ABSTRACT
The immunogenicity and safety of the concomitant administration of recombinant COVID-19 vaccine and quadrivalent inactivated influenza vaccine (Split Virion) (QIIV) in Chinese adults are unclear. In this open-label, randomized controlled trial, participants aged ≥ 18 years were recruited. Eligible healthy adults were randomly assigned (1:1) to receive QIIV at the same time as the first dose of COVID-19 vaccine (simultaneous-group) or 14 days after the second dose of COVID-19 vaccine (non-simultaneous-group). The primary outcome was to compare the difference in immunogenicity of QIIV (H1N1, H3N2, Yamagata, and Victoria) between the two groups. A total of 299 participants were enrolled, 149 in the simultaneous-group and 150 in the non-simultaneous-group. There were no significant differences in geometric mean titer (GMT) [H1N1: 386.4 (95%CI: 299.2–499.0) vs. 497.4 (95%CI: 377.5–655.3); H3N2: 66.9 (95%CI: 56.1–79.8) vs. 81.4 (95%CI: 67.9–97.5); Yamagata: 95.6 (95%CI: 79.0–115.8) vs. 74.3 (95%CI: 58.6–94.0); and Victoria: 48.5 (95%CI: 37.6–62.6) vs. 65.8 (95%CI: 49.0–88.4)] and seroconversion rate (H1N1: 87.5% vs. 90.1%; H3N2: 58.1% vs. 62.0%; Yamagata: 75.0% vs. 64.5%; and Victoria: 55.1% vs. 62.8%) of QIIV antibodies between the simultaneous and non-simultaneous groups. For the seroprotection rate of QIIV antibodies, a higher seroprotection rate of Yamagata antibody was observed only in the simultaneous-group than in the non-simultaneous-group [86.0% vs. 76.0%, p = .040]. In addition, no significant difference in adverse events was observed between the two groups (14.2% vs. 23.5%, p = .053). In conclusion, no immune interference or safety concerns were found for concomitant administration of COVID-19 vaccine with QIIV in adults aged ≥ 18 years.
Introduction
The novel coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a major public health problem worldwide.Citation1,Citation2 According to the World Health Organization, there have been more than 770 million confirmed cases of COVID-19 and more than 6.9 million deaths as of October 2023.Citation3 Vaccination against SARS-CoV-2 significantly reduces disease burden and mortality.Citation4,Citation5 The health risks of influenza during a COVID-19 pandemic cannot be ignored.Citation6,Citation7 Influenza is a common acute respiratory infection caused by the influenza virus, and most people get well without treatment, but it still causes more than 290,000 deaths each year.Citation8,Citation9 Influenza vaccination is used as a key influenza prevention strategy.Citation10
Improved immunization coverage is an important factor in effectively controlling the spread of the corresponding viruses.Citation11,Citation12 As mass vaccination with the COVID-19 vaccine continues worldwide, it will inevitably overlap with influenza vaccination programs. However, there should be an interval of at least 14 days between influenza vaccination and COVID-19 vaccination according to international recommendations.Citation13–15 The main reasons for separate vaccinations are concerns that concomitant vaccinations may affect the reactogenicity of the vaccine and that there is insufficient data to demonstrate the efficacy and safety of concomitant vaccination.Citation15 Separate vaccinations require multiple clinical visits, and additional clinical visits are inconvenient for many people, which may reduce adherence and thus vaccination rates. Simultaneous vaccination shortens the vaccination period, reduces the number of visits to health care providers, and minimizes missed opportunities for influenza vaccination especially for the older adults.Citation16 However, evidence on the immunogenicity and safety of concomitant administration of recombinant COVID-19 vaccine and influenza vaccine is limited.
Herein, this study aimed to investigate the immunogenicity and safety of concomitant administration of recombinant COVID-19 vaccine and influenza vaccine based on a phase 4 clinical trial.
Methods
Study design and participants
This single-center, open-label, randomized controlled trial was conducted at the Changning Center for Disease Control and Prevention, Hunan Province, China from September 3, 2021 to March 4, 2022. Participants were recruited from the community. This trail was registered at ClinicalTrials.gov (https://clinicaltrials.gov/, NCT05107375). This study was approved by the Ethics Committee of the Hunan Provincial Center for Disease Control and Prevention (No. IRB-PJ2021023), and all participants signed an informed consent form.
The inclusion criteria for participants were as follows: (1) participants aged ≥18 years; (2) voluntary participation in the study; and (3) participants with no pregnancy plans during the study period. Exclusion criteria were as follows: (1) participants with confirmed or asymptomatic SARS-CoV-2 infection or a positive history of SARS-CoV-2 nucleic acid testing; (2) participants with a history of SARS virus infection; (3) participants with axillary temperature ≥ 37.3°C; (4) participants with a history of severe allergy to any vaccine or allergy to test vaccine components and substances used in the manufacturing process (e.g., aluminum preparations, egg proteins, neomycin, formaldehyde, and TritonX-100); (5) participants with uncontrolled epilepsy and other serious neurological disorders (e.g., transverse myelitis, Guillain-Barre syndrome, demyelinating diseases); (6) participants with an acute illness, or an acute exacerbation of a chronic illness, or an uncontrolled severe chronic illness (e.g., hypertension that cannot be controlled by medication); (7) participants with an active autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, desiccation syndrome, etc.), congenital or acquired immunodeficiency, or malignant tumor; (8) participants without a spleen or with a history of spleen surgery; (9) participants treated with immunomodulators (e.g., glucocorticoids, monoclonal antibodies) in the 6 months prior to the trial; (10) participants who had received blood or blood-related products (rabies immune globulin, tetanus immune globulin) within 3 months prior to the trial vaccination; (11) participants who received subunit and inactivated vaccines within 7 days prior to the trial vaccination or live attenuated vaccines less than 14 days prior to the trial vaccination; (12) nursing or pregnant women; and (13) participants who have participated or are participating in SARS-CoV-2 related clinical trials.
Randomization and blinding
Participants were randomly assigned (1:1) to the simultaneous SARS-CoV-2 and quadrivalent inactivated influenza vaccine (Split Virion) (QIIV) vaccination group (simultaneous group) and the non-simultaneous SARS-CoV-2 and QIIV vaccination group (non-simultaneous group). Randomization was performed by the statistician using SAS statistical software to generate a random table to randomly assign subjects to the simultaneous group and the non-simultaneous group in a 1:1 ratio using the district group randomization method. The statistician produced random assignment cards at the same time as the randomization table, and subjects were given random assignment cards based on the order of inclusion, which was used to determine all the procedures to be carried out after the participants were randomly grouped. As this study was an open-label design, blinding was not applicable.
Interventions
The vaccines used in this study have all been approved for use in the general population. All participants were required to receive 3 doses of COVID-19 vaccine and 1 dose of QIIV during the study period. Vaccination was performed at the deltoid muscle of the participant’s upper arm. For participants in the simultaneous group, one dose of COVID-19 vaccine and one dose of QIIV in the contralateral arm were administered on day 0, a second dose of COVID-19 vaccine was administered on day 30, and a third dose of COVID-19 vaccine was administered on day 60. For participants in the non-simultaneous group, the first dose of COVID-19 vaccine was administered on day 0, the second dose of COVID-19 vaccine on day 30, one dose of QIIV on day 44, and the third dose of COVID-19 vaccine on day 60.
The recombinant COVID-19 vaccine (CHO cell) was produced by the Anhui Zhifei Longcom Biopharmaceutical Co., Ltd (Hefei, Anhui, China). Recombinant vaccines consist of genetically engineered subunits of a pathogen (e.g., surface proteins or polysaccharides) that stimulate the host immune system, together with an effective adjuvant and the necessary conjugate vectors, and are comprised of only a portion of the pathogen and do not contain or revert to the live pathogen.Citation17,Citation18 The COVID-19 vaccine was made from recombinant Chinese hamster ovary (CHO) cell-expressed SARS-CoV-2 virus spike glycoprotein receptor-binding region NCP-RBD protein, which was purified and added with aluminum hydroxide adjuvant. The COVID-19 vaccine (Lot number: A202107161) was injected with 0.5 mL (per dose) each time, containing 25 μg of NCP-RBD protein and 0.25 mg of aluminum hydroxide adjuvant. The QIIV was produced by the Jiangsu GDK Biological Technology Co., Ltd (Taizhou, Jiangsu, China). The QIIV (Lot number: A202106012V) was administered in doses of 0.5 ml (per dose), containing 15 μg of hemagglutinin for each of the two influenza A subtypes (H1N1 and H3N2) and each of the two influenza B viral lineages (Yamagata and Victoria).
Procedures
After participant enrollment, the investigator collected baseline characteristics of each participant by questionnaire or physical examination, including gender, age, ethnicity, weight, height, systolic blood pressure, diastolic blood pressure, axillary temperature, cardiopulmonary auscultation, skin examination, history of allergies, previous medications, previous vaccinations, and past/present medical history. Participants were injected with the appropriate vaccine according to their group. Two blood samples were collected from each participant: one before all vaccinations (day 0) and the other 30 days after QIIV vaccination (the simultaneous group on day 30 and the non-simultaneous group on day 73). The first sample on day 0 was used to measure the baseline QIIV-related antibodies. Both samples were used to measure QIIV-associated antibodies (H1N1, H3N2, Yamagata, and Victoria antibodies). Hemagglutination inhibition (HI) assay was used to detect QIIV antibody titer.Citation19 In addition, adverse events related to post vaccination were recorded.
Outcomes and definition
The primary outcome of this study was a comparison of QIIV immunogenicity between participants in the simultaneous group and the non-simultaneous group 30 days after QIIV vaccination. The secondary outcome was the incidence of vaccine-related adverse events reported during vaccination. The immunogenicity evaluation of QIIV included the geometric mean titer (GMT) and geometric mean increase (GMI) of QIIV antibodies (H1N1, H3N2, Yamagata, and Victoria), the seroconversion rate of QIIV antibodies, the seroprotection rate of QIIV antibodies, and the levels of QIIV antibodies. GMI is calculated as the GMT on day 30 after QIIV vaccination/GMT before QIIV vaccination. Seroconversion rate of QIIV antibodies was defined as: post-vaccination influenza antibody titers ≥ 40 for participants with pre-vaccination antibody titers < 10, and post-vaccination influenza antibody titers that reached a 4-fold or greater increase from pre-vaccination for participants with pre-vaccination antibody titers ≥ 10. Seroprotection rate of QIIV antibodies was defied as post-vaccination influenza antibody titers ≥ 40 for all participants.
Vaccine-related adverse events were monitored based on the World Health Organization manual for the Causality assessment of an adverse event following immunization (AEFI) (second edition).Citation20 Adverse events within 30 minutes, 7 days, and 30 days after vaccination were recorded by participants using a diary card. Investigators used a surveillance system on adverse events to collect participant-recorded adverse events within 1 month of vaccination. Adverse events at the vaccination site included erythema, pain, pruritus, swelling, induration, and rash. Systemic adverse events included fever, malaise, fatigue, headache, drowsiness, diarrhea, nausea, vomiting, cough, and myalgia. Vaccine-related adverse events were graded in accordance with the National Medical Products Administration’s Guidelines for Classification of Adverse Events in Clinical Trials of Preventive Vaccines (2019 edition).
Statistical analysis
For baseline characteristics, continuous variables were expressed as mean and standard deviation [mean ± SD] and categorical variables were expressed as frequencies and percentages [n (%)]. To determine differences between groups, t-tests, chi-square test or Fisher’s exact test were performed. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI) for the percentages (e.g., 95%CI for the seroprotection rate). Antibody titers and their multiplicity of increase were expressed as geometric means and 95% CI. The GMT was obtained by inverse logarithmic transformation of the mean of the logarithmic original titer, and its 95% CI was obtained by constructing a 95% CI for the mean of the logarithmic original titer by the WALD method, and then inverse logarithmic transformation was performed on the upper and lower bounds of this CI, respectively. In addition, the primary outcomes were also stratified by age group (18–59 years and ≥60 years). All statistical analyses were performed using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). P-value <.05 was considered statistically significant.
The data sets for this study included the full-analysis set (FAS), the per-protocol set (PPS), and the safety set (SS). The results of the analysis on the PPS dataset were used as the main results. FAS was defined as subjects who completed QIIV vaccination after randomization into groups, completed pre-vaccination blood collection, and had valid pre-vaccination immunogenicity results. PPS was defined as subjects who completed protocol-specified QIIV vaccination and COVID-19 vaccination, completed pre-vaccination and 30-day post-QIIV vaccination blood collection, and had valid immunogenicity results. SS was defined as subjects who had received at least one dose of vaccine.
Results
Baseline characteristics
Between September 3, 2021 and March 4, 2022, 317 individuals were recruited, of whom 18 were excluded, and 299 were randomly assigned to the simultaneous group (149 individuals) and the non-simultaneous group (150 individuals). In the simultaneous group, 147 (98.7%) participants completed the QIIV vaccination, 139 (92.7%) completed the full vaccination, and 134 (89.9%) completed the entire trial. In the non-simultaneous group, 143 (95.3%) participants completed the QIIV vaccination, 139 (93.3%) completed the full vaccination, and 137 (91.3%) completed the entire trial (). The number of participants who were lost to follow-up in the simultaneous group and the non-simultaneous group was 15 (10.1%) and 13 (8.7%), respectively. In addition, the number of participants in the FAS dataset and PPS dataset was: the simultaneous group [147 (98.7%) for the FAS and 136 (91.3%) for the PPS] and the non-simultaneous group [143 (95.3%) for the FAS and 121 (80.7%) for the PPS]. shows the baseline characteristics of participants in the FAS dataset, and the baseline characteristics of participants in the PPS dataset were shown in Supplement . The mean age in the simultaneous group and the non-simultaneous group was 48.2 ± 15.5 years and 46.7 ± 15.5 years, respectively. There were 78 (53.1%) males in the simultaneous group and 81 (56.6%) males in the non-simultaneous group. The mean body mass index (BMI) in the simultaneous group and the non-simultaneous group was 23.8 ± 3.2 kg/m2 and 23.8 ± 3.5 kg/m2, respectively.
Figure 1. Trial profile. The simultaneous group, receive QIIV at the same time as the first dose of COVID-19 vaccine; the non-simultaneous group, receive QIIV at 14 days after the second dose of COVID-19 vaccine; QIIV, quadrivalent inactivated influenza vaccine; FAS (the full-analysis set) was defined as subjects who completed QIIV vaccination after randomization into groups, completed pre-vaccination blood collection, and had valid pre-vaccination immunogenicity results; PPS (the per-protocol set) was defined as subjects who completed protocol-specified QIIV vaccination and COVID-19 vaccination, completed pre-vaccination and 30-day post-QIIV vaccination blood collection, and had valid immunogenicity results; SS (the safety set) was defined as subjects who had received at least one dose of vaccine; “*FAS,” one subject assigned to the non-simultaneous group was actually inoculated according to the simultaneous group procedure, and this subject was categorized as the non-simultaneous group in the FAS analysis and the simultaneous group in the PPS and SS analyses.
Table 1. Baseline characteristics of participants in the full-analysis set (FAS).
lists the titer of QIIV antibodies for participants in the PPS dataset before vaccination. In the simultaneous group, the GMT values for H1N1, H3N2, Yamagata, and Victoria antibodies were 15.8 (95%CI: 13.0–19.3), 15.3 (95%CI: 13.2–17.7), 12.0 (95%CI: 10.2–14.0), and 6.9 (95%CI: 6.2–7.7), respectively. In the non-simultaneous group, the GMT values for H1N1, H3N2, Yamagata, and Victoria antibodies were 20.7 (95%CI: 16.8–25.6), 16.5 (95%CI: 14.2–19.1), 11.5 (95%CI: 9.7–13.7), and 7.9 (95%CI: 6.7–9.3), respectively. There were no statistically significant differences in the antibody titer for H1N1, H3N2, Yamagata, and Victoria between the two groups (p > .05). Except for the number of people with H1N1 antibody titers ≥ 10, which was higher in the non-simultaneous group than in the simultaneous group [91 (75.2%) vs. 86 (63.2%), p = .039], the number of people with antibody titers ≥ 10 and antibody titers ≥ 40 of other subtypes and the corresponding GMT values were not statistically different between the two groups (p > .05).
Table 2. Titer of QIIV antibodies for participants in the per-protocol set (PPS) before vaccination.
Comparison of immunogenicity in two groups of participants 30 days after QIIV vaccination
presents the QIIV antibody titer for participants in the PPS dataset 30 days after QIIV vaccination. Among participants in the simultaneous group, the GMT values for H1N1, H3N2, Yamagata, and Victoria antibodies were 386.4 (95%CI: 299.2–499.0), 66.9 (95%CI: 56.1–79.8), 95.6 (95%CI: 79.0–115.8), and 48.5 (95%CI: 37.6–62.6), respectively. For participants in the non-simultaneous group, the GMT values for H1N1, H3N2, Yamagata, and Victoria antibodies were 497.4 (95%CI: 377.5–655.3), 81.4 (95%CI: 67.9–97.5), 74.3 (95%CI: 58.6–94.0), and 65.8 (95%CI: 49.0–88.4), respectively. No significant differences in H1N1, H3N2, Yamagata, and Victoria antibody titers were found between the two groups 30 days after QIIV vaccination (p > .05). In age-stratified analyses, significant differences were observed between the simultaneous and non-simultaneous groups in H1N1 (381.2 vs. 612.0, p = .027) and Victoria (48.3 vs. 79.4, p = .026) antibody titers for those aged 18–59 years. Furthermore, antibody titer for all four subtypes (H1N1, H3N2, Yamagata, and Victoria) showed at least a 4-fold increase 30 days after QIIV vaccination, and there was no significant difference in the multiplicity of increase between the simultaneous and non-simultaneous groups (p > .05).
Table 3. The QIIV antibody titer for participants in the PPS dataset 30 days after QIIV vaccination.
The seroconversion rates of antibodies after 30 days of QIIV vaccination in the PPS dataset was shown in . For participants in the simultaneous group, the seroconversion rates for H1N1, H3N2, Yamagata, and Victoria antibodies were 87.5% (95%CI: 80.7–92.5), 58.1% (95%CI: 49.3–66.5), 75.0% (95%CI: 66.9–82.0), and 55.1% (95%CI: 46.4–63.7), respectively. Among participants in the non-simultaneous group, the seroconversion rates for H1N1, H3N2, Yamagata, and Victoria antibodies were 90.1% (95%CI: 83.3–94.8), 62.0% (95%CI: 52.7–70.6), 64.5% (95%CI: 55.2–72.9), and 62.8% (95%CI: 53.6–71.4), respectively. No statistically significant difference in the seroconversion rates of H1N1, H3N2, Yamagata, and Victoria antibodies were found between the simultaneous and non-simultaneous groups (p > .05).
Table 4. The seroconversion rates of antibodies after 30 days of QIIV vaccination (PPS).
presents the seroprotection rate of the antibodies 30 days after QIIV vaccination in the PPS. There was significant difference in the seroprotection rate of the Yamagata antibody [simultaneous group: 86.0% (95%CI: 79.0–91.4) vs. non-simultaneous group: 76.0% (95%CI: 67.4–83.3), p = .040] between the two groups. In age-stratified analyses, there were significant difference in the seroprotection rate of the Yamagata antibody [simultaneous group: 92.5% (95%CI: 85.8–96.7) vs. non-simultaneous group: 79.6% (95%CI: 70.0–87.2), p = .007] and Victoria antibody [simultaneous group: 57.0% (95%CI: 47.1–66.5) vs. non-simultaneous group: 74.2% (95%CI: 64.1–82.7), p = .011] between the two groups for those aged 18–59 years.
Table 5. The seroprotection rate of the antibodies 30 days after QIIV vaccination (PPS).
The distribution of antibody titers before and 30 days after QIIV vaccination was shown in (Supplement ). For the distribution of HIN1 antibody titers, the GMT primary range of antibodies for participants in the ultaneous group was 80 to 5,120, with the largest number of participants having GMT values of 640–1,280 [30 (22.1%) individuals] and 1,280–2,560 [29 (21.3%) individuals]. The GMT primary range of HIN1 antibody titers for participants in the non-simultaneous group was 40 to 5,120, with the largest number of participants having GMT values of 640–1,280 [25 (22.7%) individuals] and 1,280–2,560 [25 (20.7%) individuals]. For the distribution of H3N2 antibody titers, the largest number of participants having GMT values of 40–80 [25 (22.7%) individuals] and 80–160 both in the simultaneous group and the non-simultaneous group. For the distribution of Yamagata antibody titers, the GMT values of the simultaneous group were mainly concentrated in the ranges of 80–160 [34 (25.0%) individuals] and 160–320 [32 (23.5%) individuals], and those of the non-simultaneous group were mainly concentrated in the ranges of 40–80 [29 (24.0%) individuals] and 160–320 [20 (16.5%) individuals]. For the distribution of Victoria antibody titers, the main range of GMT was 20 to 640 in the simultaneous group [20–40: 30 (22.1%) individuals; 160–320: 19 (14.0%) individuals] and 20 to 320 in the non-simultaneous group [80–160: 23 (19.0%) individuals; 160–320: 18 (14.9%) individuals]. In the total population, the distribution of titers of H1N1 (p = .174), H3N2 (p = .161), Yamagata (p = .081), and Victoria (p = .179) antibodies was not statistically significant different between the simultaneous group and the non-simultaneous group.
Figure 2. The distribution of antibody titers (H1N1, H3N2, Yamagata, and Victoria) before and 30 days after QIIV vaccination (PPS). (a) H1N1; (b) H3N2; (c) Yamagata; (d) Victoria. PPS, the per-protocol set; QIIV, quadrivalent inactivated influenza vaccine.
Safety assessment of the simultaneous group and non-simultaneous group
shows the incidence of vaccine-related adverse events during vaccination. Throughout the trial period, there were 21 participants in the simultaneous group who had a total of 49 adverse events, with an adverse event rate of 14.2%, and 35 participants in the non-simultaneous group who had a total of 97 adverse events, with an adverse event rate of 23.5%. There was no statistically significant difference in adverse events between the two groups (14.2% vs. 23.5%, p = .053). The most common adverse events in the simultaneous group were pain (5.4%) and itching (2.7%) at the vaccination site, fever (2.7%), diarrhea (2.7%), and headache (2.7%). For participants in the non-simultaneous group, the most common adverse events were pain (10.7%) and itching (6.7%) at the vaccination site, and fever (7.4%). Almost all adverse events occurred within 7 days of vaccination, with 14.2% in the non-simultaneous group and 23.5% in the non-simultaneous group. Among the different doses of vaccination, adverse events in the simultaneous group occurred mainly in the first vaccination (i.e., simultaneous COVID-19 and QIIV vaccination) (incidence 10.8%), and adverse events in the non-simultaneous group did not differ significantly among the three COVID-19 vaccinations [incidence: one dose (15.4%), second dose (11.2%), and third dose (10.1%)] (Supplement ).
Table 6. The incidence of vaccine-related adverse events during vaccination.
Discussion
This study reported on the immunogenicity and safety of QIIV when the recombinant COVID-19 vaccine concomitantly administered with QIIV among adults aged ≥18 years. Our results showed that both simultaneous or non-simultaneous vaccination with COVID-19 vaccine and QIIV induced sufficient immunogenicity of QIIV. In addition, there was no statistically significant difference in the incidence of adverse events between the simultaneous and non-simultaneous vaccination groups.
During the COVID-19 pandemic, influenza control and prevention play an important role for public health.Citation21,Citation22 In China, influenza epidemics and influenza-related deaths are mainly concentrated in the winter months (January-March and November-December), and influenza vaccination is the main preventive measure.Citation23 The efficacy and safety of concomitant vaccination with COVID-19 vaccine and influenza vaccine has become a concern. Previous large-sample randomized controlled trials have shown that two doses of COVID-19 vaccine significantly reduce the risk of symptomatic COVID-19 in adults.Citation24 Therefore, our study compared the immunogenicity and safety of the influenza vaccine between the group that received the influenza vaccine concurrently with the first dose of the COVID-19 vaccine and the group that received the influenza vaccine 14 days after the second dose of the COVID-19 vaccine. Our results revealed no statistically significant differences in antibody titers, multiplicative increase in antibody titers, and seroconversion rates between the simultaneous and non-simultaneous vaccination groups 30 days after influenza vaccination. The seroprotection rate of Yamagata antibody was higher in the simultaneous vaccination group than in the non-simultaneous vaccination group (86.0% vs. 76.0%), whereas the seroprotection rate of H1N1, H3N2, and Victoria antibodies was not significantly different between the two groups. Age-based stratified analyses found that the difference in the seroprotection rate by Yamagata antibody between the two groups was only observed in those aged 18–59 years, whereas no such difference was observed in those aged ≥60 years.
Studies of concomitant vaccination of influenza vaccine with different types of COVID-19 vaccines including recombinant COVID-19 vaccine,Citation25 inactivated COVID-19 vaccine,Citation26,Citation27 and adenoviral-vectored or mRNA COVID-19 vaccineCitation15,Citation28 have been reported. Toback et al. showed no difference was observed in GMT of antibodies to any of the influenza vaccines (H1N1, H3N2, Victoria, and Yamagata) between the recombinant COVID-19 vaccine plus influenza vaccine group and the placebo plus influenza vaccine group.Citation25 A study by Wang et al. on concomitant and separate vaccinations of inactivated COVID-19 vaccine and influenza vaccine demonstrated that only the seropositivity rate of H1N1 antibody decreased in the separate vaccination group (87.3% vs. 93.6%).Citation27 The distribution of antibody levels after immunization showed that the distribution of Yamagata antibody levels was not significantly different between the two groups, but the GMT of Yamagata antibody in the simultaneous group was more concentrated above 40. The study by Lazarus et al. did not observe significant differences in influenza antibody titers (H1N1, H3N2, Victoria, and Yamagata) between the simultaneous and non-simultaneous groups of the COVID-19 and influenza vaccines.Citation15 This may suggest that concomitant administration of the COVID-19 vaccine and influenza vaccine does not affect the immunogenicity of the influenza vaccine. Furthermore, regarding the safety of simultaneous vaccination, our study is consistent with previous studies in that simultaneous vaccination with COVID-19 vaccine and influenza vaccine did not result in significantly different adverse events compared to the non-simultaneous vaccination group. These results suggest that simultaneous vaccination of recombinant COVID-19 vaccine and QIIV is safe, well tolerated, and immunogenic.
This study compared differences in influenza vaccine immunogenicity and safety in the simultaneous vaccination of recombinant COVID-19 vaccine and influenza vaccine group and non-simultaneous vaccination group. Our study may provide additional clinical evidence for simultaneous vaccination with COVID-19 vaccine and influenza vaccine. However, our trial has some limitations. First, individuals under the age of 18 were not recruited for this study, and the applicability of the analyzed results to the under-18 population may require further study. Second, this study did not include a parallel control group that received only the COVID-19 vaccine or influenza vaccine, which may affect the interpretation of the absolute immune response to both the COVID-19 vaccine and influenza vaccine. Third, we only analyzed the effect of concomitant vaccination with recombinant COVID-19 vaccine and influenza vaccine on the immunogenicity of influenza vaccine, and we were unable to analyze the effect of concomitant vaccination on the immunogenicity of recombinant COVID-19 vaccine due to the lack of access to relevant data.
Conclusions
This study evaluated the safety of concomitant administration of recombinant COVID-19 vaccine and influenza vaccine and its effect on influenza vaccine immunogenicity. Our results demonstrated that no statistically significant differences in immunogenicity and safety were observed between the simultaneous group and non-simultaneous group. This suggests that simultaneous vaccination of recombinant COVID-19 vaccine and QIIV is safe, well tolerated, and immunogenic.
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JY and YZ are full-time employees of Jiangsu GDK Biological Technology Co., Ltd. TH, SZ, DT, DD, and LG have no conflicts of interest to report.
Supplementary data
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2330770.
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References
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