Safety of simultaneous vaccination with COVID-19 vaccines in the Vaccine Safety Datalink

Abstract

Introduction

Safety data on simultaneous vaccination (SV) with primary series monovalent COVID-19 vaccines and other vaccines are limited. We describe SV with primary series COVID-19 vaccines and assess 23 pre-specified health outcomes following SV among persons aged ≥5 years in the Vaccine Safety Datalink (VSD).

Methods

We utilized VSD’s COVID-19 vaccine surveillance data from December 11, 2020-May 21, 2022. Analyses assessed frequency of SV. Rate ratios (RRs) were estimated by Poisson regression when the number of outcomes was ≥5 across both doses, comparing outcome rates between COVID-19 vaccinees receiving SV and COVID-19 vaccinees receiving no SV in the 1–21 days following COVID-19 vaccine dose 1 and 1–42 days following dose 2 by SV type received (“All SV”, “Influenza SV”, “Non-influenza SV”).

Results

SV with COVID-19 vaccines was not common practice (dose 1: 0.7 % of 8,455,037 persons, dose 2: 0.3 % of 7,787,013 persons). The most frequent simultaneous vaccines were influenza, HPV, Tdap, and meningococcal. Outcomes following SV with COVID-19 vaccines were rare (total of 56 outcomes observed after dose 1 and dose 2). Overall rate of outcomes among COVID-19 vaccinees who received SV was not statistically significantly different than the rate among those who did not receive SV (6.5 vs. 6.8 per 10,000 persons). Statistically significant elevated RRs were observed for appendicitis (2.09; 95 % CI, 1.06–4.13) and convulsions/seizures (2.78; 95 % CI, 1.10–7.06) in the “All SV” group following dose 1, and for Bell’s palsy (2.82; 95 % CI, 1.14–6.97) in the “Influenza SV” group following dose 2.

Conclusion

Combined pre-specified health outcomes observed among persons who received SV with COVID-19 vaccine were rare and not statistically significantly different compared to persons who did not receive SV with COVID-19 vaccine. Statistically significant adjusted rate ratios were observed for some individual outcomes, but the number of outcomes was small and there was no adjustment for multiple testing.

1. Introduction

During the first two years of the U.S. COVID-19 vaccination program, the U.S. Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for three monovalent COVID-19 vaccines used for the primary series: BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad.26.COV2.S (Janssen). Initially, these COVID-19 vaccines were authorized for persons aged ≥16 years old (Pfizer-BioNTech) and ≥18 years old (Moderna, Janssen). On May 10, 2021, FDA amended the Pfizer-BioNTech EUA to include adolescents 12–15 years of age, and on October 29, 2021, to include children 5–11 years of age [1]. Subsequently, Pfizer-BioNTech and Moderna EUAs were amended to include younger ages down to 6 months, and on August 31, 2022, FDA authorized bivalent formulations of Pfizer-BioNTech and Moderna COVID-19 vaccines [1].

Evidence from clinical trials, observational studies, and clinical experience support the general practice of simultaneous vaccination [2], [3]. For the purpose of this analysis, we used the Advisory Committee on Immunization Practices (ACIP) definition of simultaneous vaccination, which defines it as administering more than one vaccine on the same clinic day, at different anatomic sites, and not combined in the same syringe [4]. Although rare, some studies have identified a possible increased risk in adverse events among persons receiving simultaneous vaccination with non-COVID-19 vaccines. One study found an increased risk for Bell's palsy in a cohort aged 11 to 21 years when subjects received simultaneous vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM), but no increased risk among those who received MenACWY-CRM alone [5]. Other studies found an elevated risk of febrile seizures among children ages 6–23 months during the 2010–11, 2013–14, and 2014–15 influenza seasons among children who received trivalent inactivated influenza vaccine (IIV3) simultaneously with 13-valent pneumococcal conjugate vaccine (PCV13) [6], [7], [8]. Therefore, out of an abundance of caution, initial ACIP recommendations for COVID-19 vaccines specified that the vaccines be administered alone in the primary series, with a minimum interval of 14 days before or after administering any other vaccine [9]. On May 12, 2021, with sufficient safety data available on COVID-19 vaccine administration, the Centers for Disease Control and Prevention (CDC) updated its Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States (i.e., clinical considerations), stating that COVID-19 vaccines and other vaccines may be administered without regard to timing, including on the same day [10].

There are few peer-reviewed publications that describe the occurrence and safety of simultaneous vaccination with primary series COVID-19 vaccines [11], [12], [13], [14]. This study aims to describe simultaneous vaccination with U.S.-authorized or approved monovalent primary series COVID-19 vaccines between December 11, 2020 and May 21, 2022, and to evaluate pre-specified health outcomes following simultaneous vaccination with monovalent primary series COVID-19 vaccines among persons aged ≥5 years in Vaccine Safety Datalink (VSD) surveillance.

2. Methods

2.1. Population and study design

The VSD is a collaboration between CDC and integrated health care organizations (sites), with a long history of monitoring and evaluating the safety of U.S. vaccines. VSD sites capture health care information on their members, including insurance enrollment, demographic characteristics, clinical encounters from all settings, and vaccination [15], [16], [17]. VSD sites also capture COVID-19 and other routine vaccines administered outside of the health care system, including in retail pharmacies, mass vaccination clinics, and workplaces [18]. Sites insure over 12.5 million persons annually, representing 3.6 % of the U.S. population; 20 % of this population is younger than 18 years old and 16 % is ≥65 years old [19]. VSD began monitoring uptake and safety of COVID-19 vaccines when they first became available in December 2020. By May 2022, 78.3 % of the age-eligible VSD population had received at least one dose of primary series COVID-19 vaccine, and 76.3 % were fully vaccinated (i.e., received two doses of Pfizer-BioNTech or Moderna vaccine, or one dose of Janssen vaccine).

This retrospective cohort study utilized data obtained from VSD’s COVID-19 vaccine rapid cycle analysis (RCA) surveillance [19], [20]. The source population consisted of persons aged ≥5 years who received an age-appropriate monovalent COVID-19 vaccine and were enrolled in one of the eight VSD data-providing sites on the day of COVID-19 vaccination between December 11, 2020, and May 21, 2022. The primary analyses assessed the frequency of, and factors associated with, receiving simultaneous vaccination with COVID-19 vaccine, and compared outcome rates between COVID-19 vaccinees receiving ≥1 simultaneous vaccines with COVID-19 vaccinees receiving no simultaneous vaccines. This study was approved by the Institutional Review Boards of all participating VSD sites and by CDC with a waiver of informed consent.

2.2. Vaccines, pre-specified health outcomes, and other variables

2.2.1. Vaccines and comparison groups

The following monovalent COVID-19 vaccines were assessed: Pfizer-BioNTech, Moderna, and Janssen for dose 1; Pfizer-BioNTech and Moderna for dose 2. Simultaneous vaccination was defined as receipt of any non-COVID-19 vaccine (≥1 vaccine) on the same day as either a first or second dose of the primary series COVID-19 vaccine. The two study comparison groups consisted of 1) persons who received COVID-19 vaccine with simultaneous vaccination (i.e., received simultaneous vaccination), and 2) persons who received COVID-19 vaccine alone (i.e., no simultaneous vaccination) during the study period. Simultaneous vaccines were grouped into mutually exclusive vaccine groups for analysis; for example, all influenza vaccine types were grouped into one “Influenza” vaccine group. See Supplemental Table 1 for a crosswalk of vaccine groups, CVX codes, and CVX short descriptions included in analyses.

2.2.2. Pre-specified health outcomes

This study assessed 23 pre-specified safety outcomes from VSD COVID-19 vaccine RCA surveillance (Supplemental Table 2) [19]. We used automated healthcare data to identify outcomes following receipt of primary series COVID-19 vaccines using International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes representing medically attended events in the outpatient, inpatient, and emergency department settings [19]. A person may have had more than one outcome and may therefore be in separate outcome-specific analyses. Using medical record review, we confirmed the status of simultaneous vaccination and the incident occurrence of Bell’s palsy in the 1–42 days following simultaneous vaccination with COVID-19 vaccine dose 2 because analyses of automated cases showed a significant association. Due to limited resources, we did not conduct any other medical record reviews.

2.2.3. Other variables

History of COVID-19 disease was identified using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) COVID-19 diagnosis codes and site-specific internal diagnosis codes, and/or a positive laboratory test for SARS-CoV-2 on or after January 1, 2020 [21]. Pregnancies were identified using the VSD’s dynamic pregnancy algorithm (DPA) [22]. A person was considered “high risk for severe COVID-19 illness if s/he had at least one of 125 conditions in 2019 (e.g., asthma, Type 2 diabetes mellitus; excluding COVID-19 disease); these 125 conditions were based on internal diagnosis codes and selected in consultation with CDC and study investigators as part of the COVID-19 vaccine RCA [23]. Timing of COVID-19 vaccine receipt was categorized as “before May 12, 2021” or “after May 12, 2021”, corresponding to the date that CDC’s clinical considerations for simultaneous vaccination were updated. Quarter when COVID-19 vaccine was received was categorized into four intervals: Q1: January 1-March 31, Q2: April 1-June 30, Q3: July 1-September 30, and Q4: October 1-December 31 of each study period year.

2.3. Data analysis

2.3.1. Simultaneous vaccine administration and factors associated with simultaneous vaccination

The number and proportion of persons who received simultaneous vaccination with COVID-19 vaccine and those who received COVID-19 vaccine alone were calculated. We also calculated the number and proportion of simultaneous vaccines received with COVID-19 vaccine by simultaneous vaccine group received, as defined above. Logistic regression was used to compute odds ratios (OR and 95 % confidence intervals) to understand which factors were associated with receiving simultaneous vaccination vs. not receiving simultaneous vaccination with COVID-19 vaccine. The dependent variable was receipt of simultaneous vaccination with COVID-19 vaccine (yes/no). The independent variables were COVID-19 vaccine dose number, COVID-19 vaccine type, sex, age group, race and ethnicity, high risk for severe COVID-19 illness status, history of COVID-19 disease status, timing of COVID-19 vaccine receipt, and quarter.

2.3.2. Analysis of outcomes

The number, proportion of outcomes, and the rate of outcomes per 10,000 COVID-19 vaccinees among persons who received simultaneous vaccination and persons who received no simultaneous vaccination with COVID-19 vaccine were calculated. We used the chi-square test to compare the rates; p-values were based on two-sided tests.

Poisson regression was used to compare outcome rates between COVID-19 vaccinees receiving simultaneous vaccination with COVID-19 vaccinees receiving no simultaneous vaccination, when the total number of cases among persons who received simultaneous vaccination with COVID-19 vaccine across both COVID-19 doses was ≥5. For COVID-19 vaccine dose 1, we compared outcome incidence among COVID-19 vaccinees receiving simultaneous vaccination with COVID-19 vaccinees receiving no simultaneous vaccination during a follow-up period of 1–21 days after receipt of COVID-19 vaccine dose 1. For COVID-19 vaccine dose 2, we compared outcome incidence among COVID-19 vaccinees receiving simultaneous vaccination with COVID-19 vaccinees receiving no simultaneous vaccination during a follow-up period of 1–42 days after receipt of COVID-19 dose 2. For the anaphylaxis outcome, a follow-up period of 0–1 days after either COVID-19 vaccine dose was used. To reduce confounding, analyses were adjusted for age group, sex, high-risk for COVID-19 disease status, timing of COVID-19 vaccine receipt (i.e., before or after CDC’s updated clinical considerations for simultaneous vaccination), and quarter when COVID-19 vaccine was received. Adjustment for multiple comparisons was not made. Analyses were run by COVID-19 vaccine dose number and stratified by type of simultaneous vaccine received (all simultaneous vaccines, influenza simultaneous vaccines, and non-influenza simultaneous vaccines). Statistical significance of α = 0.05 was used and 95 % confidence intervals (CI) were estimated. SAS software version 9.4 (SAS Institute) was used to conduct all analyses.

3. Results

3.1. Simultaneous vaccine administration and factors associated with simultaneous

3.1.1. Vaccination

From December 11, 2020, through May 21, 2022, of the 8,455,037 persons who received a first dose of COVID-19 vaccine in the VSD, 59,870 (0.7%) persons received simultaneous vaccination, and of the 7,787,013 persons who received a second dose of COVID-19 vaccine, 25,904 (0.3%) persons received simultaneous vaccination (Table 1 ). The majority of persons (72%) received a COVID-19 vaccine prior to May 12, 2021, when CDC’s clinical considerations for simultaneous vaccination were updated. Simultaneous vaccination was significantly more likely to be received with COVID-19 vaccine dose 1 than dose 2 (OR 2.41; 95 % CI: 2.37–2.44), and there was significantly less receipt of simultaneous vaccination in the period before May 12, 2021, vs. after that date. In addition, simultaneous vaccination was also significantly more likely to be received in the last quarter (October 1 to December 31) when compared to first quarter (January 1 to March 31). Across all age groups, the proportion of simultaneous vaccination was highest in the 5–11-year age group (OR: 1.43; 95 % CI, 1.39–1.46), with persons aged 5–29 and ≥50 years significantly more likely to receive simultaneous vaccination with COVID-19 vaccine compared to persons aged 30–49 years. Persons who identified as American Indian or Alaska Native non-Hispanic (OR: 1.20; 95 % CI, 1.07–1.34) were also more likely to receive simultaneous vaccination with COVID-19 vaccine compared to persons who identified as White non-Hispanic.

Table 1.

Characteristics of persons ≥5 years old who received a COVID-19 vaccine in the Vaccine Safety Datalink, by simultaneous vaccination (SV) status, December 11, 2020-May 21, 2022.

	No. (%)
Characteristic	SV(N = 85,774)	No SV(N = 16,156,276)	OR (95 % CI)a
COVID-19 vaccine dose
Dose 1	59,870 (0.7)	8,395,167 (99.3)	2.41 (2.37–2.44)
Dose 2	25,904 (0.4)	7,761,109 (99.7)	1.00 (ref)
COVID-19 vaccine type
Pfizer-BioNTech	71,924 (0.7)	9,804,939 (99.3)	1.00 (ref)
Moderna	11,734 (0.2)	5,916,620 (99.8)	1.08 (1.05–1.10)
Janssen	2,116 (0.5)	434,717 (99.5)	0.65 (0.62–0.68)
Sex
Female	43,335 (0.5)	8,660,110 (99.5)	0.98 (0.97–0.99)
Male	42,439 (0.6)	7,496,166 (99.4)	1.00 (ref)
Age Group, years
5–11	30,242 (4.1)	712,840 (95.9)	1.43 (1.39–1.46)
12–17	15,882 (1.3)	1,190,321 (98.7)	1.96 (1.91–2.01)
18–29	11,300 (0.5)	2,444,256 (99.5)	1.14 (1.11–1.17)
30–49	14,092 (0.3)	4,933,560 (99.7)	1.00 (ref)
50–64	8,322 (0.2)	3,678,660 (99.8)	1.24 (1.20–1.27)
65+	5,936 (0.2)	3,196,639 (99.8)	2.03 (1.97–2.10)
Race & Ethnicity (NH = Non-Hispanic)b
Hispanic or Latino (Hispanic)	28,290 (0.7)	4,012,558 (99.3)	0.99 (0.98–1.01)
American Indian or Alaska Native, NH	320 (0.7)	48,710 (99.3)	1.20 (1.07–1.34)
Asian, NH	8,717 (0.4)	2,407,244 (99.6)	0.70 (0.68–0.72)
Black or African American (Black), NH	8,026 (0.8)	993,221 (99.2)	1.02 (0.99–1.04)
Native Hawaiian or Pacific Islander, NH	612 (0.6)	103,467 (99.4)	0.95 (0.87–1.03)
White, NH	28,198 (0.4)	6,575,040 (99.6)	1.00 (ref)
Multiple or Other, NH	3,530 (0.6)	575,518 (99.4)	0.94 (0.91–0.98)
Unknown	8,081 (0.6)	1,440,518 (99.4)	0.78 (0.76–0.80)
High Risk for severe COVID-19 illness?
No	70,030 (0.6)	11,123,521 (99.4)	1.00 (ref)
Yes	15,744 (0.3)	5,032,755 (99.7)	1.12 (1.09–1.14)
History of COVID-19 disease?
No	67,772 (0.5)	13,262,431 (99.5)	1.00 (ref)
Yes	18,002 (0.6)	2,893,845 (99.4)	1.04 (1.02–1.06)
Timing of COVID-19 vaccine receipt
Before May 12	2,773 (0.0)	11,628,006 (100.0)	0.01 (0.01–0.01)
After May 12	83,001 (1.8)	4,528,270 (98.2)	1.00 (ref)
Quarter
Jan 1 – Mar 31	16,396 (0.2)	7,536,082 (99.8)	1.00 (ref)
Apr 1 – Jun 30	7,177 (0.1)	6,075,765 (99.9)	0.13 (0.12–0.13)
Jul 1 – Sep 30	18,129 (1.3)	1,350,049 (98.7)	0.40 (0.38–0.41)
Oct 1 – Dec 31	44,072 (3.6)	1,194,380 (96.4)	1.30 (1.28–1.33)

^aAdjusted odds ratio (OR) and 95 % confidence interval (CI) from a logistic regression model with all variables listed in the table.

^b“Multiple or Other, NH” includes persons with more than 1 non-Hispanic race and ethnicity and all other non-Hispanic races and ethnicities.

Approximately 90 % of persons who received simultaneous vaccination with either dose of COVID-19 vaccine received only one simultaneous vaccine (dose 1: 52,612 (87.9%); dose 2: 23,906 (92.3%); data not shown in tables). The most frequently administered simultaneous vaccines with either dose of COVID-19 vaccine were influenza (dose 1: 48,425 (68.6%); dose 2: 20,459 (71.0%)), HPV (dose 1: 7,490 (10.6%); dose 2: 2,566 (8.9%)), Tdap (dose 1: 5,720 (8.1%); dose 2: 2,277 (7.9%)), and meningococcal (dose 1: 4,416 (6.3%); dose 2: 1,444 (5.0%)) vaccines (Supplemental Table 3).

3.2. Pre-specified health outcomes following simultaneous vaccination with COVID-19 vaccine

Pre-specified health outcomes among persons who received simultaneous vaccination with COVID-19 vaccine were uncommon (Table 2 ). From December 11, 2020, through May 21, 2022, 32 (0.9%) outcomes were observed among persons who received simultaneous vaccination in the 1–21 days following COVID-19 vaccine dose 1, and 24 (0.3%) outcomes were observed among persons who received simultaneous vaccination in the 1–42 days following COVID-19 vaccine dose 2; this totals to 56 (0.5%) outcomes overall out of 10,847 outcomes observed following receipt of either dose of COVID-19 vaccine identified during surveillance. Overall, the combined outcome rate among persons who received simultaneous vaccination with COVID-19 vaccine was not statistically significantly different than the rate among those who did not receive simultaneous vaccination with COVID-19 vaccine (6.5 per 10,000 doses vs. 6.8 per 10,000 doses).

Table 2.

Total number of pre-specified health outcomes among persons aged ≥5 years who received a COVID-19 vaccine in the Vaccine Safety Datalink, by simultaneous vaccination (SV) status and COVID-19 vaccine dose number - December 11, 2020-May 21, 2022.^a

	COVID-19 Vaccine Dose 1 (n outcomes = 3,646)
SV Status	No. (%)	Denominator(n vaccines)	Rate per 10,000 persons (95 % CI)	p-valueb
Simultaneous vaccine	32 (0.9)	59,870	5.3 (3.7, 7.5)	0.222
No simultaneous vaccine	3,614 (99.1)	8,395,167	4.3 (4.2, 4.4)
	COVID-19 Vaccine Dose 2 (n outcomes = 7,201)
SV Status	No. (%)	Denominator(n vaccines)	Rate per 10,000 persons (95 % CI)b	p-valueb
Simultaneous vaccine	24 (0.3)	25,904	9.3 (5.9, 13.8)	0.993
No simultaneous vaccine	7,177 (99.7)	7,761,109	9.2 (9.0, 9.5)
	Overall Total (n outcomes = 10,847)
SV Status	No. (%)	Denominator(n vaccines)	Rate per 10,000 persons (95 % CI)b	p-valueb
Simultaneous vaccine	56 (0.5)	85,774	6.5 (4.9, 8.5)	0.865
No simultaneous vaccine	10,791 (99.5)	16,145,485	6.7 (6.5, 6.8)

^aOutcomes following COVID-19 vaccine dose 1 occurred in the 1–21 day risk interval; outcomes following COVID-19 vaccine dose 2 occurred in the 1–42 day risk interval. ANAPH outcomes only, occurred in the 0–1 day risk interval following either dose of COVID-19 vaccine.

^bA chi-square test was used to compare the rate in those receiving SV with the rate in those receiving no SV with COVID-19 vaccine.

Of the 23 pre-specified outcomes assessed, 13 different outcome types were observed among persons who received simultaneous vaccination (Supplemental Table 4). The most frequently occurring outcomes following either dose of COVID-19 vaccine administered with simultaneous vaccination were appendicitis (APPND), convulsions/seizures (SZ), Bell's palsy (BP), and venous thromboembolism (VTE). None of the observed outcomes following simultaneous vaccination with COVID-19 vaccine occurred in a pregnant person. The most frequently received simultaneous vaccine across all outcomes following simultaneous vaccination with either dose of COVID-19 vaccine was influenza vaccine (received in 45 out of 56 observed outcomes).

3.3. Statistical analyses of the most frequently occurring pre-specified health outcomes, comparing simultaneous vaccines with COVID-19 vaccine alone

Adjusted rate ratios for the “All Simultaneous Vaccines” group were statistically significantly elevated for APPND (2.09, 95 % CI: 1.06–4.13) and SZ (2.78, 95 % CI: 1.10–7.06) in the 1–21 days following COVID-19 vaccine dose 1 (Table 3 ). Of the nine APPND cases, eight received Pfizer-BioNTech and one received Moderna COVID-19 vaccines; five of nine were female; four cases occurred in 11–17-year-olds, and five cases were among persons aged > 18 years (range: 20–64 years); days to diagnosis ranged from 3 to 20 days post vaccination (median 15 days). Out of the five SZ cases, three received Pfizer-BioNTech and two received Moderna COVID-19 vaccines; two of five were female; one case occurred in an 8-year-old and four cases were among persons aged > 18 years (range: 19–44 years); days to diagnosis ranged from 1 to 14 days post vaccination (median 13 days).

Table 3.

Poisson regression results for the most frequently occurring pre-specified health outcomes following mRNA COVID-19 vaccine dose 1 and dose 2 among persons aged ≥5 years who received simultaneous vaccination (SV) compared to outcomes among persons aged ≥5 years who did not receive SV with mRNA COVID-19 vaccine in the Vaccine Safety Datalink - December 11, 2020-May 21, 2022.

				No. outcomes		No. persons vaccinated		Rate per 10,000 personsb
Outcome	COVID-19 Vaccine Dose No.	Follow-up (days) after vaccination	SV Typea	SVc	No SV	SVc	No SV	SV	No SV	Rate Ratio(95 % CI)d
Appendicitis	1	1–21	All SV	9	577	57,754	7,961,741	1.56	0.72	2.09 (1.06, 4.13)
			Influenza SV	5	324	44,745	5,157,923	1.12	0.63	1.47 (0.59, 3.65)
			Non-influenza SV	3	577	10,994	7,961,741	2.73	0.72	3.09 (0.98, 9.70)
	2	1–42	All SV	5	1,266	25,904	7,761,464	1.93	1.63	1.04 (0.43, 2.53)
			Influenza SV	4	540	18,818	3,731,494	2.13	1.45	1.30 (0.48, 3.52)
			Non-influenza SV	0	1,266	5,445	7,761,464	N/A	1.63	Not Available
Bell’s palsy	1	1–21	All SV	3	339	57,754	7,961,741	0.52	0.43	2.30 (0.72, 7.37)
			Influenza SV	2	234	44,745	5,157,923	0.45	0.45	1.55 (0.37, 6.53)
			Non-influenza SV	1	339	10,994	7,961,741	0.91	0.43	3.33 (0.46, 24.09)
	2	1–42	All SV	5	716	25,904	7,761,464	1.93	0.92	2.38 (0.97, 5.82)
			Influenza SV	5	358	18,818	3,731,494	2.66	0.96	2.82 (1.14, 6.97)
			Non-influenza SV	0	716	5,445	7,761,464	N/A	0.92	Not Available
Convulsions/ Seizures	1	1–21	All SV	5	210	57,754	7,961,741	0.87	0.26	2.78 (1.10, 7.06)
			Influenza SV	4	144	44,745	5,157,923	0.89	0.28	2.13 (0.80, 6.44)
			Non-influenza	1	210	10,994	7,961,741	0.91	0.26	2.96 (0.41, 21.42)
	2	1–42	All SV	4	411	25,904	7,761,464	1.54	0.53	2.47 (0.91, 6.68)
			Influenza SV	3	168	18,818	3,731,494	1.59	0.45	2.58 (0.81, 8.28)
			Non-influenza	1	411	5,445	7,761,464	1.84	0.53	2.78 (0.39, 19.87)
Venous thromboembolism	1	1–21	All SV	2	374	57,754	7,961,741	0.35	0.47	0.74 (0.18, 2.96)*
			Influenza SV	1	290	44,745	5,157,923	0.22	0.56	0.40 (0.06, 2.83)*
			Non-influenza	0	374	10,994	7,961,741	N/A	0.47	Not Available
	2	1–42	All SV	3	723	25,904	7,761,464	1.16	0.93	1.62 (0.15, 5.11)
			Influenza SV	3	394	18,818	3,731,494	1.59	1.06	1.51 (0.48, 4.70)*
			Non-influenza	0	723	5,445	7,761,464	N/A	0.93	Not Available

^a“All SV” category includes outcomes where person received any type of SV; number of persons vaccinated includes any person who received a COVID-19 vaccine. “Influenza SV” category includes only outcomes where a person received an influenza vaccine (any type) as their SV between September 1-March 31; number of persons vaccinated includes persons who received a COVID-19 vaccine between September 1-March 31 only. “Non-influenza SV” category includes only outcomes where a person received all non-influenza simultaneous vaccines only as their SV; number of persons vaccinated includes any person who received a COVID-19 vaccine.

^bDenominator is the total number of persons who received a dose of COVID-19 vaccine within the respective SV type and COVID-19 vaccine dose number.

^cIn the “SV” columns, the numbers in the “Influenza SV” and “Non-Influenza SV” rows may not add up to the number in the “All SV” row because a person who received a simultaneous influenza vaccine outside of the September 1 – March 31 timeframe would be counted in the “All SV” row but not counted in the “Influenza SV” row nor the “Non-Influenza SV” row.

^dUnless denoted with “*”, all models were adjusted for age group, sex, high risk for severe COVID-19 illness status, timing of COVID-19 vaccine receipt (before/after May 12, 2021), and quarter; models denoted with “*” did not converge when adjusted for one or more covariates and therefore reported analyses do not include adjustment. “Age” includes six categories: 5–11, 12–17, 18–29, 30–49, 50–64, and 65+. “Sex” includes two categories: female, male. “High risk for severe COVID-19 illness” includes two categories: 1 = Yes, 0 = No. “Timing of COVID-19 vaccine receipt” includes two categories: 1 = person received COVID-19 vaccine before May 12, 2021, and 0 = person received COVID-19 vaccine after May 12, 2021. “Quarter” includes four intervals: Q1: January 1-March 31, Q2: April 1-June 30, Q3: July 1-September 30, Q4: October 1-December 31 of each study period year.

After stratifying the “All Simultaneous Vaccines” group by “Influenza Simultaneous Vaccines” and “Non-influenza Simultaneous Vaccines,” the only rate ratio that was statistically significantly elevated was for BP “Influenza Simultaneous Vaccines” following COVID-19 vaccine dose 2 (2.82, 95 % CI: 1.14–6.97; p-value = 0.0250). All five BP cases following receipt of COVID-19 vaccine dose 2 received two doses of Pfizer-BioNTech COVID-19 vaccine; four of five cases were female; one case occurred in a 17-year-old and four cases were among persons aged > 18 years (range: 20–54 years); days to diagnosis ranged from 2 to 22 days post vaccination (median 21 days). Medical record review confirmed that four of the five automated BP cases were incident events following receipt of COVID-19 vaccine with simultaneous influenza vaccine. The case that was not confirmed by medical record review had a historical diagnosis of BP.

4. Discussion

Our study found that overall, between December 11, 2020, and May 21, 2022, the practice of receiving simultaneous vaccination with monovalent primary series COVID-19 vaccines was rare (0.5%) in the VSD. Overall, simultaneous vaccination was significantly more likely to be received with COVID-19 vaccine dose 1 vs. dose 2. We also found that compared to persons aged 30–49 years, persons aged 5–29 and ≥50 years were more likely to receive simultaneous vaccination with COVID-19 vaccine, as well as persons who identified as American Indian or Alaska Native non-Hispanic compared to persons who identified as White non-Hispanic. Pre-specified health outcomes following receipt of simultaneous vaccination with primary series COVID-19 vaccines were rare, with only 56 outcomes observed in the 1–21 days after dose 1 and 1–42 days after dose 2. In addition, the overall rate of pre-specified health outcomes among persons who received simultaneous vaccination with COVID-19 vaccine was not statistically significantly different than the rate of outcomes among those who did not receive simultaneous vaccination with COVID-19 vaccine.

Similar to other studies, we found that simultaneous vaccination with primary series COVID-19 vaccines was low, and the most frequently administered simultaneous vaccine types were influenza, HPV, Tdap, and meningococcal vaccines [11], [12]. In one study, Hause et al. analyzed post-authorization surveillance data on the safety of Pfizer-BioNTech vaccination in U.S. children ages 5–11 years across three surveillance systems: v-safe, Vaccine Adverse Event Reporting System (VAERS), and the VSD [12]. The frequency of simultaneous vaccination was low across all three data systems. In v-safe data, the frequency of simultaneous vaccination with Pfizer-BioNTech vaccine among 5–11-year-old children was 3.6 % with dose 1 and 0.7 % with dose 2; seasonal influenza vaccine was the most frequently administered simultaneous vaccine (3.2 % with dose 1 and 0.6 % with dose 2), followed by tetanus-containing, HPV, and meningococcal vaccines. In VAERS data, out of 7,578 reports of adverse events, 2.3 % received simultaneous vaccination; the most frequently received simultaneous vaccine was seasonal influenza vaccine (148; 2.0%), followed by Tdap, meningococcal, and MMRV vaccines. While the Hause et al. study reported on outcomes in the VSD following Pfizer-BioNTech vaccine among children aged 5–11 years from October 31, 2021, to February 26, 2022, the current study adds new information, analyzing VSD data on all persons aged ≥5 years who received a COVID-19 vaccine, assessing both mRNA COVID-19 vaccines dose 1 and dose 2 and Janssen vaccine dose 1 from December 2020, to May 21, 2022, and assessing outcomes for those who received simultaneous vaccination with COVID-19 vaccine vs. those who received COVID-19 vaccine alone.

In our analysis of pre-specified health outcomes, we found statistically significant elevated rate ratios in the “All Simultaneous Vaccines” group for both appendicitis and convulsions/seizures in the 1–21 days following COVID-19 vaccine dose 1 among COVID-19 vaccinees receiving simultaneous vaccination vs. COVID-19 vaccinees not receiving simultaneous vaccination. When analyses were stratified by type of simultaneous vaccination received (“Influenza Simultaneous Vaccines” and “Non-influenza Simultaneous Vaccines”), Bell’s palsy “Influenza Simultaneous Vaccines” following COVID-19 vaccine dose 2 was statistically significant. The FDA listed appendicitis as a serious adverse event on the Pfizer-BioNTech information fact sheet after a large clinical trial showed higher numbers of appendicitis cases in the vaccinated group compared to the placebo group [24]. Subsequent studies found no increased risk of appendicitis following mRNA COVID-19 vaccination [19], [25]. In interim analyses of mRNA COVID-19 vaccine RCA surveillance in the VSD, Klein et al. compared outcome events in the 21-day risk interval after either primary series mRNA COVID-19 vaccine doses with outcomes in individuals 22–42 days after their most recent dose and found an adjusted rate ratio of 0.82 (95 % CI: 0.73–0.93) for appendicitis, indicating a slightly protective finding overall [19]. In a nationwide Danish cohort study that compared mRNA COVID-19 vaccine recipients with an unvaccinated reference group, the adjusted risk ratio of appendicitis was 0.93 (95 % CI: 0.79–1.11) following mRNA COVID-19 vaccine dose 1, and 0.99 (95 % CI: 0.79–1.99) following mRNA COVID-19 vaccine dose 2. The rate of appendicitis in this study was 8.1 and 8.6 cases per 100,000 persons following mRNA COVID-19 vaccine dose 1 and dose 2, respectively [25]. Our study findings show that the rate of appendicitis among those who received no simultaneous vaccination with COVID-19 vaccine (0.72 per 10,000 persons, or 7.2 per 100,000 persons) was similar to the rate of appendicitis observed in the Danish study (8.1 per 100,000 persons). However, our rate of appendicitis among persons who received simultaneous vaccination with mRNA COVID-19 vaccine was almost doubled, at 1.56 per 10,000 persons (15.6 per 100,000 persons). This warrants further assessment, as there may be unmeasured confounding, including why certain people received simultaneous vaccination with a COVID-19 vaccine.

To provide context and aid in the assessment of adverse events temporally associated with COVID-19 vaccines, a publication by Gubernot et al. listed the U.S. population-based background incidence rates of selected medical conditions, including seizures [26]. They found that the rate of first unprovoked seizures across all ages ranged from 41.1 to 61 per 100,000 person-years. Another systematic review and meta-analysis study across several countries found that the median incidence rate of unprovoked seizures across all ages was 56 per 100,000 person-years [27]. In our study, although the adjusted rate ratio was significantly elevated for convulsions/seizures following COVID-19 vaccine dose 1 (age range: 8–44 years), the incidence rate among those who received simultaneous vaccination with COVID-19 vaccine was 0.87 per 10,000 (8.7 per 100,000), well below the background incidence rate. Additionally, in interim analyses of mRNA COVID-19 vaccine surveillance in the VSD, Klein et al. did not find evidence of an association between convulsions/seizures and the mRNA COVID-19 vaccines [19].

In the Pfizer-BioNTech phase 3 clinical trial, it was noted that incidence of Bell’s palsy was higher in the vaccine group than in the placebo group [28]. However, in interim analyses of mRNA COVID-19 vaccine surveillance in the VSD, Klein et al. did not find evidence of an association between Bell’s palsy and mRNA vaccines, which was consistent with analyses of data reported to the World Health Organization database at that time [19], [29]. Subsequent VSD COVID-19 vaccine RCA surveillance to date has not identified associations between Bell’s palsy and primary series mRNA vaccines. Additionally, a case series and nested case-control study by Wan et al., which assessed Bell’s palsy following receipt of Pfizer-BioNTech (Fosun–BioNTech [equivalent to Pfizer–BioNTech]) or CoronaVac (from Sinovac Biotech, Hong Kong) in Hong Kong, did not find a significant increased risk of Bell’s palsy after receipt of Pfizer-BioNTech vaccine. However, an increased risk for Bell’s palsy was observed after CoronaVac vaccination [30]. In our study, we found a statistically significant elevated adjusted rate ratio for Bell’s palsy among persons who received simultaneous influenza vaccine with COVID-19 vaccine, but the number of cases who received simultaneous vaccination after medical record verification was small (n = 4). Although some previous studies have shown an elevated incidence of BP among influenza vaccine recipients, studies assessing COVID-19 vaccine administered simultaneously with influenza vaccine did not find an elevated risk of adverse events [31], [32], [33], [13], [14].

This study has several limitations. First, it used automated healthcare data for analysis of pre-specified health outcomes, which cannot be used to establish causation due to potential error (e.g., unmeasured confounding, selection bias, misclassification of ICD-10 codes, inaccurate assessment of disease onset date, etc.) Second, there may be unmeasured confounding present in the analyses that were not controlled for (e.g., high risk status for influenza). Alternative approaches to analyzing the safety of simultaneous vaccination data in the future may help to account for potential unmeasured confounding, including adjusting for multiple testing. One example to explore in the future could use methods from a 2020 publication by Wang et. al., who used a systematic process to determine which of the simultaneously administered vaccine(s) were most likely to have caused an observed increased risk of an adverse event. The authors of that paper were able to determine which vaccines contributed to excess risk using both simulated and empirical data [34]. Third, the number of outcomes among persons who received simultaneous vaccination with COVID-19 vaccine was small, limiting statistical power to detect differences in rates for rare outcomes, and in most instances was too small to conduct statistical analyses. In practical terms, it is reassuring that the occurrence of outcomes following simultaneous vaccination with COVID-19 vaccines was rare. Fourth, we conducted multiple tests on the same data set, which increases the chances of obtaining statistically significant results that are spurious. Fifth, due to resource limitations, we did not conduct medical record reviews of the appendicitis or convulsions/seizures cases, nor of Bell’s palsy cases who received COVID-19 vaccine alone; and it is possible that analyses using only medical record confirmed cases may have yielded different results. Sixth, vaccine administration data may be incomplete; however, VSD sites do capture COVID-19 and other routine vaccinations administered outside the healthcare system (e.g., retail pharmacies, mass vaccination clinics, state-wide immunization information systems) [18]. Lastly, vaccines may be inaccurately recorded in a patient’s medical record, showing numerous vaccines administered on one day (e.g., 5–10), and more than one vaccine in a respective vaccine group being administered on the same day or within a short time frame not consistent with ACIP vaccine recommendations. To account for this, when counting types of simultaneous vaccines received, we only counted a simultaneous vaccine group dose once (e.g., person received two influenza vaccines with different CVX codes on the same day as COVID-19 vaccine dose 1 would only be counted as having received one simultaneous dose of the influenza vaccine with COVID-19 vaccine dose 1).

After assessing 23 pre-specified health outcomes among persons who received 16,156,276 monovalent primary series COVID-19 vaccine dose 1 and dose 2 doses, we found that only 56 outcomes were observed following simultaneous vaccination with COVID-19 vaccine dose 1 and dose 2. Of these outcomes, only four warranted additional investigation (appendicitis, seizures/convulsions, Bell’s palsy, and venous thromboembolism). Occurrence of all other outcomes was too infrequent and did not warrant additional investigation (e.g., ischemic stroke, myocarditis/pericarditis, anaphylaxis; Supplemental Table 4). There may be something unique about persons who receive simultaneous vaccination with COVID-19 vaccine compared to those who do not that needs to be accounted for in future studies. There may be an opportunity to assess the frequency of simultaneous vaccination and pre-specified health outcomes following receipt of simultaneous vaccination with bivalent formulations of COVID-19 vaccines in the VSD. The ongoing COVID-19 vaccine RCA surveillance on bivalent boosters indicates that simultaneous vaccination receipt is more frequent with bivalent boosters than what was observed with monovalent primary series COVID-19 vaccines.

5. Conclusion

Within the Vaccine Safety Datalink, simultaneous vaccination with either dose of monovalent primary series COVID-19 vaccine was rare. Overall, the combined pre-specified health outcomes observed among persons who received simultaneous vaccines with COVID-19 vaccine were also rare and not at a statistically significantly different rate compared with those who did not receive simultaneous vaccination with the COVID-19 vaccine. Statistically significant adjusted rate ratios were observed for some individual outcomes (appendicitis, convulsions/seizures, and Bell’s palsy), but the number of cases was small, there was no adjustment for multiple testing, and the possible effect of residual unmeasured confounding in these analyses may have contributed to these findings.

Funding/support

This work was supported by the Centers for Disease Control and Prevention (CDC). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. See, for example, 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.

Conflict of interest disclosures

KEH reports research support from Seqirus for unrelated studies. NPK reports research support from Pfizer for COVID vaccine clinical trials and from Merck, Pfizer, GlaxoSmithKline and Sanofi Pasteur for unrelated studies. WKY has received research funding from Pfizer in the past. All other co-authors have no conflicts of interest to report.

Contributors’ statement

The CDC-affiliated authors conceptualized the study and interpreted the data. TAK performed data collection, management, analysis, and led the manuscript writing. All VSD coauthors were involved in the review and approval of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. The CDC-affiliated authors participated as coinvestigators and contributed to protocol development, conduct of the study, interpretation of the data, review and revision of the manuscript, approval of the manuscript through official CDC scientific clearance processes, and the decision to submit the manuscript for publication. CDC authors must receive approval through the CDC scientific clearance process to submit an article for publication. Final decision to submit rested with the first author. The study sponsor did not have the right to direct the submission to a particular journal.

Disclaimer

The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kayla E. Hanson reports a relationship with Seqirus that includes: funding grants. Nicola P. Klein reports a relationship with Pfizer that includes: funding grants. Nicola P. Klein reports a relationship with Merck & Co Inc that includes: funding grants. Nicola P. Klein reports a relationship with GlaxoSmithKline that includes: funding grants. Nicola P. Klein reports a relationship with Sanofi Pasteur that includes: funding grants. W. Katherine Yih reports a relationship with Pfizer that includes: funding grants.

Appendix A. Supplementary material

The following are the Supplementary data to this article:

Data availability

The authors do not have permission to share data.