No immunological interference or concerns about safety when seasonal quadrivalent influenza vaccine is co-administered with a COVID-19 mRNA-1273 booster vaccine in adults: A randomized trial

Figures & data

Figure 1. Participant flow.

D, day; LTFU, long term follow-up; N, number of subjects; PPS, per protocol set.

Table 1. Demographic characteristics of study participants (exposed set).

	Seq group (N = 497)	Coad group (N = 498)	All participants (N = 995)
Age (years)
Mean (SD)	48.7 (16.10)	49.5 (15.45)	49.1 (15.77)
Median	47.0	48.0	48.0
Min, Max	19, 88	19, 86	19, 88
Age (years), n (%)
18–64	393 (79.1%)	396 (79.5%)	789 (79.3%)
≥65	104 (20.9%)	102 (20.5%)	206 (20.7%)
Sex, n (%)
Male	195 (39.2%)	224 (45.0%)	419 (42.1%)
Female	302 (60.8%)	274 (55.0%)	576 (57.9%)
Race
Black/African American	28 (5.6%)	30 (6.0%)	58 (5.8%)
White	436 (87.7%)	435 (87.3%)	871 (87.5%)
Asian	17 (3.4%)	15 (3.0%)	32 (3.2%)
Other	16 (3.2%)	18 (3.6%)	34 (3.4%)
Ethnicity
Hispanic/Latino	84 (16.9%)	80 (16.1%)	164 (16.5%)
Not Hispanic/Latino	413 (83.1%)	418 (83.9%)	831 (83.5%)

Min, Max, minimum and maximum values; N, number of participants; n (%), number and percentage of participants in the indicated category; SD, standard deviation.

Seq group received the mRNA-1273 booster dose followed 2 weeks later by quadrivalent influenza vaccine (QIV). Coad group received co-administration of the mRNA-1273 booster and QIV.

Figure 2. Adjusted geometric mean ratios (95% confidence intervals) of anti-spike antibodies and hemagglutinin inhibition 1 month post-vaccination (seq divided by Coad group) (per protocol set).

Figure 3. Percentage of solicited local and systemic adverse events reported per participant after the mRNA-1273 and QIV vaccinations (exposed set).

AE, adverse event; GI, gastrointestinal; mRNA-1273, Moderna’s mRNA COVID-19 vaccine; QIV, quadrivalent influenza vaccine.

Seq group received the mRNA-1273 booster dose followed 2 weeks later by QIV. Coad group received co-administration of the mRNA-1273 booster and QIV.

Grade 3 pain: Significant pain at rest. Prevents normal everyday activities; Grade 3 redness or swelling: >100 mm diameter; Grade 3 fever > 39.0°C (102.2°F); for other symptoms Grade 3 defined as prevented normal everyday activities.

Table 2. Summary of published studies of mRNA COVID-19 booster doses co-administered with influenza vaccines.

Author	Design	Study groups	Population	COVID-19 vaccine	Influenza vaccine	Outcome	Key findings Immunogenicity	Safety	Conclusion
Mudoch et al.^Citation32	Randomized controlled observer blind	Co-administration vs sequential administration (1 month)	18–64 ears	mRNA (Pfizer- BioNtech)	Inactivated quadrivalent	Non-inferiority compared to administration alone	Non-inferiority demonstrated for all 4 influenza strains and anti-S antibodies	Co-administration was well tolerated. Systemic AEs were higher in the co-administration group.	The results support co-administration
Dulfer et al.^Citation33	Single-blind, randomized, controlled	Co-administration vs sequential administration vs mRNA COVID-19 alone	≥60 ears	mRNA (Pfizer- BioNtech)	Inactivated quadrivalent	Non-inferiority in terms of anti-S antibodies	Non-inferiority criteria were not met.	Relative risks of side-effects did not differ in the co-administration group compared to COVID-19 vaccine alone	Immune interference could not be excluded.
Lazarus et al.^Citation34	Randomized controlled	Co-administration vs sequential administration (3 weeks)	≥18 ears	mRNA (Pfizer-BioNtech)	Cellular quadrivalent	Non-inferiority compared to COVID-19vaccine alone in terms of any systemic AE within 7 d	No evidence of immune interference	Non-inferior	Concomitant administration raised no safety concerns
					MF59C adjuvanted trivalent		No evidence of immune interference	Non-inferior
					Recombinant quadrivalent		No evidence of immune interference	Non-inferiority not reached
Ramsay et al.^Citation35	Single-blind, randomized, controlled	Co-administration vs sequential administration (1 week apart)	≥18ears	mRNA (Pfizer- BioNtech)	Inactivated quadrivalent for < 65 yoa, adjuvanted quadrivalent for ≥ 65 yoa	Non-inferiority compared to COVID-19 vaccine in terms of any systemic AE within 7 d	Not assessed	Non-inferiority criteria were not met but the study was limited by smaller than expected sample size.	Adverse events following SIV and COVID-19 co-administration were generally mild and occurred with similar frequency to events following COVID-19 vaccine alone.
Izikson et al.^Citation36	Open-label, randomized, controlled	Co-administration vs administration alone	≥65 ears	mRNA (Moderna)	High-dose, inactivated quadrivalent	Descriptive	No evidence of immune interference	Reactogenicity was similar in the COVID-19 alone and co-administration groups and lower in those who received influenza vaccine alone.	The results support co-administration recommendations
Radner et al.^Citation37	Open label, non-randomized	Co-administration vs administration alone	Healthcare workers	mRNA (Pfizer- BioNtech)	Inactivated quadrivalent	Descriptive	24% decrease in anti-S titers	Reactogenicity was similar in the COVID-19 alone and co-administration groups and lower in the influenza vaccine alone group.	Concomitant administration raised no safety concerns but provides evidence of reduced immunogenicity
Gonen et al.^Citation38	Prospective cohort	Self-selected for co-administration	Healthcare workers	mRNA (Pfizer- BioNtech)	Inactivated quadrivalent	Descriptive	16% decrease in anti-S titers	Reactogenicity was similar in the COVID-19 alone and co-administration groups and lower in the influenza vaccine alone group.	Reactogenicity and immunogenicity were mostly unchanged with co-administration
Moscara et al.^Citation39	Prospective observational	Self-selected for co-administration	Healthcare workers	mRNA (Pfizer-BioNtech)	Cellular inactivated quadrivalent	Effectiveness against symptomatic SARS-CoV-2 infection	Not assessed	Reactogenicity was similar in the COVID-19 alone and co-administration cohorts and lower in those who received influenza vaccine alone.	Co-administration had no effect on safety or the risk of breakthrough SARS-CoV-2 infections
Wagonhäuser et al.^Citation40	Prospective observational	Self-selected for co-administration	Healthcare workers	mRNA (Pfizer- BioNtech or Moderna)	Inactivated quadrivalent	Descriptive	25% decrease in anti-S titers for both mRNA vaccines	Co-administration was well tolerated.	Co-administration significantly limits anti-SARS-CoV-2-spike IgG levels

AE, adverse event; COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SIV, seasonal influenza vaccine; yo, year of age.

Murdoch L, Quan K, Baber JA, Ho AWY, Zhang Y, Xu X, Lu C, Cooper D, Koury K, Lockhart SP, et al. Safety and immunogenicity of the BNT162b2 vaccine coadministered with seasonal inactivated influenza vaccine in adults. Infect Dis Ther. 2023;12(9):2241–2258. doi:10.1007/s40121-023-00863-5.

 PubMed Web of Science ®Google Scholar

Dulfer EA, Geckin B, Taks EJM, GeurtsvanKessel CH, Dijkstra H, van Emst L, van der Gaast – de Jongh CE, van Mourik D, Koopmans PC, Domínguez-Andrés J, et al. Timing and sequence of vaccination against COVID-19 and influenza (TACTIC): a single-blind, placebo-controlled randomized clinical trial. Lancet Reg Health Eur. 2023;29:100628. doi:10.1016/j.lanepe.2023.100628.

 PubMedGoogle Scholar

Lazarus R, Baos S, Cappel-Porter H, Carson-Stevens A, Clout M, Culliford L, Emmett SR, Garstang J, Gbadamoshi L, Hallis B, et al. Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdox1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial. The Lancet. 2021;398:2277–2287. doi:10.1016/S0140-6736(21)02329-1.

 Web of Science ®Google Scholar

Ramsay JA, Jones M, Vande More AM, Hunt SL, Williams PCM, Messer M, Wood N, Macartney K, Lee FJ, Britton WJ, et al. A single blinded, phase IV, adaptive randomised control trial to evaluate the safety of coadministration of seasonal influenza and COVID-19 vaccines (the FluVID study). Vaccine. 2023;41(48):7250–7258. doi:10.1016/j.vaccine.2023.10.050.

 Web of Science ®Google Scholar

Izikson R, Brune D, Bolduc JS, Bourron P, Fournier M, Moore TM, Pandey A, Perez L, Sater N, Shrestha A, et al. Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study. Lancet Respir Med. 2022;10:392–402. doi:10.1016/S2213-2600(21)00557-9.

 PubMed Web of Science ®Google Scholar

Radner H, Sieghart D, Jorda A, Fedrizzi C, Hasenohrl T, Zdravkovic A, Redlberger-Fritz M, Puchammer-Stoeckl E, Anderle K, Bergmann F, et al. Reduced immunogenicity of BNT162b2 booster vaccination in combination with a tetravalent influenza vaccination: results of a prospective cohort study in 838 health workers. Clin Microbiol Infect. 2023;29:635–641. doi:10.1016/j.cmi.2022.12.008.

 Web of Science ®Google Scholar

Gonen T, Barda N, Asraf K, Joseph G, Weiss-Ottolenghi Y, Doolman R, Kreiss Y, Lustig Y, Regev-Yochay G. Immunogenicity and reactogenicity of coadministration of COVID-19 and influenza vaccines. JAMA Netw Open. 2023;6(9):e2332813. doi:10.1001/jamanetworkopen.2023.32813.

 Web of Science ®Google Scholar

Moscara L, Venerito V, Martinelli A, Di Lorenzo A, Toro F, Violante F, Tafuri S, Stefanizzi P. Safety profile and SARS-CoV-2 breakthrough infections among HCWs receiving anti-SARS-CoV-2 and influenza vaccines simultaneously: an Italian observational study. Vaccine. 2023;41(38):5655–5661. doi:10.1016/j.vaccine.2023.07.043.

 PubMed Web of Science ®Google Scholar

Wagenhauser I, Reusch J, Gabel A, Hohn A, Lam TT, Almanzar G, Prelog M, Krone LB, Frey A, Schubert-Unkmeir A, et al. Immunogenicity and safety of coadministration of COVID-19 and influenza vaccination. Eur Respir J. 2023;61:61. doi:10.1183/13993003.01390-2022.

 Web of Science ®Google Scholar

Data availability statement

Please refer to GSK weblink to access GSK’s data sharing policies and as applicable seek anonymized subject level data via the link https://www.gsk-studyregister.com/en/.