Evaluating a multi-vaccine respiratory immunization strategy involving SARS-CoV-2, pneumococcal, and influenza vaccines in adults: A randomized, open-label, multicenter, controlled, non-inferiority Phase IV trial in China

Xuanwen Shi; Shasha Han; Cong Wu; Xuejuan Wang; Jiao Huang; Wei Chen; Xiaoqin Liu; Sheng Wei; Jun Liu; Xiang Guo; Chenhao Wang; Shengyi Wang; Min Zhang; Xue Guo; Wei Zhao; Haiping Chen; Qingliang Li

doi:10.1080/21645515.2026.2747495

. 2026 Oct 21;22(1):2747495. doi: 10.1080/21645515.2026.2747495

Evaluating a multi-vaccine respiratory immunization strategy involving SARS-CoV-2, pneumococcal, and influenza vaccines in adults: A randomized, open-label, multicenter, controlled, non-inferiority Phase IV trial in China

Xuanwen Shi ^a,^*, Shasha Han ^a,^*, Cong Wu ^b,^c,^*, Xuejuan Wang ^b,^c, Jiao Huang ^d, Wei Chen ^b,^e, Xiaoqin Liu ^a, Sheng Wei ^f, Jun Liu ^b,^c, Xiang Guo ^b,^c, Chenhao Wang ^g, Shengyi Wang ^a, Min Zhang ^h, Xue Guo ^g, Wei Zhao ^h, Haiping Chen ^a, Qingliang Li ^b,^e,^✉

^aMedical Affairs Department, China National Biotec Group Company Limited, Beijing, China

^bWuhan Institute of Biological Products Co., Ltd., Wuhan, China

^cNational Engineering Technology Research Center for Combined Vaccines, Wuhan, China

^dCenter for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

^eNational Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases, Wuhan, China

^fTongji Medical College, Huazhong University of Science and Technology, Wuhan, China

^gMedical Affairs Department, Changchun Institute of Biological Products Co., Ltd., Changchun, China

^hMedical Affairs Department, Chengdu Institute of Biological Products Co., Ltd., Chengdu, China

^✉

CONTACT Qingliang Li qingll26123@gmail.com Wuhan Institute of Biological Products Co., Ltd., Wuhan 430207, China; National Key Laboratory for Novel Vaccines Research and Development of Emerging Infectious Diseases, Wuhan 430207, China

Co-first author

Roles

Xuanwen Shi: Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

Shasha Han: Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

Cong Wu: Investigation, Writing – original draft, Writing – review & editing

Xuejuan Wang: Conceptualization, Writing – review & editing

Jiao Huang: Data curation, Formal analysis, Methodology, Visualization, Writing – review & editing

Wei Chen: Writing – review & editing

Xiaoqin Liu: Investigation, Writing – review & editing

Sheng Wei: Data curation, Formal analysis, Methodology, Writing – review & editing

Jun Liu: Investigation, Visualization, Writing – review & editing

Xiang Guo: Investigation, Visualization, Writing – review & editing

Chenhao Wang: Investigation, Writing – review & editing

Shengyi Wang: Investigation, Writing – review & editing

Min Zhang: Investigation, Writing – review & editing

Xue Guo: Investigation, Writing – review & editing

Wei Zhao: Investigation, Writing – review & editing

Haiping Chen: Conceptualization, Methodology, Writing – review & editing

Qingliang Li: Supervision, Funding acquisition, Writing – review & editing

PMCID: PMC13690285 PMID: 42904667

ABSTRACT

Co-administration of vaccines targeting multiple respiratory pathogens may enhance coverage and streamline adult immunization programs. We conducted a randomized, multicentre, open-label Phase IV trial registered at Chinese Clinical Trial Registry (ChiCTR2100046227) in China to evaluate the immunogenicity and safety of co-administering an inactivated SARS-CoV-2 vaccine (WIBP-CorV) with the 23-valent pneumococcal polysaccharide vaccine (PPV23) and a quadrivalent inactivated influenza vaccine (IIV4). A total of 1,404 adults aged ≥ 18 year, including equal numbers of adults aged 18–59 year and ≥60 year, were randomized 1:1:1 to receive WIBP-CorV + PPV23 on Day 0 followed by WIBP-CorV + IIV4 on Day 28, WIBP-CorV alone on Days 0 and 28, or PPV23 on Day 0 followed by IIV4 on Day 28. Co-administration preserved humoral immune responses across vaccine platforms. Non-inferiority in geometric mean titers or concentrations was demonstrated for SARS-CoV-2 neutralizing antibodies and pneumococcal serotype-specific IgG responses. Seroconversion rates were non-inferior to those following separate administration for all pneumococcal serotypes, though results were less consistent for SARS-CoV-2 (after the second dose) and influenza A(H1N1). Age-stratified analyses showed age- and strain-specific non-inferiority findings that should be interpreted cautiously. Co-administration demonstrated an acceptable safety profile, with only slightly higher rates of mild, transient local reactions and no vaccine-related serious adverse events (SAEs). These findings support the feasibility of co-administering WIBP-CorV with PPV23 and IIV4 while maintaining immunogenicity and safety in adults represented in this study.

Trial registration The study was registered in the Chinese Clinical Trial Registry (ChiCTR) under registration number ChiCTR2100046227.

KEYWORDS: Co-administration, SARS-CoV-2 vaccine, PPV23, IIV4, immunogenicity, safety

HIGHLIGHTS

A Phase IV trial evaluated co-administration of COVID-19, PPV23 and IIV4.
Co-administration preserved immunogenicity across multiple vaccine platforms.
Non-inferiority was achieved for most predefined immunogenicity endpoints.
No vaccine-related serious adverse events were observed.
Findings support integrated adult respiratory vaccination strategies.

Introduction

Respiratory infectious diseases such as coronavirus disease 2019 (COVID-19), seasonal influenza, and pneumococcal infection continue to exact a tremendous global toll. As of March 2023, over 760 million cases of COVID-19 and 6.8 million associated deaths had been reported worldwide, and COVID-19 remained a global health threat.^1,2 Influenza viruses cause up to 5 million severe cases of seasonal influenza and 290,000–650,000 influenza-associated respiratory deaths each year, while pneumococcal disease is a leading cause of pneumonia and sepsis – responsible for about one million child deaths annually (mostly in developing countries) and substantial pneumonia mortality in older adults, underscoring that these three infections rank among the leading causes of infectious disease mortality worldwide.^3–5

Vaccination is the most effective and cost-effective strategy to prevent COVID-19, influenza, and pneumococcal disease. Immunization programs save millions of lives each year and are among the best investments in public health.⁶ For example, COVID-19 vaccines have drastically reduced pandemic mortality – modeling estimates suggest that vaccination averted roughly 14–20 million deaths globally in 2021.^7,8 Likewise, annual influenza vaccination remains the best way to avert severe flu illness and associated hospitalizations, and pneumococcal vaccines have significantly reduced invasive pneumococcal disease and pneumonia in high-risk groups.^9,10 Thus, broad vaccine coverage against these pathogens is critical to curb their disease burden.

In recognition of these benefits, WHO and many countries now promote co-administration of vaccines, as giving all needed shots in the same visit improves convenience, immunization efficiency, and community protection.^11,12 WHO notes that administering COVID-19 and influenza vaccines together can streamline campaigns without safety or efficacy concerns.¹³ Immunization authorities (e.g., the U.S. ACIP) similarly advise offering multiple vaccines at once to minimize visits and close immunity gaps.¹⁴ Integrated adult vaccination strategies not only improve coverage but also strengthen preparedness for future respiratory epidemics; for example, robust influenza vaccine programs reduce annual flu burden and improve readiness for threats like COVID-19.¹⁵ Developing combined vaccine approaches for adults is therefore an important step to reinforce defenses against respiratory pathogens.

Because older adults and those with chronic conditions are at highest risk for severe influenza and pneumococcal disease, many countries already recommend both influenza and pneumococcal vaccines in these groups, often administered together.^16–18 The addition of COVID-19 vaccines to adult schedules raises questions about co-administering them with these other vaccines. Limited evidence is available so far, but initial studies are encouraging: a UK trial found no safety issues or immune interference when an mRNA (BNT162b2) or adenoviral COVID-19 vaccine (ChAdOx1) was co-administered with a flu shot, and a phase IV clinical trial in China reported that giving an inactivated COVID-19 vaccine with influenza on Day 0 and PPV23 on Day 28 was immunogenic and safe in adults.^19,20 However, these studies were relatively small or population-specific, and comprehensive evidence from large randomized trials in a general adult population remains limited.

Here we report a large multicenter trial in China evaluating co-administration of WIBP-CorV with IIV4 or PPV23 vaccines in adults across age subgroups. Therefore, we conducted a large, randomized, multicenter, open-label, controlled, non-inferiority Phase IV trial in China to evaluate the immunogenicity and safety of co-administering WIBP-CorV with PPV23 on Day 0 and with IIV4 on Day 28 in adults aged ≥ 18 years, including predefined age groups of 18–59 years and ≥60 years.

Methods

Trial design

This was a randomized, open-label, multicenter, controlled, non-inferiority Phase IV clinical trial conducted in China. Healthy adults aged ≥ 18 years were enrolled at three provincial study centers (Hubei, Guangdong, and Henan). The study protocol was approved by the ethics committees of the Hubei Provincial Center for Disease Control and Prevention (Hubei Academy of Preventive Medicine; approval no. 2021–008-02), the Guangdong Provincial Center for Disease Control and Prevention (approval no. 2019V005-E08), and the Henan Provincial Center for Disease Control and Prevention (approval no. 2021-YM-008–01), as well as by the China National Human Genetic Resources Administration (approval no. [2021]CJ1085). The trial was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Written informed consent was obtained from all participants prior to any study-related procedures. All vaccinations were administered by trained and qualified healthcare professionals in accordance with the study protocol. This trial was registered at Chinese Clinical Trial Registry (ChiCTR2100046227).

Participants

Eligible participants were healthy Chinese adults aged ≥ 18 years at enrollment who were able to comply with study procedures and attend all scheduled follow-up visits. Key inclusion criteria included provision of written informed consent; no prior receipt of any pneumococcal or COVID-19 vaccine; no seasonal influenza vaccination during the current influenza season prior to enrollment; and an interval of at least 14 d since receipt of any other vaccine. Screening assessments required a normal medical history and physical examination, including an axillary temperature < 37.3°C.

Key exclusion criteria for the first dose included a previous diagnosis of COVID-19 or a documented history of a positive SARS-CoV-2 nucleic acid test; personal or family history of vaccine hypersensitivity, seizures, epilepsy, or neurological or psychiatric disorders; known severe allergy or contraindication to vaccination; immunodeficiency or receipt of nonspecific immunoglobulin within one month prior to enrollment; acute febrile or infectious illness; or active infectious, suppurative, or allergic skin disease. Before enrollment, all participants were required to provide a negative SARS-CoV-2 nucleic acid test result. Additional exclusion criteria for administration of the second dose included any SAE related to a study vaccine after the first dose or the occurrence of any condition meeting first-dose exclusion criteria.

Vaccines

The inactivated SARS-CoV-2 vaccine (Vero cell) (WIBP-CorV; 0.5 mL per dose, lot no. 202,102,034, expiry 20 February 2024) was manufactured by Wuhan Institute of Biological Products Co., Ltd. (Sinopharm) and contained 200 WU of inactivated SARS-CoV-2 antigen per dose with aluminum hydroxide as an adjuvant. The 23-valent pneumococcal polysaccharide vaccine (PPV23; 0.5 mL per dose, lot no. 20,200,734, expiry 27 July 2022) was manufactured by Chengdu Institute of Biological Products Co., Ltd. and contained 25 μg of purified capsular polysaccharide from each of 23 Streptococcus pneumoniae serotypes per dose. The split-virion quadrivalent inactivated influenza vaccine (IIV4; 0.5 mL per dose, lot no. Q20200925, expiry 6 September 2021) was manufactured by Changchun Institute of Biological Products Co., Ltd. and contained 15 μg of hemagglutinin from each of four influenza strains (A(H1N1), A(H3N2), B/Yamagata, and B/Victoria) per dose. All vaccines were administered intramuscularly.

Outcomes

Primary immunogenicity endpoints were as follows: (1) seroconversion rates and neutralizing antibody titers against SARS-CoV-2 at Days 28 and 56 in the co-administration group compared with the WIBP-CorV-only group; (2) seroconversion rates and serotype-specific IgG concentrations for 23 pneumococcal serotypes at Day 28 in the co-administration group compared with the PPV23/IIV4-only group; and (3) seroconversion rates and hemagglutination inhibition (HI) antibody titers against influenza strains at Day 56 in the co-administration group compared with the PPV23/IIV4-only group.

Secondary endpoints included safety outcomes, including the incidence of solicited adverse events (AEs) within 7 days after each dose, unsolicited AEs within 28 days after each dose, and SAEs during the 6-month follow-up period, as well as immunogenicity analyses stratified by age group (18–59 years vs. ≥60 years).

Sample size

Sample size calculations for non-inferiority testing of immunogenicity endpoints were performed using PASS version 11. Based on Phase III data for the quadrivalent influenza vaccine, the lowest observed seroconversion rate (74.15% for the B/Victoria strain in adults aged < 60 years) and the largest standard deviation of log-transformed H1N1 geometric mean titers (GMTs) (0.63) were applied. Assuming a one-sided significance level (α) of 0.025, 90% power, and a non-inferiority margin (δ) of 10%, a minimum of 404 participants per group was required for seroconversion rate analyses, and 271 participants per group for GMT-based analyses. Allowing for an anticipated dropout rate of 15%, the target enrollment was set at 468 participants per group, yielding a total sample size of 1,404 participants.

Randomization

Participants were randomized in a 1:1:1 ratio to one of three study groups: (a) co-administration group (WIBP-CorV + PPV23 on Day 0, and WIBP-CorV + IIV4 on Day 28); (b) WIBP-CorV-only group (WIBP-CorV on Days 0 and 28); or (c) PPV23/IIV4-only group (PPV23 on Day 0 and IIV4 on Day 28). Participants were prospectively stratified into two predefined age groups (18–59 years and ≥60 years), with approximately equal allocation to each age stratum, before randomization. A stratified block randomization scheme was used, with stratification by age group and study center. An independent statistician generated the randomization sequence. Investigators enrolling participants had access to the pre-generated randomization list and assigned allocation codes sequentially according to the order of participant enrollment. Allocation codes were not reused.

This was an open-label trial; participants and vaccinators were aware of group assignment. Laboratory personnel and statisticians performing immunogenicity and safety analyses were blinded to treatment allocation.

Immunogenicity assessments

Blood samples were collected at baseline (Day 0, prior to vaccination), Day 28, and Day 56. Baseline samples were used to determine pre-vaccination serostatus. Samples collected approximately 28 days (±5 d) after Dose 1 were used to assess SARS-CoV-2 neutralizing antibodies and pneumococcal serotype-specific IgG antibodies. Samples collected approximately 28 days (±5 d) after Dose 2 were used to assess SARS-CoV-2 neutralizing antibodies and influenza strain-specific antibodies.

SARS-CoV-2 neutralizing antibodies were measured using a plaque reduction neutralization test (PRNT) at the Wuhan Institute of Virology, Chinese Academy of Sciences. Seroconversion was defined as a ≥ 4-fold increase in neutralizing antibody titers from baseline. Pneumococcal IgG antibodies were measured by enzyme-linked immunosorbent assay (ELISA) at Chengdu Institute of Biological Products Co., Ltd., with seroconversion defined as a ≥ 2-fold increase in serotype-specific IgG concentration from baseline for each serotype. Influenza antibodies were measured by hemagglutination inhibition (HI) assay at the Virology Laboratory of the Jilin Provincial Center for Disease Control and Prevention. An HI titer ≥ 1:40 was considered seropositive. Influenza seroconversion was defined as a change from a pre-vaccination titer < 1:10 to a post-vaccination titer ≥ 1:40, or a ≥ 4-fold increase for participants with baseline titers ≥ 1:10.

Safety assessments

After each vaccination, participants were provided with diary cards to record solicited local and systemic AEs for 7 days and unsolicited AEs and concomitant medication use for 28 days post-vaccination. Safety data were collected through scheduled telephone or on-site follow-up visits and supplemented by passive surveillance via the China CDC Adverse Events Following Immunization (AEFI) reporting system for SAEs up to 6 months after vaccination.

Solicited local AEs included injection-site pain, swelling, redness, induration, pruritus, and rash. Solicited systemic AEs included fever, fatigue, dizziness, diarrhea, myalgia, arthralgia, headache, cough, somnolence, chest discomfort, acute allergic reaction, nausea, vomiting, and facial paralysis. AE severity and causality were assessed according to the National Medical Products Administration “Guiding Principles for Grading Adverse Reactions in Clinical Trials of Preventive Vaccines.”²¹ According to the study protocol, AEs occurring within 7 days after vaccination were considered at least possibly related to vaccination, whereas AEs occurring during Days 8–28 after vaccination were individually assessed for causality by the investigators.

Statistical analysis

Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Antibody GMTs/geometric mean concentrations (GMCs) and geometric mean increases (GMIs) were summarized with 95% confidence intervals (CIs). Between-group comparisons of GMTs/GMCs and GMIs were conducted using t-tests on log-transformed data when normality assumptions were met, or non-parametric methods otherwise. For log-normally distributed data, 95% CIs for between-group ratios were estimated using the t-distribution; otherwise, the Hodges–Lehmann estimator was applied.

Non-inferiority was concluded if the lower bound of the two-sided 95% CI for the GMT/GMC ratio was ≥ 0.67 or if the lower bound of the between-group difference in seroconversion rates was ≥ −10%. Seropositivity and seroconversion rates were calculated with corresponding 95% CIs for each antigen. Prespecified subgroup analyses by age group (18–59 years vs. ≥60 years) were conducted for primary immunogenicity endpoints. Differences in AE incidence were compared using the Pearson’s χ² test or Fisher’s exact test, as appropriate. The Kruskal–Wallis test was used to compare AE severity and relatedness across groups. A two-sided P value < 0.05 was considered statistically significant. Primary immunogenicity analyses were performed in the per-protocol set (PPS), whereas safety analyses were performed in the safety set (SS). Missing values were queried and verified against source documents whenever possible. Values that could not be verified remained missing and were analyzed without imputation. All statistical analyses were conducted by investigators from academic institutions, including the School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, and Zhongnan Hospital of Wuhan University.

Results

Baseline characteristics

Between May and June 2021, 1,404 adults were enrolled at study centers in three provinces of China (Hubei, Guangdong, and Henan) and randomly assigned in a 1:1:1 ratio to the co-administration group (WIBP-CorV + PPV23/IIV4), the WIBP-CorV-only group, or the PPV23/IIV4-only group. Participant follow-up was completed in December 2021. Participants in the co-administration group received WIBP-CorV and PPV23 on Day 0 and WIBP-CorV and IIV4 on Day 28, while the other two groups received their assigned vaccines according to the same schedule. Blood samples were collected on Days 0, 28, and 56 for immunogenicity assessments, and safety was monitored for 6 months.

A total of 465, 465, and 467 participants received the first dose in the three groups, respectively, and 451, 454, and 454 were included in the PPS (Figure 1). All participants were Chinese, and baseline characteristics were well balanced across groups. No significant differences were observed in age, sex, body temperature, blood pressure, cardiopulmonary examination, comorbidities, or concomitant medication use (Table 1).

A flowchart showing participant disposition in three randomized groups with exclusions and withdrawals detailed. The flowchart details participant distribution in three groups: WIBP-CorV plus PPV23/IIV4, WIBP-CorV and PPV23/IIV4. Initially, 1404 participants were screened and randomized. In the WIBP-CorV plus PPV23/IIV4 group, 468 were randomized; 3 withdrew consent. 465 received dose 1 (232 aged 18-59, 233 aged 60+). After 6 withdrawals, 459 received dose 2 (230 aged 18-59, 229 aged 60+). 457 completed the Day 56 blood draw; 6 were excluded, leaving 451 in PPS. In the WIBP-CorV group, 468 were randomized; 3 were excluded. 465 received dose 1 (234 aged 18-59, 231 aged 60+). After 6 withdrawals, 459 received dose 2 (233 aged 18-59, 226 aged 60+). 455 completed the Day 56 blood draw; 1 was excluded, leaving 454 in PPS. In the PPV23/IIV4 group, 468 were randomized; 1 withdrew consent. 467 received dose 1 (234 aged 18-59, 233 aged 60+). After 9 withdrawals, 458 received dose 2 (231 aged 18-59, 227 aged 60+). 456 completed the Day 56 blood draw; 2 were excluded, leaving 454 in PPS. — Participant disposition and analysis populations.

This CONSORT flow diagram summarizes participant screening, randomization, allocation to the three study groups, receipt of study vaccinations, completion of follow-up procedures, and inclusion in the predefined analysis populations.

The full analysis set (FAS) included all randomized participants who received at least one dose of a study vaccine. The per-protocol set (PPS) comprised participants who fulfilled all eligibility criteria, completed all scheduled visits within protocol-defined time windows, and provided valid immunogenicity data without major protocol deviations. The safety set (SS) included all participants who received at least one dose of a study vaccine and were assessed for safety outcomes.

Participants in the co-administration group received WIBP-CorV + PPV23 on Day 0, followed by WIBP-CorV + IIV4 on Day 28. Participants in the WIBP-CorV-only group received WIBP-CorV on Days 0 and 28. Participants in the PPV23/IIV4-only group received PPV23 on Day 0 and IIV4 on Day 28.

WIBP-CorV, inactivated SARS-CoV-2 vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine; IIV4, quadrivalent inactivated influenza vaccine.

Table 1.

Baseline demographic and clinical characteristics of participants, SS.

Variables	WIBP-CorV + PPV23/IIV4 (N = 465)	WIBP-CorV (N = 465)	PPV23 /IIV4 (N = 467)	P value
Age, year
Mean (SD)	53.96 (17.50)	54.09 (17.92)	54.13 (17.76)	.989
Median	60.07	59.08	59.54
Gender
Male, n (%)	229 (49.25)	225 (48.39)	239 (51.18)	.683
Female, n (%)	236 (50.75)	240 (51.61)	228 (48.82)
Body temperature,°C
Mean (SD)	36.28 (0.30)	36.27 (0.29)	36.26 (0.30)	.498
Median	36.2	36.2	36.2
Systolic blood pressure, mmHg
Mean (SD)	130.74 (17.10)	129.22 (17.48)	129.89 (16.28)	.390
Median	131	130	130
Diastolic blood pressure, mmHg
Mean (SD)	80.19 (9.15)	80.13 (9.46)	80.72 (9.05)	.557
Median	80	80	80
Cardiopulmonary auscultation
Normal, n (%)	465 (100.00)	465 (100.00)	467 (100.00)	1.000
Abnormal, n (%)	0 (0.00)	0 (0.00)	0 (0.00)
Comorbidities
Yes, n (%)	90 (19.35)	93 (20.00)	97 (20.77)	.864
No, n (%)	375 (80.65)	372 (80.00)	370 (79.23)
Concomitant medication use
Yes, n (%)	90 (19.35)	93 (20.00)	97 (20.77)	.864
No, n (%)	375 (80.65)	372 (80.00)	370 (79.23)

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Data are presented as mean (standard deviation, SD), median, or number (%) unless otherwise specified.

Baseline characteristics were compared across study groups using two-sided statistical tests; no statistically significant differences were observed among groups.

Participants in the co-administration group received WIBP-CorV + PPV23 on Day 0, followed by WIBP-CorV + IIV4 on Day 28. Participants in the WIBP-CorV-only group received WIBP-CorV on Days 0 and 28. Participants in the PPV23/IIV4-only group received PPV23 on Day 0 and IIV4 on Day 28.

WIBP-CorV, inactivated SARS-CoV-2 vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine; IIV4, quadrivalent inactivated influenza vaccine; SS, Safety Set; SD, standard deviation.

Immunogenicity

Co-administration of WIBP-CorV with PPV23 or IIV4 preserved the overall magnitude of vaccine-induced humoral immunity across all platforms.

SARS-CoV-2 neutralizing antibodies

Vaccination with WIBP-CorV, whether administered alone or co-administered with PPV23 or IIV4, induced substantial increases in neutralizing antibody responses. Seroconversion rates and GMTs rose markedly from baseline in both groups, with the greatest increases observed following the second WIBP-CorV dose (Figure 2(a, b)). In the overall population and in participants aged 18–59 years, GMTs at Days 28 and 56 were comparable between groups, and geometric mean titer ratios (GMRs) met the pre-specified non-inferiority criterion (lower bound ≥ 0.67). However, among participants aged ≥ 60 years, non-inferiority was not met at Day 56, as the lower bound of the GMR 95% CI fell below 0.67 (Figure 2(b)).

Two dot and whisker plots comparing log10 geometric mean titer and geometric mean titer ratio by group. Image A compares WIBP CorV plus PPV23/IIV4 and WIBP CorV using a dot and whisker plot. The x-axis shows log10 geometric mean titer from 1.25 to 2.25, with categories: Overall, 18-59 years and greater than or equal to 60 years, each at Day 28 after Dose 1 and Dose 2. WIBP CorV plus PPV23/IIV4 points: Overall Dose 1 at 1.45, Dose 2 at 2.00; 18-59 Dose 1 at 1.68, Dose 2 at 2.08; greater than or equal to 60 Dose 1 at 1.30, Dose 2 at 1.85. WIBP CorV points: Overall Dose 1 at 1.52, Dose 2 at 2.10; 18-59 Dose 1 at 1.72, Dose 2 at 2.18; greater than or equal to 60 Dose 1 at 1.38, Dose 2 at 1.95. Image B, titled ′Non-inferiority margin,′ shows geometric mean titer ratio from 0.6 to 1.2 with a reference line near 0.7. Six estimates with confidence intervals match Image A′s categories: 0.85, 0.90, 0.88, 0.92, 0.82, 0.86, intervals from 0.75 to 1.00, 0.78 to 1.08, 0.74 to 1.06, 0.72 to 1.18, 0.60 to 1.05, 0.70 to 1.10. — Continued.

A grouped horizontal bar chart and a dot and whisker plot of seroconversion rates by group and age. Two-part figure. A) A grouped horizontal bar chart of seroconversion rate. The x-axis label is, Seroconversion rate percent. The x-axis range is 0 to 75. The y-axis lists six rows grouped by, Overall, 18 to 59 years and 60 years or older, each with, Day 28 after Dose 2 and, Day 28 after Dose 1. Legend entries are, WIBP CorV plus PPV23 slash IIV4 and, WIBP CorV. Approximate bar endpoints: Overall, Day 28 after Dose 2, about 75 for WIBP CorV plus PPV23 slash IIV4 and about 85 for WIBP CorV; Overall, Day 28 after Dose 1, about 40 for both groups. 18 to 59 years, Day 28 after Dose 2, about 85 for WIBP CorV plus PPV23 slash IIV4 and about 90 for WIBP CorV; 18 to 59 years, Day 28 after Dose 1, about 55 for WIBP CorV plus PPV23 slash IIV4 and about 50 for WIBP CorV. 60 years or older, Day 28 after Dose 2, about 65 for WIBP CorV plus PPV23 slash IIV4 and about 80 for WIBP CorV; 60 years or older, Day 28 after Dose 1, about 25 for WIBP CorV plus PPV23 slash IIV4 and about 30 for WIBP CorV. Each bar has a right-side horizontal whisker style error bar. B) A dot and whisker plot labeled, Non inferiority margin. The x-axis label is, Difference in seroconversion rate percent, with parenthetical text, WIBP CorV plus PPV23 slash IIV4 vs WIBP CorV. The x-axis range is negative 20 to 10, with ticks at negative 20, negative 10, 0 and 10. A vertical dotted reference line is at negative 10. Six points with horizontal whiskers align to the same six rows as A. Approximate point locations from top to bottom: about negative 8, about 0, about negative 2, about 2, about negative 12 and about negative 2. Whiskers span roughly: top about negative 12 to negative 4; second about negative 6 to 4; third about negative 9 to 2; fourth about negative 6 to 10; fifth about negative 20 to negative 8; sixth about negative 10 to 6. — SARS-CoV-2–specific neutralizing antibody seroconversion rates and GMTs at Day 28 after dose 1 and dose 2, stratified by age group, PPS.

(a) Seroconversion rates, defined as a ≥ 4-fold increase in SARS-CoV-2 neutralizing antibody titers from baseline, are shown with 95% CIs for each vaccination group in the overall population and stratified by age (18–59 years; ≥60 years). Non-inferiority of the co-administration group relative to the WIBP-CorV–only group was assessed using a pre-specified margin of -10% points.

(b) Log₁₀-transformed GMTs with 95% CIs are presented for each vaccination group at Day 28 after Dose 1 and Dose 2, overall and by age subgroup. GMRs comparing the co-administration group with the WIBP-CorV–only group are shown with corresponding 95% CIs. Non-inferiority was concluded if the lower bound of the 95% CI for the GMR was ≥ 0.67.

(c) Violin plots display individual log₁₀-transformed neutralizing antibody titers for each vaccination group in the overall population and by age subgroup, with superimposed box plots indicating the median and IQR. The width of each violin reflects the underlying data density.

The co-administration group received WIBP-CorV + PPV23 on Day 0, followed by WIBP-CorV + IIV4 on Day 28. The WIBP-CorV–only group received WIBP-CorV on Days 0 and 28. Sample sizes were 451 participants in the co-administration group (18–59 years: n = 225; ≥60 years: n = 226) and 454 participants in the WIBP-CorV–only group (18–59 years: n = 230; ≥60 years: n = 224).

GMT, geometric mean titer; GMR, geometric mean titer ratio; IQR, interquartile range; PPS, per-protocol set; CI, confidence interval; WIBP-CorV, inactivated SARS-CoV-2 vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine; IIV4, quadrivalent inactivated influenza vaccine.

Despite this, neutralizing antibody levels at both timepoints remained similar between groups, and GMIs showed no statistically significant differences across all age strata (Figure 2(c); Supplementary Table S3). These findings indicate that co-administration preserves vaccine-induced humoral responses in most adults, although reduced neutralization responses in older adults warrant further consideration in co-administration strategies.

Two violin plots comparing log10GMT across age groups after dose 1 and dose 2 for two vaccines. Two violin plots compare data 28 days after Dose 1 and Dose 2. The y-axis is labeled log10GMT, ranging from 1.0 to 3.5 and the x-axis categorizes by age: Overall, 18-59 years and greater than or equal to 60 y. Each category features two violins with jittered points and a box plot. For Dose 1: - Overall: Points cluster near 1.0 and 2.0-2.2, with a box from 1.0 to 2.1 and a median around 1.9-2.0. Points extend up to 3.0-3.3. - Age 18-59: Similar distribution, points from 0.9 to 3.0-3.4, median near 2.0. - Age greater than or equal to 60: More points near 1.0, fewer high values, points up to 2.8-3.0, median around 1.3-1.6. For Dose 2: - Overall: Higher central values, points from 0.9 to 3.2, box centered around 2.1-2.3, median near 2.2. - Age 18-59: Points from 1.0 to 3.1, box centered near 2.1-2.3. - Age greater than or equal to 60: Points from 0.9 to 3.0-3.2, box centered near 2.0-2.3. — Continued.

Pneumococcal polysaccharide antibodies

For PPV23, seroconversion rates at Day 28 in the co-administration group ranged from 62.75% to 95.79% across the 23 pneumococcal serotypes in the overall population, meeting the pre-specified non-inferiority criterion (lower bound of the between-group 95% CIs difference ≥ −10%). In adults aged 18–59 years, a small number of serotypes showed slightly lower seroconversion rates compared to the PPV23/IIV4-only group, whereas participants aged ≥ 60 years all exhibited higher rates, with positive between-group differences (Figure 3(a)).

Plots compare seroconversion rates by serotype and age for WIBP-CorV+PPV23/IIV4 vs. PPV23/IIV4. Panel A shows seroconversion rates for serotypes ST-33F to ST-1 and overall. X-axis: Seroconversion rate (%) from 0 to 100. WIBP-CorV+PPV23/IIV4 (blue) generally shows higher rates than PPV23/IIV4 (orange). Panel A differences plot shows most differences above 0, with confidence intervals mostly above the non-inferiority margin of -10 percent. Panel B, labeled ′18 to 59 y′, follows the same format. WIBP-CorV+PPV23/IIV4 often exceeds PPV23/IIV4, with differences clustering above 0. Panel C, labeled ′60 y′, shows similar trends, with WIBP-CorV+PPV23/IIV4 outperforming PPV23/IIV4. Notable serotypes with large differences include ST-19A and ST-6B. Dot plots show horizontal whiskers indicating confidence intervals, with most staying above -10 percent. The legend differentiates groups by color: blue for WIBP-CorV+PPV23/IIV4 and orange for PPV23/IIV4. — Pneumococcal serotype-specific IgG seroconversion rates and GMCs at Day 28, stratified by age group, PPS. (a) Seroconversion rates, defined as a ≥ 2-fold increase in serotype-specific IgG concentrations from baseline to Day 28, are shown with 95% CIs for each vaccination group in the overall population and stratified by age (18–59 years; ≥60 years). Non-inferiority of the co-administration group relative to the PPV23/IIV4–only group was assessed using a pre-specified margin of –10% points.

GMC ratios in the overall population ranged from 0.88 to 1.07, with all lower bounds of the 95% CIs ≥ 0.67, indicating that co-administration did not compromise IgG responses (Figure 3(b, c)). Baseline GMC values for all serotypes are presented in Supplementary Table S1, and post-vaccination GMIs demonstrated robust and consistent rises across both age subgroups (Supplementary Table S4).

Three forest plots of log10 geometric mean concentration and geometric mean concentration ratio by serotype. Image A displays paired forest plots for various serotypes, including ST-33F to ST-1 and Overall. Plot 1 uses log10GMC on the x-axis with ticks at 0.5, 1.0, 1.5, showing two series: WIBP-CorV plus PPV23/IIV4 and PPV23/IIV4, each with a point and horizontal confidence interval. Plot 2 shows GMC ratio (WIBP-CorV plus PPV23/IIV4 vs PPV23/IIV4) on the x-axis with ticks at 0.8, 1.0, 1.2 and a non-inferiority margin at 0.8; most estimates range from 0.9 to 1.1. Image B presents similar plots for ages 18-59, maintaining the same x-axis labels, ticks and non-inferiority margin, with ratio estimates clustering around 0.9 to 1.1. Image C shows the same plots for ages 60+, with consistent x-axis labels, ticks and non-inferiority margin and ratio estimates again clustering around 0.9 to 1.1. — (b) Log10-transformed GMCs with 95% CIs are presented for each vaccination group in the overall and age-stratified populations. GMRs comparing the co-administration group with the PPV23/IIV4-only group are shown with corresponding 95% CIs. Non-inferiority was concluded if the lower bound of the 95% CI for the GMR was ≥ 0.67.

These findings indicate that co-administration preserved the T cell–independent immunogenicity of PPV23, with potential enhancement in older adults.

A set of violin plots comparing log10 concentration by age group across ST sites for two vaccine groups. The text describes 23 violin plots labeled ST-1 to ST-33F, comparing vaccine groups WIPB-CorV plus PPV23 plus IIV4 and PPV23 plus IIV4 across age categories: Overall, 18-59 years and greater than or equal to 60 y. Each plot features individual data points overlaid on two violin shapes per age group. The X-axis is labeled ′Age Group,′ while the Y-axis, ′log10Conc,′ varies in tick ranges like -1 to 2, 0 to 2.5 and 0 to 3. Across ST sites, vaccine groups show overlapping distributions within age categories, with point clouds mainly between 0.5 and 1.8 on the log10Conc scale. Some sites have points from -1 to 3. Age categories within sites generally cluster similarly, though some sites show higher upper tails for greater than or equal to 60 y. The figure illustrates log10Conc distribution differences by age and vaccine group across ST sites. — (c) Violin plots show individual log10-transformed serotype-specific IgG concentrations for each vaccination group overall and by age group, with superimposed box plots indicating the median and IQR. The width of each violin reflects the data density. The co-administration group received WIBP-CorV + PPV23 on Day 0, followed by WIBP-CorV + IIV4 on Day 28. The PPV23/IIV4-only group received PPV23 on Day 0 and IIV4 on Day 28. Sample sizes were 451 participants in the co-administration group (18–59 years: n = 225; ≥60 years: n = 226) and 454 in the PPV23/IIV4-only group (18–59 years: n = 227; ≥60 years: n = 227). IgG, immunoglobulin G; GMC, geometric mean concentration; GMR, geometric mean ratio; PPS, per-protocol set; IQR, interquartile range; PPV23, 23-valent pneumococcal polysaccharide vaccine; IIV4, quadrivalent inactivated influenza vaccine; CI, confidence interval.

Influenza antibodies

By Day 56, seroconversion rates for the four influenza strains – A (H1N1), A(H3N2), B/Yamagata, and B/Victoria – ranged from 74.28% to 90.97% in the overall population (Figure 4(a). When compared with the PPV23+IIV4-only group, the co-administration group met the pre-specified non-inferiority criterion for all strains except A(H1N1) in the overall cohort, for which the lower bound of the 95% CI for the between-group difference marginally crossed the predefined −10% margin. Age-stratified analyses indicated that non-inferiority was narrowly missed for A (H3N2) among adults aged 18–59 years, and for A(H1N1), B/Yamagata, and B/Victoria among adults aged ≥ 60 years. Notably, these instances reflected modest numerical differences rather than consistent directional reductions across strains or age groups (Figure 4(a)). Because this trial was designed and powered to evaluate overall non-inferiority rather than differences between age subgroups, these subgroup findings should be interpreted with caution.

A grouped bar chart and dot whisker plot showing influenza seroconversion rates and differences. A composite figure with two graphs. The image A showing a grouped horizontal bar chart of seroconversion rate percent by influenza strain and age group for two groups, WIBP CorV plus PPV23 slash IIV4 and PPV23 slash IIV4. The x axis label is, Seroconversion rate percent, ranging from 0 to 100 with ticks at 0, 25, 50, 75, 100. The years axis lists strains within three sections: Overall, 18.5 to 59 years and greater than or equal to 60 years. Strains listed in each section are B slash Yamagata, B slash Victoria, A left parenthesis H3N2 right parenthesis, A left parenthesis H1N1 right parenthesis. Bars extend approximately as follows. Overall: B slash Yamagata about 80 to 85 for both; B slash Victoria about 90 to 95 for both; A left parenthesis H3N2 right parenthesis about 75 to 80 for both; A left parenthesis H1N1 right parenthesis about 85 to 95 with PPV23 slash IIV4 higher. 18.5 to 59 years: B slash Yamagata about 70 for PPV23 slash IIV4 and about 85 for WIBP CorV plus PPV23 slash IIV4; B slash Victoria about 90 to 95 for both; A left parenthesis H3N2 right parenthesis about 75 to 85 with PPV23 slash IIV4 higher; A left parenthesis H1N1 right parenthesis about 90 to 95 for both. Greater than or equal to 60 years: B slash Yamagata about 75 for WIBP CorV plus PPV23 slash IIV4 and about 90 for PPV23 slash IIV4; B slash Victoria about 90 to 95 for both; A left parenthesis H3N2 right parenthesis about 75 to 80 for both; A left parenthesis H1N1 right parenthesis about 80 for WIBP CorV plus PPV23 slash IIV4 and about 95 for PPV23 slash IIV4. Each bar has a horizontal error bar. The image B showing a dot and horizontal whisker plot of between group differences. The x axis label is, Difference in seroconversion rate percent left parenthesis WIBP CorV plus PPV23 slash IIV4 vs PPV23 slash IIV4 right parenthesis, ranging from negative 20 to 20 with ticks at negative 20, negative 10, 0, 10, 20. A vertical dotted line at negative 10 is labeled, Non inferiority margin. Eight points with whiskers are plotted, aligned to the same ordering as the bar chart groups. Approximate point locations are: near negative 2, near negative 3, near negative 2, near negative 6, near positive 18, near negative 2, near negative 6, near negative 2. Whiskers span several units around each point, with the positive 18 point spanning roughly positive 12 to positive 22. — Influenza-specific HI antibody seroconversion rates and GMTs at Day 56, stratified by age group, PPS.

(a) Seroconversion rates, defined as a post-vaccination HI titer ≥ 1:40 in participants with a pre-vaccination titer < 1:10, or a ≥ 4-fold increase in those with a baseline titer ≥ 1:10, are shown with 95% CIs for each vaccination group in the overall population and stratified by age (18–59 years; ≥60 years). Non-inferiority of the co-administration group relative to the PPV23/IIV4-only group was assessed using a pre-specified margin of -10% points.

(b) Log₁₀-transformed GMTs with 95% CIs are presented for each vaccination group, overall and by age subgroup. GMRs comparing the co-administration group with the PPV23/IIV4-only group are shown with corresponding 95% CIs. Non-inferiority was concluded if the lower bound of the 95% CI for the GMR was ≥ 0.67.

(c) Violin plots display individual log₁₀-transformed HI titers for each vaccination group in the overall population and by age subgroup, with superimposed box plots indicating the median and IQR. The width of each violin reflects the underlying data density.

The co-administration group received WIBP-CorV + PPV23 on Day 0, followed by WIBP-CorV + IIV4 on Day 28. The PPV23/IIV4-only group received PPV23 on Day 0 and IIV4 on Day 28. Sample sizes were 451 participants in the co-administration group (18–59 years: n = 225; ≥60 years: n = 226) and 454 participants in the PPV23/IIV4-only group (18–59 years: n = 227; ≥60 years: n = 227).

HI, hemagglutination inhibition; GMT, geometric mean titer; PPS, per-protocol set; WIBP-CorV, inactivated SARS-CoV-2 vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine; IIV4, quadrivalent inactivated influenza vaccine; CI, confidence interval; GMR, geometric mean titer ratio; IQR, interquartile range.

Importantly, the observed differences in seroconversion rates were not mirrored in GMT-based immunogenicity endpoints. For all four strains, GMTs increased substantially from baseline in both groups, reaching high post-vaccination levels by Day 56 (for example, A (H1N1) GMTs increased from 58.02 to 580.34 in the co-administration group) (Figure 4(b); Supplementary Table S2 and S5). In adults aged 18–59 years, GMRs consistently satisfied the non-inferiority criterion for all strains, with the lower bounds of the 95% CIs remaining ≥ 0.67.

Two forest plots comparing log10 geometric mean titer and geometric mean titer ratio across strains and ages. Image A displays a forest plot of geometric mean titers by influenza strain and age group for two vaccine groups. The x-axis is labeled ′log10 geometric mean titer′ with ticks at 2.0, 2.5 and 3.0. The y-axis lists categories: Overall, B/Yamagata, B/Victoria, A(H3N2), A(H1N1), followed by age groups 18-59 and greater than or equal to 60 years with the same strains. Each row shows two point estimates with horizontal confidence intervals for WIBP-CorV plus PPV23/IIV4 and PPV23/IIV4. Image B presents a forest plot titled ′Non-inferiority margin.′ The x-axis is labeled ′geometric mean titer ratio (WIBP-CorV plus PPV23/IIV4 vs PPV23/IIV4)′ with ticks at 0.6, 0.9, 1.2 and 1.5. A vertical dashed line is at 0.8. The y-axis has four unlabeled rows, each with a point estimate and horizontal confidence interval. Estimates are near 0.9, 0.9, 1.2 and 0.8, with intervals spanning 0.8-1.0, 0.8-1.0, 1.1-1.3 and 0.7-0.9. — Continued.

Across age strata, adults aged 18–59 years generally exhibited higher post-vaccination GMTs, whereas antibody responses among older adults (≥60 years) were more narrowly distributed, particularly for A (H3N2), suggesting a more homogeneous but moderately attenuated humoral response in this age group (Figure 4(b); Figure 4(c)). Violin plot visualizations further illustrated comparable central tendencies and distributional patterns of log-transformed GMTs between groups across strains and age subgroups (Figure 4(c)).

A violin plot showing log10GMT by age group for A(H1N1), A(H3N2), B/Victoria and B/Yamagata. The image showing four violin plots arranged in a two by two layout titled A(H1N1), A(H3N2), B/Victoria and B/Yamagata. The horizontal axis label is Age Group with categories Overall, 18 to 59 years and greater than or equal to 60 years. The vertical axis label is log10GMT with tick labels 1, 2, 3, 4. In A(H3N2), the vertical axis also shows 1.5, 2.0, 2.5, 3.0, 3.5, 4.0. Each age group contains two side by side violin distributions with overlaid individual points and an internal box plot. A legend at the top lists two groups: WIBP CorV plus PPV23 slash IIV4 and PPV23 slash IIV4. Across all four plots, point clouds and violin widths concentrate mainly between 2 and 3.5 on log10GMT, with scattered points extending to near 1 and near 4 depending on subplot and age group. — Continued.

Baseline GMT values for all strains are provided in Supplementary Table S2. Consistent with GMT findings, GMIs at Day 56 confirmed comparable fold rises between groups. Notably, for certain strains – such as B/Yamagata in adults aged 18–59 years – the co-administration group demonstrated numerically higher GMIs (Supplementary Table S5), further supporting the preservation of influenza vaccine–induced humoral immunogenicity under the co-administration strategy.

Summary

Co-administration of WIBP-CorV with either PPV23 or IIV4 largely preserved humoral immune responses across vaccine platforms. Non-inferiority based on geometric mean antibody responses was demonstrated for SARS-CoV-2 and all 23 pneumococcal serotypes. For influenza, most strains met non-inferiority criteria, except A(H1N1) and B/Yamagata. Seroconversion-based analyses similarly demonstrated non-inferiority for all pneumococcal serotypes, whereas the prespecified non-inferiority criterion was not met for SARS-CoV-2 among adults aged ≥ 60 years. These findings support the immunological feasibility of this multi-pathogen vaccination strategy in the adult populations evaluated in this study while indicating age- and strain-specific non-inferiority findings that should be interpreted cautiously.

Safety

Co-administration was associated with a higher incidence of vaccine-related solicited local AEs compared with the PPV23/IIV4-only group, largely driven by injection-site pain (Table 2; Supplementary Table S6; Figure 5). Local AEs were reported in 31.83% of participants in the co-administration group, compared with 27.96% in the WIBP-CorV-only group and 20.13% in the PPV23/IIV4-only group. Risk difference analyses demonstrated that the largest absolute increases were consistently observed when comparing the co-administration group with the PPV23/IIV4-only group across Dose 1, Dose 2, and any dose (Figure 5).

Table 2.

Summary of vaccine-related adverse events occurring within 7 days after any dose, ss.

Variables	WIBP-CorV + PPV23/IIV4 (A, N = 465)	WIBP-CorV (B, N = 465)	PPV23/IIV4 (C, N = 467)	p value
Variables	WIBP-CorV + PPV23/IIV4 (A, N = 465)	WIBP-CorV (B, N = 465)	PPV23/IIV4 (C, N = 467)	A vs. B	A vs. C
Any AEs, n (%)	164 (35.27)	148 (31.83)	114 (24.41)	0.267	0.001
Solicited AEs, n (%)	162 (34.84)	146 (31.40)	110 (23.55)	0.265	0.001
Local AEs, n (%)	148 (31.83)	130 (27.96)	94 (20.13)	0.197	<0.001
Systemic AEs, n (%)	34 (7.31)	31 (6.67)	23 (4.93)	0.700	0.128
Unsolicited AEs, n (%)	5 (1.08)	9 (1.94)	10 (2.14)	0.281	0.196

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Data are presented as the number (%) of participants experiencing at least one vaccine-related AE within 7 days after any dose.

Solicited local AEs refer to injection-site reactions, whereas solicited systemic AEs refer to systemic symptoms occurring at sites other than the injection site. Unsolicited AEs include any additional events not prespecified in the solicited AE list.

Comparisons between groups were performed using Pearson’s χ² test or Fisher’s exact test, as appropriate. ReportedPvalues correspond to pairwise comparisons (A vs. B and A vs. C).

A, WIBP-CorV + PPV23/IIV4 (co-administration group); B, WIBP-CorV-only group; C, PPV23/IIV4-only group; SS, Safety Set; AE, adverse event.

A forest plot of adverse event rate differences by dose across two vaccine group comparisons. A forest plot with three row blocks labeled Dose 1, Dose 2 and Any dose. Each block lists five variables: Any AE, Solicited AEs, Local AEs, Systemic AEs, Unsolicited AEs. Two side by side plots compare groups labeled, WIBP CorV plus PPV23 slash IIV4 vs WIBP CorV and WIBP CorV plus PPV23 slash IIV4 vs PPV23 slash IIV4. For both plots, the x axis label is, Difference in AE rate percent, with ticks at minus 10, minus 5, 0, 5, 10, 15, 20. A vertical dashed reference line is at 0. Each row shows a square point estimate with a horizontal confidence interval line. Dose 1: left plot squares near 5 for Any AE, about 4 for Solicited AEs, about 5 for Local AEs, about 0 for Systemic AEs, about minus 1 for Unsolicited AEs. Right plot squares near 10 for Any AE, about 10 for Solicited AEs, about 10 for Local AEs, about 0 for Systemic AEs, about minus 1 for Unsolicited AEs. Dose 2: left plot squares near minus 2 for Any AE, about minus 2 for Solicited AEs, about minus 3 for Local AEs, about 0 for Systemic AEs, about minus 1 for Unsolicited AEs. Right plot squares near 8 for Any AE, about 9 for Solicited AEs, about 6 for Local AEs, about 2 for Systemic AEs, about 0 for Unsolicited AEs. Any dose: left plot squares near 3 for Any AE, about 3 for Solicited AEs, about 3 for Local AEs, about 0 for Systemic AEs, about minus 1 for Unsolicited AEs. Right plot squares near 12 for Any AE, about 12 for Solicited AEs, about 12 for Local AEs, about 2 for Systemic AEs, about minus 1 for Unsolicited AEs. — Risk differences in vaccine-related adverse event incidence after each dose, SS.

Risk differences (RDs) represent the absolute percentage-point differences in the proportion of participants reporting at least one vaccine-related AE between the co-administration group and each single-vaccine comparator (WIBP-CorV-only or PPV23/IIV4-only groups). Positive RD values indicate a higher incidence of AEs in the co-administration group.

RDs and corresponding 95% CIs were calculated using the Newcombe–Wilson method. Solicited local AEs, solicited systemic AEs, and unsolicited AEs occurring within 7 days after Dose 1, Dose 2, and any dose are shown.

AE, adverse event; CI, confidence interval; RD, risk difference; SS, Safety Set.

Solicited systemic AEs were infrequent across all groups, occurring in 7.31%, 6.67%, and 4.93% of participants in the co-administration, WIBP-CorV-only, and PPV23/IIV4-only groups, respectively (Table 2). The most commonly reported systemic events included fatigue, fever, dizziness, and gastrointestinal symptoms. No individual systemic symptom showed a consistent or clinically meaningful increase in the co-administration group, and risk differences for systemic AEs were small and not statistically significant across doses (Figure 5; Supplementary Table S6).

Unsolicited AEs were rare and occurred at comparable frequencies among groups (1.08%, 1.94%, and 2.14%, respectively) (Table 2; Figure 5). During Days 8–28 after any dose, unsolicited AEs remained uncommon, with no statistically significant differences in the incidence of overall unsolicited AEs, vaccine-related unsolicited AEs, or Grade ≥ 3 unsolicited AEs between the co-administration group and either comparator group (Supplementary Table S8).

Across all vaccination groups, the majority of vaccine-related AEs reported within 7 days after vaccination were mild (Grade 1), with few moderate (Grade 2) and very few severe (Grade 3) events, and no evidence of increased AE severity associated with co-administration (Supplementary Table S7). Similarly, the severity distribution of unsolicited AEs occurring during Days 8–28 after vaccination was comparable across the three groups, with no apparent increase in Grade ≥ 3 events following co-administration (Supplementary Table S9).

During the 6-month follow-up period, 14 participants experienced SAEs, corresponding to incidences of 1.29%, 0.86%, and 0.86% in the co-administration, WIBP-CorV-only, and PPV23/IIV4-only groups, respectively, with no statistically significant differences between groups. All reported SAEs were assessed as unrelated to study vaccination, no vaccine-related SAEs or deaths occurred, and the distribution of SAEs by MedDRA System Organ Class was comparable across groups (Supplementary Table S10).

Discussion

This multicentre randomized Phase IV trial demonstrates that co-administration of WIBP-CorV with PPV23 on Day 0 and IIV4 on Day 28 according to the study vaccination schedule elicits immune responses comparable to separate vaccination and maintains an acceptable safety profile. Although non‑inferiority for seroconversion was not met in some subgroups – particularly for A(H1N1) and B/Yamagata in older adults and certain pneumococcal serotypes in adults aged 18–59 years – GMTs/GMCs remained robust, suggesting that the overall immunogenicity of the co-administration strategy was preserved within the age groups evaluated in this study.

Age-stratified analyses revealed expected patterns of immunosenescence. Older adults exhibited lower seroconversion to SARS-CoV-2 and influenza, reflecting age-related reductions in naïve B- and T-cell pools, impaired germinal-center activity, and limited helper T-cell expansion, which collectively weaken primary antibody and CD8⁺ responses to novel antigens.^22–26 In this context, the use of an adjuvanted inactivated SARS-CoV-2 vaccine may be relevant in older adults, as adjuvants may enhance immune activation in the setting of age-related immune decline.²³ However, because this study did not include an unadjuvanted SARS-CoV-2 vaccine comparator, the specific contribution of the aluminum hydroxide adjuvant to the observed immune responses cannot be determined. In contrast, responses to PPV23 remained strong in older adults, consistent with the T-cell–independent nature of polysaccharide antigens and their reliance on preexisting memory B-cell pools accumulated through lifelong pneumococcal exposure.^27–29 Thus, antigen type and immunological pathway fundamentally shape vaccine responsiveness in aging populations and support integrated co-administration strategies that leverage the robust responses observed with PPV23 while acknowledging the constraints imposed by immunosenescence. Notably, immune responses against A(H3N2), a historically drift-prone influenza strain, were preserved but merit continued monitoring, particularly in older adults who are more susceptible to antigenic mismatch and reduced vaccine effectiveness.³⁰ These findings highlight how antigen type and immunological pathway influence vaccine responsiveness and support integrated adult vaccination strategies that consider age-specific immunogenicity profiles.

The acceptable safety profile supports practical implementation. Local reactions were slightly more frequent with co‑administration but were predominantly mild and transient, while systemic reactions remained uncommon. This finding was expected and is likely attributable to the known reactogenicity profile of the inactivated SARS-CoV-2 vaccine, as participants in both the co-administration group and the WIBP-CorV-only group received WIBP-CorV, whereas participants in the PPV23/IIV4-only group did not. Similar observations have been reported in previous COVID-19 vaccine co-administration studies. No vaccine‑related SAEs occurred. This pattern aligns with earlier trials in which concurrent COVID‑19 and influenza vaccination showed no new safety concerns and preserved immunogenicity.¹⁹

By incorporating prospective age stratification with approximately equal enrollment of adults aged 18–59 years and ≥60 years, this study provides important insights into the immunogenicity of COVID-19 vaccine co-administration with both PPV23 and IIV4 according to the study vaccination schedule across predefined adult age groups. Furthermore, by evaluating these co-administration schedules across different dosing visits within a single randomized trial, our findings provide additional evidence supporting integrated respiratory vaccination strategies. Together with previous randomized studies of COVID-19 vaccine co-administration with influenza and pneumococcal vaccines,^19,31–35 this study provides one of the most comprehensive datasets reported to date, encompassing neutralizing responses to SARS-CoV-2, antibodies to 23 pneumococcal serotypes, and immunogenicity across four influenza strains.

Given the antigenic differences among SARS-CoV-2, pneumococcal, and influenza vaccines, direct antigen-specific cross-reactivity would not generally be expected. Nevertheless, nonspecific immunological interactions may occur during co-administration.³⁶ The generally preserved antigen-specific responses observed in this study provide no clear evidence of clinically meaningful immune interference, although mechanistic studies would be required to characterize such interactions directly.

The vaccine landscape has evolved substantially since this trial was conducted in 2021, which should be considered when interpreting the generalizability of our findings. Influenza vaccination strategies have increasingly transitioned from quadrivalent to trivalent formulations following the move away from the B/Yamagata component,³⁷ while higher-valency pneumococcal conjugate vaccines have been incorporated into adult immunization programs in some settings.¹⁷ In addition, SARS-CoV-2 variants and corresponding vaccine formulations have continued to evolve.³⁸ Because this trial specifically evaluated WIBP-CorV, IIV4, and PPV23, the findings should not be directly extrapolated to variant-adapted SARS-CoV-2 vaccines, trivalent or alternative-platform influenza vaccines, or newer pneumococcal conjugate vaccines. Differences in antigen composition, vaccine platform, route of administration, and immune mechanisms may influence responses to co-administration. Nevertheless, the preservation of immune responses across the three vaccine targets supports the broader feasibility of multi-pathogen adult vaccination strategies. Further studies incorporating contemporary vaccine formulations are warranted.

Although the WHO declared in May 2023 that COVID-19 no longer constitutes a Public Health Emergency of International Concern, the organization emphasized that SARS-CoV-2 remains a global health threat, continues to cause deaths, and continues to evolve; countries were therefore cautioned not to scale back preparedness efforts. The WHO further called for the incorporation of COVID-19 vaccination into life-course immunization programs and for the maintenance of sustained emergency readiness.³⁹ Similarly, in November 2025, the US CDC recommended updated 2025–2026 COVID-19 vaccines for all individuals aged ≥ 6 months, noting the waning of immunity over time and strongly emphasizing vaccination for adults aged ≥ 65 years and those at high risk.⁴⁰ Together, these policy positions underscore that, although the acute emergency phase has passed, SARS-CoV-2 continues to circulate, and integrated co-administration strategies remain relevant in practice and provide a foundational layer of protection against potential future variants or emerging respiratory pathogens.

The strengths of this study include its large sample size, scientifically grounded age stratification, and the use of rigorous non-inferiority analyses across multiple antigenic endpoints. Nevertheless, several limitations should be acknowledged. Cellular immune responses were not assessed, an aspect that is particularly relevant for older adults. Although participants were prospectively stratified into adults aged 18–59 years and ≥60 years with approximately equal allocation, the findings should be interpreted in the context of the enrolled study population. Because this trial was powered to evaluate non-inferiority rather than age-group differences, the subgroup analyses were exploratory and should not be interpreted as evidence of statistically confirmed differences between younger and older adults. Additional studies including broader and more diverse adult populations are warranted to further evaluate the generalizability of these findings. The study population consisted exclusively of Chinese adults, which may limit generalizability to other demographic or geographic settings. In addition, immunogenicity durability beyond Day 56 was not evaluated. Given the age- and strain-specific non-inferiority findings observed in this study, continued surveillance and adaptive vaccination strategies remain warranted. Future research should further assess the durability of immune responses following co-administration, booster immunogenicity in individuals with prior infection, real-world vaccine effectiveness, and the performance of co-administration strategies using updated vaccine formulations.

In summary, administration of WIBP-CorV with both PPV23 and IIV4 according to the study vaccination schedule (PPV23 on Day 0 and IIV4 on Day 28) preserved immunogenicity and demonstrated an acceptable safety profile, providing important evidence to support integrated respiratory vaccination strategies for adults in the post-pandemic era. These findings should be interpreted in the context of the predefined age groups evaluated in this study.

Supplementary Material

Supplemental Material

KHVI_A_2747495_SM6875.docx^{(105.5KB, docx)}

Funding Statement

This study was sponsored by Wuhan Institute of Biological Products Co., Ltd. The sponsor participated in study design, study coordination and logistical support. Data analysis and interpretation were conducted by investigators from academic institutions. The sponsor had no role in the decision to submit the manuscript for publication. All authors had full access to the study data and approved the final manuscript.

Disclosure statement

Several authors are employees of China National Biotec Group Company Limited and its affiliated companies, including Wuhan Institute of Biological Products Co., Ltd., Changchun Institute of Biological Products Co., Ltd., and Chengdu Institute of Biological Products Co., Ltd. The sponsor had no role in data analysis, interpretation of the results, or the decision to submit the manuscript for publication. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors used generative artificial intelligence tools solely for language editing purposes. No AI tools were used for data analysis, data interpretation, figure generation, or any scientific content development. The authors reviewed and approved the final manuscript and take full responsibility for the integrity and accuracy of the work.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request, subject to applicable privacy and ethical restrictions.

Code availability

The custom code used for statistical analyses is not publicly available but can be obtained from the corresponding author upon reasonable request.

Ethics statement

Ethical approval for this study was obtained from the ethics committees of the Hubei Provincial Center for Disease Control and Prevention (Hubei Academy of Preventive Medicine; approval no. 2021–008-02), the Guangdong Provincial Center for Disease Control and Prevention (approval no. 2019V005-E08), and the Henan Provincial Center for Disease Control and Prevention (approval no. 2021-YM-008–01). The study was also approved by the China National Human Genetic Resources Administration (approval no. [2021]CJ1085). The trial was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki, and complied with relevant national regulations. Written informed consent was obtained from all participants prior to enrollment and before any study-related procedures were performed. The trial was registered at Chinese Clinical Trial Registry (ChiCTR2100046227).

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2026.2747495

References

1.World Health Organization . COVID-19 weekly epidemiological update – 16 March 2023. Geneva: WHO; 2023. [Google Scholar]
2.World Health Organization . WHO Director-General’s opening remarks at the media briefing – 5 May 2023. Geneva: WHO; 2023. [Google Scholar]
3.World Health Organization . The burden of influenza. Geneva: WHO; 2018. (updated 2020). [Google Scholar]
4.World Health Organization . Pneumococcal disease. Geneva: WHO; 2019. [Google Scholar]
5.von Mollendorf C, Licciardi PV.. Adult pneumococcal vaccination: what are the gaps? The Lancet Infect Dis. 2024;24(10):1068–20. doi: 10.1016/S1473-3099(24)00400-6. [DOI] [PubMed] [Google Scholar]
6.World Health Organization . Vaccines and immunization: overview. Geneva: WHO; 2021. [Google Scholar]
7.Lives saved by COVID-19 vaccines. J Paediatr Child Health. 2022;58(11):2129. doi: 10.1111/jpc.16213. [DOI] [Google Scholar]
8.Watson OJ, Barnsley G, Toor J, Hogan AB, Winskill P, Ghani AC. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. The Lancet Infect Dis. 2022;22(9):1293–1302. doi: 10.1016/S1473-3099(22)00320-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.World Health Organization . Seasonal influenza – fact sheets. Copenhagen: WHO Regional Office for Europe; 2010. [Google Scholar]
10.Vo NX, Pham HL, Bui UM, Ho HT, Bui TT. Cost-effectiveness of the pneumococcal vaccine in the adult population: a systematic review. Healthcare (Basel). 2024;12(23):2490. doi: 10.3390/healthcare12232490. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.National Vaccine Advisory Committee . Recommendations from the National vaccine advisory committee: standards for adult immunization practice. Public Health Rep. 2014;129(2):115–123. doi: 10.1177/003335491412900203. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Bonanni P, Steffen R, Schelling J, Balaisyte-Jazone L, Posiuniene I, Zatoński M, Van Damme P. Vaccine co-administration in adults: an effective way to improve vaccination coverage. Hum Vaccin Immunother. 2023;19(1):2195786. doi: 10.1080/21645515.2023.2195786. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.World Health Organization . Coadministration of seasonal inactivated influenza and COVID-19 vaccines: interim guidance, 21 October 2021. WHO/2019-nCoV/SAGE/Vaccines_coadministration/Influenza/2021.1. Geneva: WHO; 2021. [Google Scholar]
14.Immunize.org . Strategies to improve adult vaccination coverage. Saint Paul (MN): Immunize.org; 2023. [Google Scholar]
15.World Health Organization . Strengthening influenza vaccination policies and programmes. Geneva: WHO; 2025. [Google Scholar]
16.Weinberger B. Vaccination of older adults: influenza, pneumococcal disease, herpes zoster, COVID-19 and beyond. Immun Ageing. 2021;18(1):38. doi: 10.1186/s12979-021-00249-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Kobayashi M, Leidner AJ, Gierke R, Xing W, Accorsi E, Moro P, Kamboj M, Kuchel GA, Schechter R, Loehr J, et al. Expanded recommendations for use of pneumococcal conjugate vaccines among adults aged ≥50 years: recommendations of the advisory committee on immunization practices — United States, 2024. Morb Mortal Wkly Rep. 2025;74(1):1–8. doi: 10.15585/mmwr.mm7401a1. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Thompson AR, Klein NP, Downey HJ, Patterson S, Sundaraiyer V, Watson W, Clarke K, Jansen KU, Sebastian S, Gruber WC, et al. Coadministration of 13-valent pneumococcal conjugate and quadrivalent inactivated influenza vaccines in adults previously immunized with polysaccharide pneumococcal vaccine 23: a randomized clinical trial. Hum Vaccin Immunother. 2019;15(2):444–451. doi: 10.1080/21645515.2018.1533777. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.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. Lancet. 2021;398(10318):2277–2287. doi: 10.1016/S0140-6736(21)02329-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Chen H, Huang Z, Chang S, Hu M, Lu Q, Zhang Y, Wang H, Xiao Y, Wang H, Ge Y, et al. Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine (sinopharm BBIBP-CorV) coadministered with quadrivalent split-virion inactivated influenza vaccine and 23-valent pneumococcal polysaccharide vaccine in China: a multicentre, non-inferiority, open-label, randomised, controlled, phase 4 trial. Vaccine. 2022;40(36):5322–5332. doi: 10.1016/j.vaccine.2022.07.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.National Medical Products Administration . The guiding principles for grading adverse reactions in clinical trials of preventive vaccines (no. 102). Beijing: NMPA; 2019. [Google Scholar]
22.Nikolich-Žugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 2018;19(1):10–19. doi: 10.1038/s41590-017-0006-x. [DOI] [PubMed] [Google Scholar]
23.Hou Y, Chen M, Bian Y, Hu Y, Chuan J, Zhong L, Zhu Y, Tong R. Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. NPJ Vaccines. 2024;9(1):77. doi: 10.1038/s41541-024-00874-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Jo N, Hidaka Y, Kikuchi O, Fukahori M, Sawada T, Aoki M, Yamamoto M, Nagao M, Morita S, Nakajima TE, et al. Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination. Nat Aging. 2023;3(1):82–92. doi: 10.1038/s43587-022-00343-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Gustafson CE, Kim C, Weyand CM, Goronzy JJ. Influence of immune aging on vaccine responses. J Allergy Clin Immunol. 2020;145(5):1309–1321. doi: 10.1016/j.jaci.2020.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Collier DA, Ferreira IATM, Kotagiri P, Datir RP, Lim EY, Touizer E, Meng B, Abdullahi A, Baker S, Dougan G, et al. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature. 2021;596(7872):417–422. doi: 10.1038/s41586-021-03739-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Wojtakowski T, van de Sand L, Helmer L, Mokanis M, Witzke O, Horn PA, Krawczyk A, Sondermann W, Lindemann M. Evaluation of T-Cell responses following sequential vaccination with PCV13 and PPSV23 against Streptococcus pneumoniae in patients with psoriasis. Vaccines (Basel). 2025;13(9):920. doi: 10.3390/vaccines13090920. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Artz AS, Ershler WB, Longo DL. Pneumococcal vaccination and revaccination of older adults. Clin Microbiol Rev. 2003;16(2):308–318. doi: 10.1128/CMR.16.2.308-318.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Papadatou I, Tzovara I, Licciardi PV. The role of serotype-specific immunological memory in pneumococcal vaccination: current knowledge and future prospects. Vaccines (Basel). 2019;7(1):13. doi: 10.3390/vaccines7010013. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Pawelec G, McElhaney J. Recent advances in influenza vaccines. F1000Res. 2020;9:305. doi: 10.12688/f1000research.22611.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Huang T, Yu J, Zhang S, Teng D, Dai D, Zhu Y, Gao L. Immunogenicity and safety of concomitant administration of recombinant COVID-19 vaccine and quadrivalent inactivated influenza vaccine in Chinese adults: an open-label, randomized, controlled trial. Hum Vaccin Immunother. 2024;20(1):2330770. doi: 10.1080/21645515.2024.2330770. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Shenyu W, Xiaoqian D, Bo C, Xuan D, Zeng W, Hangjie Z, Qianhui Z, Zhenzhen L, Chuanfu Y, Juan Y, et al. Immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac) co-administered with an inactivated quadrivalent influenza vaccine: a randomized, open-label, controlled study in healthy adults aged 18 to 59 years in China. Vaccine. 2022;40(36):5356–5365. doi: 10.1016/j.vaccine.2022.07.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Walter EB, Schlaudecker EP, Talaat KR, Rountree W, Broder KR, Duffy J, Grohskopf LA, Poniewierski MS, Spreng RL, Staat MA, et al. Safety of simultaneous vs sequential mRNA COVID-19 and inactivated influenza vaccines. JAMA Netw Open. 2024;7(11):e2443166. doi: 10.1001/jamanetworkopen.2024.43166. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Naficy A, Kuxhausen A, Seifert H, Hastie A, Leav B, Miller J, Anteyi K, Mwakingwe-Omari A. 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. Hum Vaccin Immunother. 2024;20(1):2327736. doi: 10.1080/21645515.2024.2327736. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Bai S, Zhou S, Zhang J, Chen W, Lv M, Wang J, Zhang A, Wu J, Zhao W. Immunogenicity and safety of different combinations involving a third booster dose of SARS-CoV-2 inactivated vaccine, inactivated quadrivalent influenza vaccine, and 23-valent pneumococcal polysaccharide vaccine in adults aged ≥60 years: a phase 4, randomized, open-label study. Front Immunol. 2024;15:1437267. doi: 10.3389/fimmu.2024.1437267. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Xie Y, Tian X, Zhang X, Yao H, Wu N. Immune interference in effectiveness of influenza and COVID-19 vaccination. Front Immunol. 2023;14:1167214. doi: 10.3389/fimmu.2023.1167214. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.World Health Organization . Frequently asked questions: transitioning to trivalent seasonal influenza vaccines. Geneva: World Health Organization; 2025. [Google Scholar]
38.World Health Organization . Statement on the antigen composition of COVID-19 vaccines. Geneva: World Health Organization; 2026. May 16. [Google Scholar]
39.World Health Organization . Statement on the fifteenth meeting of the IHR (2005) emergency committee –. 2023. May 5. https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic.
40.Centers for Disease Control and Prevention . Staying up to date with COVID-19 vaccines. 2025. https://www.cdc.gov/covid/vaccines/stay-up-to-date.html.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Material

KHVI_A_2747495_SM6875.docx^{(105.5KB, docx)}

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request, subject to applicable privacy and ethical restrictions.

[cit0001] 1.World Health Organization . COVID-19 weekly epidemiological update – 16 March 2023. Geneva: WHO; 2023. [Google Scholar]

[cit0002] 2.World Health Organization . WHO Director-General’s opening remarks at the media briefing – 5 May 2023. Geneva: WHO; 2023. [Google Scholar]

[cit0003] 3.World Health Organization . The burden of influenza. Geneva: WHO; 2018. (updated 2020). [Google Scholar]

[cit0004] 4.World Health Organization . Pneumococcal disease. Geneva: WHO; 2019. [Google Scholar]

[cit0005] 5.von Mollendorf C, Licciardi PV.. Adult pneumococcal vaccination: what are the gaps? The Lancet Infect Dis. 2024;24(10):1068–20. doi: 10.1016/S1473-3099(24)00400-6. [DOI] [PubMed] [Google Scholar]

[cit0006] 6.World Health Organization . Vaccines and immunization: overview. Geneva: WHO; 2021. [Google Scholar]

[cit0007] 7.Lives saved by COVID-19 vaccines. J Paediatr Child Health. 2022;58(11):2129. doi: 10.1111/jpc.16213. [DOI] [Google Scholar]

[cit0008] 8.Watson OJ, Barnsley G, Toor J, Hogan AB, Winskill P, Ghani AC. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. The Lancet Infect Dis. 2022;22(9):1293–1302. doi: 10.1016/S1473-3099(22)00320-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0009] 9.World Health Organization . Seasonal influenza – fact sheets. Copenhagen: WHO Regional Office for Europe; 2010. [Google Scholar]

[cit0010] 10.Vo NX, Pham HL, Bui UM, Ho HT, Bui TT. Cost-effectiveness of the pneumococcal vaccine in the adult population: a systematic review. Healthcare (Basel). 2024;12(23):2490. doi: 10.3390/healthcare12232490. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0011] 11.National Vaccine Advisory Committee . Recommendations from the National vaccine advisory committee: standards for adult immunization practice. Public Health Rep. 2014;129(2):115–123. doi: 10.1177/003335491412900203. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0012] 12.Bonanni P, Steffen R, Schelling J, Balaisyte-Jazone L, Posiuniene I, Zatoński M, Van Damme P. Vaccine co-administration in adults: an effective way to improve vaccination coverage. Hum Vaccin Immunother. 2023;19(1):2195786. doi: 10.1080/21645515.2023.2195786. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0013] 13.World Health Organization . Coadministration of seasonal inactivated influenza and COVID-19 vaccines: interim guidance, 21 October 2021. WHO/2019-nCoV/SAGE/Vaccines_coadministration/Influenza/2021.1. Geneva: WHO; 2021. [Google Scholar]

[cit0014] 14.Immunize.org . Strategies to improve adult vaccination coverage. Saint Paul (MN): Immunize.org; 2023. [Google Scholar]

[cit0015] 15.World Health Organization . Strengthening influenza vaccination policies and programmes. Geneva: WHO; 2025. [Google Scholar]

[cit0016] 16.Weinberger B. Vaccination of older adults: influenza, pneumococcal disease, herpes zoster, COVID-19 and beyond. Immun Ageing. 2021;18(1):38. doi: 10.1186/s12979-021-00249-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0017] 17.Kobayashi M, Leidner AJ, Gierke R, Xing W, Accorsi E, Moro P, Kamboj M, Kuchel GA, Schechter R, Loehr J, et al. Expanded recommendations for use of pneumococcal conjugate vaccines among adults aged ≥50 years: recommendations of the advisory committee on immunization practices — United States, 2024. Morb Mortal Wkly Rep. 2025;74(1):1–8. doi: 10.15585/mmwr.mm7401a1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0018] 18.Thompson AR, Klein NP, Downey HJ, Patterson S, Sundaraiyer V, Watson W, Clarke K, Jansen KU, Sebastian S, Gruber WC, et al. Coadministration of 13-valent pneumococcal conjugate and quadrivalent inactivated influenza vaccines in adults previously immunized with polysaccharide pneumococcal vaccine 23: a randomized clinical trial. Hum Vaccin Immunother. 2019;15(2):444–451. doi: 10.1080/21645515.2018.1533777. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0019] 19.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. Lancet. 2021;398(10318):2277–2287. doi: 10.1016/S0140-6736(21)02329-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0020] 20.Chen H, Huang Z, Chang S, Hu M, Lu Q, Zhang Y, Wang H, Xiao Y, Wang H, Ge Y, et al. Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine (sinopharm BBIBP-CorV) coadministered with quadrivalent split-virion inactivated influenza vaccine and 23-valent pneumococcal polysaccharide vaccine in China: a multicentre, non-inferiority, open-label, randomised, controlled, phase 4 trial. Vaccine. 2022;40(36):5322–5332. doi: 10.1016/j.vaccine.2022.07.033. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0021] 21.National Medical Products Administration . The guiding principles for grading adverse reactions in clinical trials of preventive vaccines (no. 102). Beijing: NMPA; 2019. [Google Scholar]

[cit0022] 22.Nikolich-Žugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 2018;19(1):10–19. doi: 10.1038/s41590-017-0006-x. [DOI] [PubMed] [Google Scholar]

[cit0023] 23.Hou Y, Chen M, Bian Y, Hu Y, Chuan J, Zhong L, Zhu Y, Tong R. Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. NPJ Vaccines. 2024;9(1):77. doi: 10.1038/s41541-024-00874-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0024] 24.Jo N, Hidaka Y, Kikuchi O, Fukahori M, Sawada T, Aoki M, Yamamoto M, Nagao M, Morita S, Nakajima TE, et al. Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination. Nat Aging. 2023;3(1):82–92. doi: 10.1038/s43587-022-00343-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0025] 25.Gustafson CE, Kim C, Weyand CM, Goronzy JJ. Influence of immune aging on vaccine responses. J Allergy Clin Immunol. 2020;145(5):1309–1321. doi: 10.1016/j.jaci.2020.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0026] 26.Collier DA, Ferreira IATM, Kotagiri P, Datir RP, Lim EY, Touizer E, Meng B, Abdullahi A, Baker S, Dougan G, et al. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature. 2021;596(7872):417–422. doi: 10.1038/s41586-021-03739-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0027] 27.Wojtakowski T, van de Sand L, Helmer L, Mokanis M, Witzke O, Horn PA, Krawczyk A, Sondermann W, Lindemann M. Evaluation of T-Cell responses following sequential vaccination with PCV13 and PPSV23 against Streptococcus pneumoniae in patients with psoriasis. Vaccines (Basel). 2025;13(9):920. doi: 10.3390/vaccines13090920. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0028] 28.Artz AS, Ershler WB, Longo DL. Pneumococcal vaccination and revaccination of older adults. Clin Microbiol Rev. 2003;16(2):308–318. doi: 10.1128/CMR.16.2.308-318.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0029] 29.Papadatou I, Tzovara I, Licciardi PV. The role of serotype-specific immunological memory in pneumococcal vaccination: current knowledge and future prospects. Vaccines (Basel). 2019;7(1):13. doi: 10.3390/vaccines7010013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0030] 30.Pawelec G, McElhaney J. Recent advances in influenza vaccines. F1000Res. 2020;9:305. doi: 10.12688/f1000research.22611.1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0031] 31.Huang T, Yu J, Zhang S, Teng D, Dai D, Zhu Y, Gao L. Immunogenicity and safety of concomitant administration of recombinant COVID-19 vaccine and quadrivalent inactivated influenza vaccine in Chinese adults: an open-label, randomized, controlled trial. Hum Vaccin Immunother. 2024;20(1):2330770. doi: 10.1080/21645515.2024.2330770. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0032] 32.Shenyu W, Xiaoqian D, Bo C, Xuan D, Zeng W, Hangjie Z, Qianhui Z, Zhenzhen L, Chuanfu Y, Juan Y, et al. Immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac) co-administered with an inactivated quadrivalent influenza vaccine: a randomized, open-label, controlled study in healthy adults aged 18 to 59 years in China. Vaccine. 2022;40(36):5356–5365. doi: 10.1016/j.vaccine.2022.07.021. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0033] 33.Walter EB, Schlaudecker EP, Talaat KR, Rountree W, Broder KR, Duffy J, Grohskopf LA, Poniewierski MS, Spreng RL, Staat MA, et al. Safety of simultaneous vs sequential mRNA COVID-19 and inactivated influenza vaccines. JAMA Netw Open. 2024;7(11):e2443166. doi: 10.1001/jamanetworkopen.2024.43166. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0034] 34.Naficy A, Kuxhausen A, Seifert H, Hastie A, Leav B, Miller J, Anteyi K, Mwakingwe-Omari A. 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. Hum Vaccin Immunother. 2024;20(1):2327736. doi: 10.1080/21645515.2024.2327736. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0035] 35.Bai S, Zhou S, Zhang J, Chen W, Lv M, Wang J, Zhang A, Wu J, Zhao W. Immunogenicity and safety of different combinations involving a third booster dose of SARS-CoV-2 inactivated vaccine, inactivated quadrivalent influenza vaccine, and 23-valent pneumococcal polysaccharide vaccine in adults aged ≥60 years: a phase 4, randomized, open-label study. Front Immunol. 2024;15:1437267. doi: 10.3389/fimmu.2024.1437267. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0036] 36.Xie Y, Tian X, Zhang X, Yao H, Wu N. Immune interference in effectiveness of influenza and COVID-19 vaccination. Front Immunol. 2023;14:1167214. doi: 10.3389/fimmu.2023.1167214. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0037] 37.World Health Organization . Frequently asked questions: transitioning to trivalent seasonal influenza vaccines. Geneva: World Health Organization; 2025. [Google Scholar]

[cit0038] 38.World Health Organization . Statement on the antigen composition of COVID-19 vaccines. Geneva: World Health Organization; 2026. May 16. [Google Scholar]

[cit0039] 39.World Health Organization . Statement on the fifteenth meeting of the IHR (2005) emergency committee –. 2023. May 5. https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic.

[cit0040] 40.Centers for Disease Control and Prevention . Staying up to date with COVID-19 vaccines. 2025. https://www.cdc.gov/covid/vaccines/stay-up-to-date.html.

PERMALINK

Evaluating a multi-vaccine respiratory immunization strategy involving SARS-CoV-2, pneumococcal, and influenza vaccines in adults: A randomized, open-label, multicenter, controlled, non-inferiority Phase IV trial in China

Xuanwen Shi

Shasha Han

Cong Wu

Xuejuan Wang

Jiao Huang

Wei Chen

Xiaoqin Liu

Sheng Wei

Jun Liu

Xiang Guo

Chenhao Wang

Shengyi Wang

Min Zhang

Xue Guo

Wei Zhao

Haiping Chen

Qingliang Li

Roles

ABSTRACT

HIGHLIGHTS

Introduction

Methods

Trial design

Participants

Vaccines

Outcomes

Sample size

Randomization

Immunogenicity assessments

Safety assessments

Statistical analysis

Results

Baseline characteristics

Figure 1.

Table 1.

Immunogenicity

SARS-CoV-2 neutralizing antibodies

Figure 2.

Figure 2.

Figure 2.

Pneumococcal polysaccharide antibodies

Figure 3.

Figure 3.

Figure 3.

Influenza antibodies

Figure 4.

Figure 4.

Figure 4.

Summary

Safety

Table 2.

Figure 5.

Discussion

Supplementary Material

Funding Statement

Disclosure statement

Data availability

Code availability

Ethics statement

Supplemental material

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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