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Randomized Controlled Trial
. 2024 Nov 4;7(11):e2443166.
doi: 10.1001/jamanetworkopen.2024.43166.

Safety of Simultaneous vs Sequential mRNA COVID-19 and Inactivated Influenza Vaccines: A Randomized Clinical Trial

Emmanuel B Walter  1   2 , Elizabeth P Schlaudecker  3 , Kawsar R Talaat  4 , Wes Rountree  2 , Karen R Broder  5   6 , Jonathan Duffy  5   6 , Lisa A Grohskopf  6 , Marek S Poniewierski  2 , Rachel L Spreng  2 , Mary A Staat  3 , Rediet Tekalign  4 , Oidda Museru  5 , Anju Goel  5   7 , Grace N Davis  2 , Kenneth E Schmader  8
Affiliations
Randomized Controlled Trial

Safety of Simultaneous vs Sequential mRNA COVID-19 and Inactivated Influenza Vaccines: A Randomized Clinical Trial

Emmanuel B Walter et al. JAMA Netw Open. .

Abstract

Importance: Limited randomized clinical trial data exist on the safety of simultaneous administration of COVID-19 and influenza vaccines.

Objective: To compare the reactogenicity, safety, and changes in health-related quality of life (HRQOL) after simultaneous vs sequential receipt of messenger RNA (mRNA) COVID-19 vaccine and quadrivalent inactivated influenza vaccine (IIV4).

Design, setting, and participants: This randomized, placebo-controlled clinical trial was conducted between October 8, 2021, and June 14, 2023, at 3 US sites. Participants were nonpregnant persons aged 5 years or older with the intention of receiving both influenza and mRNA COVID-19 vaccines.

Interventions: Intramuscular administration in opposite arms of either IIV4 or saline placebo simultaneously with mRNA COVID-19 vaccine at visit 1. Those who received placebo at visit 1 received IIV4 and those who received IIV4 at visit 1 received placebo 1 to 2 weeks later at visit 2.

Main outcomes and measures: The primary composite reactogenicity outcome was the proportion of participants with fever, chills, myalgia, and/or arthralgia of moderate or greater severity within 7 days after vaccination visits 1 and/or 2, using a 10% noninferiority margin. Secondary outcomes were solicited reactogenicity events and unsolicited adverse events (AEs) for 7 days after each visit separately and HRQOL after visit 1, assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index. Serious AEs (SAEs) and AEs of special interest (AESIs) were assessed for 121 days. Outcomes were compared between groups.

Results: A total of 335 persons (mean [SD] age, 33.4 [15.1] years) were randomized (169 to the simultaneous group and 166 to the sequential group); 211 (63.0%) were female, and 255 (76.1%) received bivalent BNT162b2 mRNA COVID-19 vaccine. The proportion with the primary composite reactogenicity outcome in the simultaneous group (25.6% [n = 43]) was noninferior to the proportion in the sequential group (31.3% [n = 52]) (site-adjusted difference, -5.6 percentage points [pp]; 95% CI, -15.2 to 4.0 pp). Respective proportions in each group were similar after each visit separately (visit 1, 40 [23.8%] vs 47 [28.3%]; visit 2, 5 [3.0%] vs 9 [5.4%]). No significant group differences in participants with AEs (21 [12.4%] vs 16 [9.6%]), SAEs (1 [0.6%] vs 1 [0.6%]), and AESIs (19 [11.2%] vs 9 [5.4%]) were observed in the simultaneous vs sequential groups, respectively. Among participants with severe reactogenicity, the mean (SD) EQ-5D-5L Index score decreased from 0.92 (0.08) to 0.92 (0.09) prevaccination to 0.81 (0.09) to 0.82 (0.12) postvaccination.

Conclusions and relevance: In this randomized clinical trial assessing simultaneous vs sequential administration of mRNA COVID-19 and IIV4 vaccines, reactogenicity was comparable in both groups. These findings support the option of simultaneous administration of these vaccines.

Trial registration: ClinicalTrials.gov Identifier: NCT05028361.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Walter reported being funded by the Centers for Disease Control and Prevention (CDC) under a contract between the CDC and Duke University during the conduct of the study; receiving grants from Pfizer, Moderna, Seqirus, Clinetic, and Najit as an investigator for clinical trials or clinical studies; and receiving personal fees from Pfizer and Vaxcyte for serving on the advisory board, from ILiAD Biotechnologies for serving as a consultant, and from Shionogi for serving on the data safety monitoring board outside the submitted work. Dr Schlaudecker reported receiving grants from the CDC during the conduct of the study and receiving grants from Pfizer and serving on the advisory committee for Sanofi Pasteur outside the submitted work. Dr Talaat reported receiving grants from Pfizer to the institution for clinical trials of COVID-19 mRNA vaccines, from the National Institutes of Health (NIH) to the institution for testing of an intranasal COVID-19 vaccine, and from Sanofi to the institution for testing of a yellow fever vaccine outside the submitted work. Dr Staat reported receiving grants from the CDC during the conduct of the study and from the NIH, Cepheid, and Merck outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Flow Diagram
SAE indicates serious adverse effect.
Figure 2.
Figure 2.. Injection Site and Systemic Reactogenicity Within 7 Days After Visit for the Full Analysis Population, by Severity
The simultaneous group received messenger RNA (mRNA) COVID-19 and quadrivalent inactivated influenza vaccine at visit 1 and saline placebo at visit 2. The sequential group received mRNA COVID-19 vaccine and saline placebo at visit 1 and influenza vaccine at visit 2. Severity grading is described in eTable 1 in Supplement 2. aThe 95% CI of the difference in the percentages of participants with a reaction does not include 0.
Figure 3.
Figure 3.. Mean Health-Related Quality-of-Life Scores in the 7 Days After Visit 1
At visit 1, the simultaneous group received the messenger RNA (mRNA) COVID-19 and quadrivalent inactivated influenza vaccine and the sequential group received the mRNA COVID-19 vaccine and saline placebo. Health-related quality of life was assessed by the EuroQol 5-Dimension 5-Level Index (EQ-5D-5L), which was scored from −0.109 to 1, and the EQ-5D-5L Visual Analogue Scale (EQ-VAS), which was scored from 0 to 100, with higher scores indicating better quality of life. Severe events were any grade 3 reactogenicity event.
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