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Johnson & Johnson/Janssen COVID-19 Vaccine

Last reviewed: April 20, 2021

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Overview

Johnson & Johnson/Janssen Biotech Inc.’s COVID-19 vaccine Ad26.COV2.S is an adenovirus vectored vaccine that has been shown to be highly effective in preventing symptomatic COVID-19 disease.  

On April 13, 2021, CDC and FDA recommended a pause in the use of the Johnson & Johnson/Janssen COVID-19 vaccine due to six reported U.S. cases of cerebral venous sinus thrombosis (CVST), a rare and severe type of blood clot, associated with thrombocytopenia that occurred after receiving the vaccine, which were identified in the Vaccine Adverse Event Reporting System (VAERS) - one of these cases was also published as a case reportAll six cases occurred between 6-13 days after receipt of the Janssen COVID-19 Vaccine (Ad26.COV2.S) and all occurred in women aged 18-48 years. In the published case report, the patient was found to have detectable antibodies against platelet factor 4 (PF4)-polyanion complexes – similar findings have also been described in case series of thrombotic events following receipt of the Oxford-AstraZeneca COVID-19 Vaccine (ChAdOx1), as well as in a letter from the investigators involved in the Ad26.COV2.S phase 3 study about a single clinical trial participant. 

This pause does not affect ongoing U.S. administration of the Pfizer-BioNTech and Moderna COVID-19 vaccines.  

This pause will remain in place while CDC’s Advisory Committee on Immunization Practices (ACIP) reviews the reported cases following its April 14 emergency meeting. ACIP plans to publicly reconvene on Friday, April 23 to consider whether to revise the current pause. FDA is investigating the cases as well.   

CDC has issued a Health Alert to inform the health care provider community about the potential for these adverse events and provide guidance about proper management due to the unique treatment required with this type of blood clot. According to CDC, while these blood clots appear extremely rare, health care providers and individuals should be on alert for possible symptoms of a clot, which include severe headache, abdominal pain, leg pain, or shortness of breath. Health care providers are asked to report adverse events using VAERS.   

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Key Literature

FDA Briefing Document and Fact Sheet (February 2021)

Overall, in this interim analysis of a phase 3 randomized, stratified, double-blind, placebo-controlled trial, Ad26.COV2.S was effective at preventing symptomatic COVID-19 disease and was safe at a median time to follow up of 8 weeks.

Study population: 

  • COV2.S is a replication-incompetent adenovirus type 26 (Ad26) vectored vaccine encoding a stabilized variant of the SARS-CoV-2 S protein that is given as 1 intramuscular dose.
  • A phase 3 randomized, stratified, double-blind, placebo-controlled trial of the single-dose Ad26.COV2.S vaccine is ongoing. 
  • 44,325 participants over 18 years of age from 8 countries (United States, South Africa, Brazil, Chile, Argentina, Colombia, Peru, Mexico) were randomized in a 1:1 manner to receive an injection of either Ad26.COV2.S (N=22,174) or placebo (N=22,151) on day 1.
    • 5% (N=29,111) of the study population included in the efficacy analysis was composed of patients 18-59 years of age, of whom 10,408 (35.8%) had comorbidities associated with an elevated risk for progression to severe COVID-19.
    • 5% (N=14,672) of the study population included in the efficacy analysis was composed of patients >=60 years of age, of whom 7,450 (50.8%) had comorbidities associated with an elevated risk for progression to severe COVID-19.
      • Comorbidities considered to be associated with an elevated risk for severe disease included: obesity, hypertension, type 2 diabetes mellitus, serious heart condition, asthma, HIV infection, COPD, liver disease, cancer, immunocompromised from blood transplant, or neurologic conditions.
      • There were 1,218 patients living with HIV in the trial; data on this specific group has not yet been reported. 
    • Patients included in the per-protocol efficacy analysis had a negative SARS-CoV-2-status at baseline (with a negative RT-PCR and negative serology against the SARS-CoV-2 nucleocapsid at day 1). 
      • 6% of study participants had serologic evidence of prior COVID-19.
    • Participants were excluded if they were pregnant or breastfeeding, or pediatric.
    • Data were presented to the FDA in February 2021 as an interim analysis of the trial; a publication of this data is forthcoming, and additional publications are pending.
    • The interim primary efficacy analysis was based on the Per-Protocol Set, which consisted of 43,783 participants with negative baseline SARS-CoV-2 status and who received 1 dose of investigational product per schedule with no major protocol deviations. 
      • The set included 21,895 patients in the vaccine group and 21,888 patients in the placebo group.

Primary endpoints: 

Efficacy
The reduction in incidence of moderate to severe/critical COVID-19 among participants without evidence of SARS-CoV-2 infection before the first dose of vaccine in the periods starting 14 days after vaccination and 28 days after vaccination on day 1. 

  • The case definition of moderate COVID-19 was:
    • Any 1 of the following new or worsening signs or symptoms: respiratory rate >=20 breaths/minute, abnormal oxygen saturation (SpO2) but still >93% on room air at sea level, clinical or radiologic evidence of pneumonia, radiologic evidence of deep venous thrombosis, shortness of breath or difficulty breathing; or
    • Any 2 of the following new or worsening signs or symptoms: fever (T >=38°C or >=100.4°F), heart rate >=90 beats/minute, shaking chills/rigors, sore throat, cough, malaise as evidenced by loss of appetite, fatigue, physical weakness, and/or feeling unwell, headache, myalgia, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), new or changing olfactory or taste disorders, red or bruised looking feet or toes; and
    • Respiratory tract (nasal, throat, sputum, or saliva) or other sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.
  • The case definition of severe/critical COVID-19 was:
    • Any 1 of the following: clinical signs at rest indicative of severe systemic illness (respiratory rate >=30 breaths/minute, heart rate >=125 beats/minute, SpO2 <=93% on room air at sea level, or partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) <300 mmHg), respiratory failure (needing high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO), evidence of shock (systolic blood pressure <90 mmHg, diastolic blood pressure <60 mmHg, or requiring vasopressors), significant acute renal, hepatic, or neurologic dysfunction, admission to ICU, or death; and
    • Respiratory tract (nasal, throat, sputum, or saliva) or other sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.

Safety
To describe the safety of Ad26.COV2.S after vaccination.

  • Solicited events: participants recorded local reactions and systemic events from day 1 through day 7 after vaccination.
  • Unsolicited adverse events were collected from days 1 to 28 after vaccination.
  • Medically attended adverse events were collected through 6 months after vaccination.
  • Serious adverse events and adverse events leading to study discontinuation were also collected for the duration of the study.

Key Findings:

Efficacy

  • The Per-Protocol set included 44.5% females and 20.4% individuals > 65 years of age. The median age in the total group was 53 years.
    • 7% of participants represented communities of color with 17.2% of participants being Black or African American, 3.5% Asian, and 8.3% American Indian or Alaska Native; 45.1% were Hispanic/Latino.
    • At least 1 high-risk condition for severe COVID-19 was present in 39.9% of participants.
    • There were no differences in demographics in the vaccines and placebo groups.
  • The median time to follow up for the efficacy data in the interim analysis (data cutoff January 22, 2021) was 8 weeks after vaccination.
  • There were 116 cases of COVID-19 disease at least 14 days after vaccination in the Ad26.COV2.S vaccinated group and 348 in the placebo group, with a vaccine efficacy of 66.9% (95% CI 59.0-73.4%).
  • There were 66 cases of COVID-19 disease at least 28 days after vaccination in the Ad26.COV2.S vaccinated group and 193 in the placebo group, with a vaccine efficacy of 66.1% (95% CI 55.0-74.8%).
    • Subgroup analyses of the primary efficacy endpoint showed similar efficacy across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19.
    • Follow-up case data up until February 8, 2021 correlated with a vaccine efficacy of 67.4% and 66.2% for COVID-19 disease at least 14 days and at least 28 days after vaccination, respectively.
    • When stratified by age, the vaccine efficacy was 66.1% (95% CI: 53.3- 75.8) for participants 18 to <60 years of age and 66.2% (95% CI: 36.7-83.0) for participants ≥60 years of age at least 28 days after vaccination.
  • When including patients with and without evidence of prior COVID-19 infection (N=43,210), there were 176 cases in the vaccinated group and 513 in the placebo group, with a vaccine efficacy of 66.1% (95% CI 59.7-71.6) at least 14 days after vaccination.
  • Three of 2122 participants with serologic evidence of prior COVID-19 in the vaccinated group developed symptomatic COVID-19, while 4 of 2030 in the placebo group did.
  • A secondary endpoint of the study is prevention of severe COVID-19 disease. In the Per-Protocol set there were 14 cases of severe/critical COVID-19 in the vaccinated group and 60 in the placebo group at least 14 days after vaccination (vaccine efficacy of 76.7%; 95% CI 54.6-89.1). Similarly, there were 5 cases of severe/critical COVID-19 in the vaccination group and 34 cases in the placebo group at least 28 days after vaccination (vaccine efficacy of 85.4%; 95% CI 54.2-96.9).
  • Another secondary endpoint was prevention of COVID-19 requiring medical intervention (defined as participant requiring hospitalization, ICU admission, mechanical ventilation, and/or extracorporeal membrane oxygenation). For this endpoint, 10 events occurred, 8 in the placebo group, and 2 in the vaccine group at least 14 days after vaccination; in the period at least 28 days after vaccination, there were 5 events all of which occurred in the placebo group.
  • As of February 5, 2021, there were 7 COVID-19 related deaths reported in the study, all among participants in the placebo group, and all of whom had one or more comorbidities associated with high risk of severe COVID-19.
  • Additional analyses were done to assess efficacy against asymptomatic SARS-CoV-2 infection, which was defined as a participant who did not fulfill the criteria for suspected COVID-19 based on signs and symptoms (specified as no symptoms on the day preceding, day of, or at any time after the positive PCR test) and has a SARS-CoV-2 positive RT-PCR test result OR develops a positive serology during the study.
    • An interim analysis of day 71 serology results was based on 2,892 participants, who comprised just 28.8% of the 10,045 participants who had completed the day 71 visit by the data cutoff date.
      • From day 1 to day 29, there was non-statistically significant vaccine efficacy against asymptomatic SARS-CoV-2 infections.
      • After day 29, there were 22 cases of asymptomatic SARS-CoV-2 infection in the vaccinated group and 54 in the placebo group (vaccine efficacy of 59.7%; 95% CI 32.8-76.6).
    • During the conduct of the study, new SARS-CoV-2 variants emerged in participating countries. In subgroup analyses of vaccine efficacy against moderate to severe/critical COVID-19 by country of participation, vaccine efficacy was lower in South Africa (vaccine efficacy of 52.0%; 95%CI 30.3-67.4) compared to the United States (vaccine efficacy of 74.4%; 95%CI 65.0-81.6).
      • Strain sequencing analyses of COVID-19 cases in the study is being performed, and as of February 12, 2021, 71.7% of cases have been sequenced.
        • In the United States, 73.5% of cases have been sequenced, of which 96.4% were identified as SARS-CoV-2 Wuhan-H1 variant D614G.
        • In South Africa, 66.9% of cases have been sequenced, of which 94.5% were identified as 20H/501Y.V2 variant (B.1.351).

Safety

  • Safety data at the time of the interim analysis was available for 43,783 participants, with a median of 8 weeks of follow-up after vaccination.
  • Data on solicited local and systemic reactions through 7 days after vaccination and unsolicited adverse events through 28 days after vaccination were available from a safety subset of 6,736 participants.
    • 3% of the participants in this safety subset analysis were female, and the median age was 54 years; 23.0% of the group was >=65 years of age.
    • 8% of participants represented communities of color, with 7.8% of participants being Black or African American, 3.3% Asian, 0.3% American Indian or Alaska Native; 38.2% were Hispanic/Latino.
    • At least one high-risk condition for severe COVID-19 was present in 34.1% of participants.
    • There were no differences in demographics in the vaccines and placebo groups.
  • Adverse events were either solicited or unsolicited.
    • The most common solicited adverse reactions in the vaccinated group were injection site pain (48.6%), headache (38.9%), fatigue (38.2%), muscle pain (33.2%), nausea (14.2%), and fever (9.0%).
      • These were more common in patients younger than 60 years of age.
      • Grade 3 local reactions occurred in 0.7% of participants that received Ad26.COV2.S, compared with 0.2% of those who received placebo. There were no grade 4 local or systemic reactions in either group.
    • Only 1 hypersensitivity event was reported in a vaccine recipient.
      • No cases of anaphylactic reactions were reported around the time of vaccine administration.
    • The proportions of participants reporting any local adverse reaction were 50.2% in vaccine recipients, compared to 19.4% in placebo recipients.
      • The median time to onset of local adverse reactions was 2 days after vaccination, and the median duration was 2 days for erythema and pain, and 3 days for swelling.
      • Overall, across both age cohorts, the most frequently reported local adverse reaction was pain, reported by 48.6% and 16.7% of vaccine and placebo recipients, respectively.
        • The median duration for pain was 2 days. The highest rates of pain were in participants 18 to 59 years, with 58.6% reporting any pain and 0.4% reporting Grade 3 pain.
      • Fever was reported by 9.0% of vaccine participants and 0.6% of placebo recipients.
        • In participants 18 to 59 years, any fever was reported in 12.8% of participants compared with 3.1% of participants >=60 years of age.

Limitations:

  • To date, complete data on all participants who are more than 2 months out from vaccine are not available.
  • The primary efficacy endpoint was clinical disease; asymptomatic infection was not assessed, although additional data utilizing a serologic endpoint is being collected.
  • The trial did not include children less than 18 years of age, pregnant or lactating individuals, or immunocompromised individuals (not including persons living with HIV). 
  • While there was a small group of people with evidence of prior COVID-19 infection at the time of analysis, the number of cases in this group was too small to draw any conclusions about the efficacy of the vaccine in individuals with prior infection; this may change as the trial continues.
  • Serial RT-PCR testing was not performed, and so the efficacy of the vaccine in potentially preventing spread of SARS-CoV-2 could not be determined. 

 

Additional Literature

Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine (Sadoff, January 2021): In this phase 1-2a placebo-controlled trial of Ad26.COV2.S in 805 adults, who were stratified according to age (18-55 years or ≥65 years), participants were assigned in a 1:1:1:1:1 ratio to receive zero, one, or two doses of low-dose (5 x 1010 vp) or high-dose (1 x 1011 vp) vaccine (placebo followed by placebo, low dose followed by low dose, low dose followed by placebo, high dose followed by high dose, high dose followed by placebo) administered 56 days apart. Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent. By day 29 after vaccination, 99% or more participants in all treatment arms had seroconverted. Antibody levels as measured by ELISA correlated with those measured by a wild-type virus neutralization assay. Levels of baseline Ad26 neutralizing antibodies did not correlate with SARS-CoV-2 neutralizing antibody levels following vaccination. All CD4+ T cell responses elicited by vaccine were Th1 skewed.

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