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

ABSTRACT

The objective of the study was to assess the safety and immunogenicity of mRNA-1273 COVID-19 booster vaccination when co-administered with an egg-based standard dose seasonal quadrivalent influenza vaccine (QIV). This was a phase 3, randomized, open-label study. Eligible adults aged ≥ 18 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and QIV 2 weeks apart (Seq group) or concomitantly (Coad group). Primary objectives were non-inferiority of haemagglutinin inhibition (HI) and anti-Spike protein antibody responses in the Coad compared to Seq group. 497/498 participants were randomized and vaccinated in the Seq/Coad groups, respectively. The adjusted geometric mean titer/concentration ratios (95% confidence intervals) (Seq/Coad) for HI antibodies were 1.02 (0.89–1.18) for A/H1N1, 0.93 (0.82–1.05) for A/H3N2, 1.00 (0.89–1.14] for B/Victoria, and 1.04 (0.93–1.17) for B/Yamagata; and 0.98 (0.84–1.13) for anti-Spike antibodies, thus meeting the protocol-specified non-inferiority criteria. The most frequently reported adverse events in both groups were pain at the injection site and myalgia. The 2 groups were similar in terms of the overall frequency, intensity, and duration of adverse events. In conclusion, co-administration of mRNA-1273 booster vaccine with QIV in adults was immunologically non-inferior to sequential administration. Safety and reactogenicity profiles were similar in both groups (clinicaltrials.gov NCT05047770).

Plain Language Summary

What is the context?

• Updated booster shots against COVID-19 disease are likely to offer more protection as the virus is changing over time.

• It is important for doctors, other healthcare providers and patients to know whether COVID-19 booster vaccines can be given at the same time as other vaccines recommended for adults.

What is new?

• The results of our study showed that an mRNA-based COVID-19 booster vaccine could be given at the same time as the seasonal influenza vaccine.

• When given together, both vaccines led to immune responses and had side effects that were similar to those observed when they were given at separate times.

What is the impact?

• The potential benefits of administering more than 1 vaccine during a healthcare visit include improved coverage and a reduced number of doctor visits needed to receive all vaccines.

• Co-administration of COVID-19 booster vaccines and influenza vaccines could be an attractive option for patients and healthcare professionals.

KEYWORDS:

• Co-administration
• COVID-19 vaccine
• immunogenicity
• influenza vaccine
• mRNA-1273

Introduction

Naturally occurring and vaccine-induced immunity to several respiratory viruses, including influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is short-lived.¹ Waning immunity, combined with the characteristic of both of these viruses to undergo frequent mutation and immune escape, means that regular booster vaccination with periodically modified vaccines that reflect predominant circulating strains is required for protection.^2,3 Annual booster vaccination against influenza has been recommended for high-risk groups for many decades, with recommendations expanding to include the broader population of children and adults in many countries.⁴ It has become apparent that an approach that is analogous to influenza control (i.e., regular seasonal vaccination with periodically modified vaccines), may be needed for long-term control of coronavirus disease 2019 (COVID-19).⁵ Booster vaccination against COVID-19 has therefore become an essential part of long-term COVID-19 control.^6–8 In parallel, recommendations for health authorities have evolved to include the provision that, in the absence of specific contraindications, COVID-19 booster doses can be administered on the same day as other vaccines, such as seasonal influenza vaccines.^9–12

There are numerous countries, including the United States (US), Canada, France, and Australia, that recommend influenza vaccination every season for all children (varying from the age of 6 months to 17 y) and adults.^13–16 Vaccine co-administration can reduce the number of healthcare visits required to complete the recommended schedule, and can provide health benefits for patients by improving vaccine uptake and coverage. However, there is a need for clinical data to support recommendations for COVID-19 and influenza vaccines across a broad range of commercially available influenza vaccines.¹⁷

We conducted a clinical trial to evaluate the safety and immunogenicity of co-administration of a booster dose of an mRNA COVID-19 vaccine with either an egg-based standard dose seasonal quadrivalent influenza vaccine (QIV) in adults aged ≥18 y, or the recombinant zoster vaccine in adults aged ≥50 y.¹⁸ The goal of the study was to assess immunological interference and changes to the reactogenicity and safety profile when mRNA COVID-19 booster vaccination was co-administered with other recommended vaccines compared to their sequential administration.

This study used a booster dose (50 μg) of mRNA-1273, which is a single mRNA sequence encoding the pre-fusion stabilized Spike (S) protein of SARS-CoV-2, Wuhan strain, encapsulated in a lipid nanoparticle. During the study, mRNA-1273 (50 μg) was approved as Spikevax (Moderna) as a booster dose for the prevention of COVID-19 in ≥6-month-olds in the European Union (EU) and was under Emergency Use Authorization in ≥18-year-olds in the US.^19,20

GSK’s QIV (Fluarix Quadrivalent) is indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine and is approved for use in persons aged ≥6 months.²¹ This study used the 2021–2022 Northern hemisphere QIV composition which contained the A/Victoria/2570/2019 [H1N1], A/Tasmania/503/2020 [H3N2], B/Washington/02/2019, and B/Phuket/3073/2013 influenza strains.

This study also evaluated co-administration of recombinant zoster vaccine and mRNA-1273 booster and the results pertaining to these groups have been reported previously.¹⁸ The results of co-administration of QIV and mRNA-1273 booster are reported here.

Patients and methods

Study design and participants

This phase 3, randomized, open-label, multi-center clinical trial was conducted at 47 sites in the US between 7 October 2021 and 29 August 2022 (clinicaltrials.gov NCT05047770). Participants were healthy or medically stable male or non-pregnant females aged ≥18 y who had a documented 2-dose mRNA-1273 primary vaccination series completed at least 6 months prior to the first study vaccination. Individuals with any history of myocarditis or pericarditis, Guillain-Barré syndrome, confirmed or suspected immunosuppressive or immunodeficient condition, or history of any reaction or hypersensitivity likely to be exacerbated by any component of the study interventions were excluded from participation. Receipt of a seasonal influenza vaccine during the 6 months preceding entry into the study was also an exclusion criterion.

Consenting participants were randomly assigned (1:1) to receive a booster dose of mRNA-1273 (50 µg) and a dose of QIV either co-administered on Day 1 (Coad group), or administered sequentially 2 weeks apart i.e., mRNA-1273 booster followed 2 weeks later by QIV (Sequential [Seq] group). Participants were stratified by age (18 to 64 and ≥65 y) and were centrally randomized to either group.

The study was conducted according to Good Clinical Practice guidelines. The protocol and associated documents were approved by all applicable institutional review boards. Each participant provided written informed consent prior to enrollment.

Objectives

The primary study objectives were to demonstrate non-inferiority in terms of humoral immunogenicity of (1) QIV when co-administered with an mRNA-1273 booster dose compared to QIV administered 2 weeks after mRNA-1273; and (2) of a mRNA-1273 booster when co-administered with QIV compared to its administration 2 weeks prior to QIV.

The key secondary objective was to demonstrate non-inferiority of the Coad vs. the Seq group’s humoral immune response to QIV in terms of seroconversion rates (SCRs) 1 month after vaccination. Other secondary immunogenicity, safety, and reactogenicity objectives are provided in the Supplement.

Study interventions and procedures

QIV contains 15 µg hemagglutinin antigen per strain in 0.5 mL and was administered via intramuscular injection into the left deltoid. mRNA-1273 was administered as a 0.25 ml dose containing 50 μg of mRNA administered as an intramuscular injection in the right deltoid.

Blood samples (15 ml) were collected before each vaccination, 4 weeks after the mRNA-1273 booster dose, and 4 weeks post-QIV. Hemagglutinin inhibition (HI) antibodies were measured for each influenza vaccine strain at Q² Solution laboratories. Anti-S immunoglobulin G antibodies were measured at PPD Laboratory Services using a Multiplex Electrochemiluminescence assay.

Reactogenicity and safety were assessed in all participants. Solicited local (pain, redness, swelling, and axillary swelling or tenderness) and systemic (fatigue, myalgia, headache, shivering/chills, fever, gastrointestinal symptoms [nausea, vomiting, abdominal pain, diarrhea], and arthralgia) adverse events (AEs) with onset within 7 d after each vaccination were recorded using electronic diaries. All other (unsolicited) AEs were recorded for 30 d after each vaccination. Serious adverse events (SAEs), AEs of special interest (AESIs, protocol-defined and listed in the Supplement), cases of COVID-19, and pregnancies were collected for 6 months after the last study vaccination. All solicited AEs were considered causally related to study vaccination. Causal relationships between all other AEs and vaccination were assessed by the investigators and independently by the sponsor. A safety review team comprised of representatives from GSK and Moderna oversaw participant safety during the study. As per protocol, randomization was temporarily paused for safety assessment after 5% of participants were vaccinated and had safety data for the first 7 d post-vaccination.

Study holding rules were defined in the protocol and are provided in the Supplement.

Statistical analysis

The assessment of reactogenicity was descriptive and conducted using the Exposed Set, which included all participants who received at least 1 dose of a study vaccine. The percentage of participants with at least 1 AE during the specified follow-up periods (Any or Grade 3) was calculated with exact 95% confidence intervals (CIs).

The frequency of solicited systemic AEs in the sequential group was calculated by counting for events occurring following mRNA-1273 or following QIV administered 2 weeks later. If the same event was reported by a participant after both mRNA-1273 and QIV, it was counted only once at maximum severity.

The assessment of immunogenicity was conducted using the Per-Protocol Set (PPS). The PPS included eligible participants who received all vaccinations according to their random assignment, did not receive prohibited medications/vaccines, complied with protocol-defined procedures, had post-vaccination immunogenicity data available, and where the administration site was known.

Geometric mean concentrations/titers (GMCs/GMTs) were calculated by taking the anti-log of the mean of the log concentration/titer transformations. HI antibody titers and anti-S protein antibody concentrations were expressed as between-group ratios of the GMTs/GMCs 1 month post-QIV and 1 month post-mRNA-1273 booster, respectively. The 95% CIs of the between-group GMT/GMC ratios were derived using an analysis of covariance model on the log10 transformation of the titers/concentrations. Pre-vaccination log-transformed antibody titers/concentrations and age strata were covariates, and vaccine group was a fixed effect.

Non-inferiority of the HI antibody response was demonstrated if the upper limit of the 95% CI of the adjusted GMT ratio (Seq over Coad) was <1.5, 1 month post-QIV for each influenza strain in QIV. Non-inferiority of the anti-S antibody response was demonstrated if the upper limit of the 95% CI of the adjusted GMC ratio (Seq over Coad) was <1.5, 1 month post-mRNA-1273 booster.

SCR was defined as the percentage of participants with either a pre-vaccination titer <1:10 and a post-vaccination titer ≥1:40, or a pre-vaccination titer ≥1:10 and a ≥4-fold greater post-vaccination titer. Non-inferiority was demonstrated if the upper limit of the 95% CI of the SCR difference between groups (Seq minus Coad) at 1 month post-QIV was <10% for each strain included in QIV.

Other descriptive immunogenicity analyses included assessment of seroprotection rates (SPRs), defined as the percentage of participants with a serum HI titer ≥1:40; mean geometric increase (MGI), defined as the within participant ratios of the post-vaccination to the pre-vaccination reciprocal HI titers or anti-S antibody concentrations, thereby representing fold-rises; immunogenicity by age stratum (18 to 64, ≥65 y); and according to Center for Biologics Evaluation and Research (CBER) criteria for licensure of seasonal inactivated influenza vaccines.²²

All statistical analyses were performed using SAS version 9.4.

Sample size

Assuming a GMC ratio of 1.1 (standard deviation [SD] 0.45) and GMT ratios of 1.04 (SD 0.6) for each influenza strain between the Seq and Coad groups, and an alpha of 2.5%, the global power to meet both co-primary objectives with 450 evaluable participants in the Seq and Coad groups was 91%. Assuming that approximately 10% of randomized participants would be excluded from the PPS, 500 participants in each study group were planned.

Results

Participants

A total of 1000 participants were randomized and 995 were vaccinated, 497 in the Seq group and 498 in the Coad group (Exposed Set). Forty-nine participants withdrew from the study, 22 (4.4%) in the Seq group and 27 (5.4%) in the Coad group. There were no withdrawals due to AEs (Figure 1).

Figure 1. Participant flow.

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

Study groups were well balanced in terms of demographic characteristics (Table 1). The median age of participants was 48 y (range 19–88 y) and 20.7% were aged ≥65 y. Among all participants, 42.1% were male, 87.5% were White, 5.8% were Black, 3.2% were Asian, and 16.5% were Hispanic.

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.

Immunogenicity: QIV

Non-inferiority of the humoral immune response in terms of HI antibody responses was demonstrated according to the protocol-specified criteria. For the PPS, the adjusted GMT ratio (Seq over Coad) for HI antibodies was 1.02 (95% CI, 0.89–1.18) for A/H1N1, 0.93 (95% CI, 0.82–1.05) for A/H3N2, 1.00 (95% CI, 0.89–1.14] for B/Victoria and 1.04 (95% CI, 0.93–1.17] for B/Yamagata (Figure 2).

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).

The success criterion for non-inferiority was also met for the Exposed set. The adjusted GMT ratio (Seq over Coad) for HI antibodies was 1.03 (95% CI, 0.89–1.18) for A/H1N1, 0.94 (95% CI, 0.84–1.06) for A/H3N2, 1.00 (95% CI, 0.89–1.13] for B/Victoria and 1.05 (95% CI, 0.94–1.17] for B/Yamagata (Table S1).

The key secondary objective was met. Non-inferiority of the HI antibody response was demonstrated 1 month following QIV administration, the upper limit of the 95% CIs for the difference in SCRs between the Seq and Coad groups was <10% for all influenza virus vaccine strains (Table S2).

The MGI in HI antibody titers relative to pre-vaccination levels was similar in the Seq and Coad groups for all influenza viral strains; 9.20 and 9.38 for A/H1N1, 3.78 and 4.23 for A/H3N2, 2.68 and 2.70 for B/Victoria, and 2.36 and 2.38 for B/Yamagata, respectively (Table S2).

SPRs 1 month after QIV administration were also similar between the Seq and Coad groups; 98.9% and 98.5% for A/H1N1, 96.9% and 95.7% for A/H3N2, 63.2% and 64.7% for B/Victoria, and 68.3% and 65.6% for B/Yamagata strains, respectively (Table S2).

The SPR and SCR at 1 month following the QIV dose met CBER criteria²² for the 18–64 and the ≥65 year age categories for A/H1N1 and H3N2 in both the Seq and Coad groups (Table S3).

Immunogenicity: mRNA-1273 booster

Non-inferiority of the humoral immune response in terms of anti-S antibodies 1 month after vaccination was demonstrated according to the protocol-specified criteria. For the PPS, the adjusted GMC ratio was 0.98 (95% CI, 0.84–1.13) for anti-S antibodies 1-month post-mRNA-1273 booster (Figure 2). In a secondary analysis on the Exposed Set, the corresponding GMC ratio was 0.98 (95% CI, 0.85–1.13) (Table S4).

One month post-mRNA-1273 booster, the MGI in anti-S antibodies was 14.78 in the Seq group and 14.71 in the Coad group (Table S5).

Safety results

Solicited local and systemic AEs

The frequency of any or Grade 3 intensity solicited local AEs was similar in both study groups, with the exception of local pain at the injection site, which was reported more frequently at the QIV injection site in the Coad group (Figure 3). Injection site pain was the most frequent solicited local AE for both mRNA-1273 (Seq group 75.8%¸ Coad group 71.8%) and QIV (Seq group 30.6%, Coad group, 48.1%) vaccines. The median duration of each solicited local AE was 1 to 2 d for both the mRNA-1273 booster and QIV, and was similar for both study groups.

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.

The most frequently reported Grade 3 local AE was injection site pain reported in 1.4% of participants in the Seq group and 3.0% in the Coad group for mRNA-1273, and in less than 1% of participants in either group for QIV (Figure 3). The median duration of each Grade 3 solicited AE was 1 day for both vaccines, except for a single event of redness of 3 d’ duration for QIV.

The frequency of any or Grade 3 solicited systemic AEs was similar in both study groups. The most frequently reported solicited systemic AEs in the Seq and Coad groups, respectively, were myalgia (64.3% and 58.8%), fatigue (63.7% and 57.7%), headache (51.0% and 46.7%), gastrointestinal symptoms (39.5% and 27.8%), chills (33.1% and 29.2%), and arthralgia (30.8% and 29.8%) (Figure 3).

Grade 3 solicited systemic symptoms were reported for 10.9% of participants in the Seq group and 10.1% in the Coad group, most frequently fatigue (7.5% and 6.8%, respectively), and myalgia (4.4% and 4.4%, respectively) (Figure 3). The median duration of each solicited systemic AE (any or Grade 3) was from 1 to 3 d and similar for both study groups.

Other AEs

Unsolicited AEs occurring within 30 d of any study vaccination were reported by 43.1% of participants in the Seq group and 36.9% in the Coad group (Table S6). Unsolicited AEs assessed by the investigator as causally related to study vaccination were reported for 6.2% of participants in the Seq group and 4.4% of participants in the Coad group. Unsolicited AEs assessed as related and reported by at least 1% (n = 5) of the participants in either study group were headache (3.6% and 1.6%), fatigue (3.4% and 1.4%), diarrhea (1.4% and 1.0%), nausea (1.6% and 1.0%), abdominal pain (1.0% and < 1%), chills (1.0% and < 1%), arthralgia (1.2% and < 1%), and myalgia (1.6% and 1.2%) in the Seq and Coad groups, respectively. There were 8 participants (1.6%) in the Seq group and 5 (1.0%) in the Coad group who reported Grade 3 unsolicited AEs within 30 d of any dose, of which 1 participant with abdominal pain, nausea, and diarrhea, and 1 participant with abdominal pain, both in the Seq group, having their events being assessed by the investigator as causally related to QIV (Table S7).

Seven participants in the Seq group and 2 in the Coad group reported SAEs, none of which was assessed by the investigator or sponsor as causally related to study vaccinations (Table S8). One participant only (Coad group) reported AESIs (ageusia and anosmia) that occurred more than 30 days after vaccination at the time of suspected COVID-19. Both symptoms resolved and were assessed as not related to the study vaccines by the investigator. There were no deaths during the study.

COVID-19 was reported for 7.0% of participants in the Seq group and 5.8% in the Coad group. All were mild to moderate infections except for 1 severe infection in a participant in the Seq group with onset 169 d after QIV administration.

Two participants in the Seq group became pregnant during the study. One participant experienced a spontaneous abortion 40 d after QIV administration reported as an SAE and assessed by the Investigator as unrelated to vaccination, and 1 underwent an elective termination (no apparent congenital abnormality) 64 d after QIV administration.

Discussion

This study builds on a growing body of evidence supporting the co-administration of COVID-19 booster doses with age-appropriate routine vaccinations. This study showed that mRNA-1273 and an egg-based standard dose QIV induced robust immune responses when co-administered or when administered sequentially. Non-inferiority was demonstrated for HI and anti-S antibody responses, confirming an absence of evidence for immune interference upon co-administration compared to sequential administration.

There are currently no validated mechanistic correlates of protection for HI antibodies and anti-S antibodies. For influenza vaccines, reciprocal HI antibody titers ≥ 40 have been associated with protection from influenza illness in at least 50% of adult participants in some human challenge studies.²³ For COVID-19 vaccines, available evidence supports a role for anti-S antibodies and protection.^24,25 HI and anti-S antibodies as measured in this study have therefore been considered as surrogate endpoints likely to predict clinical efficacy for the study vaccines.

There was an age-related reduction in immunogenicity to QIV that was similar in both study groups. CBER has defined serological criteria to be met for at least 1 vaccine strain for licensure of seasonal inactivated influenza vaccines based on SPR and SCR,²² The SPRs and SCRs 1 month following the QIV dose met the CBER criteria for both age categories (18 to 64 and ≥65 y) for the A/H1N1 and H3N2 strains which historically contribute most to morbidity and mortality. CBER criteria were not met for either influenza B strain, which has been observed in other studies of trivalent and QIVs.^26,27

Different periods of follow-up for solicited AEs in the Seq versus Coad groups may be one reason why reported rates of several AEs were numerically higher in the Seq group. The reactogenicity profiles of the mRNA-1273 booster and QIV dose were consistent with the Reference Safety Information for each vaccine.^20,28 We observed an increase in the frequency of pain at the QIV injection site in Coad group that was mainly of mild to moderate intensity. There was no increase in Grade 3 pain or in the duration of reported pain compared with the Seq group. This modest increase in frequency of this expected reaction is not considered of clinical concern and is consistent with evidence that pain can intensify with each subsequent injection, leading to recommendations to inject the most painful vaccine last^29,30 Thus, there was no evidence that co-administration of the mRNA-1273 booster and QIV resulted in any changes to the safety profile that were of clinical concern than when the 2 vaccines were administered sequentially. This observation is supported by a recent report on COVID-19 and seasonal influenza vaccine co-administration from the US Vaccine Adverse Event Reporting System, which concluded that co-administration of the first mRNA COVID-19 booster dose (Moderna or Pfizer-Biotech) and seasonal influenza vaccines did not reveal any unusual or unexpected pattern of AEs.³¹

mRNA COVID-19 boosters co-administered with different seasonal influenza vaccines has been assessed in nine studies, including randomized controlled trials, observational studies, and one study of vaccine effectiveness (Table 2). Results varied: two out of three randomized controlled trials met predefined non-inferiority criteria for anti-S antibodies.^32–34 On the other hand, three non-randomized studies conducted in healthcare workers showed between 16% and 25% reductions in anti-S antibodies when mRNA-1273 or BNT162b2mRNA was co-administered with QIVs.^37,38,40 Two of the studies used a preference-based study design that allowed individuals to choose if they received co-administered QIV. An observational study of vaccine efficacy that also used a preference-based design showed that co-administration had no effect on the risk of breakthrough SARS-CoV-2 infections.³⁹ Thus, the clinical significance of these findings and the underlying reasons for the disparate results observed in co-administration studies are not currently known and require further research. Of note, none of the studies reported any safety concerns associated with co-administration (Table 2).

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.

Little is known about the impact of co-administration on immunogenicity in vaccine-naïve individuals. To our knowledge there have been three reports of co-administration of COVID-19 vaccines with seasonal influenza vaccines in SARS-CoV-2-naïve individuals, none of which used mRNA vaccines.^41–43 We are not aware of any studies in influenza vaccine-naïve individuals. This is an area for further research, although the logistics of enrolling sufficient unexposed/unvaccinated individuals could be challenging.

Strengths of this study are its randomized and controlled design appropriately powered to conclude on both COVID-19 vaccine and QIV immunological endpoints. The open-label design is a potential limitation that could have led to bias in attribution of causality of AEs but is unlikely to have impacted immunogenicity findings. Future mRNA COVID-19 vaccines are expected to be formulated using the same mRNA platform, which means that a different immunological response or safety profile is not expected. The major challenge we envisage for the future is neither new nor unique to COVID-19 vaccinations but relates to the continuing challenge of maintaining public confidence in vaccines and achieving high uptake.

In conclusion, this study showed no concerns about safety and an absence of immunologic interference when a booster dose of the COVID-19 mRNA-1273 vaccine was co-administered with QIV in adults. These data build on previous studies that have assessed co-administration of COVID-19 booster doses with seasonal influenza vaccines and provide reassurance to health care providers that COVID-19 vaccines can be administered at the same time as other recommended vaccines. Moving forward after the pandemic,⁵ co-administration of age-appropriate, recommended vaccines at a single clinic visit could be beneficial, by increasing coverage rates leading to a decrease in morbidity and mortality due to vaccine preventable diseases.

Author contributions statement

All authors participated in the design or implementation or analysis, and interpretation of the study, and the development of this manuscript. All authors had full access to the data and gave final approval before submission.

Trademark statement

Fluarix is a trademark owned by or licensed to GSK.

Spikevax is a trademark of Moderna.

Patient consent statement

The study was conducted according to Good Clinical Practice guidelines and the protocol was approved by all applicable institutional review boards. Written informed consent was obtained from each participant prior to enrollment.

Acknowledgments

The authors thank the participants, site personnel and investigators who took part in the study. The authors also thank PPD (part of Thermo Fisher Scientific), Moderna, and GSK project team members for their contribution to the study and/or development of the manuscript, especially Amy Page (GSK), Marta Palla (GSK), Tomas Mrkvan (GSK). The authors also thank Business & Decision Life Sciences Medical Communication Service Center for editorial assistance and manuscript coordination, on behalf of GSK. Dr Joanne Wolter (independent, on behalf of GSK) provided writing support.

Disclosure statement

Abdi Naficy is employed by GSK and holds shares in GSK. Adrienne Kuxhausen is employed by GSK. Harry Seifert is employed by GSK and holds shares in GSK. Andrew Hastie is employed by GSK and holds shares in GSK. Brett Leav is employed by Moderna and holds shares in Moderna. Jacqueline Miller was employed by the GSK until May 2020 and is now employed by Moderna. Jacqueline Miller also reports she holds shares in GSK and Moderna. Kate Anteyi is employed by Moderna and holds shares in Moderna. Agnes Mwakingwe-Omari is employed by GSK and holds shares in GSK. All authors declare no other financial and non-financial relationships and activities or conflict of interest.

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/.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2327736

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this study and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also took in charge all costs associated with the development and publishing of this manuscript.