Janssen COVID-19 vaccine

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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, 2022 ].
SAGE/WHO Recommendation:Recommended for 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, 2022 ].

Other manufacturers

Drug substance [WHO, 2022 ]
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, 2022 ]
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, 2022 ].

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

The Janssen COVID-19 vaccine is administered as one dose of 0.5 mL or as a series of two doses (0.5 mL each).
WHO recommends two doses administrated 2-6 months apart. The updated results from Phase 3 trials suggest that a two-dose scheme has higher efficacy for symptomatic infection and severe disease compared to a single dose [WHO, 2022 ].
If administration of the second dose is inadvertently delayed beyond 6 months, it should be given as soon as possible.

The pharmaceutical form is a suspension for intramuscular injection provided in a multidose vial (5 doses of 0.5 mL per vial) [WHO, 2022 ].
The preferred site of injection is the deltoid muscle of the upper arm.


Considerations for two versus one dose [WHO, 2022 ]
WHO recommends taking all efforts to provide two doses of the Janssen COVID-19 vaccine, particularly for the high priority-use groups.

WHO recommends an inter-dose interval of up to 6 months since a longer interval increases humoral immune responses.

If countries face severe vaccine supply constraints or vaccine delivery challenges, it can be considered the use of a single dose.
A single dose may also be a preferred option for vaccinating hard-to-reach populations (for example, refugees and migrants or remote communities).


Booster dose [WHO, 2022 ]
The need for, and timing of, additional doses beyond two doses remains to be determined.


Heterologous schedule [WHO, 2022 ]
When a second dose is provided, the current standard practice is to use the same product to complete a primary series.
However, WHO supports a flexible approach to using different EUL COVID-19 vaccine products for different doses (heterologous schedule).

Recommendations will be updated as further information becomes available on interchangeability between vaccine products and platforms.


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends a second dose for all moderately and severely immunocompromised persons aged 18 years and older, provided 1-3 months after the first dose.

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 ].

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

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.


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.

Children and adolescents [WHO, 2022 ].
There are currently no efficacy or safety data on the use of Ad26.COV2.S in persons below the age of 18 years. Until such data are available, vaccination of individuals below 18 years of age is not routinely recommended.

Older persons [WHO, 2022 ].
Vaccination is recommended for older persons without an upper age limit

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 who previously received passive antibody therapy for COVID-19[WHO, 2022 ]
Although some reduction in vaccine-induced antibody titers has been observed in this group, the balance of benefits versus risks favors vaccination.

Co-administration with other vaccines [WHO, 2022 ].
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, 2022 ].

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, 2022 ].

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.

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, 2022 ].

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, 2022 ].

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, 2022 ].

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, 2022 ].

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, 2022 ].

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, 2022 ].

Administration [WHO, 2022 ]

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, 2022 ].

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

The following randomized clinical trials have reported vaccine efficacy and/or safety data:

Phase 1/2:
The COV1001 trial, (NCT04436276 [Janssen Vaccines & Prevention B.V., 2020 ]) conducted in the United States since July 2020 included 25 people in phase 1, who received 1 or 2 doses of the Janssen COVID-19 vaccine (5 × 1010 or 1×1011 viral particles) or placebo in days 1 and 57 (5 individuals per group). In phase 1/2 participants received a dose of Janssen (5 × 1010 viral particles) followed by a booster dose of 5 × 1010 viral particles or 1.25 × 1010 viral particles or placebo. [Sadoff J, 2021 ], [Sadoff J, 2022 ], [Alter G, 2021 ], [Stephenson KE, 2021 ]

Phase 2:
The COV2001 trial (NCT04535453, [Janssen Vaccines & Prevention B.V., 2020 ]), conducted in Spain, the United Kingdom, Germany and the Netherlands, started in September 2020, included 635 adolescents (12-17 years) and adults (18 years or older). Participants were randomly assigned to 1 of 10 groups. Groups 1–6 were randomized 3:3:3:3:3:1 to vaccination with 1 or 2 doses 56 days apart or placebo. Groups 7 and 8 were randomized 2:1 to receive 2 doses of vaccine 28 days apart or placebo. Groups 9 and 10 were randomized 2:1 to receive 2 doses of vaccine 84 days apart or placebo. [Sablerolles RSG, 2022 ]

The BOOST-TX trial (NCT04614948, [Janssen Vaccines & Prevention B.V., 2020 ]) conducted in Austria since May 2021, included 197 adult kidney transplant recipients after 2 months of receiving an mRNA vaccine. Participants received a third dose of the BNT162b2 vaccine (n=99) or nRNA-1273 vaccine (n=98). In the three-month follow-up of the trial, 201 kidney transplant recipients were included after two doses of an mRNA vaccine: 101 received the third dose of the same mRNA vaccine and 100 received the third dose of the Janssen vaccine. [Heinzel A, 2022 ], [Reindl-Schwaighofer R, 2021 ]

The COV-BOOST trial (ISRCTN73765130, [University Hospital Southampton NHS Foundation Trust, 2021 ]), conducted in the UK since June 2021 included 2,878 participants who were randomized 1:1:1:1 into Group A, 1:1:1:1:1 in group B and 1:1:1:1 in group C to receive an experimental or control vaccine as booster dose after a primary schedule of the AstraZeneca or Pfizer-BioNTech COVID-19 vaccine. The intervention was administered as follows: group A received Novavax, half-dose Novavax, AstraZeneca, or control quadrivalent meningococcal conjugate vaccine (MenACWY); group B received Pfizer, Valneva, half-dose Valneva, Janssen, or MenACWY; group C received Moderna, CureVac, half-dose Pfizer, or MenACWY. [Munro, Alasdair P S, 2021 ], [Munro APS, 2022 ], [Liu X, 2022 ]

Phase 3:
The ENSEMBLE trial, (NCT04505722 [Janssen Vaccines & Prevention B.V., 2020 ]), conducted in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States, started in August 2020 and included 39,183 participants: 19,577 in the vaccine group who received a single Janssen dose (5×1010 viral particles), and 19,608 in the placebo group. [Sadoff J, 2022 ], [Sadoff J, 2021 ], [Sadoff J, 2021 ], [Janssen Vaccines & Prevention B.V., 2020 ]

The ENSEMBLE 2 trial (NCT04614948, [Janssen Vaccines & Prevention B.V., 2020 ]) conducted in the United States, Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, and the United Kingdom. It began in November 2020 and included 31,300 adults aged 18 and older: 15,708 in the vaccine group and 15,592 in the placebo group. Participants received either a booster dose of the vaccine or placebo 2 months after the single-dose primary vaccination. [Hardt K, 2022 ], [Karin Hardt, 2022 ]

Phase 4:
The RHH-001 trial (RBR-9nn3scw, [Instituto D'Or de Pesquisa e Ensino, 2021 ]) conducted in Brazil and El Salvador since in August 2021, enrolled 1240 participants randomly assigned to receive a booster dose of Janssen (n= 306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), or Sinovac (n=290) COVID-19 vaccines at least 6 months after the second dose [Costa Clemens SA, 2022 ], [Sue Ann Costa Clemens, 2021 ].

The RECOVAC trial (NCT05030974, [University Medical Center Groningen, 2021 ]) conducted in the Netherlands, started in October 2021 and enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after an initial mRNA vaccine schedule: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. [Kho MML, 2022 ]

Other trials reporting data:
The SWITCH trial (NCT04614948, [Erasmus Medical Center, 2021 ]) conducted in the Netherlands, initiated June 2021 and September 2022, included 461 participants over the age of 18, who were randomized 1:1:1:1 to not receiving a booster, receiving a Janssen booster, receiving a Moderna booster, or receiving a Pfizer–BioNTech booster. [Sablerolles RSG, 2022 ]

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 0.36 (95% CI 0.2 to 0.65). This means Janssen COVID-19 vaccine reduced the risk of contracting any symptomatic COVID-19 in 64%, 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 1082 people not receiving Janssen COVID-19 vaccine out of 19398 presented this outcome (45 per 1000) versus 495 out of 19400 in the group that did receive it (16 per 1000). In other words, 29 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 2.9%, or that the intervention reduced the risk of contracting any symptomatic COVID-19 by 2.9 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 34. Which means that 34 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 0.36 (95% CI 0.21 to 0.64). This means Janssen COVID-19 vaccine reduced the risk of contracting moderate to severe COVID-19 in 64%, 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, 1067 people not receiving Janssen COVID-19 vaccine out of 19398 presented this outcome (45 per 1000) versus 484 out of 19400 in the group that did receive it (16 per 1000). In other words, 29 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 2.9%, or that the intervention reduced the risk of contracting moderate to severe COVID-19 by 2.9 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 34. Which means that 34 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 complete vaccination)

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 0.23 (95% CI 0.09 to 0.59). This means Janssen COVID-19 vaccine reduced the risk of contracting severe/critical COVID-19 by 77%, 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, 205 people not receiving Janssen COVID-19 vaccine out of 19398 presented this outcome (9 per 1000) versus 56 out of 19400 in the group that did receive it (2 per 1000). In other words, 7 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 0.7%, or that the intervention reduced the risk of contracting severe/critical COVID-19 by 0.7 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 143. Which means that 143 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 complete vaccination)

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 0.46 (95% CI 0.37 to 0.58). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (≥60y) by 54%, 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, 220 people not receiving Janssen COVID-19 vaccine out of 6724 presented this outcome (19 per 1000) versus 103 out of 6734 in the group that did receive it (9 per 1000). In other words, 10 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%, or that the intervention reduced the risk of contracting COVID-19 (≥60y) by 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), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 100. Which means that 100 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 high.

Contracting COVID-19 (Male) (measured at least 14 days after complete vaccination)

The relative risk of contracting COVID-19 for men in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.46 (95% CI 0.4 to 0.53). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (Male) by 54%, 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, 581 people not receiving Janssen COVID-19 vaccine out of 10742 presented this outcome (54 per 1000) versus 267 out of 10798 in the group that did receive it (25 per 1000). In other words, 29 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 2.9%, or that the intervention reduced the risk of contracting COVID-19 (Male) by 2.9 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 34. Which means that 34 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 high.

Contracting COVID-19 (Female) (measured at least 14 days after complete vaccination)

The relative risk of contracting COVID-19 for women in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.45 (95% CI 0.38 to 0.53). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (Female) by 55%, 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, 486 people not receiving Janssen COVID-19 vaccine out of 8652 presented this outcome (56 per 1000) versus 217 out of 8599 in the group that did receive it (25 per 1000). In other words, 31 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 3.1%, or that the intervention reduced the risk of contracting COVID-19 (Female) by 3.1 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), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 32. Which means that 32 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 high.

Summary of findings (iSoF)


Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials
The proportion of women in the ENSEMBLE trial was 45% (19722 out of 43783 participants) [Sadoff J, 2021 ].

Among women, the relative risk of contracting moderate to severe COVID-19 with onset at least 14 days or 28 days after vaccination, when comparing with the group that received placebo vaccine, was 0.37 (95% CI 0.29 to 0.47). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 63%, compared with the placebo vaccine. This estimate is not importantly different from the one in males and in the overall population of the trial, for this outcome.

Age
Randomized trials
The proportion of participants 65 years of age and more in the ENSEMBLE trial was 19.6% (8561 out of 43783 participants) [Sadoff J, 2021 ].

Among participants 65 years or older, the relative risk of contracting moderate to severe COVID-19, with onset at least 14 or 28 days after vaccination, when comparing the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine, was 0.24 (95% CI 0.14 to 0.41). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 76%, compared with the placebo vaccine. This number is not importantly different from the estimate for this outcome in younger patients, and in the overall population of the trial
   
ENSEMBLE 2 was a randomized clinical trial that included 31 300 participants: 15 ,708 in vaccine group and 15, 592 in placebo group. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose. Vaccine efficacy against moderate to severe-critical COVID-19 in people over 60 years of age was 66.2% (95 CI, -14.0- 92.2). [Hardt K, 2022 ]

Children and adolescents
Randomized trials
Children were excluded from the ENSEMBLE trial, therefore no efficacy data are available from participants aged 17 years and younger  [Sadoff J, 2021 ].

The randomized phase 2 ongoing trial COV2001 (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 (VAC31518COV3006) is currently evaluating the efficacy and safety of the vaccine in healthy children from birth to 17 years [Janssen Vaccines & Prevention B.V., 2021 ].

Pregnancy
Randomized trials
Pregnant women were excluded from the ENSEMBLE trial, so no efficacy data are available [Sadoff J, 2021 ].

The open-label, phase 2 ongoing trial HORIZON 1 (CR108962 and VAC31518COV2004) plans to recruit 240 pregnant women. Is currently evaluating the efficacy and 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 ].
   

Breastfeeding
Randomized trials
Breastfeeding women were excluded from the ENSEMBLE trial, therefore no efficacy data are available [Sadoff J, 2021 ]. 
    
Immunocompromised persons
Randomized trials
The proportion of individuals living with HIV in the ENSEMBLE trial was 2.8% (1218 out of 43783 participants) [Sadoff J, 2021 ].

The relative risk of contracting COVID-19 in participants with HIV that received 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.

The ongoing phase 2, randomized, single-blinded study BOOST-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients in Austria [Medical University of Vienna, 2021 ].

At the four-week follow-up of BOOST-TX, 197 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies after two doses of an mRNA vaccine were included: 99 received a 3rd dose of the same RNA vaccine, and 98 received a 3rd dose of the Janssen COVID-19 vaccine. The primary endpoint was seroconversion after four weeks (29-42 days) following the third vaccine dose. Secondary endpoints included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). Four weeks after the third vaccination, 76 patients had developed antibodies against the SARS-CoV-2 spike protein(>0.8 U/mL) for an overall response rate of 39%. There was no statistically significant difference between the homologous and heterologous vaccination strategies, with a response rate of 35% vs 42% for mRNA vs Janssen vaccine (OR, 1.31; 95% CI, 0.71-2.44; P = 0.38) [Reindl-Schwaighofer R, 2021 ].

At the three-month follow-up of BOOST-TX, 201 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies following two doses of an mRNA vaccine were included: 85 received the 3rd dose of the same RNA vaccine, and 84 received the 3rd dose of the Janssen COVID-19 vaccine. Study participants were followed up for antibody assessment at the outpatient transplant clinic of the Medical University of Vienna for a second follow-up between 60 and 120 days after the 3rd vaccine dose. Results showed that absolute antibody titers between the two groups were not significantly different (median mRNA: 0.2 U/ml and vector: 0.81 U/ml, p=0.104). However, when examining higher antibody cut-off levels at the 1-month follow up, a significantly higher number of patients in the Janssen group reached antibody levels above 141 and 264 BAU/ml (>141 BAU/ml: 4 vs. 15% OR: 4.96, 95%CI: 1.29 to 28.21, p = 0.009, and >264 BAU/ml: 1 vs. 10% OR = 8.75, 95% CI: 1.13 to 396.17, p =0.018, for mRNA vs. Janssen vaccine groups, respectively). [Heinzel A, 2022 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after mRNA vaccination: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination. The seroreponse rates were, 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group. [Kho MML, 2022 ]

Other comparative studies
Coburn SB et al was a cohort study conducted in United States. The study included 113,994 patients (33,029 people with HIV and 80,965 people without HIV). The aim of the study was to determine whether HIV status was associated with increased rate or risk of COVID-19 breakthrough infection among fully vaccinated patients in the United States by vaccination type and, among people with HIV, by immune and viral suppression status. The incidence rate of breakthrough infections was higher in people with HIV (55 [95% CI, 52-58] cases per 1000 person-years) vs people without HIV (43 [95% CI, 42-45] cases per 1000 person-years). The breakthrough rate was highest with the Janssen vaccine (70 [95% CI, 63-78] cases per 1000 person-years), followed by Pfizer (54 [95% CI, 52-56] cases per 1000 person-years), and Moderna (34 [95% CI, 32-36] cases per 1000 person-years). [Coburn SB, 2022 ]

Embi P et al. conducted a case-control study with a test-negative design among eight VISION Network sites in the United States during the Delta variant predominance. Persons aged 18 years and older with ≥1 immunocompromising conditions were included and compared with non-immunocompromised individuals. 10,329 ED/UC events (5% immunocompromised) and 4,202 hospitalizations (23% immunocompromised) were among Janssen vaccine recipients. In the immunocompromised population, adjusted vaccine effectiveness (VE) for the Janssen vaccine was 7% (95% CI, -26-31) for ED/UC events, and 45% (95% CI, 29-57) for hospitalization, measured 14 days after the first dose. After a second dose of either Janssen or any mRNA vaccine, VE was 71% (CI 95%, 6-91), and 70% (CI 95% 25-88) for ED/UC encounters and hospitalization, respectively. Preprint [Peter J. Embi, 2022 ].

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Corchado Garcia J et al. was a comparative cohort study conducted in the 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 ]

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 the Janssen vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. The study showed evidence of waning protection against infections starting in month 2 from vaccination for 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 month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S [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 rates 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 ].

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 ].

Mayr FB et al was a test-negative case-control design study conducted in the United States. The study included 4,805,942 participants: 1,289,639 with mRNA-1273, 971,750 with BNT162b2, 196,344 with Ad26.COV2.S and 2,348,209 Unvaccinated. The study used data from the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infections before December 11, 2020. This study estimated vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Vaccine effectiveness against symptomatic infection at one month since full vaccination was 25.4 (95% CI 2.9 to 42.6). Vaccine effectiveness against symptomatic infection at six months since full vaccination was 11.0 (95% CI -11.1 to 28.6). [Mayr FB, 2022 ]

Winkelman TNA was a test-negative design study conducted in the United States. The study included 4,431,190 individuals: 3 013 704 fully vaccinated with Pfizer, Moderna, or Janssen and 1 417 486 not fully vaccinated. This study 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 of Janssen vaccine for Medically Attended SARS-CoV-2 Infections was 33% (95 CI 30 to 37). [Winkelman TNA, 2022 ]

Reynolds M et al was a case-control study (test-negative design) conducted in the United States that included data from 2,481 participants who were tested and reported vaccination status (Pfizer–BioNTech, Moderna, or Janssen): 695 cases with a positive COVID-19 test and 1,786 controls with negative tests. Vaccine effectiveness was examined in two ways: considering cases who tested positive for COVID-19 and who tested positive with at least one moderate/severe COVID-19 symptom. Adjusted Odds of having a COVID-19 positive test was 0.04 (95% CI 0.02-0.09) [Reynolds MW, 2022 ].

Cerqueira-Silva et al was a case-control study (negative-test design) conducted in Brazil that included data from three national registries, including 22,566 participants as cases with positive RT-PCR test and 145,055 participants as controls with negative RT-PCR test. This study evaluated the effectiveness of four vaccines: CoronaVac, AstraZeneca, Janssen, and Pfizer–BioNTech. Demographic characteristics were similar among vaccine recipients, but recipients of AstraZeneca tended to be older and have more comorbidities. Vaccine effectiveness against symptomatic infection ≥ 14 days from vaccine series completion was: CoronaVac: 39.4% (95% CI 36.1-42.6), AstraZeneca: 56.0% (95% CI 51.4-60.2), Janssen 44.0% (95% CI 31.5-54.2), Pfizer–BioNTech: 64.8% (95% CI 54.9-72.4).  [Thiago Cerqueira-Silva, 2021 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Janssen effectiveness against infection was 70.6% (95% CI 68.8 to 72.3) and 48.8% (95% CI 47.2 to 50.4), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ]

Monge S et al. was a retrospective cohort study conducted in Spain that recruited 1,897 individuals vaccinated with Janssen and 9,550 controls. The study was based on data from RENAVE and REGVACU including participants aged 50-59 years old during August 2021. The vaccine effectiveness of Janssen against the confirmed infection was 64% (95% CI, 62% to 66%) and against symptomatic infection was 56% (95% CI, 53% to 59%). [Monge, Susana, 2022 ]

Contracting severe COVID-19
Moline HL et al. was a comparative cohort study conducted in the USA. The study enrolled 7,280 participants, 1,819 Vaccine group (24 received 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 the 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. The outcome was measured starting at ≥ 14 days after vaccination. The result of the study found vaccine effectiveness of 76.7% (95%CI 30.3 to 95.3). [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 the Janssen vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. The study 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 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 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 healthcare 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 and the effectiveness of 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 ].

Mayr FB et al was a test-negative case-control design study conducted in the United States. The study included 4,805,942 participants: 1,289,639 with mRNA-1273, 971,750 with BNT162b2, 196,344 with Ad26.COV2.S and 2,348,209 Unvaccinated. The study used data from the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infections before December 11, 2020. This study estimated vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Vaccine effectiveness against hospitalization at one month since full vaccination was 55.8 (95% CI 20.6 to 75.4). Vaccine effectiveness against hospitalization at six months since full vaccination was 41.0 (95% CI 2.1 to 64.4). [Mayr FB, 2022 ]

Winkelman TNA was a test-negative design study conducted in the United States. The study included 4,431,190 individuals: 3 013 704 fully vaccinated with Pfizer, Moderna, or Janssen and 1 417 486 not fully vaccinated. This study 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 against SARS-CoV-2–Related Hospitalizations was 78% (95% CI 75 to 81). [Winkelman TNA, 2022 ]

Reynolds M et al was a case-control study (test-negative design) conducted in the United States that included data from 2,481 participants who were tested and reported vaccination status (Pfizer–BioNTech, Moderna, or Janssen): 695 cases with a positive COVID-19 test and 1,786 controls with negative tests. Vaccine effectiveness was examined in two ways: considering cases who tested positive for COVID-19 and who tested positive with at least one moderate/severe COVID-19 symptom. Adjusted Odds of having a COVID-19 positive test with at least one moderate/severe symptom was 0.35 (95% CI 0.11-1.15) [Reynolds MW, 2022 ].

Cerqueira-Silva et al was a case-control study (negative-test design) conducted in Brazil that included data from three national registries, including 22,566 participants as cases with positive RT-PCR test and 145,055 participants as controls with negative RT-PCR test. This study evaluated the effectiveness of four vaccines: CoronaVac, AstraZeneca, Janssen, and Pfizer–BioNTech. Demographic characteristics were similar among vaccine recipients, but recipients of AstraZeneca tended to be older and have more comorbidities. Vaccine effectiveness against hospitalization or death ≥14 days after vaccine series completion was: CoronaVac: 81.3% (95% CI 75.3-85.8); AstraZeneca: 89.9% (95% CI 83.5-93.8); Janssen: 57.7% (95% CI -2.6-82.5); Pfizer–BioNTech : 89.7% (95% CI 54.3-97.7) [Thiago Cerqueira-Silva, 2021 ]

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Janssen effectiveness against hospitalization was 67.9% (95% CI 56.5 to 76.3) and 65.3% (95% CI 58.3 to 71.1), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ].

Chanda et al conducted a retrospective cohort study among admitted patients at eight COVID-19 treatment centers across Zambia between April 2021 and March 2022, when Delta and Omicron variants were circulating. 1821 patients had COVID-19 vaccination status documented. Adjusted effectiveness against progression to in-hospital mortality was 61.1% (95% CI 26.6-80.8) for the Janssen COVID-19 vaccine [Chanda D, 2022 ].

Lewis et al conducted a multicenter case-control analysis of US adults hospitalized March 11th - December 15th, 2021 to estimate Ad26.COV2.S vaccine effectiveness (VE). Among 3,979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2.229 controls (13% vaccinated with Ad26.COV2.S), Overall adjusted VE [95% CI] for a single dose Ad26.COV2.S vaccine against COVID-19 hospitalization was 70% (63–75) and was lower in patients who were immunocompromised (55% [31–72]) than those who were immunocompetent (72% [64–77]). Among immunocompetent patients, VEs was higher (75% [67–82]) among patients aged 18-64 years than for those aged ≥65 years (66% [50–77]). VE was higher in patients without chronic medical conditions (86% [74–93]) than those with ≥1 chronic medical condition (64% [54–73]). Among hospitalized COVID-19 case-patients, VE against disease progression to death o invasive mechanical ventilation was 46% [18–65] among immunocompetent patients. [Lewis NM, 2022 ]

Monge S et al. was a retrospective cohort study conducted in Spain that recruited 1,897 individuals vaccinated with Janssen and 9,550 controls. The study was based on data from RENAVE and REGVACU including participants aged 50-59 years old during August 2021. The vaccine effectiveness of Janssen against hospitalization was 86% (95% CI, 83% to 89%). [Monge, Susana, 2022 ]

Transmission
No studies reported or assessed this outcome.

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes

Alpha (B.1.1.7)

Alter G et al., with data from the COV1001 phase 1/2 randomized trial, reported the immunogenicity of the Janssen vaccine against SARS-CoV-2 variants in humans. The randomized trial included 403 healthy adults ≥65 years within three groups: 161 participants with Low-Dose Vaccine (5×1010 vp); 161 participants with High-Dose Vaccine (1×1011 vp); and 81 participants with placebo. For the Alpha variant, Janssen induced a median psVNA titers response of 102 on day 57 and 121 on day 71; Also on day 57, median receptor binding domain (RBD)-specific binding antibody enzyme-linked immunosorbent assay (ELISA) titers were 1,364, and 1,682 on day 71. These data show a 1.2-fold reduction of ELISA titers against the Alpha variant as compared with WA1/2020 RBD on day 71. Similar to the ELISA titers, median RBD-specific ECLA responses were reduced 1.3-fold, and median spike-specific ECLA responses were reduced 1.6-fold, as compared with WA1/2020 on day 71. On the other hand, the CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the Alpha variant and the others evaluated (WA1/2020, B.1.3.5.1, P.1, and CAL.20C). [Alter G, 2021 ]

Beta (B.1.351)

Alter G et al. with data from the COV1001 phase 1/2 randomized trial, reported the immunogenicity of the Janssen vaccine against SARS-CoV-2 variants in humans. The randomized trial included 403 healthy adults ≥65 years within three groups: 161 participants with Low-Dose Vaccine (5×1010 vp); 161 participants with High-Dose Vaccine (1×1011 vp); and 81 participants with placebo. For the Beta variant, Janssen induced a median pseudovirus neutralizing antibody titers that were 5.0-fold lower compared with WA1/2020 on day 71 following vaccination; a median binding antibody titer that was 2.9-fold lower, and preservation of the antibody-dependent cellular phagocytosis, complement deposition, and NK cell activation responses. On the other hand, CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the Beta variant and others (WA1/2020, B.1.1.7, P.1, and CAL.20C). These data show that neutralizing antibody responses induced by Janssen were reduced against the Beta variant, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. [Alter G, 2021 ]

Omicron (B.1.1.529)

Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 in the 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 ].

 

Efficacy outcomes

Alpha (B.1.1.7)

ENSEMBLE was a randomized clinical trial that included 39,183 participants: 19,577 in the vaccine group and 19,608 in the placebo group. This study was the final analysis of this randomized trial. The primary endpoints were vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Vaccine efficacy against moderate to severe–critical Covid-19 (at least 14 days after the administration) for the alpha variant was 70.1% (95% CI 35.1 to 87.6) and 70.2% (95% CI 35.3 to 87.6) at least 28 days after administration of the vaccine or placebo. [Sadoff J, 2022 ]

Beta (B.1.351)

ENSEMBLE was a randomized clinical trial that included 39,183 participants: 19,577 in the vaccine group and 19,608 in the placebo group. This study was the final analysis of this randomized trial. The primary endpoints were vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Vaccine efficacy against moderate to severe–critical Covid-19 (at least 14 days after the administration) for the beta variant was 38.1% (95% CI 4.2 to 60.4) and 51.9% (95% CI 19.1 to 72.2) at least 28 days after administration of the vaccine or placebo. [Sadoff J, 2022 ]

Gamma (P.1)

ENSEMBLE was a randomized clinical trial that included 39,183 participants: 19,577 in the vaccine group and 19,608 in the placebo group. This study was the final analysis of this randomized trial. The primary endpoints were vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Vaccine efficacy against moderate to severe–critical Covid-19 (at least 14 days after the administration) for the gamma variant was 36.4% (95% CI 13.9 to 53.2) and 36.5% (95%CI 14.1 to 53.3) at least 28 days after administration of the vaccine or placebo [Sadoff J, 2022 ].

 

Effectiveness outcomes

Alpha (B.1.1.7)

Toon Braeye et al was a study conducted in Belgium. The study estimated vaccine effectiveness (VE) against transmission of infection (VET) between January and November 2021 by two components: susceptibility of the contact (VEs) and infectiousness of breakthrough cases (VEi) for a complete schedule of Ad26.COV2.S, ChAdOx1, BNT162b2, mRNA-1273. In Covid-19-naïve persons, during the Alpha variant dominant period, VEs was 42% (95% CI 37 to 46) for Janssen. The infectiousness of breakthrough cases in Covid19-naïve persons was 35% (95% CI 24 to 43) for the Janssen COVID-19 vaccine [Toon Braeye, 2022 ].

Lewis et al conducted a multicenter case-control analysis of US adults hospitalized between March 11th and December 15th 2021 to estimate Ad26.COV2.S vaccine effectiveness (VE). Among 3,979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2.229 controls (13% vaccinated with Ad26.COV2.S), VE (95% CI) for a single dose Ad26.COV2.S vaccine was similar between periods in which the Alpha variant (68% [43–83]) and Delta variant (72% [64–78]) predominated and remained similar 14–90 days (73% [60–82]), 91–180 days (71% [59–80]), and >180 days (70% [53–81]) post-vaccination. [Lewis NM, 2022 ]

Beta (B.1.351)

Graniss SJ et al. was a case-control (test-negative) study 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 ].

Delta (B.1.617.2)

Voko Z et al was a comparative cohort study conducted in Hungary that included data from 8,087,988 individuals. This study examined the effectiveness of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection and mortality during the Delta wave. Adjusted effectiveness against registered SARS-CoV-2 infection during the Delta wave (14 - 120 days) was 39.3% (95% CI 36.1 to 42.4). The Janssen booster provided 72.9%– 100.00% adjusted effectiveness depending on primary immunization type. [Vokó Z, 2022 ]

Rennert L et al was a comparative cohort study conducted in the United States. This study included data from 21,261 individuals: 4562 fully vaccinated with Moderna Vaccine, 7276 fully vaccinated with Pfizer vaccine, and 948 fully vaccinated with Janssen vaccine. It compared the rate of SARS-CoV-2 infection between vaccinated individuals, individuals previously infected with SARS-CoV-2, and those with no record of vaccination or previous SARS-CoV-2 infection between August 8th and December 4th, 2021. The results showed effectiveness against infection with SARS-COV-2 during the period of delta variant predominance of 42.8% (95% CI 26.1 to 55.8) for the Janssen vaccine. [Rennert L, 2022 ]

Britton A et al. was a case-control study conducted in the United States. This study included 1 634 271 laboratory-based SARS-CoV-2 nucleic acid amplification tests (NAATs) from adults 20 years and older and 180 112 NAATs from adolescents 12 to 19 years old with COVID-19–like illness from March 13 to October 17, 2021. The analysis included 390 762 test-positive cases (21.5%) and 1 423 621 test-negative controls (78.5%). The Ad26.COV2.S initial OR was 0.42 (95% CI, 0.37-0.47) during the pre-Delta period and 0.62 (95% CI, 0.58-0.65) during the Delta period and did not significantly increase with time since vaccination (the OR for the association between symptomatic SARS-CoV-2 infection and COVID-19 vaccination (as an estimate of vaccine effectiveness) was higher during Delta variant predominance, suggesting lower protection) [Britton A, 2022 ].

Uschner D et al. was a Community-based cohort study conducted in North Carolina, United States. This study included 16.020 eligible participants, 310 with a positive test. The information used was self-reported by the participants via email or text surveys (COVID-19 symptoms, test results, vaccination status, and risk behavior). Vaccines evaluated were Pfizer, Moderna, and Janssen. The event rate was 7.3 breakthrough infections per 100,000 person-years. Infections were symptomatic in 286 (92%) cases. Participants vaccinated with Pfizer vs. Janssen had a higher risk of breakthrough infection HR 2.23 (95% CI 1.40 to 3.56); Moderna vs Janssen had a lower risk, HR 0.69 (95% CI 0.50 to 0.96). Participants from rural and suburban counties had a higher risk of breakthrough infections: Suburban vs. urban was HR 1.39 (95% CI 1.01 to 1.90); Rural vs. urban was HR 1.57 (95% CI 1.16 to 2.11). There was no association of breakthrough infection with sex, race/ethnicity, healthcare worker status, prior self-reported COVID-19 infection, general mask usage, or vaccination rate in the county of residence [Diane Uschner, 2021 ].

Lewis et al conducted a multicenter case-control analysis of US adults hospitalized March 11th - December 15th, 2021 to estimate Ad26.COV2.S vaccine effectiveness (VE). Among 3,979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2.229 controls (13% vaccinated with Ad26.COV2.S), VE (95% CI) for a single dose Ad26.COV2.S vaccine was similar between periods in which the Alpha variant (68% [43–83]) and Delta variant (72% [64–78]) predominated and remained similar 14–90 days (73% [60–82]), 91–180 days (71% [59–80]), and >180 days (70% [53–81]) post-vaccination. [Lewis NM, 2022 ]

Omicron (B.1.1.529)

Cerqueira-Silva et al was a case-control study conducted in Brazil. In this study 918,219 tests (899,050 individuals) were included: 476,901 cases and 441,318 controls. This study used data from national databases in Brazil between 1 January and 22 March 2022, during the period of predominant circulation of the Omicron variant. Those vaccinated received Janssen, Pfizer, AstraZeneca, or CoronaVac vaccines. Vaccine effectiveness against symptomatic infection was 24.5% (95% CI 20.6 to 28.2) 2-9 weeks after the second dose of Janssen vaccine. Vaccine effectiveness against severe outcomes was 92.3% (95% CI 64.7 to 98.3) 2-9 weeks after the second dose of Janssen vaccine [Thiago Cerqueira-Silva, 2022 ].

Simwanza J et al, was a case–control study conducted in Zambia. In this study were included 328 male participantes (21-36 years), 180 Cases and 21 Controls, incarcerated at the prison facility during the outbreak from December 15 to 20, 2021. The study was done to measure vaccine effectiveness against infection and symptomatic infection, when the Omicron variant was the dominant circulating variant. 96.3% of participants were fully vaccinated (1 doses of Jansen vaccine, 2 wo-dose AstraZeneca vaccines).Vaccination status was cross-referenced with the national registry. Effectiveness against COVID infection was 63.6% (IC 95% 33.6–80.5) and symptomatic COVID infection was  73.0% (95%CI 41.6–87.7). Effectiveness was higher for those vaccinated within the past 60 days 74.6% ( 95% CI 50.3–87.4) compared with 60 days before COVID-19 testing.

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. IBased on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of Janssen was 37.3% (95% CI 32.9 to 41.5), when the Omicron variant emerged. [Lin DY, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Janssen primary schedule and an mRNA booster (Moderna or Pfizer) was 48.0% (95% CI, 42.5–53.7) [Monge S, 2022 ].

Vaccine efficacy and effectiveness for 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–BioNTech 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–BioNTech booster; both performed better than the homologous booster (response, 72.7%) [Sablerolles RSG, 2022 ].

The updated report of the randomized trials COV1001 (phase 1/2a) and COV2001 (phase 2) included a booster dose given 6 months after primary vaccination. Phase 1/2a study included 17 vaccinated people (18-55 years) with a homologous boosting dose (5×1010) and Phase 2 study included 44 vaccinated people (18–55 years) and 29 people ≥65 years with low-dose homologous boosting (1.25×1010). Results showed that both homologous booster doses at 6 months elicited rapid and robust increases in spike binding antibody levels in all age subgroups evaluated. In Phase 1/2a study GMC was 3779 (95% CI: 2741 to 4243) at day 7 post boost, while in Phase 2 study GMC was 1719 (95% CI: 1321 to 2236) at the same time. This was increased at day 28 post boost dose (GMC: 2444 (95% CI: 1855 to 3219) [Jerald Sadoff, 2021 ].

Effectiveness outcomes

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 ].

Vaccine efficacy and effectiveness for heterologous schedule

No studies reported or assessed this outcome.

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes

COV-BOOST was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of Oxford–AstraZeneca or Pfizer/BioNTech COVID-19 vaccines. Efficacy was measured by neutralizing antibody titers at 84 days post-boost dose. The results indicated in general a significant drop between day 28 and day 84 was seen in all study arms for live virus neutralizing antibody and cellular responses. For cellular responses, Moderna (100 μg) had the highest cellular responses at D84 (75, 95%CI: 51–110), though not statistically significant compared with Pfizer–BioNTech. The cellular responses at D28 and D84, as well as the D84 to D28 ratio in the AOxford–AstraZeneca and Janssen arms were similar to the Pfizer–BioNTech arm. In the subgroup analysis, similar patterns of immunogenicity were observed in the two age groups (<70 years and >70 years) in both Oxford–AstraZeneca and Pfizer–BioNTech first doses populations. Pfizer–BioNTech-half induced similar humoral and cellular responses compared with Pfizer–BioNTech at D28 and D84. This was seen in populations primed with both Oxford–AstraZeneca/Oxford–AstraZeneca and Pfizer–BioNTech/Pfizer–BioNTech, and in both age groups. [Liu X, 2022 ]. 28-day follow-up study available from: [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 ].

At the four-week follow-up of the randomized trial BOOST-TX conducted in Austria, 197 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies after two doses of an mRNA vaccine were included: 99 received a 3rd dose of the same RNA vaccine, and 98 received a 3rd dose of the Janssen COVID-19 vaccine. The primary endpoint was seroconversion after four weeks (29-42 days) following the third vaccine dose. Secondary endpoints included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). Four weeks after the third vaccination, 76 patients had developed antibodies against the SARS-CoV-2 spike protein(>0.8 U/mL) for an overall response rate of 39%. There was no statistically significant difference between the homologous and heterologous vaccination strategies, with a response rate of 35% vs 42% for mRNA vs Janssen vaccine (OR, 1.31; 95% CI, 0.71-2.44; P = 0.38) [Reindl-Schwaighofer R, 2021 ].

At the three-month follow-up of the randomized trial BOOST-TX conducted in Austria, 201 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies following two doses of an mRNA vaccine were included: 85 received the 3rd dose of the same RNA vaccine, and 84 received the 3rd dose of the Janssen COVID-19 vaccine. Study participants were followed up for antibody assessment at the outpatient transplant clinic of the Medical University of Vienna for a second follow-up between 60 and 120 days after the 3rd vaccine dose. Results showed that absolute antibody titers between the two groups were not significantly different (median mRNA: 0.2 U/ml and vector: 0.81 U/ml, p=0.104). However, when examining higher antibody cut-off levels at the 1-month follow up, a significantly higher number of patients in the Janssen group reached antibody levels above 141 and 264 BAU/ml (>141 BAU/ml: 4 vs. 15% OR: 4.96, 95%CI: 1.29 to 28.21, p = 0.009, and >264 BAU/ml: 1 vs. 10% OR = 8.75, 95% CI: 1.13 to 396.17, p =0.018, for mRNA vs. Janssen vaccine groups, respectively) [Heinzel A, 2022 ].

Tan CS et al was a comparative cohort study conducted in the United States. The study included 68 participants vaccinated at least 6 months previously with 2 immunizations of BNT162b2: 41 boosted with Ad26.COV2.S and 27 boosted with BNT162b2. Humoral immune responses were assessed by neutralizing, binding, and functional antibody responses for 16 weeks following the boost. CD8+ and CD4+ T-cell responses were evaluated by intracellular cytokine staining assays. Ad26.COV2.S boosted median (IQR) Omicron BA.1 NAb titers from 21 (20-32) at week 0 to 591 (272-881) at week 2, a peak of 859 (467-1838) at week 4, and a decline of 2.1-fold to 403 (208-1130) at week 16 following the boost. Ad26.COV2.S boosted median Omicron BA.1 Spikespecific interferon (IFN)–γ CD8+ T-cell responses from medians (IQRs) of 0.017% (0.009%-0.030%) at week 0 to 0.093% (0.045%-0.181%) at week 2 and 0.081% (0.042%-0.200%) at week 16 and IFN-γ CD4+ T cell responses from medians (IQRs) of 0.030% (0.011%-0.047%) at week 0 to 0.092% (0.046%-0.123%) at week 2 and 0.065% (0.027%-0.110%) at week 16 [Tan CS, 2022 ].

Costa Clemens et al was a phase 4 randomized clinical trial conducted in Brazil. The study included 1205 vaccinated participants: 296 with AstraZeneca Vaccine, 281 with CoronaVac Vaccine, 295 with Janssen Vaccine, and 333 with Pfizer Vaccine. The study assessed the immunogenicity of a third heterologous booster dose of either AstraZeneca vaccine, Pfizer vaccine, or Janssen vaccine, compared with a third homologous booster dose of CoronaVac in Brazilian adults who had received two doses of CoronaVac 6 months previously. The geometric fold-rise (GMFR) from baseline to day 28 was 77 (95%CI 67 to 88) for the Janssen vaccine. All heterologous regimes had anti-spike IgG at Day 28 that were superior to those induced by the homologous boost. Geometric mean ratios (GMR) (heterologous vs homologous) was Geometric mean ratios (GMR) (heterologous vs homologous) was 6.7 (95% CI 5.8 to 7.7) for the Janssen vaccine. [Sue Ann Costa Clemens, 2021 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after mRNA vaccination: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination. The seroreponse rates were 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group. [Kho MML, 2022 ]

Effectiveness outcomes

Voko Z et al was a comparative cohort study conducted in Hungary that included data from 8,087,988 individuals. The study examined the effectiveness of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection and mortality during the Delta wave. Adjusted effectiveness against registered SARS-CoV-2 infection during the Delta wave (14 - 120 days) was 39.3% (95% CI 36.1 to 42.4). The Janssen booster provided 72.9%– 100.00% adjusted effectiveness depending on primary immunization type.

Monge S et al was a nationwide Cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Janssen primary schedule and an mRNA booster (Moderna or Pfizer) was 48.0% (95% CI, 42.5–53.7) [Monge S, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of Pfizer-BioNTech booster after Janssen schedule was 46.0% (95%CI 38.8 to  52.3) after 1 month, the effectiveness of Moderna vaccine booster after Janssen primary schedule was 60.4% (95%CI 54.9 to 65.2). [Lin DY, 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 1.23). 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 2.95 (95% CI 2.47 to 3.52). This means that, in relative terms, Janssen COVID-19 vaccine increased the risk of local adverse events by 195%, 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 1.61 (95% CI 1.48 to 1.75). This means that, in relative terms, Janssen COVID-19 vaccine increased the risk of systemic adverse events by 61%, compared with placebo vaccine.

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

Sex

Randomized trials

The ENSEMBLE trial showed no differences between sex regarding advers events [Sadoff J, 2021 ].

 

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.

In the Phase 1/2a study included 17 vaccinated people (18–55 years) with a homologous boosting dose (5×1010), the post-booster reactogenicity was similar compared to the reported in the primary vaccination. In the Phase 2 study, included 44 vaccinated people (18–55 years) and 29 people ≥65 years with low-dose homologous boosting (1.25×1010) in 81 participants, solicited AEs after the primary dose versus after the booster were 67.9% versus 54%, respectively, and for grade 3 solicited AEs, 1.2% versus 0%, for solicited local AEs, 51.9% versus 47%, for solicited local AEs of grade 3 or more 0% versus 0%, for solicited systemic AEs, 66.7% versus 28%, and for solicited systemic AEs of grade 3 or more, 1.2% vs 0%. [Jerald Sadoff, 2021 ]

 

Children and adolescents

Randomized trials

Children were excluded from the ENSEMBLE trial, therefore 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

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 ].

Wesselink AK et al. was a cohort study conducted in the United States and Canada. The study enrolled 2,126 participants: 1,299 vaccine group; 897 control group. Based on questionnaires on sociodemographics, lifestyle, and reproductive and medical histories with follow-up every 8 weeks during December 2020-September 2021 and followed through November 2021, the study objective was to examine the associations of female and male COVID-19 vaccination with fecundability, the per-cycle probability of conception. The study results showed that COVID-19 vaccination was not appreciably associated with fecundability, with a female Fecundability Rate (FR) of 1.08 (95% CI 0.95 to 1.23) and a male FR=0.95 (95% CI 0.83 to 1.10) in vaccinated individuals [Wesselink AK, 2022 ].

Wang S et al was a comparative cohort study conducted in the United States and Canada. This study aimed to examine the associations of SARS-CoV-2 infection and COVID-19 vaccination with menstrual cycle characteristics. Data from 3858 women were analyzed. The results showed an OR of change in cycle length or regularity of 2.00 (95% CI 1,04 to 3,85) [Wang S, 2022 ].

Botton J et al. was a self-controlled case series conducted in France. The study included participants  (593 first dose of Ad26.COV2.S; and 9 second dose of Ad26.COV2.S) aged 18 to 74 years hospitalized for pulmonary embolism, acute myocardial infarction, hemorrhagic stroke, or ischemic stroke between December 27, 2020, and December 20, 2021. This study assessed the short-term risk for severe cardiovascular events after COVID-19 vaccination in France's 46.5 million adults. The primary outcome was hospitalizations for cardiovascular events (Myocardial infarction, pulmonary embolism, or stroke). The RI during the second week after the dose of the Ad26.COV2.S vaccine for Myocardial Infarction was 1.75 (95 % CI, 1.16 - 2.62),  0.42 (95 % CI, 0.13 - 1.32) for Pulmonary Embolism,  1.09 (95 % CI, 0.66 - 1.81) for  Ischemic Stroke, and  1.59 (95 % CI, 0.60 - 4.21) for  Hemorrhagic Stroke [Botton J, 2022 ].

Lloyd PC et al was a retrospective cohort study conducted in the United States. The study included data from 9,604,918 vaccine doses from the Optum database, 14,146,413 doses from the HealthCore database, and 14,146,413 doses from the CVS Health database. This study utilized sequential testing to detect potential safety signals following vaccination by comparing observed rates of adverse events following vaccination to historical background rates. Rate ratios (RR) of observed adverse events rates compared to historical (or expected) rates prior to COVID-19 vaccination from the Optum, HealthCore, and CVS Health Databases were 1.05, 1.18, and 1.41 for acute myocardial infarction, 1.08, 0.89, and 1.34 for deep vein thrombosis, 1.39, 1.23, and 2,14 for pulmonary embolism, and 0.00, 2.04, and 0.00 for Disseminated Intravascular Coagulation. [Lloyd PC, 2022 ]

Corrao G et al. was a retrospective cohort study conducted in Italy that included 9,184,146 vaccine recipients. The study was based on data from the Lombardy Vaccine Integrated Platform and evaluated the risk of myocarditis and pericarditis after vaccination. The adjusted hazard ratio (aHR) for developing pericarditis was 1.1 (95% CI, 0.41–2.95) after Janssen vaccine. [Corrao G, 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-authorized COVID-19 vaccines from Pfizer-BioNTech (94,818 doses), Moderna (36,350 doses), and Janssen (1,745 doses) were studied and among people who received one of the 10 FDA-approved non-COVID-19 vaccines (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 Moderna or Janssen 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 [Pawlowski C, 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 50977 (AstraZeneca (AZ, n=2093), Janssen/Johnson & Johnson (J&J&J, n=3888), Moderna (n=23776; M1, 14553 first dose; M2, 9223 second dose), or Pfizer/BioNTech (n=35929; P&B1, 22387 first dose; P&B2, 13542 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 ].

Albalawi O et al. was a study conducted in the United States. The study enrolled the general population that received Pfizer-BioNTech, Moderna, and Janssen vaccines. Based on data from Vaccine Adverse Event Reporting System (VAERS) between 15 December 2020 to 19 March 2021. Total non-serious reporting rate was 51.7 per 100,000 doses administered and total serious reporting rate was 2.7 per 100,000 doses administered. Results of the study showed that the Moderna group had more deaths than the Pfizer-BioNTech group (7% 95% CI-14% to 33%). [Albalawi OM, 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 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 and describes surveillance data and reports rates of all reported Thrombosis with thrombocytopenia syndrome (TTS) cases after COVID-19 vaccination [See I, 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 ]

Rodríguez L et al. was a retrospective study conducted in Colombia. In total, 950 women completed the survey, and 408 women met the inclusion criteria of which 184 reported alterations in the menstrual cycle and were included in the study. 51 women reported having Pfizer–BioNTech vaccine, 53 CoronaVac, 33 Janssen, 15 Moderna and 13 Oxford–AstraZeneca. Of the women who were vaccinated with Janssen, 39 reported normal post-vaccination menstrual frequency, 42% reported normal post-vaccination menstrual regularity, 67% reported normal menstrual duration and 33% reported normal menstrual volume. [Rodríguez Quejada L, 2022 ].

Scher A et al was a cohort study conducted in United States. This study included 2789 adults who were vaccinated between December 2020 and December 2021 (202 received Janssen vaccine). Severe side effects were most common with the Ad26.COV2.S (Janssen/Johnson and Johnson) vaccine, followed by mRNA-1273 (Moderna) then BNT162b2 (Pfizer/BioNTech). Of the participants who received the Janssen vaccine, 23% had no adverse events, 33% had mild adverse events, 32% had moderate adverse events and 12% had serious adverse events. [Scher AI, 2022 ]

Nguyen S et al. was a observational, cross-sectional, pharmacovigilance cohort study that examined individual case safety reports from VigiBase®, the World Health Organization’s pharmacovigilance database. The study aimed to identify cases of tranverse myelitis (TM) following SARS-CoV-2 vaccination with Pfizer/BioNTech, Moderna, Oxford–AstraZeneca and Novavax vaccines. The study results showed that 6,921,165 adverse events were reported, with 818 reports correspoding to TM. 41 (8%) of the cases were related to the Janssen vaccine. [Nguyen S, 2022 ].

Costa Clemens et al was a phase 4 randomized clinical trial conducted in Brazil. The study included 1205 vaccinated participants: 296 with AstraZeneca Vaccine, 281 with CoronaVac Vaccine, 295 with Janssen Vaccine and 333 with Pfizer Vaccine. The study assessed immunogenicity and safety of a third heterologous booster dose of either AstraZeneca vaccine, Pfizer vaccine, or Janssen vaccine, compared with a third homologous booster dose of CoronaVac in Brazilian adults who had received two doses of CoronaVac 6 months previously. The most common solicited local vaccine reaction in the first seven days was injection site pain, experienced by 60% 46% reported headaches, 10% reported myalgia. Fever and Chills were common for Janssen (12 and 26% respectively). 89256115fcc0240472c559543dd08d433214e977].

Toledo-Salinas et al. conducted a nationwide observational study among recipients of 61,414,803 doses of seven different COVID-19 vaccines, between December 2020 - October 2021 in Mexico, to identify the observed incidence of anaphylaxis in recipients of different anti-SARS-CoV-2 vaccines. Unadjusted incidence of anaphylaxis per million doses administered was 0 (95% CI 0) for Ad26.COV2-S. [Toledo-Salinas C, 2022 ]

García-Grimshaw M was a non-comparative study conducted in Mexico that reported the incidence of Guillain-Barré syndrome (GBS) following COVID-19 vaccination. The study informed the adverse events of 81,842,426 first or second doses of seven COVID-19 vaccines (Coronavac, Moderna, Pfizer, AstraZeneca, Sputnik V, CanSino, and Janssen), with 1,035,859 doses corresponding to the Janssen vaccine. 97 cases of GBS were identified through passive epidemiological surveillance, 4 of them related to the Janssen vaccination, with an unadjusted incidence of 3.86 (95% CI 1.50-9.93) per million doses administered. [García-Grimshaw M, 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

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