What are the reactions occurring across the US with the Janssen (J&J) COVID-19 vaccine with patients? When do these reactions occur?

What are the reactions occurring across the US with the Janssen (J&J) COVID-19 vaccine with patients? Are these reactions concern for stopping the J&J COVID-19 vaccine? What time period are these reactions occurring?

Comment by InpharmD Researcher

Six cases of rare thromboembolic events in patients (all female) with thrombocytopenia (at least one fatal) have prompted a safety review of the Janssen (Johnson & Johnson) COVID-19 vaccine, leading to announcements that use of the Janssen vaccine should be paused for now. Venous thromboembolism following the Janssen COVID-19 vaccine occurred between 2 and 44 days after vaccination, while these serious cases of cerebral venous sinus thrombosis occurred 6-13 days after vaccination. While there was a case of Guillain-Barré Syndrome following Janssen COVID-19 vaccination, a similar case was also seen in the placebo group; researchers do not suggest there is causality between the Janssen COVID-19 vaccine and Guillain-Barré Syndrome.

Background

A joint statement by the US Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) announces there have been six reported cases of cerebral venous sinus thrombosis in patients with thrombocytopenia after receiving the Janssen (Johnson & Johnson) COVID-19 vaccine (Ad26.COV2.S). All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination. The CDC will convene a meeting of the Advisory Committee on Immunization Practices (ACIP) on Wednesday (April 13) to further review these cases and assess their potential significance, while the FDA will also conduct their own analysis and investigation. Until these processes are complete, the agencies recommend a pause in the use of this vaccine out of an abundance of caution. [1]

Early data from the ongoing phase III ENSEMBLE (COV3001) trial of the Janssen (Johnson & Johnson) COVID-19 vaccine (Ad26.COV2.S) has come with some safety concerns due to reports of thromboembolic events in patients who received the experimental vaccine. Additional review found four serious cases of unusual blood clots with low blood platelets reported post-vaccination. One of these cases occurred in a clinical trial, and three occurred during vaccine rollout in the United States. One of these cases was fatal. The causality and relevance of these cases are not yet known but have prompted further investigation. Additional information regarding thromboembolic events reported in this phase 3 study can be seen in Table 1. [2], [3]

The acting head of the US Centers for Medicare and Medicaid Services gave reassurances on April 5th, 2021 that the Johnson & Johnson vaccine was safe, even though there were concerns due to a production mishap that ruined 15 million potential doses. This announcement is in regard to a mistake where ingredients for the AstraZeneca and Johnson & Johnson vaccines were accidentally mixed. The problem was detected in quality control checks before the manufacture of any vaccines was completed, and these botched batches are not going to be used. [4]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Please see Tables 1-3 for your response.

Thromboembolic Adverse Events of Interest during the Phase III COV3001 Study
Study Group	Age/Sex	Event	Serious	Time to event	Outcome	Relevant Medical History	Other Notes
Vaccine	63/M	Deep Vein Thrombosis	Yes	20 days	Recovered	Depression, obesity and a 'genetic mutation that made him susceptible to thromboembolism	Was taken off rivaroxaban as 'he did not like taking it' 7 months prior to onset, following his retirement
Vaccine	52/M	Deep Vein Thrombosis	No	25 days	Recovering	Obesity	---
Vaccine	42/M	Deep Vein Thrombosis	No	19 days	Not recovered	---	---
Vaccine	90/M	Deep Vein Thrombosis	No	13 days	Recovering	Chronic kidney disease, hypertension, hypothyroidism, major depression	---
Vaccine	63/M	Venous Thrombosis Limb	No	23 days	Recovered	Hypertension, diabetes, osteoarthritis	Event was reported as secondary to trauma
Vaccine	30/F	Pulmonary Embolism	Yes	2 days	Recovered	Drug and alcohol abuse, contraceptive use (medroxyprogesterone)	---
Vaccine	72/M	Pulmonary Embolism	Yes	35 days	Not recovered	Hypertension, obesity	Positive COVID-19 case. Participant developed, while hospitalized kidney, failure and PE
Vaccine	52/M	Pulmonary Embolism	Yes	44 days	Recovered	Obesity, hypertension, hereditary hemochromatosis	---
Vaccine	68/M	Pulmonary Embolism	No	20 days	Not recovered	COPD, hypertension, dyslipidaemia, Gout, hypothyroidism, insulin resistance, tonsillitis, urinary tract infection	---
Placebo	44/M	Deep Vein Thrombosis	Yes	5 days	Not recovered	Family history of DVT, 4.5-hour air travel 4 days after vaccination (1 day to onset of symptoms)	---
Placebo	57/M	Deep Vein Thrombosis	No	3 days	Not recovered	Obesity, deep vein thrombosis, hypothyroidism, oropharyngeal cancer	---
Placebo	53/M	Pulmonary Embolism	Yes	29 days	Recovering	Obesity, obstructive sleep apnea, hyperlipidemia, hypertension	Positive COVID-19 test

References:

U.S. Food and Drug Administration. Janssen Biotech Vaccines and Related Biological Products Advisory Committee COVID-19 Vaccine Ad26.COV2.S Briefing Document. https://www.fda.gov/media/146219/download. Published February 26, 2021. Accessed April 12, 2021.

US Centers for Disease Control and Prevention. Overview of Janssen’s Single-Dose
COVID-19 Vaccine, Ad26.COV2.S. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/28-03-01/02-COVID-Douoguih.pdf. Published February 28, 2021. Accessed April 12, 2021.

Guillain-Barré Syndrome in the Placebo and Active Arms of a COVID-19 Vaccine Clinical Trial: Temporal Associations Do Not Imply Causality
Design	Case Report
Case Presentation	A 60-year old female with a history of migraines enrolled in a Johnson & Johnson COVID-19 vaccine trial. When the patient enrolled in the trial, the patient was in a usual state of health and had tested negative for COVID-19 via PCR assay and antibody test during screening. The patient was vaccinated on December 10th, 2020. Ten days after receiving the vaccine, the patient began to experience back and leg pain. Five days later, she awoke with headache, nausea, and double vision. By December 28th, the patient began to develop bilateral facial weakness and numbness and weakness in both legs. The patient's brain MRI was normal but the MRI of the lumbar spine showed an enhancement of the cauda equina nerve roots. The patient underwent a lumbar puncture that revealed an elevated opening pressure of 29 centimeters of water and elevated protein levels of 140 mg/dL within the cerebrospinal fluid. Needle electromyography revealed fast-firing motor units in the leg muscles, indicative of early Guillain-Barré Syndrome (GBS). The patient was treated with IV immunoglobulin 2g/kg over 2 days, slowly improved, and was later discharged to rehab after 10 days of admission.
Study Author Conclusion	Two patients in the Johnson & Johnson COVID-19 vaccine trial developed Guillain-Barré Syndrome (GBS) 10 days after injection; one was in the placebo arm and one was in the active vaccine arm; the incidence of GBS was identical in both arms of the trial. This patient in the vaccine arm did not have any clinical features differentiating her from patients with typical GBS. From the available evidence, it is not possible to draw causal inferences about the association of the COVID-19 vaccination and the development of GBS. We must be careful to avoid misattributing adverse events to the vaccination program. Temporal associations do not imply causality. The fact that one other participant in the Johnson & Johnson vaccine trial also developed GBS 10 days after being injected with placebo supports the argument for a coincidental rather than a causal association.

References:

Loza AMM, Holroyd KB, Johnson SA, Pilgrim DM, Amato AA. Guillain- Barré Syndrome in the Placebo and Active Arms of a COVID-19 Vaccine Clinical Trial: Temporal Associations Do Not Imply Causality. Neurology. Published April 6, 2021. doi: 10.1212/WNL.0000000000011881

Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine
Design	Randomized, multicenter, double-blind, placebo-controlled, phase 1/2a clinical trial N=805
Objective	To evaluate the safety, reactogenicity, and immunogenicity of Ad26.COV2.S, a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike (S) protein
Study Groups	Younger cohort (n=402) Low-dose (n=162) High-dose (n=158) Placebo (n=82)	Older cohort (n=403) Low-dose (n=161) High-dose (n=161) Placebo (n=81)
Inclusion Criteria	healthy adults (considered to in good or stable health if underlying illness is present); aged 18-55 years or ≥65 years; body mass index <40 mg/k²; females with a negative pregnancy test
Exclusion Criteria	Clinically significant acute illness or fever (≥38 °C) within 24 hours before first dose; history of malignancy within 5 years before screening; known allergy or history of anaphylaxis or other serious adverse reactions to vaccines or their excipients; abnormal immune system due to clinical conditions (e.g., autoimmune disease or immunodeficiency); Chronic (>10 days) or recurrent use of systemic corticosteroids within 6 months; administration of antineoplastic and immunomodulating agents or radiotherapy within 6 months; history of acute polyneuropathy; plans to receive a live vaccine within 28 days of planned administration or other vaccines within 14 days of planned administration; diagnosis of HIV infection
Methods	Participants were randomized to one of five vaccination groups: low dose followed by low dose, low dose followed by placebo, high dose followed by high dose, high dose followed by placebo, and placebo followed by placebo. Vaccinations were administered intramuscularly 56 days (2 months) apart. Data in the older population is only after the first vaccination. The Ad26.COV2.S vaccine low-dose was 5×10¹⁰ viral particles/mL and the high-dose was 1×10¹¹ viral particles/mL. Immunogenicity was assessed using an enzyme-linked immunosorbent assay (ELISA) to measure SARS-CoV-2 S-specific binding antibodies. Seropositivity was defined as a titer above the lower limit of quantitation of the assay (50.3 EU[ELISA units]/mL). Seroconversion was measured from a random subgroup of participants in each group.
Duration	July 22 to October 30, 2020 (interim analysis); the study is still ongoing Follow-up: 7, 28, and 71 days after vaccination
Outcome Measures	Primary: safety and reactogenicity of each dose schedule Solicited local adverse events: erythema, pain, swelling Solicited systemic adverse events: fatigue, headache, myalgia, nausea, pyrexia Secondary: immunogenicity via humoral and cellular immunity to the SARS-CoV-2 S protein; seroconversion Humoral immunity as reported as binding-antibody geometric mean concentration (GMC) against a full-length spike protein
Baseline Characteristics		Low-dose (n=323)	High-dose (n=319)	Placebo (n=163)
	Age, years Younger cohort Older cohort	36.1±10.1 69.6±4.0	34.8±10.3 70.0±4.2	35.4±10.0 69.9±3.7
	Female	49.8%	52.0%	52.1%
	White	95.0%	95.0%	92.6%
Results		Low-dose (n=323)	High-dose (n=319)	Placebo (n=163)
	Solicited local adverse events Younger cohort Older cohort	64% 41%	78% 42%	9% 14%
	Solicited systemic adverse events Younger cohort Older cohort	65% 46%	84% 55%	26% 23%
	Unsolicited adverse events Younger cohort Older cohort	21% 17%	35% 24%	17% 16%
	The most solicited local adverse event was pain, and the most solicited systemic adverse events were fatigue, headache, and myalgia. Reactogenicity was lower after the second dose.
	Humoral immunogenicity, GMC (seroconversion): younger cohort Day 1 Day 29 Day 57 Day 71	<53 586 (99%) 754 (100%) 1677 (100%)	<53 788 (100%) 1100 (100%) 2292 (100%)	<53 <53 <53 <53
	Humoral immunogenicity, GMC (seroconversion): older cohort Day 1 Day 15 Day 29	<53 121 (75%) 312 (96%)	<53 141 (77%) 350 (96%)	<53 <53 <53
	A control of human convalescent plasma resulted in a GMC of 899 using the same ELISA. The vaccine then placebo groups were similar to the two-dose vaccine groups, except the GMCs did not rise on day 71. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all non-placebo participants on day 29. When compared to a wild-type virus neutralization assay, antibody levels were strongly correlated in both age groups; however, the older patients had a wider range, suggesting more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults.
	Cellular immunity was seen via CD4+ T-cell responses were seen in 76-83% of younger patients and 60-67% of older patients by day 15. CD8+ T-cell responses were seen in 51-64% of younger patients and 24-36% (the low-dose group had 36%) of older patients by day 15.
Adverse Events	No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. After the second dose among participants between the ages of 18 and 55 years, the incidence of grade 3 solicited systemic adverse events was much lower than that after the first immunization in both the low-dose and high-dose groups.
	Only one serious adverse event was deemed to be related to the vaccine: fever that resulted in hospitalization because of suspicion of Covid-19 (recovered within 12 hours). Other serious adverse events (deemed to be unrelated to vaccination) were: hypotension, bilateral nephrolithiasis, Legionella pneumonia, and worsening of multiple sclerosis.
	No participant discontinued the trial because of an adverse event.
Study Author Conclusions	The interim analysis of this phase 1/2a trial showed that the Ad26.COV2.S vaccine had an acceptable safety and reactogenicity profile and was immunogenic after a single vaccination with either the low or high dose.
InpharmD Researcher Critique	This is data from an interim analysis of a phase 1/2 study, as it is still ongoing. These results only represent the first dose for the older cohort. The participants of this study lack minority representation, which will likely be fulfilled in phase 3 studies. This study only measured in vitro efficacy through the use of assays, so the clinical efficacy of this vaccine candidate cannot be established through this data. The ELISA used measured SARS-CoV-2 S protein-specific binding antibodies; however, there is no standard assay used. This means these results cannot be directly compared to studies using a different assay nor can the results be extrapolated to determine efficacy. The comparison with a convalescent plasma sample is also arbitrary, since the reported titers have varied according to the composition of the panels (i.e., COVID-19 severity of the donors, time of sampling since disease onset, and other factors).

References:

Sadoff J, Le Gars M, Shukarev G, et al. Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine. N Engl J Med. Published online January 13, 2021:NEJMoa2034201.