].
As for all COVID-19 vaccines, the Janssen COVID-19 vaccine should be given under health care supervision, with an observation period of 15 min after vaccination.

Thrombosis with thrombocytopenia syndrome [WHO, 2022 ].
A very rare syndrome of blood clotting combined with low platelet counts, which is described as thrombosis with thrombocytopenia syndrome (TTS) has been reported following vaccination with the first dose of the Janssen COVID-19 vaccine. A causal relationship between the vaccine and TTS is considered plausible although the biological mechanism for this syndrome is still being investigated.
No TTS cases have been reported after a second or subsequent dose.

There is a considerable geographical variation regarding the reported incidence since most of these cases were notified from the United Kingdom and the European Union (EU) and very few from non-European countries, despite the extensive use of the Janssen COVID-19 vaccine in these countries.

In countries with ongoing SARS-CoV-2 transmission, the benefit of vaccination in protecting against COVID-19 far outweighs the risks. However, benefit–risk assessments may differ from country to country. As data from additional studies become available, enabling a better understanding of the pathophysiology of TTS and its relationship to the vaccine, recommendations on vaccination will be updated.

Neurological events [WHO, 2022 ].
Guillain-Barré syndrome (GBS) has been reported very rarely following vaccination with the Janssen COVID-19 vaccine. Based on the available data, the potential benefits of the Janssen COVID-19 vaccine continue to outweigh any potential risk of GBS, particularly given the increase in the more transmissible variants. Health workers should be alert to possible signs and symptoms of GBS to ensure timely and accurate diagnosis (or to rule out other causes) and management of potential cases.

Pregnancy [WHO, 2022 ].
WHO recommends the use of Janssen COVID-19 vaccine 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, 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.

Breastfeeding [WHO, 2022 ].
Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults. Janssen COVID-19 vaccine is not a live virus vaccine and it is biologically and clinically unlikely to pose a risk to the breastfeeding child. Based on this considerations, WHO recommends the use of the Janssen COVID-19 vaccine in breastfeeding women as in other adults.
WHO does not recommend discontinuing breastfeeding because of vaccination.

Persons living with HIV [WHO, 2022 ].
Persons living with HIV who are well controlled on highly active antiretroviral therapy should be vaccinated. It is not necessary to test for HIV infection before administration of the vaccine.

Persons with previous SARS-CoV-2 infection [WHO, 2022 ].
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.
The optimal time interval between a natural infection and vaccination is not yet known. An interval of 3 months could be considered.

Persons with current acute COVID-19 [WHO, 2022 ].
Persons with acute PCR-confirmed COVID-19 should not be vaccinated until after they have recovered from acute illness and the criteria for discontinuation of isolation have been met.

Other precautions
EMA recommends that individuals who have previously had capillary leak syndrome must not be vaccinated with the 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 ].

As with other intramuscular injections, the vaccine should be given with caution for individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [WHO, 2021 ].

Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5ºC) until they are afebrile [WHO, 2022 ].

Syncope (fainting) may occur in association with administration of injectable vaccines, in particular in adolescents. Procedures should be in place to avoid injury from fainting [WHO, 2021 ].

Co-administration with other vaccines [WHO, 2022 ].
For adults, COVID-19 vaccines may be administered concomitantly or at any time before or after other adult vaccines, including: live attenuated vaccines, inactivated, adjuvanted, or non-adjuvanted vaccines.
When administered concomitantly, the vaccines should be injected at separate sites, preferably different extremities.

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

Storage and logistics

Storage

The Janssen COVID-19 vaccine is provided as a frozen suspension stored at -25ºC to -15°C (-13°F to 5°F) for up to 24 months [WHO, 2021 ].

The shelf life of Janssen COVID-19 vaccine is up to 11 months stored between 2°C and 8°C (36°F to 46°F) [WHO, 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.


Administration logistics
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 taking the first dose from the multidose vial, the vial should be used immediately or held at 2-8ºC for up to 6 hours. Discard after 6 hours or at the end of the immunization session, whichever comes first [WHO, 2022 ].

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 × 1011 viral particles per milliliter administered at a dose of 5 × 1010 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 × 1010 viral particles or 1 × 1011 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 ].

COV-BOOST was a blinded, multicentre, randomized, controlled, phase 2 trial sponsored by University Hospital Southampton NHS Foundation Trust and conducted in United Kingdom between May 2021 - August 2022. It was registered with ISRCTN73765130. The trial included adults aged 30 years or older, in good physical health (mild to moderate well-controlled comorbidities were permitted), who had received two doses of either Pfizer or AstraZeneca COVID-19 vaccine. The sample size was 2883. The median age of ChAd/ChAd-primed group was 53 years in the younger age group and 76 years in the older age group. In the BNT/BNT-primed group, the median age was 51 years in the younger age group and 78 years in the older age group. The proportion of females was 46.7% in the ChAd/ChAD-primed and 53.6% in BNT/BNT-primed group. Participants were randomly assigned in a 1:1:1:1 ratio in group A, 1:1:1:1:1 in group B, and 1:1:1:1 in Group C to receive an experimental vaccine or control. The intervention was administered as:

  1. Group A received NVX-CoV2373( Novavax), a half dose of NVX, AstraZeneca, or control quadrivalent meningococcal conjugate vaccine (MenACWY).
  2. Group B received Pfizer, VLA2001 (Valneva), a half dose of VLA, Ad26.COV2.S (Janssen) or MenACWY .
  3. Group C received mRNA1273 (Moderna), CVnCov (CureVac), a half dose of BNT, or MenACWY [Munro, Alasdair P S, 2021 ].

SWITCH was a single-blind, multicenter, randomized, controlled trial sponsored by Erasmus Medical Center and conducted Netherlands between June 2021 to September 2022. It was registered with NCT04927936. The trial included Health care workers between 18 and 65 years of age. The sample size was 461. The mean age of the participants was 40 years and the proportion of women was 65%. Participants were randomly assigned in a 1:1:1:1 ratio to receive no booster, an Janssen booster, an Moderna booster, or a Pfizer booster. The intervention was administered as Janssen COVID-19 vaccine (≥8.92×1010 viral particles), Moderna COVID-19 vaccine (100 μg), and Pfizer COVID-19 vaccine (30 μg) [Sablerolles RSG, 2022 ].

ENSEMBLE 2 is a randomized, double-blind, placebo-controlled, phase 3 trial (registered with the numbers NCT04614948) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in United States, Belgium, Brazil, Colombia, France, Germany, Philippines, South Africa, Spain, and United Kingdom [Karin Hardt, 2022 ]. It was first registered in November 2020 and plans to enroll 31,836 adults aged 18 years and older who had received a single dose of Janssen COVID-19 vaccine. Participants will receive a booster dose of the vaccine or placebo 2 months after primary single-dose vaccination. It is expected to run for until May 2023.

Ongoing randomized trials

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 1,450 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.

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 over 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 3,675 healthy children from birth to 17 years and healthy adults aged 18 to 55 years that will receive different dose levels of the 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.

Stegall MD et al. is an ongoing randomized phase 3, open-label trial (registered with the number NCT04894305 [Mark Stegall, 2022 ]) sponsored by Mark Stegall that is being conducted in United States. It was first registered in February 2022 and plans to enroll 1200 kidney transplant recipients 18 years old and over who have had two or three doses of Pfizer or Moderna COVID-19 vaccine. Those participants will receive an additional dose of the Janssen COVID-19 vaccine after the primary vaccination series or the booster dose. It is expected to run until March 2025.

Other studies providing efficacy or safety data

See I et al. was a non-comparative study conducted in the United States. The study enrolled 57 participants describes surveillance data and reports thrombosis rates with thrombocytopenia syndrome (TTS) cases after vaccination with Janssen, Moderna and Pfizer-BioTech COVID-19 vaccine [See I, 2022 ].

PRESTO was a cohort study conducted in the United States and Canada that assessed the association of female and male COVID-19 vaccination with fecundability from December 2020 to September 2021 [Wesselink AK, 2022 ].

Johnson AG et al. was a comparative cohort study conducted in United States [Johnson AG, 2022 ], evaluating the effectiveness of a booster dose of Pfizer, Moderna, and Janssen COVID-19 vaccines in adults during periods of Delta and Omicron variant emergence.

Lytras T et al. was a comparative cohort study conducted in Greece [Theodore Lytras, 2022 ], evaluating vaccine effectiveness from individuals aged 15 years and over who had received two doses of Pfizer, Moderna, AstraZeneca COVID-19 vaccine or a single-dose of Janssen COVID-19 vaccine.

ACCL21C2 is an ongoing prospective Cohort study (registered with the number NCT05228275 [Children's Oncology Group, 2022 ]) sponsored by Children's Oncology Group that is being conducted in United States. It was first registered in February 2022 and plans to enroll 532 individuals aged between 6 and 37 years old that will receive one of the FDA-EUA approved COVID-19 vaccines: Pfizer-BioNTech, Moderna or Janssen COVID-19 vaccines. It is expected to run until December 2024.

7 vaccines against COVID 19 is an ongoing prospective Cohort study (registered with the number NCT05228912 [Hospital Clinica Nova, 2021 ]) sponsored by Hospital Clinica Nova that is being conducted in Mexico. It was first registered in February 2022 and plans to enroll 1870 Children, Adult and Older Adult that will receive Pfizer-BioNTech, Moderna, Gamaleya, Cansino, Sinovac, Astrazeneca and Janssen COVID-19 vaccines. It is expected to run until October 2024.

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 over, 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 over, 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 over 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.

Stupica D et al. is an ongoing observational study (registered with the number NCT05198453) sponsored by University Medical Centre Ljubljana that is being conducted in Slovenia [University Medical Centre Ljubljana, 2021 ]. It was first registered in January 2022 and plans to enroll 529 participants 18 years and over that received Pfizer, Moderna, AstraZeneca, or Janssen COVID-19 vaccine. It is expected to run for until February 2022.

Covicompare-J is an ongoing phase 4 non-randomized clinical trial (registered with the number EudraCT 2021-003191-14 [CHU SAINT-ETIENNE, 2021 ]) sponsored by CHU Saint-Etienne that is being conducted in France. It was first registered in June 2021 and plans to enroll 180 adults aged 18 years old who will receive a single dose of Janssen COVID-19 vaccine.

STOPCoV is an ongoing cohort study (registered with the number NCT05208983 [University Health Network, Toronto, 2021 ]) sponsored by University Health Network, Toronto that is being conducted in Canada. It was first registered in January 2022 and plans to enroll 1286 individuals aged 30-50 years and individuals aged 70 years and over that will receive Pfizer, Moderna, Janssen, or AstraZeneca COVID-19 vaccines. It is expected to run until March 2024.

Methods used to assess efficacy

The following methods are in use to assess efficacy in the phase 3 trials evaluating the vaccine:

ENSEMBLE trial [Sadoff J, 2021 ].

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. 

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 1010 [or 1.25 x 1010 viral particles]/GMC 5 x 1010 viral particles).

Safety evaluation methods

The following methods are in use to assess safety in the phase 3 trials evaluating the vaccine:

ENSEMBLE trial [Sadoff J, 2021 ]

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.

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

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.

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

Main efficacy outcomes of Janssen COVID-19 vaccine

Contracting 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. Which means that 83 people need to receive the vaccine for one of them to experienced contracting any symptomatic COVID-19.

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/critical 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. Which means that 83 people need to receive the vaccine for one of them to experienced contracting moderate to severe COVID-19

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%, or that the intervention reduced the risk of contracting severe/critical COVID-19 by 0.3 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 333. Which means that 333 people need to receive the vaccine for one of them to experienced contracting 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.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (≥60y) (measured at least 14 days after the injection)

The relative risk of contracting COVID-19 (≥60y) in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.24 (95% CI 0.15 to 0.38). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (≥60y) by 76%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (≥60y). Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 88 people not receiving Janssen COVID-19 vaccine out of 19544 presented this outcome (5 per 1000) versus 21 out of 19514 in the group that did receive it (1 per 1000). In other words, 4 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 0.4%, or that the intervention reduced the risk of contracting COVID-19 (≥60y) by 0.4 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 250. Which means that 250 people need to receive the vaccine for one of them to experienced contracting COVID-19 (≥60y)

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

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

The relative risk of contracting COVID-19 (Male) in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.32 (95% CI 0.25 to 0.4). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (Male) by 68%, compared with placebo vaccine.

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

In the trial identified in this review, 269 people not receiving Janssen COVID-19 vaccine out of 10832 presented this outcome (25 per 1000) versus 85 out of 10861 in the group that did receive it (8 per 1000). In other words, 17 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 1.7%, or that the intervention reduced the risk of contracting COVID-19 (Male) by 1.7 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 59. Which means that 59 people need to receive the vaccine for one of them to experienced contracting COVID-19 (Male)

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

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

The relative risk of contracting COVID-19 (Female) in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.37 (95% CI 0.29 to 0.47). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (Female) by 63%, compared with placebo vaccine.

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

In the trial identified in this review, 240 people not receiving Janssen COVID-19 vaccine out of 8708 presented this outcome (28 per 1000) versus 88 out of 8649 in the group that did receive it (10 per 1000). In other words, 18 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 1.8%, or that the intervention reduced the risk of contracting COVID-19 (Female) by 1.8 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 56. Which means that 56 people need to receive the vaccine for one of them to experienced contracting COVID-19 (Female)

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

Summary of findings (iSoF)


Efficacy and effectiveness 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, 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% (19,722 out of 43,783 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, the 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 the Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.33 (95% CI 0.26 to 0.41). This means the 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% (8,561 out of 43,783 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 the 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, the 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, 2022 ].

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, 2022 ].

 

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% (12,492 out of 43,783 participants) [Sadoff J, 2021 ].

The relative risk of contracting severe COVID-19 in participants with obesity that received the 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, the 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 over, who will received BNT162b2 vaccine, ChAdOx1 nCoV-19 vaccine, or Ad26.COV2.S vaccine [Ospedale di Circolo - Fondazione Macchi, 2021 ].

The randomized study">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% (1,218 out of 43,783 participants) [Sadoff J, 2021 ].

The relative risk of contracting COVID-19 in participants with HIV that received the 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 43,783 participants) [Sadoff J, 2021 ].The relative risk of contracting severe COVID-19 in the participants with chronic lung disease that received the 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% (1,008 out of 43,783 participants) [Sadoff J, 2021 ].

The relative risk of contracting severe COVID-19 in the participants with cardiac disease that received the 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, the 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% (3,194 out of 43,783 participants) [Sadoff J, 2021 ].

The relative risk of contracting severe COVID-19 in the participants with diabetes type 2 that received the 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, the 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 on vaccine efficacy and effectiveness

Main effectiveness outcomes of Janssen COVID-19 vaccine (Other studies)

Contracting COVID-19

Corchado Garcia J et al. was a comparative cohort study conducted in USA. The study enrolled 23,945 participants (2,195 vaccine group; 21,950 Control group). Based on a leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system between February 27th and April 14th 2021. Outcome measured starting at ≥ 14 days after vaccination. The result of the study found a vaccine effectiveness of 76.7% (95%CI 30.3 to 95.3). [Juan Corchado-Garcia, 2021 ].

Malinis M et al. was a comparative cohort study conducted in USA. The study enrolled 557 in the vaccine group (27 received the Janssen vaccine). Based on a retrospective analysis by charts review of solid organ transplant recipients at Yale New Haven Hospital as of May 18, 2021. The outcome was measured 14 days after vaccination. The result of the study found a vaccine infection rate of 0% for the Janssen vaccine [Malinis M, 2021 ].

Amanda Zheutlin et al. was a case-control study conducted in the United States. The study included data from 168,857,729 participants with 1,764,474 receiving Janssen vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing incident breakthrough infection, hospitalization or ICU admission in months two through six following full vaccination were estimated relative to the first month after full vaccination. The study results showed evidence of waning protection against infections starting in month 2 from vaccination for both BNT162b2 and mRNA-1273 and in month 4 for Ad26.COV2.S. Evidence of waning protection against hospitalization started in month 2 for BNT162b2 and in month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S. No waning of protection was observed at any time for ICU admissions for all three vaccines [Amanda Zheutlin, 2022 ].

Johnson AG et al. included 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Data were collected between April 4, 2021, to December 25, 2021. Combined results showed that age-standardized case incidence rate ratios among unvaccinated persons compared with fully vaccinated persons with a booster dose declined from 13.9 during October–November to 4.9 during December, representing potential decreases in crude vaccine effectiveness for infection from 93% to 80%, respectively. Comparing unvaccinated persons with fully vaccinated persons without a booster dose, age-standardized case incidence rate ratios during October–November, and December were 4.0 and 2.8 respectively, representing decreases in vaccine effectiveness from 75% to 64% [Johnson AG, 2022 ].

Molani S et al. was a cohort study conducted in the United States. The study included 7,620,084 records of 2,627,914 vaccinated participants with either Pfizer-BioNTech, Moderna or Janssen, and 191,722 non-vaccinated individuals with history of COVID-19 infection. The study was based on data from Providence-St. Joseph Health electronic health records. The vaccine-induced cohort period data was collected from December 12, 2020, the infection-induced cohort data was collected from the beginning of the pandemic, data collection finished in to May 11, 2021. Survival against breakthrough for Janssen was 99.2% in 180 days. [Sevda Molani, 2022 ]

 

Winkelman TNA et al  was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021 that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for Medically Attended SARS-CoV-2 Infections was 78% (95% CI 75 to 81) and 60% (95% CI 50 to 68) for adults ≥ 65 years. [Winkelman TNA, 2022 ]

 

Contracting severe COVID-19

Moline HL et al. was a comparative cohort study conducted in USA. The study enrolled 7,280 participants, 1,819 Vaccine group (24 received the Janssen vaccine) 5,461 Control group. Based on data from persons aged ≥65 years from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) between February 1 and April 30, 2021. The outcome was measured 14 days after vaccination. The results of the study found vaccine effectiveness of 84% (95% CI 64% to 93%) for people aged 65–74 years and 85% (95% CI 72% to 92%) for people ≥ 75 years. [Moline HL, 2021 ].

Corchado Garcia J et al. was a comparative cohort study conducted in USA. The study enrolled 23,945 participants (2,195 vaccine group; 21,950 Control group). Based on a leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system between February 27th and April 14th 2021. Outcome measured starting at ≥ 14 days after vaccination. The study states that between the 13 infected vaccinated individuals and the 262 infected unvaccinated individuals no difference in hospitalization rate or ICU admission rates were observed. [Juan Corchado-Garcia, 2021 ].

Amanda Zheutlin et al. was a case-control study conducted in the United States. The study included data from 168,857,729 participants with 1,764,474 receiving Janssen vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing incident breakthrough infection, hospitalization or ICU admission in months two through six following full vaccination were estimated relative to the first month after full vaccination. The study results showed evidence of waning protection against infections starting in month 2 from vaccination for both BNT162b2 and mRNA-1273 and in month 4 for Ad26.COV2.S. Evidence of waning protection against hospitalization started in month 2 for BNT162b2 and in month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S. No waning of protection was observed at any time for ICU admissions for all three vaccines [Amanda Zheutlin, 2022 ].

Lytras T et al. included a total of 14,676,605 vaccine administered doses ( Pfizer= 11,427,784; Moderna=mRNA-1273 1,161,905; AstraZeneca=1,505,334; Janssen= 581,582). Data were collected between 11 January 2020 and 8 December 2021. The study showed that two doses of Pfizer, Moderna, or AstraZeneca COVID-19 vaccines offered vaccine effectiveness >90% against both intubation and death across all age groups. The effectiveness of the Janssen COVID-19 vaccine was ranged between 61-81%. There was some waning over time but vaccine effectiveness remained >80% at six months, and three doses increased vaccine effectiveness again to near 100%. Vaccination prevented an estimated 19,691 COVID-19 deaths (95% CI 18,890 to 20,788) over the study period [Theodore Lytras, 2022 ].

Wright BJ et al. was a case-control study conducted in the United States. It included data from 9,667 admissions for severe COVID-19 and 38,668 controls. Based on hospital admission registries from a large health-care system (Providence). to analyze vaccine effectiveness against severe COVID-19 over time. Between April 1, 2021, and Oct 26, 2021. The effectiveness of the vaccine was 78.5% (95% CI 71.3 to 83.9) between 50 to 100 days after the 2nd dose and it wanned to 72.6% (53.7 to 83.8) between 200-250 days after the 2nd dose. [Wright BJ, 2022 ]

Arregocés-Castillo et al. was a retrospective cohort study conducted in Colombia. The study included 2,828,294 participants: 1,414,147 fully vaccinated (any vaccine) and 1,414,147 unvaccinated. The study evaluated the effectiveness of vaccines against COVID-19-related hospitalization and death in people aged 60 years and older. Participant follow-up was done between March 11, 2021, and Oct 26, 2021.It was estimated the overall effectiveness of being fully vaccinated, as well as effectiveness for each vaccine. The aim results showed that vaccine effectiveness against hospitalization without death was 60.9% (95% CI 36.8 to 75.8) in adults > 60 years. Effectiveness against death after hospitalization was 85.5% (95% CI 77.1 to 91.2) and against death without hospitalization was 95.5% (95% CI 82.0 to 98.9) in adults > 60 years. [Arregocés-Castillo L, 2022 ]

 

Winkelman TNA et al  was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021 that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for SARS-CoV-2–Related Hospitalizations: was 78% (95% CI 75 to 81)and 60% (95% CI 50 to 68) [Winkelman TNA, 2022 ]

 

Transmission

No studies reported or assessed this outcome.

 

SARS-CoV-2 variants

Immunogenicity outcomes

Takuya Tada et al. was a non-comparative study (neutralizing capacity from recipients' sera) conducted in the United States, which included 10 healthy adults and reported data from 82 days post-immunization. The results showed that the antibodies caused by Ad26.COV2. S of a significant fraction of vaccinated individuals had a low neutralizing titer. The Ad26.COV2.S sera neutralized alpha variants with mean IC50 titers of 232 [Takuya Tada, 2021 ].

Takuya Tada et al. was a non-comparative study (neutralizing capacity from recipients' sera) carried out in the United States, which included 10 healthy adults and reported data from 82 days post-immunization. The results showed a 6.7-fold reduction in neutralization capacity [Takuya Tada, 2021 ].

Mandy Jongeneelen et al. carried out a non-comparative study (neutralizing capacity from recipients' sera) carried out in the Netherlands, which included 8 healthy adults and reported data from 71 days post-immunization. The results showed a reduction of the neutralization capacity of 3.6-fold. The relative neutralizing titers for the Beta variants were similar in subjects that were seronegative at baseline compared to the ones with pre‐existing ELISA responses at baseline [Mandy Jongeneelen, 2021 ].

Takuya Tada et al. was a non-comparative study (neutralizing capacity from recipients' sera) carried out in the United States, which included 10 healthy adults and reported data from 82 days post-immunization. The results showed a reduction in the neutralizing capacity of 5.4-fold. Ad26.COV2.S sera neutralized Delta variants with average IC50 titers of 221 [Takuya Tada, 2021 ].

Mandy Jongeneelen et al. carried out a non-comparative study (neutralizing capacity from recipients' sera) carried out in the Netherlands, which included 8 healthy adults and reported data from 71 days post immunization. The results showed a reduction in the neutralizing capacity of 1.6-fold. The relative neutralizing titers for the Delta variants were similar in subjects that were seronegative at baseline compared to the ones with pre‐existing ELISA responses at baseline [Mandy Jongeneelen, 2021 ].

Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine group (20 participants received the Janssen vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated individuals and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ].

Randomized trials

Sadoff J et al. are conducting a two-year phase three, multicenter, randomized, controlled trial (ENSEMBLE) in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. They included 4,969 participants (2,473 vaccine group and 2,496 control group). The study reported data measured at least 14 days after vaccine administration. The results showed an efficacy against moderate to severe COVID-19 - critical of 52.0% (95% CI: 30.3% to 67.4%) and against severe and critical COVID-19 of 73.1% (95% CI %: 40.0% to 89.4%) [Sadoff J, 2021 ].

Other studies

Graniss SJ et al. was a case-control study (test-negative) carried out in the United States, which included 7,418 participants (458 vaccine group and 6,960 unvaccinated group). The study seeks to evaluate the effectiveness of the vaccine against laboratory-confirmed COVID-19 among adults during SARS-CoV-2 B.1.617.2 (Delta) variant predominance June–August 2021. The results showed an effectiveness against severe COVID-19 of 60% (95% CI 31% to 77%) [Grannis SJ, 2021 ].

Kislaya I et al. was a case-control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on data from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against Omicron variant ranged between -7.1% and 28.1% for Janssen primary scheme. [Irina Kislaya, 2022 ]

 

Booster dose

Immunogenicity outcomes

SWITCH was a randomized trial sponsored by Erasmus Medical Center and conducted in the Netherlands between June 2021 to September 2022. Immunogenicity was assessed 28 days after homologous or heterologous booster vaccination. Results showed that the Janssen COVID-19 vaccine and mRNA boosters vaccines were immunogenic in health care workers who had received a priming dose of the Janssen vaccine. In addition, the Moderna and Pfizer COVID-19 boosters vaccines led to higher T-cell responses than the Janssen COVID-19 booster vaccine. The immune response was 91.7% with the Moderna booster and 91.5% with the Pfizer booster; both performed better than the homologous booster (response, 72.7%) [Sablerolles RSG, 2022 ].

The ENSEMBLE 2 study included 31,300 Janssen vaccinated participants. Data were collected 14 days after the booster dose. The study showed that the Janssen booster was immunogenic in adults who had received a priming dose of the Janssen vaccine. Geometric mean increases (GMI) at day 29 and 71 after booster vaccination were 4.2-fold and 40.5-fold, respectively [Karin Hardt, 2022 ].

Efficacy

The ENSEMBLE 2 study included 31,300 Janssen vaccinated participants. Outcomes were measured at least 14 days after booster dose, with follow-up of at least 36 days. The study showed that the Janssen homologous booster administered 2 months after primary single-dose vaccination in adults led to high vaccine efficacy. Vaccine efficacy were 75.2 (95% CI 54.6 to 87.3) in COVID-19 moderate to severe-critical, 75.6 (95% CI 55.5 to 87.5) in symptomatic COVID-19, 34.2 (95% CI−6.4 to 59.8) in asymptomatic SARS-CoV-2 [Karin Hardt, 2022 ].

Johnson AG et al. included 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Data were collected between April 4, 2021, to December 25, 2021. The study showed that rates of COVID-19 cases were lowest among fully vaccinated persons with a booster dose of Janssen COVID-19 vaccine, compared with fully vaccinated persons without a booster dose, and much lower than rates among unvaccinated persons. During October - November (Delta predominance period), average weekly incidence rate ratios were 3.2 (95% CI 2.9 to 3.6) among fully vaccine persons without booster dose and 13.4 (95% CI 10.6 to16.9) among fully vaccinated persons with a booster dose. During December (Omicron Emergence period), average weekly incidence rate ratios were 2.9 (95% CI 1.8 to 4.8) among fully vaccine persons without booster dose and 5.5 (95% CI 3.2 to 9.4) among fully vaccinated persons with a booster dose [Johnson AG, 2022 ].

Heterologous vaccine regimens

Immunogenicity outcomes

Three randomized clinical trials have included a booster-heterologous vaccine regimen [Erasmus Medical Center, 2021 ], [Janssen Vaccines & Prevention B.V., 2021 ], [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ] but their results are still not published.

 

Heterologous-booster regimens

Immunogenicity outcomes

Three randomized clinical trials have included a booster- heterologous vaccine regimen [Erasmus Medical Center, 2021 ], [Janssen Vaccines & Prevention B.V., 2021 ], [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ] but their results are still not published.

COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralizing responses after AstraZeneca/AstraZeneca's initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

SWITCH  was a randomized trial sponsored by Erasmus Medical Center and conducted in the Netherlands between June 2021 to September 2022. Immunogenicity was assessed 28 days after homologous or heterologous booster vaccination. Results showed that the Janssen COVID-19 vaccine and mRNA boosters vaccines were immunogenic in health care workers who had received a priming dose of the Janssen vaccine. In addition, the Moderna and Pfizer COVID-19 boosters vaccines led to higher T-cell responses than the Janssen COVID-19 booster vaccine. The immune response was 91.7% with the Moderna booster and 91.5% with the Pfizer booster; both performed better than the homologous booster (response, 72.7%) [Sablerolles RSG, 2022 ].

RHH-001 was a phase 4 randomized study, conducted in Brazil and El Salvador, that analyzed the immune response generated by homologous and heterologous booster vaccines based on a primary vaccination regimen with the Sinovac vaccine. The study recruited 1240 participants randomly assigned to receive a booster dose with Janssen (n=306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), and Sinovac (n=290) vaccines at least 6 months after the second dose. Results found all booster doses substantially increased binding and neutralizing antibody levels, the geometric fold-rise at day 28 post booster was 77 (67–88) for Janssen, 152 (134–173) for Pfizer-BioNTech, 90 (95% CI 77–104) for AstraZeneca, and 12 (11–14) for Sinovac. Heterologous booster regimens were superior to the homologous regimen with GMRs of 8.7 (5.9–12.9) for Janssen, 21.5 (14.5–31.9) for Pfizer-BioNTech, and 10.6 (7.2–15.6) for AstraZeneca. Neutralizing antibody titres were above the lower limit of detection in 75 (94%) of 80 participants tested at day 28 for the delta variant and in 61 (76%) of 80 participants for the omicron variant [Costa Clemens SA, 2022 ].

 

Vaccine safety

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

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.

Local adverse events (7 days following vaccination)

The relative risk of local adverse events 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 by 158%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events . 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 a local 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 (7 days following vaccination)

The relative risk of systemic adverse events 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 by 57%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events . 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 a systemic 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 (during 28 days post-vaccination)

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). No statistically significant differences between groups were found for serious adverse events.

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% (19,722 out of 43,783 participants) [Sadoff J, 2021 ]. The proportion of women that experienced adverse effects with the Janssen COVID-19 vaccine versus the group that received the 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 ]. 

 

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

Edelman A et al. was a cohort study conducted in the United States. The study enrolled 3,959 participants: 2,403 vaccine group (55% Pfizer, 35% Moderna, 7% Janssen); 1,556 control group. Based on prospectively tracked menstrual cycle data using the application "Natural Cycles”, between October 2020 and September 2021, the study assessed whether coronavirus disease 2019 (COVID-19) vaccination is associated with changes in cycle or menses length in those receiving vaccination as compared with an unvaccinated cohort. The study results showed a change in menstrual cycle length of less than 1 day compared with prevaccine cycles. The study also reports a mean change of 0.64 days, (98.75% CI 0.27-1.01) after the first dose and a mean change of 0.79 days, (98.75% CI 0.40-1.18) after the second dose when comparing with unvaccinated individuals [Edelman A, 2022 ].

PRESTO study showed no association between vaccines and fecundability in 2,126 participants vaccinated with Pfizer, Moderna or Janssen COVID-19 vaccine. The fecundability rate in vaccinated versus non-vaccinated individuals was 1.08 in females (95% CI 0.95 to 1.23) and 0.95 in males (95% CI 0.83 to 1.10) [Wesselink AK, 2022 ].

Knowlton KU et al was a cohort study conducted in the United States. The study enrolled 67 participants: 21 vaccine group; 46 control group; and was based on data from Intermountain Healthcare, a not-for-profit healthcare system throughout Utah and parts of Idaho and Nevada between December 15, 2020 and June 15, 2021 with the objective of examining the risk of inflammatory heart disease, including pericarditis and myocarditis, after SARS-CoV-2 vaccination. The study results showed an inflammatory heart disease Relative Rate (RR) of 1.63 (95%CI 0.95 to 2.71) in vaccinated individuals (Data from COVID-19 vaccines analyzed: aggregated data from Pfizer, Janssen, and Moderna)[Knowlton KU, 2022 ].

Gallo K et al. was a comparative study conducted in the United State. The study evaluated 580.000 cases from the Vaccination Adverse Event Reporting System. Data for vaccination associated side effects were obtained from VAERS, between 1 January and 24 September 2021. The prevalence of adverse events in the general population was assessed based on previously published studies concerning each condition. The OR for Janssen adverse events compared to the general population was: 11 for cerebral thrombosis, 11.6 for Guillán-Barre syndrome, 0.2 for myocarditis and 0.6 for pericarditis [Gallo K, 2022 ].

Non-comparative studies

Pawlowsky C et al. conducted a non-comparative study in the United States, which included 266,094 participants. The frequencies of cerebral venous sinus thrombosis (CVST) observed among people who received FDA-cleared COVID-19 vaccines from Pfizer-BioNTech (n = 94,818 doses), Moderna (n = 36,350 doses), and Johnson & Johnson were studied. Johnson - J&J (n = 1,745 doses), and among people who received one of the 10 FDA-approved non-COVID-19 vaccines (n = 771,805 doses). When comparing CVST incidence rates in 30-day time windows before and after vaccination, no statistically significant differences were found for COVID-19 vaccines or any other vaccine studied in this population. In total, 3 cases of CVST were observed within 30 days of vaccination with Pfizer-BioNTech (2 female, 1 male; Ages (years): [79, 80, 84]), including one individual with a history of thrombosis and another individual with recent trauma in the past 30 days. No cases of CVST are believed among patients who received the Moderna or J&J vaccines in this study population. Overall, this real-world evidence-based study highlights that TSVC is rare and not significantly associated with the COVID-19 vaccine [Colin Pawlowski, 2021 ].

Pushkar Aggarwal conducted a non-comparative study in the United States, in which he reported 68,123 adverse events (Pfizer, Moderna or Janssen vaccines). A statistically significant signal was found between cerebrovascular accidents (CVA) events and each of the three COVID-19 vaccines (Pfizer / BioNTech's, Moderna's, and Janssen's) in the vaccine adverse event reporting system (VAERS). Women and people 65 and older had higher number of case reports of stroke events with COVID-19 vaccines. Women also had more reports of COVID-19 adverse events in which stroke was reported and resulted in the patient having permanent disability or death [Pushkar Aggarwal, 2021 ].

David Presby et al. is a retrospective cohort conducted in United States. The study enrolled 50,977 (AstraZeneca (AZ, n=2,093), Janssen/Johnson & Johnson (J&J&J, n=3,888), Moderna (n=23,776; M1, 14,553 first dose; M2, 9,223 second dose), or Pfizer/BioNTech (n=35,929; P&B1, 22 387 first dose; P&B2, 13 542 second dose) participants. Based on data from subscribers to the WHOOP platform using data collected through April 14, 2021 [David Presby, 2021 ].

Maria Abbattista et al. conducted a non-comparative study in Europe, which included 748 248 reports of adverse drug reactions (Pfizer-BioNTech, Janssen, Moderna and AstraZeneca vaccines). The notification rate of cerebral venous thrombosis (CVT) per 1 million vaccinated persons-days was 1.92 (95% CI, 1.71-2.12) for Tozinameran, 5.63 (95% CI, 4, 74-6.64) for CX-024414, 21.60 (95% CI, 20.16-23.11) for CHADOX1 NCOV-19 and 11.48 (95% CI, 9.57-13, 67) for AD26.COV2.S. CVT occurred in conjunction with thrombocytopenia for all four vaccines. The observed-to-expected (OE) analysis ratio was greater than one for all four vaccines, both with the lowest and highest background incidence of CVT [Abbattista M, 2021 ].

Omar M Albalawi et al. was a study conducted in United States. The study enrolled General population that received Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S vaccines. Based on data from Vaccine Adverse Event Reporting System (VAERS) between 15 December 2020 to 19 March 2021. Results of the study showed that the Moderna group had more deaths than Pfizer group (7% 95% CI-14% to 33%). [Omar M Albalawi, 2021 ].

Hause AM et al. conducted a non-comparative cohort study in the United States, which included 7.98 million doses administered. Five mass vaccination sites reported 64 anxiety-related events, including 17 syncope (fainting) events after receiving the Janssen COVID-19 vaccine. Syncope reporting rates to the vaccine adverse event reporting system (VAERS) after the Janssen COVID-19 and influenza vaccines (2019-20) were 8.2 and 0.05 per 100,000 doses, respectively [Hause AM, 2021 ].

Shay DK et al. conducted a non-comparative study in the United States, which included 338,765 Janssen vaccine recipients. Recipients of the Janssen COVID-19 vaccine completed at least one v-safe survey during the week after vaccination; 76% reported a systemic reaction, 61% reported a local reaction, and 34% reported a health impact. Fatigue and pain were typical symptoms reported in both the vaccine adverse event reporting system (VAERS) and v-safe. The overall safety profile is consistent with data from pre-authorization clinical trials. The rapid review of vaccine safety data detected three additional cases of non-cerebral venous sinus thrombosis (CVST) thrombocytopenia syndrome (TTS), in addition to previously recognized CVST cases that initiated the pause in the use of the Janssen COVID-19 vaccine. Continuous monitoring of adverse events after COVID-19 vaccination, including vaccination with the single-dose Janssen vaccine, is essential to assess the risks and benefits of each vaccine [Shay DK, 2021 ].

Woo EJ et al. was a non-comparative cohort study conducted in the United States assessing reports of Guillain-Barré Syndrome received in the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination. A total of 130 reports of presumptive Guillain-Barré Syndrome were identified in US Vaccine Adverse Event Reporting System following Ad26.COV2.S vaccination [Woo EJ, 2021 ]. 

See I et al. was a non-comparative study conducted in the United States. The study enrolled 57 participants describes surveillance data and reports thrombosis rates with thrombocytopenia syndrome (TTS) cases after vaccination with Janssen, Moderna and Pfizer-BioTech COVID-19 vaccine  [See I, 2022 ].

Kant A et al. was a non-comparative study conducted in the Netherlands. The study included 27,554 participants and assessed systemic adverse events following immunization and adverse events of special interest following immunization for Pfizer-BioNTech, Moderna, Janssen and AstraZeneca vaccines [Kant A, 2022 ].

Zhang B et al. was a non-comparative study conducted in the United States. The study included 14.431 reports of menstrual disorders, analyzing the relationship between COVID-19 vaccines and menstrual disorders in females. [Zhang B, 2022 ]

Lee K.M et al was a non-comparative study conducted in the United States. The study enrolled 39,129 participants aged 18 to 80 years old and investigated unexpected menstrual bleeding after SARS-CoV-2 vaccination using an exploratory, mixed-methods survey instrument intended to capture a wide range of responses from current and formerly menstruating adults, between April 7, 2021 and June 29, 2021. The study reported that 42% of people with regular menstrual cycles bled more heavily than usual, while 44% reported no change after being vaccinated [Lee, K. M., 2022 ].

Kanack AJ et al. was a non-comparative study conducted in the United States. The study included 9 participants that presented vaccine-induced immune thrombotic thrombocytopenia (VITT) [Kanack AJ, 2022 ]

Orfanoudaki E et al. was a cross-sectional study conducted in Greece. The study included 1,007 inflammatory bowel disease (IBD) patients and aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines. The study results showed that adverse events were reported by 81% after first dose and 76% after second dose. Systemic adverse events were more common after the second dose (51% vs. 44%). Very few patients reported new onset abdominal symptoms, mainly abdominal pain in 4% after first dose, 6% after second dose and diarrhea in 5% after first dose, 7% after second dose. There were no serious adverse events leading to emergency room visit or hospitalization [Orfanoudaki E, 2022 ].

 

Monitoring

WHO recommends the following research and post-authorization monitoring activities:

Safety surveillance and monitoring
- Serious adverse events, anaphylaxis and other serious allergic reactions, Bell’s palsy, cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.

Vaccine effectiveness
− 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.

Subgroups
− Prospective studies on the safety of 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 people, including patients living with HIV and autoimmune disease.

Vaccination logistics
− Immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− 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, 2022] WHO. Interim recommendations for the use of the Janssen Ad26.COV2.S (COVID-19) vaccine. 2022; WHO. Interim recommendations for the use of the Janssen Ad26.COV2.S (COVID-19) vaccine. 2022;
[EMA, 2022] EMA. Jcovden (previously COVID-19 Vaccine Janssen). SUMMARY OF PRODUCT CHARACTERISTICS JANSSEN VACCINE. 2022; EMA. Jcovden (previously COVID-19 Vaccine Janssen). SUMMARY OF PRODUCT CHARACTERISTICS JANSSEN VACCINE. 2022;
[ANMAT, 2022] ANMAT. Vacunas contra el SARS-CoV-2. 2022; ANMAT. Vacunas contra el SARS-CoV-2. 2022;
[Anvisa, 2022] Anvisa. Janssen Vaccine (Janssen-Cilag). 2022; Anvisa. Janssen Vaccine (Janssen-Cilag). 2022;
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