Post-authorization safety surveillance of Ad.26.COV2.S vaccine: Reports to the Vaccine Adverse Event Reporting System and v-safe, February 2021–February 2022

Abstract

Background

On 2/27/2021, FDA authorized Janssen COVID-19 Vaccine (Ad.26.COV2.S) for use in individuals 18 years of age and older. Vaccine safety was monitored using the Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system, and v-safe, a smartphone-based surveillance system.

Methods

VAERS and v-safe data from 2/27/2021 to 2/28/2022 were analyzed. Descriptive analyses included sex, age, race/ethnicity, seriousness, AEs of special interest (AESIs), and cause of death. For prespecified AESIs, reporting rates were calculated using the total number of doses of Ad26.COV2.S administered. For myopericarditis, observed-to-expected (O/E) analysis was performed based on the number verified cases, vaccine administration data, and published background rates. Proportions of v-safe participants reporting local and systemic reactions, as well as health impacts, were calculated.

Results

During the analytic period, 17,018,042 doses of Ad26.COV2.S were administered in the United States, and VAERS received 67,995 reports of AEs after Ad26.COV2.S vaccination. Most AEs (59,750; 87.9 %) were non-serious and were similar to those observed during clinical trials. Serious AEs included COVID-19 disease, coagulopathy (including thrombosis with thrombocytopenia syndrome; TTS), myocardial infarction, Bell’s Palsy, and Guillain-Barré syndrome (GBS). Among AESIs, reporting rates per million doses of Ad26.COV2.S administered ranged from 0.06 for multisystem inflammatory syndrome in children to 263.43 for COVID-19 disease. O/E analysis revealed elevated reporting rate ratios (RRs) for myopericarditis; among adults ages 18–64 years, the RR was 3.19 (95 % CI 2.00, 4.83) within 7 days and 1.79 (95 % CI 1.26, 2.46) within 21 days of vaccination. Of 416,384 Ad26.COV2.S recipients enrolled into v-safe, 60.9 % reported local symptoms (e.g. injection site pain) and 75.9 % reported systemic symptoms (e.g., fatigue, headache). One-third of participants (141,334; 33.9 %) reported a health impact, but only 1.4 % sought medical care.

Conclusion

Our review confirmed previously established safety risks for TTS and GBS and identified a potential safety concern for myocarditis.

1. Introduction

On February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Ad.26.COV2.S (Janssen/Johnson & Johnson COVID-19 Vaccine) for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in people ages ≥ 18 years [1]. On February 28, 2021, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of Ad.26.COV2.S in people ages ≥ 18 years for the prevention of COVID-19 [2].

Ad.26.COV2.S uses a replication-incompetent human adenoviral type 26 vector platform and, during the period of this review, was authorized as a single intramuscular dose for primary vaccination [3]. The FDA’s EUA review focused on a randomized, double-blind, placebo-controlled trial including 21,895 Ad26.COV2.S vaccine recipients and 21,888 individuals who received placebo [4]. The safety subset included 3,356 individuals who received Ad26.COV2.S and 3380 who received placebo. Local solicited adverse events (AEs), such as erythema, pain, and swelling, were more common after the vaccine compared to placebo (50.3 % vs 19.5 %), as were systemic solicited AEs, including fever, headache, fatigue, nausea, myalgia, and swelling (55.2 % vs 35.1 %). Unsolicited events were reported in 13.1 % of vaccine recipients and 12.0 % of participants who received placebo. Unsolicited AEs that were deemed related to vaccination, such as chills, malaise, injection site reactions, myalgia, and arthralgia, were more frequent after the vaccine. However, severity was similar in the two groups, and no subjects discontinued the study due to AEs. The safety profile was further supported by data from more than 193,000 individuals who have been exposed to Janssen’s AdVac‑based vaccines in the context of clinical studies and programs [4].

Post-authorization safety monitoring is necessary to characterize the safety profiles of vaccines in larger and more heterogeneous populations [5]. To improve our understanding of the safety profile of Ad26.COV2.S, the FDA and Centers for Disease Control and Prevention (CDC) have relied on existing safety systems, such as the Vaccine Adverse Event Reporting System (VAERS), a spontaneous safety monitoring system in the United States [6], [7] and v-safe, a new smartphone-based active COVID-19 vaccine safety monitoring system [8]. Regular updates from these systems have been provided through websites, publications, and presentations to FDA and CDC advisory committees [9], [10].

Within the first two months of post-authorization safety surveillance in VAERS identified reports of cerebral venous sinus thrombosis (CVST) and other unusual thrombi with thrombocytopenia (later termed “thrombosis with thrombocytopenia syndrome”; TTS) after Ad.26.COV2.S [11], [12]. As a result, on April 13, 2021, use of the vaccine in the United States was temporarily paused due to concerns about this potential association with the vaccine [13]. Upon review by the FDA, CDC, and ACIP, the pause was lifted on April 23, 2021 [14]. The product Fact Sheets were updated to include a Warning about TTS [3]. Continuous review of TTS reports is ongoing.

Post-authorization surveillance in VAERS also identified increased reporting of Guillain-Barré syndrome (GBS) after Ad.26.COV2.S [15]. Based on preliminary review of these reports (i.e., not expert case adjudication based on review of medical records), the overall estimated observed-to-expected (O/E) rate ratio was 4.18, corresponding to an absolute rate increase of 6.36/100,000 person-years [15]. The product Fact Sheet was updated to include a Warning about GBS [3].

Here, we review VAERS and v-safe data during the first year (February 24, 2021 to February 28, 2022) of the U.S. vaccination program, when over 17 million doses of Ad26.COV2.S were administered.

2. Methods

2.1. VAERS

VAERS is a national passive (spontaneous) surveillance system for monitoring vaccine safety that receives reports from health care providers, vaccine manufacturers, and the public [6], [7]. Established in 1990, VAERS is jointly managed by the FDA and CDC. Reports of adverse events following vaccination are submitted by health care providers, vaccine recipients or their parents or guardians, vaccine manufacturers, and other interested parties. FDA physicians review reports of serious events, defined as events that are fatal, disabling, or life-threatening; require or prolong hospitalization; congenital anomalies; require medical intervention to prevent such outcomes; or are deemed to be other medically important conditions [16]. CDC and FDA clinicians review reports of AEs of special interest (AESIs), and cause of death. For reports classified as serious, the VAERS contractor requests associated health records, such as inpatient records including hospital discharge summaries; medical, radiological, and laboratory results;, and death certificates and autopsy reports [7]. For serious AEs from which the patient has not recovered by the time the report was filed or recovery status was unknown, a follow-up letter is sent a year later to request further information [7]. Vaccine manufacturers are responsible for obtaining follow-up information about serious and unexpected adverse event reports [16].

We searched VAERS for U.S. reports received during February 27, 2021, through February 28, 2022, pertaining to AEs reported after Ad.26.COV2.S. VAERS reports were processed, quality-checked, and coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology [7]. Each VAERS report may be assigned more than one MedDRA Preferred Term (PT). PTs include signs and symptoms of illness and results of diagnostic tests and do not necessarily indicate a medically confirmed diagnosis, and reports can have more than one PT (i.e., PTs are not mutually exclusive). For both serious and non-serious reports, we summarized the most frequent PTs.

Prespecified AEs of special interest (AESIs) were selected for enhanced COVID-19 vaccine safety monitoring based on biological plausibility, previous vaccine safety experience, and theoretical concerns related to COVID-19 [17] including acute myocardial infarction, anaphylaxis, appendicitis, Bell’s Palsy, coagulopathy (specifically, deep venous thromboembolism, disseminated intravascular coagulopathy, and thrombocytopenia), COVID-19 disease, GBS, multisystem inflammatory syndrome in adults, multisystem inflammatory syndrome in children, myopericarditis, narcolepsy, seizure, stroke, and transverse myelitis. For serious reports and AESIs (both serious and non-serious), we clinically assessed cases based on the narrative description of the event, vaccine(s) administered, time course, treatment, medical history, and any available medical records to assess evidence and potentially verify whether particular events met standardized case definitions. Medical review was selectively performed in order to distinguish incident versus pre-existing conditions; to identify any concomitant exposures; to characterize risk factors; to determine symptom onset with respect to timing of vaccination; and to determine if cases met standardized case definitions and/or if a clinical impression or diagnosis could be determined based on available clinical records.

Based on previously described methods [18], we identified reports of potential myopericarditis for analysis and included cases that had been verified to meet the CDC case definition by provider interview or medical record review. An FDA physician also manually read and reviewed all serious reports submitted directly to VAERS by health care providers, vaccine recipients, recipients’ caregivers, or attorneys. Based on clinical judgment and/or unusual reporting patterns, AEs that were not initially specified as AESIs [17] were identified for further scrutiny, e.g., TTS and immune thrombocytopenia (ITP). Serious reports pertaining to vaccination during pregnancy were manually reviewed by a physician.

FDA and CDC physicians reviewed each report of death, as well as any available medical records, death certificates, and autopsy reports to ascertain the cause of death or form an impression about the cause. Those impressions and documented causes of death were classified into categories defined by the National Center for Health Statistics’ most common major diagnostic categories reported on U.S. death certificates [19]; COVID-19-related; other (i.e., diagnosis did not belong in one of the other prespecified categories); or unknown/unclear if a likely cause could not be determined.

2.2. V-safe

V-safe is a voluntary smartphone-based system that uses text messaging and secure web-based surveys to actively monitor COVID-19 vaccine safety, particularly for common local injection site and systemic reactions and health impact events [8]. V-safe participants receive text messages that link to web-based health check-in surveys following vaccination, initially daily (days 0–7), then weekly (days 14–42) and lastly at 3, 6 and 12 months post vaccination. The system resets to the initial survey frequency after receipt of a booster dose of COVID-19 vaccine. Participants who reported receiving medical care were actively contacted, informed about VAERS, and offered an opportunity to fill out a VAERS report over the phone.

V-safe participants who completed at least one health check-in survey during days 0 to 7 post-Ad.26.COV2.S vaccination were included in the analysis. We conducted descriptive analyses of participants’ characteristics, solicited local and systemic reactions, severity (mild, moderate, severe), and health impact (unable to conduct normal daily activities, unable to work, and/or received care from a medical professional) [8].

2.3. Data analyses

We conducted descriptive analyses of available VAERS and v-safe data from February 27, 2021, through February 28, 2022. These descriptive analyses of U.S. VAERS reports included sex, age groups, race/ethnicity, and serious AEs, and cause of death (if applicable). Reporting rates to VAERS were calculated using the total number of doses of Ad26.COV2.S vaccine administered during the twelve-month period, as provided through CDC’s COVID-19 Data Tracker [20]. Reporting rates for deaths within 7 days following vaccination and 42 days following vaccination were calculated per doses of vaccine administered and compared to expected background rates [21].

An increased risk of myocarditis after mRNA-based COVID-19 vaccines has been observed, particularly among adolescent males and young men [18]. We analyzed VAERS reports of myopericarditis and performed O/E analysis based on the number of cases verified to meet the CDC case definition, vaccine administration data [20], and published background rates among US adults [22], [23]. The person-time at risk was calculated based on the cumulative vaccine administration data [20]. The expected number of cases was calculated as Exp_cases = (person-years) × (BR/100,000), where person-years was the accumulated person-time in years and BR was the background rate per 100,000 person-years. The reporting rate ratio (RR) was then estimated as RR = N_cases/Exp_cases, where N_cases was the number of verified (observed) cases. The 95 % confidence intervals (i.e., assuming a two-sided type 1 error of 0.05) for the RRs were provided. These were based on the exact confidence intervals for the number of observed cases, assumed to be a Poisson random variable, and were given as:

$$\left(\frac{1}{2}{\chi }_{2c;\frac{\alpha }{2}}^2,\frac{1}{2}{\chi }_{2(c+1);1-\frac{\alpha }{2}}^2\right)$$

where $c$ was the observed number of cases, ${\chi }_{2c;\frac{\alpha }{2}}^2$ was the $\frac{\alpha }{2}$ -th quantile of the ${\chi }^2$ distribution with 2c degrees of freedom [24]. The respective CI for the RR was derived by dividing the above CI’s limits by the expected number of cases Exp_cases. No adjustment of the type 1 error for multiple testing was conducted. The calculations were performed in R (version 3.6.1).

V-safe participants who completed at least one health check-in survey during days 0 to 7 post-Ad.26.COV2.S vaccination were included in the analysis. We conducted descriptive analyses of participants’ characteristics, solicited local and systemic reactions, severity (mild, moderate, severe), and health impact (unable to conduct normal daily activities, unable to work, and/or received care from a medical professional) [8]. Analyses were done using SAS (version 9.4).

2.4. Protection of human subjects

This work was conducted as part of routine vaccine safety activities and public health surveillance based on existing documents. No interventional treatments, exposures, or procedures were performed. These surveillance activities were reviewed by CDC and conducted consistent with applicable federal law and CDC policy (45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq.).

3. Results

3.1. VAERS

During the analytic period, 17,018,042 doses of Ad26.COV2.S were administered [20]. During the same period, VAERS received and processed a total of 67,995 reports after Ad26.COV2.S vaccine (Table 1 ). Most adverse events (59,750; 87.9 %) were categorized as non-serious; 8245 (12.1 %) events were serious, including 1528 (2.2 %) deaths (Table 1). Fifty-seven percent of reports were in females. Median age was 46 years (interquartile range 32–58 years), and 45.6 % of individuals were 18–49 years of age. Forty-seven percent identified as non-Hispanic White; for 37.9 % of vaccinees, the race/ethnicity was not reported.

Table 1.

Characteristics of reports received and processed by the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination – February 27, 2021–February 28, 2022.

Reports	N = 67,995
	n (%)
Non-serious adverse event reports	59,750 (87.9)
Serious a reports, including death	8245 (12.1)
Serious non-fatal	6717 (9.9)
vDeath	1528 (2.2)
Age (years)
0–17	1319 (1.9)
18–49	30,995 (45.6)
50–64	16,906 (24.9)
65–84	5144 (7.6)
≥85	674 (1.0)
Unknown	12,957 (19.1)
Sex
Female	38,440 (56.5)
Male	24,646 (36.3)
Unknown	4909 (7.2)
Race/Ethnicity
Hispanic	5014 (7.4)
Non-Hispanic
White	31,844 (46.8)
Black	2724 (4.0)
Asian	1397 (2.1)
American Indian or Alaska Native	217 (0.3)
Native Hawaiian or Other Pacific Islander	79 (0.1)
Multiple races	660 (1.0)
Other races	294 (0.4)
Unknown ethnicity	25,766 (37.9)
Most frequent signs/symptomsb: non-serious reports	N = 59,750
Headache	15,768 (26.4)
Pyrexia	13,175 (22.1)
Chills	11,395 (19.1)
Pain	11,002 (18.4)
Fatigue	10,778 (18.0)
Dizziness	8344 (14.0)
Nausea	7924 (13.3)
Pain in extremity	6,383 (10.7)
Myalgia	4228 (7.1)
Injection site pain	3812 (6.4)
Most frequent signs/symptomsb: seriousareports	N = 8,245
COVID-19 disease	2182 (26.5)
Dyspnoea	1787 (21.7)
SARS-COV-2 test positive	1768 (21.4)
Headache	1062 (12.9)
Pyrexia	1009 (12.2)
Fatigue	969 (11.8)
Cough	876 (10.6)
Pain	851 (10.3)
Asthenia	833 (10.1)
Nausea	760 (9.2)

^aSerious adverse events are those that are reported as fatal, disabling, or life-threatening; require or prolong hospitalization; result in congenital anomalies; require medical intervention to prevent such outcomes [16].

^bMedical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs) are not medically confirmed diagnoses; PTs are not mutually exclusive.

Among reports classified as non-serious, the most common MedDRA PTs were headache (15,768; 26.4 %), pyrexia (13,175; 22.1 %), chills (11,395; 19.1 %), pain (11,002; 18.4 %), and fatigue (10,778; 18.0 %) (Table 1). Among serious reports, the most common MedDRA PTs were COVID-19 (2182; 26.5 %), dyspnoea (1787; 21.7 %), SARS-COV-2 test positive (1768; 21.4 %), headache (1062; 12.9 %), and pyrexia (1009; 12.2 %) (Table 1).

Of the most frequent PTs for non-serious and serious reports, none pertained to anaphylaxis or other allergic reactions. Of 61 reports of TTS verified to meet the CDC case definition by provider interview and/or medical record review, all were serious, including 9 deaths. Forty (66 %) of the TTS case reports were in females, median age was 45 years (interquartile range: 36–52 years), and median onset was 9 days (interquartile range: 7–11 days); disposition included discharged to home (43; 66 %), to rehabilitation (6; 10 %), and to long-term care (2; 3 %). Of 15 reports of ITP with a documented platelet count < 150,000 per µL, all were serious; platelet counts as low as 0 per µL were reported.

Based on 17,018,042 doses of Ad26.COV2.S that were administered during the analytic period [20], the overall reporting rate to VAERS was 3,995 reports per million doses administered (Table 2 ). Among the prespecified AESIs [17], reporting rates ranged from 0.06 reports of multisystem inflammatory syndrome in children per million doses administered to 263 reports of COVID-19 disease per million doses administered. There were no reports of vaccine-associated enhanced disease (VAED) or vaccine-associated enhanced respiratory disease (VAERD).

Table 2.

Vaccine Adverse Event Reporting System (VAERS): Frequency and reporting rates of adverse events following Ad.26.COV2.S vaccination.

	n				Reporting Rate b
	Nonserious	Serious a	Death	Total
Any adverse event	59,750	8245	1528	67,995	3,995.47
Adverse Events of Special Interest (AESIs)c
COVID-19 disease	2081	2402	512	4483	263.43
Coagulopathy	1033	1457	257	2490	146.32
Seizure	683	197	37	880	51.71
Stroke	129	556	87	685	40.25
Bell’s Palsy	327	281	11	608	35.73
Acute Myocardial Infarction	53	277	103	330	19.39
Guillain-Barré Syndrome	75	234	8	309	18.16
Myopericarditis	79	110	16	189	11.11
Anaphylaxis	140	45	2	185	10.87
Appendicitis	10	53	1	63	3.70
Transverse Myelitis	6	36	0	42	2.47
Multisystem Inflammatory Syndrome in Adults	3	17	1	20	1.18
Narcolepsy	5	0	0	5	0.29
Multisystem Inflammatory Syndrome in Children	1	0	0	1	0.06

^aSerious adverse events are those that are reported as fatal, disabling, or life-threatening; require or prolong hospitalization; result in congenital anomalies; require medical intervention to prevent such outcomes [16].

^bReporting rate per million doses administered, based on 17,018,042 doses through February 28, 2022 [20]. Doses of vaccine administered in the study period do not include doses administered in Texas, as data for Texas were reported to CDC in aggregate.

^cCounts of prespecified adverse events of special interest (AESIs) were identified based on automated searches (not medically confirmed diagnoses) and may include aggregate terms, as previously described [17]. AESIs are not mutually exclusive.

Of 189 cases of myopericarditis reported, 52 were verified to meet CDC’s case definition, and affected individuals spanned the adult age range (Table 3a ). The O/E analysis revealed elevated RRs among multiple age strata, although the increases were concentrated among younger groups (Table 3b ). Among adults 18 years of age and older, the RR was 3.19 (95 % CI 2.00–4.83) within 7 days and 1.79 (95 % CI 1.26, 2.46) within 21 days of vaccination (Table 3b), compared with the lower of the background rates used. RRs were highest among individuals 18–29 years of age: 10.24 (95 % 5.60, 17.18) within 7 days, 3.90 (95 % CI 2.23, 6.33) within 21 days, and 1.95 (95 % CI 1.11, 3.17) within 42 days of vaccination (Table 3b).

Table 3a.

Vaccine Adverse Event Reporting System (VAERS): Verified^* cases of myopericarditis following Ad.26.COV2.S vaccination.

Age (years)	≤ 7 days	≤ 21 days	≤ 42 days	Total†
Age 18–29	14	16	16	19
Age 30–39	3	9	11	12
Age 40–49	1	4	5	6
Age 50–64	2	4	4	6
Age ≥ 65	2	4	5	8
Age missing	0	0	0	1
Total	22	37	41	52

^*Verified cases are determined through medical record review or provider interview using CDC case definition.

^†For 10 cases, onset was >42 days. For 1 case, onset time was unknown.

Table 3b.

Vaccine Adverse Event Reporting System (VAERS): Observed/Expected (O/E) analysis of verified cases of myopericarditis following Ad.26.COV2.S vaccination.

Age (years)	Background Rate per 100,000	O/E ratio (95 % CI)
		7 days	21 days	42 days
Age ≥ 18	2.16a	3.19 (2.00, 4.83)	1.79 (1.26, 2.46)	0.99 (0.71, 1.34)
	6.10b	1.13 (0.71, 1.71)	0.63 (0.45, 0.87)	0.35 (0.25, 0.48)
Age 18–64	2.16a	3.37 (2.06, 5.20)	1.85 (1.27, 2.60)	1.01 (0.71, 1.40)
	6.10b	1.19 (0.73, 1.84)	0.66 (0.45, 0.92)	0.36 (0.25, 0.50)
Age 18–29	2.16a	10.24 (5.60, 17.18)	3.90 (2.23, 6.33)	1.95 (1.11, 3.17)
	6.10b	3.63 (1.98, 6.08)	1.38 (0.79, 2.24)	0.69 (0.39, 1.12)
Age 30–39	2.16a	2.35 (0.48, 6.86)	2.35 (1.07, 4.46)	1.44 (0.72, 2.57)
	6.10b	0.83 (0.17, 2.43)	0.83 (0.38, 1.58)	0.51 (0.25, 0.91)
Age 40–49	2.16a	0.81 (0.02, 4.49)	1.08 (0.29, 2.75)	0.67 (0.22, 1.57)
	6.10b	0.29 (0.01, 1.59)	0.38 (0.10, 0.98)	0.24 (0.08, 0.56)
Age 50–64	2.16a	0.97 (0.12, 3.51)	0.65 (0.18, 1.66)	0.32 (0.09, 0.83)
	6.10b	0.34 (0.04, 1.24)	0.23 (0.06, 0.59)	0.11 (0.03, 0.29)
Age ≥ 65	2.16a	2.07 (0.25, 7.48)	1.38 (0.38, 3.54)	0.86 (0.28, 2.01)
	6.10b	0.73 (0.09, 2.65)	0.49 (0.13, 1.25)	0.31 (0.10, 0.71)

^aGubernot et al. [22].

^bRoth et al. [23].

Of the 309 GBS reports identified through an automated VAERS search, we identified 283 de-duplicated reports with medical records. Among 283 preliminary reports of GBS, 81 (28.6 %) cases met the Brighton Collaboration GBS case definition [25], in which Level 1 is the highest level of certainty: Level 1 (n = 25), Level 2 (n = 47), Level 2 Miller Fisher Syndrome (n = 1), Level 3 (n = 8) (Supplemental Table 1). Of the 81 patients who met the Brighton Collaboration GBS case definition based upon provider interview and/or medical record review, 45 (55.6 %) were male, 56 (69.1 %) were White, non-Hispanic, 79 (97.5 %) were hospitalized, and one death (1.2 %) was reported. The median age of these 81 patients was 57 years (interquartile range, 50–65). The median time from vaccination to symptoms onset was 13 days (interquartile range, 7–22).

Although rhabdomyolysis was not a prespecified AESI [17], manual review of reports identified 34 reports (33 serious), with patients’ creatinine kinase levels as high at 750,000 mg/dL and loss of more than 9 kg of muscle mass. Median symptom onset was 7.5 days (interquartile range 3–28), median age was 60.5 years (interquartile range 37–72), and 17 (50 %) individuals were female. Ten reports mentioned cerebrovascular accident and one attributed rhabdomyolysis to atorvastatin, but most cases appeared to have occurred without any traumatic or metabolic provocation.

3.2. Pregnancy

There were 409 VAERS reports related to pregnancy and none pertaining to lactation. Most (320; 78.2 %) were non-serious and did not describe an adverse health event (i.e., they merely stated that a woman had been vaccinated during pregnancy). Among non-serious reports, the most common PTs were exposure during pregnancy (150 reports), pyrexia (62), chills (55), fatigue (55), and headache (52).

Of the 89 pregnancy reports classified as serious, the timing of vaccination was during the first trimester (33 reports), second trimester (19), third trimester (24), within 4 weeks before conception (4), immediately post-partum (1), or unknown (8). Based on medical review, pregnancy loss (spontaneous abortion, stillbirth, or elective termination) and non-obstetrical conditions (e.g., COVID-19 infection) were among the most common serious adverse events reported in pregnancy (Table 4 ).

Table 4.

Vaccine Adverse Event Reporting System (VAERS): serious adverse events in pregnancy reported following Ad.26.COV2.S vaccination.

Serious[16]adverse eventsa	n = 89
Pregnancy loss  < 20 weeks (n = 20)  ≥ 20 weeks (n = 7) b,c	27
Non-obstetrical conditions (e.g., COVID-19, myocarditis, or Bell’s palsy)	18
General obstetrical conditions (e.g., Braxton Hicks contractions)	15
Preeclampsia, eclampsia, or hemolysis, elevated liver enzymes and low platelets (HELLP syndrome) c	14
Coagulopathy (e.g., deep vein thrombosis or thrombosis with thrombocytopenia syndrome)	13
Placental abruption b	7
Congenital anomaly b,c	5

^aDiagnosis or clinical impression based on manual review of reports by a physician; events are not mutually exclusive.

^bFour cases of placental abruption resulted in stillbirth.

^cCongenital anomalies included dextrocardia, bilateral talipes, isomerism of atrial appendages (pregnancy electively terminated), cystic hygroma in the setting of Turner syndrome (spontaneous abortion), and chordee (mother also had preeclampsia).

Coagulopathy related outcomes in pregnancy included deep vein thromboses, pulmonary embolism, ITP (including exacerbation of chronic ITP), thrombotic thrombocytopenic purpura, and dural sinus thrombosis. Six days after an uncomplicated vaginal delivery, a woman in her mid-thirties experienced dural sinus thrombosis with normal platelet counts (232,000–279,000 per µL), and she recovered. This patient did not have TTS.

One death during pregnancy was reported. A woman in her early forties (gravida 1, para 1) experienced a coccyx fracture during labor. A liveborn infant was delivered. Approximately four weeks post-partum, the woman developed a blood clot in an unspecified location and died. Whether an autopsy was performed is unknown.

3.3. Deaths

There were 1528 deaths reported to VAERS (Table 5 ). Death certificates or autopsy reports were available for clinical review for 418 (27.4 %) reports of deaths analyzed. Among these, the most common causes of death were COVID-19 disease (194; 46.4 %), diseases of the heart (117; 28.0 %), and cerebrovascular diseases (36; 8.6 %) (Table 5). Among the 1,110 (72.6 %) death reports for which neither an autopsy nor death certificate was available, the impression of the cause of death most commonly included unknown/unclear (552; 49.7 %), COVID-19 disease (294; 26.5 %), cerebrovascular diseases (66; 5.9 %), and diseases of the heart (134; 12.1 %). Reporting rates for all-cause deaths per million doses after Ad26.COV2.S vaccination were 8–20 times lower than the expected rate within 7 days of vaccination and 19–53 times lower than the expected rate within 42 days of vaccination [21] (Table 6 ).

Table 5.

Vaccine Adverse Event Reporting System (VAERS): Causes of death following Ad.26.COV2.S vaccination.

International Classification of Diseases (ICD-10) Major Category	Death or autopsy certificate available (N = 418)	No death certificate or autopsy availablea(N = 1,110)
	n (%)	n (%)
COVID-19 disease	194 (46.4)	294 (26.5)
Diseases of the Heart	117 (28.0)	134 (12.1)
Cerebrovascular Diseases	36 (8.6)	66 (5.9)
Unknown/Unclear	14 (3.3)	552 (49.7)
Septicemia	10 (2.4)	13 (1.2)
Chronic Lower Respiratory Diseases	10 (2.4)	3 (0.3)
Other	9 (2.2)	13 (1.2)
Influenza and Pneumonia (other than COVID-19)	7 (1.7)	10 (0.9)
Malignant Neoplasms	7 (1.7)	3 (0.3)
Accidents/Unintentional Injuries	6 (1.4)	1 (0.1)
Dementia, including Alzheimer’s and Parkinson’s	3 (0.7)	2 (0.2)
Renal Diseases, Including Nephritis and Chronic Disease	2 (0.5)	4 (0.4)
Hematologic Diseases Other than Malignancy	1 (0.2)	9 (0.8)
Diabetes Mellitus	1 (0.2)	3 (0.3)
Intentional Self-harm	1 (0.2)	1 (0.1)
Chronic Liver Disease, Including Cirrhosis	–	1 (0.1)
Pneumonitis due to Solids or Liquids	–	1 (0.1)

^aCause of death based on clinical review of available medical records.

Table 6.

Observed to Expected Analysis of all-cause deaths within 7 days and 42 days after Ad.26.COV2.S vaccination – VAERS.

	All-cause death rate (deaths/million vaccinated persons)
	Observed		Expected[21]
	Within 7 days of vaccination*	Within 42 days of vaccination*	Within 7 days of vaccination	Within 42 days of vaccination
Age*(years)
16–24	1.1	4.4	14.2†	85.1†
25–34	1.8	6.4	25.5	152.7
35–44	3.7	11.7	37.4	224.5
45–54	8.8	19.1	77.0	461.7
55–64	12.1	35.1	169.8	1,018.6
65–74	21.9	57.1	343.2	2,059.4
75–84	43.5	127.4	857.2	5,143.0
≥ 85	125.1	293.5	2,601.4	15,608.3
Total	11.5	29.9	165.6	993.3

^*13 unknown (7 days), 16 unknown (42 days).

^†The expected rates are among individuals aged 15–24 years.

3.4. V-safe

During the study period, 416,384 Ad26.COV2.S vaccine recipients enrolled in v-safe and completed at least one postvaccination health survey during days 0–7 after vaccination (Table 7 ). The median age of v-safe participants was 46 years (interquartile range 33–57). More than half (241,089; 57.9 %) were female, and most participants (275,244; 66.1 %) identified as non-Hispanic White. Among v-safe participants, 253,665 (60.9 %) reported any type of injection site reaction and 315,998 (75.9 %) reported any type of systemic reaction (Table 8 ). The most common local and systemic reactions included injection site pain, fatigue, headache, myalgia, chills, joint pain, and fever; all were reported most frequently the day after vaccination (Day 1) (Supplemental Tables 2-4). More than one-third of participants (141,334; 33.9 %) reported a health impact (e.g., unable to do normal daily activities, unable to work), but only 6,021 (1.4 %) reported seeking medical care, including 196 (0.05 %) who were hospitalized and 1441 (0.3 %) who sought care in the emergency department (Table 8).

Table 7.

V-safe: Demographic characteristics of v-safe participants reporting receipt of Ad26.COV2.S and completing at least one health survey 0–7 days after vaccination.

Characteristics	N = 416,384
	n (%)
Sex
Female	241,089 (57.9)
Male	173,288 (41.6)
Unknown	2007 (0.5)
Age (years)
18–49	241,787 (58.1)
50–64	139,686 (33.5)
65–74	29,462 (7.1)
75–84	4564 (1.1)
≥85	885 (0.2)
Race/Ethnicity
Hispanic	52,342 (12.6)
Non-Hispanic
White	275,244 (66.1)
Black	28,056 (6.7)
Asian	25,429 (6.1)
American Indian or Alaska Native	1428 (0.3)
Native Hawaiian or Other Pacific Islander	1180 (0.3)
Multiple races	7468 (1.8)
Other races	2671 (0.6)
Unknown race	1333 (0.3)
Unknown ethnicity*
White	6986 (1.7)
Asian	1968 (0.5)
Black	1902 (0.5)
American Indian or Alaska Native	176 (0.04)
Native Hawaiian or Other Pacific Islander	132 (0.03)
Multiple races	479 (0.1)
Other races	931 (0.2)
Unknown race and ethnicity*	8578 (2.1)
Unavailable†	81 (0.02)
Pregnant at time of vaccination	3319 (0.8)

^*Unknown indicates that v-safe participants selected unknown or preferred not to say; in this section, race was reported.

^†Unavailable refers to information that was not collected or missing in v-safe.

Table 8.

V-safe: Reported local and systemic reactions^*, and reported health impact^* following Ad26.COV2.S reported days 0–7 after vaccination.

	N = 416,384
	n (%)
Any injection site reaction*	253,665 (60.9)
Injection site pain	241,804 (58.1)
Swelling	40,164 (9.6)
Redness	31,587 (7.6)
Itching	30,624 (7.4)
Any systemic reaction*	315,998 (75.9)
Fatigue	243,965 (58.6)
Headache	215,558 (51.8)
Myalgia	198,853 (47.8)
Fever	144,169 (34.6)
Chills	138,924 (33.4)
Joint pain	110,314 (26.5)
Nausea	78,769 (18.9)
Diarrhea	40,448 (9.7)
Abdominal pain	32,206 (7.7)
Vomiting	9,100 (2.2)
Rash	8103 (1.9)
With reported health impact*	141,334 (33.9)
Unable to do normal activity	117,334 (28.2)
Unable to work	71,651 (17.2)
Reported seeking medical care	6021 (1.4)
Telehealth	2183 (0.5)
Clinic	1832 (0.4)
Emergency visit	1441 (0.3)
Hospitalization	196 (0.05)

^*Local and systemic reactions, and reported health impacts are not mutually exclusive.

4. Discussion

During the first year of use in the general population, 17,018,042 doses of Ad26.COV2.S were administered in the United States [20]. Post-authorization safety surveillance of Ad26.COV2.S in VAERS and v-safe revealed that local injection site and systemic reactions were commonly reported. In VAERS, most adverse events reported were non-serious and were similar to those observed during the clinical trials [4]. Most vaccinees were female, consistent with the sex distribution among adults throughout VAERS [7]. While VAERS and v-safe are different surveillance systems with different purposes, the data captured were comparable in that both VAERS and v-safe received reports of adverse events that were consistent with those observed during preauthorization trials (e.g., local reactions, fever, and fatigue) [4]. Because of reporting requirements for vaccination providers and manufacturers [1], [3], VAERS received reports of serious events (e.g., TTS).

The association of TTS and Ad26.COV2.S has previously been described [11], [12]. Our 12-month surveillance summary identified 61 reports of TTS. Based on these 61 cases, the reporting rate for TTS following Ad26.COV2.S vaccination is approximately 3.58 cases/million doses [12]. The product’s Fact Sheet has been updated to include a Warning about TTS [3]. Thromboembolic events other than TTS, such as saddle embolus and other severe clot burden, with or without thrombocytopenia, have also been described after Ad.26.COV2.S vaccination [26]. Thrombocytopenia, distinct from TTS, has also been described after Ad.26.COV2.S vaccination [27]. The Fact Sheet for Ad26.COV2.S has been updated to include information about ITP and venous thromboembolism [3].

We identified 81 reports of GBS that met the Brighton Collaboration GBS case definition based on chart-review and expert adjudication, including 1 death. Among GBS reports that did not meet Brighton Collaboration criteria, medical records were unavailable or contained insufficient documentation of the physical exam findings (pattern and severity of weakness, areflexia, cranial nerves), EMG/NCS, CSF, time course (i.e., monophasic within 4 weeks), and other criteria. In a separate study covering VAERS reports received through January 28, 2022, the observed number of GBS cases was significantly higher than the expected number within 21 and 42 days after Ad26.COV2.S vaccination [28]. The results of our 12-month surveillance indicate that GBS after Ad26.COV2.S is a safety concern, as previously reported [15], [29].

Our O/E analysis revealed elevated reporting rate ratios for myopericarditis within 42 days after vaccination, and particularly within the first 21 days, although these estimates are based on relatively small numbers and thus wide confidence intervals. Notably, the elevated O/E appeared among all adults 18 years of age and older, and all adults 18–64 years of age. Cases among people 18–29 years of age, who had the highest O/E in this analysis, were likely driving the overall values. For many cases who were 30 years of age or older, medical records were not available or records did not contain sufficient details (e.g., absence of confirmation through histopathologic evaluation or cardiac MRI; equivocal EKG findings); due to this limitation, we cannot determine whether the O/E values in older age strata, as reported here, reflect the inability to confirm cases or whether the risk in these age groups is truly different from that among people 18–29 years of age. On March 13, 2023, the Fact Sheet was updated to include a Warning about myocarditis and pericarditis [3]. Oster et al. [18] reported an increased risk after mRNA-based COVID-19 vaccines. However, the adenoviral type 26 platform is distinct from that of the mRNA-based vaccines. Future research might elucidate one or more biological mechanisms for myopericarditis (e.g., reaction to the spike protein of SARS-CoV2).

During pre-authorization clinical studies, rhabdomyolysis did not emerge as a potential safety concern. Assessment of VAERS reports of rhabdomyolysis is ongoing.

Regarding several adverse events, the results of our analysis were reassuring. Anaphylaxis is a potential risk after any vaccine, and we did not identify a safety concern for anaphylaxis or other hypersensitivity after Ad26.COV2.S. Multisystem inflammatory syndrome has been described as a complication of SARS-CoV-2 infection [30] and could theoretically occur after vaccination. In our review, the reporting rate of multisystem inflammatory syndrome was ∼ 1 per million doses in both adults and children. VAED and VAERD, in which infection with the wild-type virus leads to increased disease severity following vaccination, are potential risks after vaccination [31]. However, VAED and VAERD are theoretical risks and, given that SARS-CoV-2 is a novel virus and COVID-19 is an unprecedented infection, ascertaining cases is likely to be difficult. We did not identify any cases of VAED or VAERD after Ad26.COV2.S.

COVID-19 infection during pregnancy is associated with complications, hospitalization, and death [32], [33], [34], and vaccination is therefore recommended [35], [36]. Our review did not identify any unusual or concerning patterns of AEs following Ad26.COV2.S vaccination during pregnancy. Under the conditions of the EUA, the manufacturer agreed to conduct a multi-country, observational, prospective cohort study of pregnant women vaccinated with Ad26.COV2.S to assess obstetric, neonatal, and infant outcomes [1]. The evaluation is ongoing.

We found that reporting rates for all-cause deaths were 8–20 times lower than expected within one week of vaccination and 19–53 times lower than expected within six weeks of vaccination. We reviewed death certificates and autopsy reports when such documents were available. Unfortunately, medical examiners continue to be overwhelmed. Many autopsies are still to be completed. Even for postmortem examinations that have been completed, there are substantial delays in obtaining autopsy reports and death certificates (despite numerous requests), due to staffing shortages and the overwhelming number of deaths.

Our review identified more than 2000 reports of SARS-CoV-2 disease and/or COVID-19 pneumonia. These findings may be an artifact related to several factors. As a condition of the EUA [1], the manufacturer and vaccination providers are required to report cases of COVID-19 disease resulting in hospitalization or death. Thus, stimulated reporting is expected, particularly for the most severe cases of COVID-19. Second, reports of COVID-19 disease may represent confounding by indication (i.e., reporting the very condition that the vaccine is intended to prevent). Third, reporting may be heightened because Ad26.COV2.S is a novel product, and thus subject to closer scrutiny relative to other vaccines on that basis (i.e., the Weber effect [37]). It is not appropriate to estimate vaccination failure or vaccine effectiveness using VAERS reports of COVID-19 disease as a numerator and dose administration data as a denominator; differential reporting, unverified diagnosis, and unknown person-time of exposure to the wild-type infection (i.e., the “at risk” period) preclude any reliable estimates. As a condition of EUA [1], the manufacturer is conducting post-authorization studies of vaccine effectiveness.

Strengths of VAERS include its national scope, size, timeliness, ability to detect rare events that were not observed during preauthorization trials, and surveillance among special populations [6]. Passive surveillance systems such as VAERS are subject to limitations, including underreporting, incomplete information, inadequate data regarding the numbers of doses administered, and lack of direct and unbiased comparison groups [6], [7]. Because of these and other limitations, it is usually not possible to assess for causal associations between vaccines and adverse events from spontaneous reports to VAERS, and it is not appropriate to use reporting rates to compare one vaccine to another. However, the EUA [1] stipulates mandatory reporting requirements for the manufacturer and vaccination providers, helping to address some of these limitations. VAERS data have been successfully used to describe a range of potential vaccine adverse events and to look for unexpected patterns in demographics and clinical characteristics that might lead to hypotheses that can be tested with epidemiologic studies [38]. Surveillance using VAERS for adverse events after Ad26.COV2.S, including for ITP, TTS, GBS, and myocarditis, is ongoing.

FDA and CDC are also conducting active surveillance with large scale population-based studies, using claims data or electronic healthcare record data. The population-based data sources include the FDA Biologics Effectiveness and Safety System [39], the Center for Medicare and Medicaid Services databases [40], and the CDC Vaccine Safety Datalink [41]. Under the EUA [1], the manufacturer is also required to conduct both passive and active surveillance activities for continued vaccine safety monitoring. A retrospective, observational, propensity-scored matched cohort study using health insurance claims and electronic health records is in progress [1]. The goal of the study is to assess the risk of prespecified adverse events of special interest following vaccination with Ad26.COV2.S.

5. Conclusions

Safety monitoring for COVID-19 vaccines has been the most comprehensive in U.S. history. Based on the FDA and CDC’s intensive monitoring and continuous review of available safety data for Ad26.COV2.S in VAERS, VSD, and other sources, important safety findings have been presented to advisory groups, the medical community, and the public. The Fact Sheets for vaccination providers and vaccine recipients/caregivers have been revised to include statements about TTS, GBS, and other adverse events [3].

Ad.26.COV2.S was initially authorized as a single intramuscular dose for primary vaccination and was later authorized for a booster dose administered at least two months after primary vaccination with Ad.26.COV2.S [3]. After the public health notification about TTS [13], use of Ad.26.COV2.S in the US decreased. Even after the pause was lifted [14], uptake did not return to its initial level. Following an emergency meeting to discuss TTS and the benefit-risk assessment for Ad.26.COV2.S, ACIP issued a recommendation for preferential use of mRNA COVID-19 vaccines over Ad.26.COV2.S [42]. However, the committee said that Ad.26.COV2.S might be considered in certain situations, such as in individuals with a contraindication to receipt of mRNA COVID-19 vaccines [42]. Usage of the vaccine continued to decline. On May 5, 2022, FDA limited the indication of Ad.26.COV2.S: for use in individuals 18 years of age and older for whom other FDA-authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and who elect to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine [43]. Since then, use of Ad.26.COV2.S in the US decreased further.

The information summarized here may enable policy makers, health officials, clinicians, and patients to make a more informed decision regarding vaccination strategies. Monitoring of reports for primary and booster vaccination are important for understanding the range and severity of AEs after all COVID-19 vaccines.

Disclaimer

The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention or the Food and Drug Administration.

Funding

No external sources of funding were used. CDC received nonfinancial technical support to develop and maintain the v-safe infrastructure from Oracle.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Data availability

There is a public version of the VAERS dataset. However, medical records obtained as part of follow-up are confidential personal health information.