Janssen COVID-19 vaccine

Extended version of the vaccine

Janssen COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure

Status of assessment finalized on 12 March 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and over [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency in individuals aged 18 years and over [WHO, 2021 ].

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 over [EMA, 2021 ].

Regulatory Authorities of Regional Reference in the Americas

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

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

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 over [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 other jurisdictions in the Americas
Bahamas
Maldives
Peru
Saint Vincent and the Grenadines
Trinidad and Tobago

Authorization in other jurisdictions in the Americas
Andorra
Australia
Austria
Bahrain
Bangladesh
Belgium
Botswana
Bulgaria
Burkina Faso
Cameroon
Croatia
Cyprus
Czechia
Denmark
Estonia
European Union
Faroe Islands
Finland
France
Germany
Greece
Hungary
India
Indonesia
iran
Ireland
Italy
Jamaica
Kenya
Kuwait
Latvia
Libya
Liechtenstein
Lithuania
Luxembourg
Malaysia
Malta
Micronesia
Netherlands
New Zealand
Nigeria
Norway
Papua New Guinea
Poland
Portugal
Romania
Rwanda
Saudi Arabia
Senegal
Slovakia
Slovenia
South Africa
South Korea
Spain
Sweden
Switzerland
Thailand
Tunisia
Ukraine
United Republic of Tanzania
United States
Vietnam
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. Manufacturer of Janssen COVID-19 vaccine [WHO, 2021 ].
Janssen Vaccines & Prevention B.V.; The Netherlands [WHO, 2021 ].
Emergent Manufacturing Operations Baltimore LLC.; United States (USA). Site currently under investigation by USFDA due to non GMP compliance* [WHO, 2021 ].

Drug product [WHO, 2021 ]
Janssen Biologics B.V.; The Netherlands. Manufacturer of Janssen COVID-19 vaccine [WHO, 2021 ].
Janssen Pharmaceutica NV.; Belgium [WHO, 2021 ].
Aspen SVP.; South Africa [WHO, 2021 ].
Catalent Inc.; USA. Manufacturing partner with Johnson & Johnson for the Janssen COVID-19 vaccine [Catalent, 2020 ].
Catalent Inc.; Italy. Sterile manufacturings and packaging of the vaccine in Italy [Catalent, 2021 ] .
Grand River Aseptic Manufacturing, Michigan; USA. Vaccine manufacturing, including technology transfer, fill and finish process [Grand River Aseptic Manufacturing, 2020 ].
Merck Sharp & Dohme, United States.

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 ].

 

Dosage form and ingredients

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

The vaccine contains the following ingredients:

Active ingredient

The active substance is Adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2-S) no less than 2.5 x 10^10 virus particles or no less than 8.92 log10 infectious units (IU) in each 0.5 mL.

Excipients

Citric acid monohydrate
Trisodium citrate dihydrate
Ethanol
2-hydroxypropyl-β-cyclodextrin (HBCD)
Polysorbate 80
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections

Risk considerations

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

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 ].

Janssen COVID-19 vaccine was as a single dose of 0.5 mL (which is a preferred characteristic according to the WHO Target Product Profiles for COVID-19 Vaccines). If, however, clinical data would show that a second dose is needed to provide long-term protection, the company is considering minimum 2 weeks interval between doses [WHO, 2021 ].

The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose of Janssen COVID-19 vaccine.

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

There is no data available on the interchangeability of the Janssen COVID-19 vaccine with other COVID-19 vaccines to complete the vaccination series.

There is no evidence yet about the effects of the coadministration of Janssen COVID-19 vaccine with other vaccines included in routine vaccination programs.

Indications and contraindications

Indications

The Janssen COVID-19 vaccine is indicated for adults 18 years and over [WHO, 2021 ].

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, 2021 ]. (See the list of ingredients under 'General characteristics' in the extended version).

Precautions

As for all COVID-19 vaccines, Ad26.COV2.S should be given under health care supervision, with the appropriate medical treatment available in case of allergic reactions. As a precautionary measure, an observation period of 15 min after vaccination should be ensured [WHO, 2021 ].

Based on post-marketing safety surveillance, the following safety concerns were identified: thrombosis with thrombocytopenia syndrome (TTS), Guillain-Barre Syndrome (GBS) and capillary leak syndrome (CLS). 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. In countries with ongoing SARS-CoV-2 transmission, the benefit of vaccination in protecting against COVID-19 far outweighs the risks of TTS, GBS and CLS. However, benefit–risk assessments may differ from country to country, and countries should consider their epidemiological situation, individual and population-level risks, availability of other vaccines, and alternate options for risk mitigation. The benefit–risk ratio is greatest in older age groups as the risk of severe COVID-19 disease outcomes including COVID-19 related thromboembolic events increases with age [WHO, 2021 ].

Healthcare professionals should be alert to the signs and symptoms of thromboembolism and thrombocytopenia, as well as coagulopathies. Vaccinated individuals should be instructed to seek immediate medical attention if they develop the following symptoms; severe or persistent headaches, blurred vision, confusion, seizures, shortness of breath, chest pain, leg swelling, leg pain, persistent abdominal pain or unusual skin bruising and or petechia a few days after vaccination [WHO, 2021 ].

Vaccination is recommended for persons with comorbidities that have been identified as increasing the risk of severe COVID-19 [WHO, 2021 ].

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 ].

Vaccination should be postponed for individuals suffering from acute severe febrile illness, or acute infection. However, the presence of a minor infection, such as cold, and/or low-grade fever should not delay vaccination [WHO, 2021 ].

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

WHO recommends the use of Ad26.COV2.S in pregnant women only if the benefits of vaccination to the pregnant woman outweigh the potential risks. To help pregnant women make this assessment, they should be provided with information about the risks of COVID-19 in pregnancy (including, for example, that some pregnant women are at increased risk of infection or have co-morbidities that add to their risk of severe disease), the likely benefits of vaccination in the local epidemiologic context, and the current limitations of the safety data in pregnant women. WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2021 ].

Janssen COVID-19 vaccine should not be routinely used in children and adolescents below the age of 18 years [WHO, 2021 ].

The risk of severe COVID-19 and death increases steeply with age. Data from the phase 3 trial indicate that the efficacy and safety of the vaccine are comparable across all age groups (above the age of 18). Vaccination is recommended for older persons [WHO, 2021 ].

There should be a minimum interval of 14 days between administration of this vaccine and all other vaccines except inactivated influenza vaccine. This recommendation will be updated as data on co-administration with other vaccines, including live vaccines, become available [WHO, 2021 ].

There is no evidence yet about the effects of the co-administration of the Janssen COVID-19 vaccine with other vaccines included in routine vaccinations programs [WHO, 2021 ].

Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection [World Health Organization, 2021 ].

Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].

Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].

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

Clinical studies - general characteristics

Randomized trials

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

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

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 ].

 

Ongoing randomized trials

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

COV3003 is an ongoing randomized phase 3 trial (registered with the number 2020-005801-14 [Janssen Vaccines & Prevention B.V., 2021 ]), sponsored by Janssen Vaccines & Prevention B.V., that is being conducted in Poland, Germany and the United States. It was first registered in December 2020 and plans to enroll 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.

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

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

CR109060 is an ongoing randomized, double-blind, phase 2 study (registered with the number NCT04999111 [Janssen Vaccines & Prevention B.V., 2021 ]) sponsored by Janssen Vaccines & Prevention B.V. that is being conducted in United States. It was first registered in August 2021 and plans to enroll 660 adults 18 years of age and 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.

 

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.

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.

Efficacy and effectiveness of the vaccine

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, 2021 ].

Completed developmental and reproductive toxicology (DART) studies in animals have not shown harmful effects of the vaccine in pregnancy. Ad26.COV2.S is a replication-defective vaccine. While available data on Ad26.COV2.S vaccination of pregnant women are insufficient to assess vaccine efficacy or vaccine-associated risks in pregnancy, studies in pregnant women are planned in the coming months. [WHO, 2021 ].

 

Breast-feeding

Randomized trials

Females who were breast-feeding were excluded from the ENSEMBLE trial, so no efficacy data are available [Sadoff J, 2021 ].

Other studies

This group is being studied in the HORIZON 1 study (see 'ongoing registered studies') [Janssen Vaccines & Prevention B.V., 2021 ].

 

Medical comorbidities associated with high risk of severe COVID-19

Obesity

Randomized trials

The proportion of participants with obesity in the ENSEMBLE trial was 28.5% (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 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 ].

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 ].

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 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 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 ].

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 ].

 

Booster dose

Immunogenicity outcomes

Three randomized clinical trials have included booster doses [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 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, hearafter 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 neutralising responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

Safety of the vaccine

Safety of the vaccine in preclinical studies

Genotoxicity and carcinogenicity

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

Risk of thrombosis

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

Reproductive toxicity and fertility 

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

Thrombocytopenia

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

Safety of the vaccine in clinical trials

Key messages

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

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

Main safety outcomes of Janssen COVID-19 vaccine

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 Janssen COVID-19 vaccine versus the group that received placebo vaccine was not reported in detail. However, it was reported that no specific safety concerns were identified in this subgroup.

 

Age

Randomized trials

The frequency of adverse effects in the vaccinated/not vaccinated population according to age was the following:

Solicited local adverse reactions

  • 59.8 vs 20.2 (RR 2.96; difference: 39.6 percentage points) in the group 18-59 years.
  • 35.4 vs 18.3 (RR 1.93; difference: 17.1 percentage points) in the group ≥60 years.

Solicited systemic adverse reactions

  • 61.5 vs 36.4 (RR 1.69; difference: 25.1 percentage points) in the group 18-59 years.
  • 45.3 vs 33.1 (RR 1.37; difference: 12.2 percentage points) in the group ≥60 years.

Serious adverse events

  • 0.3 vs 0.4 (RR 0.75; difference: -0.1 percentage points) in the group 18-59 years.
  • 0.5 vs 0.5 (RR 1; difference: 0 percentage points) in the group ≥60 years.

 

Children and adolescents

Randomized trials

Children were excluded from the ENSEMBLE trial, so no safety data are available from participants ages 17 years and younger [Sadoff J, 2021 ].

The randomized phase 2 ongoing trial COV2001 (also known as CR108854 and VAC31518COV2001) is currently evaluating the efficacy/safety of the vaccine in adolescents (12-17 years) and adults (18 years or older) [Janssen Vaccines & Prevention B.V., 2020 ].

The randomized, double-blind, placebo-controlled, phase 2/3 ongoing trial HORIZON 2 (also known as VAC31518COV3006) is currently evaluating the efficacy/safety of the vaccine in healthy children from birth to 17 years [Janssen Vaccines & Prevention B.V., 2021 ].

 

Pregnancy

Randomized trials

Pregnant females were excluded from the ENSEMBLE trial, so no safety data are available [Sadoff J, 2021 ]. 

 

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

No comparative studies reported or assessed this outcome.

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 ]. 

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

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