The impact of influenza vaccination on the clinical severity of influenza among children aged 6 months to 6 years living in the community: a prospective cohort study

Abstract

Purpose

Evidence on whether influenza vaccination reduces disease severity in children with breakthrough infections in community settings is limited.

Materials and Methods

This prospective study enrolled 388 children (aged 6 months–6 years) diagnosed with influenza at a community health center in Shenzhen from May 2024 to October 2025. Participants were grouped by vaccination status within the prior year: vaccinated (n=196) and unvaccinated (n=192). Clinical characteristics, healthcare utilization, and outcomes were compared.

Results

Vaccinated children showed significantly lower peak body temperature (38.81°C±0.58°C vs. 39.03°C±0.64°C), shorter fever duration (2.01±1.21 days vs. 2.45±1.55 days), and fewer symptoms like myalgia and gastrointestinal issues (all p<0.01). They also had fewer outpatient visits, lower outpatient costs, and markedly reduced rates of hospitalization (4.1% vs. 21.9%) and antibiotic use (5.6% vs. 15.1%) (all p<0.05).

Conclusion

Influenza vaccination could mitigate symptoms, reduce hospitalization and antibiotic use, and lessen the healthcare burden from breakthrough infections.

INTRODUCTION

Influenza remains a significant public health concern worldwide [1]. Studies indicate that in China, influenza is associated with approximately 201,000 excess respiratory deaths annually, imposing a substantial burden on society [2,3]. The threat of influenza is particularly pronounced among children. Statistics show that the incidence of influenza in children under 5 years of age in China ranks among the highest across all age groups, with outpatient/emergency visits and hospitalization rates reaching approximately 2,200 and 224 per 100,000 population, respectively [4,5].

Influenza infection in children can not only lead to severe symptoms such as high fever and systemic myalgia but also increases the risk of secondary complications like pneumonia, thereby imposing ongoing pressures on pediatric health, household economies, and healthcare system resources [6]. Vaccination remains the most cost-effective strategy for preventing influenza and its serious complications. However, it must be recognized that the protective efficacy of influenza vaccines is not absolute, influenced by factors such as viral strain variation and host immune response heterogeneity [7,8]. Some vaccinated individuals may still experience breakthrough infections. Consequently, the evaluation of vaccine value has shifted from solely focusing on “preventing infection” to also emphasizing its “disease-modifying effect”—namely, the critical role of vaccination in mitigating clinical severity, reducing hospitalization, and lowering mortality risk [9,10]. Although the disease-modifying effect of influenza vaccines is widely acknowledged in theory, empirical evidence based on community pediatric populations in China remains relatively scarce. Existing studies have primarily focused on estimating vaccine effectiveness against infection, while real-world data on the actual protective impact—among vaccinated children who nonetheless contract influenza—in terms of alleviating clinical symptoms, reducing complications, and conserving medical resources are still insufficient.

Accordingly, this ‘prospective’ cohort study aims to evaluate the real-world effectiveness of influenza vaccination in pediatric patients by comparing disease severity, hospitalization rates, antibiotic use, and medical expenditures between vaccinated and unvaccinated children with confirmed influenza. The results intend to inform evidence-based strategies for childhood influenza prevention and clinical care.

MATERIALS AND METHODS

Research population

This study employed a prospective cohort design and was conducted at the Longdong Community Health Service Center of Shenzhen Longgang Central Hospital between May 15, 2024, and October 16, 2025. The study participants were children aged 6 months to 6 years who were clinically diagnosed with influenza at the center. The diagnosis of influenza was strictly based on the criteria outlined in the “Expert Consensus on Diagnosis and Treatment of Influenza in Children (2020 Edition)” [11]. The diagnostic criteria included: (1) influenza season epidemic period (based on local Centers for Disease Control and Prevention surveillance data); (2) acute onset of fever (axillary temperature ≥38°C) with respiratory symptoms such as cough, nasal congestion, rhinorrhea, or sore throat; and (3) clustered case occurrence or influenza exposure history. For patients meeting clinical diagnostic criteria, rapid influenza antigen detection testing was performed using a colloidal gold immunochromatographic assay (approved by the National Medical Products Administration). A subset of patients (approximately 15%) also underwent influenza virus nucleic acid detection by reverse transcription-polymerase chain reaction (PCR) for confirmatory purposes, particularly during periods of low influenza activity to rule out other respiratory pathogens. Children with positive rapid antigen tests or PCR confirmation were included as “influenza-confirmed” cases. Written informed consent was obtained from the guardians of all enrolled children, and the study protocol was approved by the Institutional Ethics Committee. The following exclusion criteria were applied: (1) presence of other acute non-influenza-related illnesses at the time of visit; (2) underlying chronic conditions that could affect the course or severity of influenza, including chronic respiratory, cardiovascular, immunodeficiency, hematologic, renal, hepatic, neurological, neuromuscular, metabolic, or endocrine diseases, or immunosuppressed status; (3) refusal by guardians to participate in telephone or community follow-up required for the study; and (4) incomplete key clinical data. Finally, a total of 388 children with community-acquired influenza who met all eligibility criteria were included in the final analysis. Regarding the epidemiological context of circulating influenza strains during the study period, data from the Chinese National Influenza Center surveillance network indicated that A(H1N1)pdm09 was the predominant subtype in southern China throughout the study period. During the 2024–2025 influenza season, A(H1N1)pdm09 accounted for approximately 94.0% of all influenza virus detections nationwide while A(H3N2) and B/Victoria lineage comprised approximately 3.6% and 2.4%, respectively. These surveillance data are consistent with the distribution observed in our study cohort, where the majority of cases were influenza A, with only a minority being influenza B [12].

Data collection

Collection of baseline data

At the time of the child's visit, baseline data were collected through medical record review and face-to-face interviews. Information gathered included general demographics (age, sex, and preschool education history), clinical manifestations (body temperature, and symptoms such as cough, nasal congestion, rhinorrhea, sore throat, myalgia, and gastrointestinal symptoms), and laboratory test results based on peripheral blood samples. Laboratory parameters comprised white blood cell count (WBC), the percentage and absolute counts of neutrophils and lymphocytes, hemoglobin level, platelet count, and C-reactive protein (CRP) level, with a CRP level >10 mg/L defined as abnormal. Additionally, use of antibiotics, as well as the number of medical visits and total outpatient expenses during the current illness episode were recorded.

Collection of follow-up data

Follow-up was conducted 7–10 days after the initial visit via telephone or at the community health service center to collect additional information on disease course and outcomes. Data included time to fever resolution (from illness onset to complete normalization of body temperature), time to cough resolution, occurrence of influenza-related hospitalization, complications, total number of medical visits, direct medical costs related to the illness and influenza vaccination history (children who had received at least one dose of influenza vaccine within the 12 months prior to the initial visit were classified as the “vaccinated group,” with all others assigned to the “unvaccinated group”). Fever resolution was defined as maintenance of axillary temperature below 37.3°C for at least 24 consecutive hours without the use of antipyretic medication, as reported by guardians during follow-up. Time to fever resolution was calculated from the reported onset of illness (based on guardian recall) to the time when the 24-hour afebrile criterion was first met. Direct medical costs related to the current influenza illness episode were calculated as the sum of all outpatient expenses incurred at our community health service center (including physician consultation fees, laboratory test fees, and medication costs) and, for hospitalized patients, the total inpatient costs (including bed fees, nursing fees, treatment fees, and medication costs) incurred at the admitting hospital. Costs were obtained from medical records and guardian-reported out-of-pocket expenses. To ensure accuracy, all data were entered and verified independently by 2 uniformly trained researchers.

Statistical analysis

All statistical analyses in this study were performed using SPSS 30.0 (IBM Corp., Armonk, NY, USA) and R language (version 4.4.3; R Foundation for Statistical Computing, Vienna, Austria). Normality of continuous variables was assessed using the Shapiro–Wilk test. Normally distributed data are presented as mean ± standard deviation and compared between groups using the independent samples t-test. Non-normally distributed data are expressed as median (interquartile range) and analyzed with the nonparametric Mann–Whitney U test. Categorical variables are summarized as frequency (percentage) and compared using the χ² test. All tests were 2-sided, and a p-value <0.05 was considered statistically significant.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Longgang Central Hospital, Shenzhen. All procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from the guardians of all participants prior to enrollment (approval number: 2024ECPJ026).

RESULTS

Demographic characteristics

A total of 388 pediatric patients were enrolled in this study, with 196 assigned to the vaccinated group and 192 to the unvaccinated group. No statistically significant differences were observed between the 2 groups in terms of age, sex, or preschool education level (all p>0.05), indicating comparability at baseline (Table 1).

Table 1. Demographic characteristics.

Variables		Total (n=388)	Unvaccinated (n=192)	Vaccinated (n=196)	p
Age (mon)		54.60±20.92	55.12±21.43	54.08±20.46	0.62
Sex					0.29
	Female	170 (43.81)	79 (41.15)	91 (46.43)
	Male	218 (56.19)	113 (58.85)	105 (53.57)
Preschool education					0.89
	No	84 (21.65)	41 (21.35)	43 (21.94)
	Yes	304 (78.35)	151 (78.65)	153 (78.06)

Values are presented as mean ± standard deviation or number (%).

Comparison of clinical symptom severity

A comparison of clinical symptoms between the 2 groups is presented in Table 2. Compared with the unvaccinated group, children in the vaccinated group had lower body temperature (38.81°C±0.58°C vs. 39.03°C±0.64°C, p<0.01), shorter time to fever resolution (2.01±1.21 days vs. 2.45±1.55 days, p<0.01), and lower incidence of myalgia (5.61% vs. 17.19%, p<0.01) and gastrointestinal symptoms (9.69% vs. 20.83%, p<0.01). No significant differences were observed in the incidence of cough, nasal congestion, rhinorrhea, or sore throat (all p>0.05).

Table 2. Comparison of clinical symptom severity.

Variables		Total (n=388)	Unvaccinated (n=192)	Vaccinated (n=196)	p
Temperature (℃)		38.92±0.62	39.03±0.64	38.81±0.58	<0.01
Time reducing fever (days)		2.23±1.40	2.45±1.55	2.01±1.21	<0.01
Cough					0.43
	No	143 (36.86)	67 (34.90)	76 (38.78)
	Yes	245 (63.14)	125 (65.10)	120 (61.22)
Nasal congestion					0.43
	No	230 (59.28)	110 (57.29)	120 (61.22)
	Yes	158 (40.72)	82 (42.71)	76 (38.78)
Runny nose					0.63
	No	169 (43.56)	86 (44.79)	83 (42.35)
	Yes	219 (56.44)	106 (55.21)	113 (57.65)
Sore throat					0.09
	No	333 (85.82)	159 (82.81)	174 (88.78)
	Yes	55 (14.18)	33 (17.19)	22 (11.22)
Myalgia					<0.01
	No	344 (88.66)	159 (82.81)	185 (94.39)
	Yes	44 (11.34)	33 (17.19)	11 (5.61)
Gastrointestinal symptoms					0.002
	No	329 (84.79)	152 (79.17)	177 (90.31)
	Yes	59 (15.21)	40 (20.83)	19 (9.69)

Values are presented as mean ± standard deviation or number (%).

Laboratory findings

Baseline laboratory results are presented in Table 3. No statistically significant differences were observed between the 2 groups in WBC, neutrophil or lymphocyte count (or their percentages), hemoglobin level, or platelet count (all p>0.05). Although the proportion of patients with elevated CRP was higher in the unvaccinated group, this difference did not reach statistical significance (p=0.06).

Table 3. Laboratory findings.

Variables		Total (n=388)	Unvaccinated (n=192)	Vaccinated (n=196)	p
WBC (×109/L)		8.76±3.45	8.97±3.40	8.55±3.49	0.24
Neutrophil (%)		63.20±14.57	63.00±15.34	63.39±13.80	0.79
Lymphocyte (%)		24.95±12.85	25.46±13.29	24.45±12.42	0.44
Neutrophil (×109/L)		5.70±2.84	5.82±2.79	5.57±2.89	0.39
Lymphocyte (×109/L)		2.03±1.27	2.12±1.44	1.94±1.07	0.16
Hemoglobin (g/L)		127.65±9.70	126.86±9.86	128.42±9.51	0.11
Platelet (×109/L)		219.58±64.07	222.92±70.34	216.30±57.27	0.31
CRP (mg/L)					0.06
	No	325 (83.76)	154 (80.21)	171 (87.24)
	Yes	63 (16.24)	38 (19.79)	25 (12.76)

Values are presented as mean ± standard deviation or number (%).

WBC, white blood cell count; CRP, C-reactive protein.

Clinical outcomes and healthcare utilization

Clinical outcomes and healthcare resource utilization are summarized in Table 4. Compared with the unvaccinated group, children in the vaccinated group had fewer average medical visits (1.55±0.82 vs. 1.78±0.91, p<0.01), lower outpatient costs (349.42±201.23 vs. 407.41±337.44, p=0.04), and significantly lower rates of hospitalization (4.1% vs. 21.9%, p<0.01) and antibiotic use (5.6% vs. 15.1%, p<0.01).

Table 4. Clinical outcomes and healthcare utilization.

Variables		Total (n=388)	Unvaccinated (n=192)	Vaccinated (n=196)	p
No. of visits (next)		1.66±0.87	1.78±0.91	1.55±0.82	<0.01
Outpatient expenses (yuan)		378.12±278.28	407.41±337.44	349.42±201.23	0.04
Hospitalization					<0.01
	No	339 (87.37)	150 (78.12)	189 (95.92)
	Yes	49 (12.63)	42 (21.88)	7 (4.08)
Antibiotic					<0.01
	No	348 (89.69)	163 (84.90)	185 (94.39)
	Yes	40 (10.31)	29 (15.10)	11 (5.61)

Values are presented as mean ± standard deviation or number (%).

DISCUSSION

This study analyzed the clinical data of 388 children aged 6 months to 6 years diagnosed with influenza at a community health service center. The results demonstrated that, among confirmed influenza cases, children who had received influenza vaccination within the preceding year exhibited milder clinical manifestations—including lower body temperature, faster fever resolution, and reduced incidence of myalgia and gastrointestinal symptoms—compared to their unvaccinated counterparts. Furthermore, vaccinated children experienced better clinical outcomes, such as a lower risk of hospitalization, fewer medical visits and lower outpatient costs. Collectively, these real-world evidence support that influenza vaccination in children offers clinical benefits, encompassing both infection prevention and disease-modifying outcomes.

The core findings of this study align with global evidence on the clinical value of influenza vaccination and further provide localized empirical data from a community-based pediatric population in China. Consistent with the fundamental expectation that influenza vaccination mitigates disease severity, vaccinated children in our cohort presented with lower body temperature and milder systemic symptoms. A systematic review of real-world effectiveness studies in children (1995–2023) concluded that influenza vaccines provide protection and reduce disease burden following infection, a finding our study supports with specific, quantifiable clinical evidence [6]. The observed reductions in hospitalization (4.1% vs. 21.9%) and antibiotic use (5.6% vs. 15.1%) in the vaccinated group indicates public health significance, reflecting the vaccine’s role in preventing serious clinical consequences. Multiple studies have demonstrated protective effects of influenza vaccination against pediatric hospitalization, severe illness, and mortality [10,13]. Furthermore, a 2022 study by Younas et al. [14] highlighted that vaccination reduces both antibiotic prescribing rates and the risk of requiring antibiotic treatment, an effect our data confirm among community-managed pediatric influenza patients. From a health economics perspective, the decreases in medical visits and outpatient costs in the vaccinated group are consistent with other reports demonstrating that influenza vaccination lowers healthcare resource utilization [4,15,16]. This further supports the cost-effectiveness of childhood influenza vaccination in terms of reduced economic burden.

The clinical pattern observed among vaccinated children—characterized by milder symptoms, prevention of severe disease, and fewer complications—may be partially explained the rapid and effective response of vaccine-induced pre-existing immunity to viral infection. Following vaccination, the body generates specific antibodies and memory immune cells (memory B cells and T cells). In the event of a breakthrough infection, these pre-existing immune components are quickly activated [17,18]. Memory B cells rapidly proliferate and produce large quantities of high-affinity antibodies to neutralize the virus, while memory T cells—particularly cytotoxic T cells—promptly recognize and eliminate virus-infected host cells. This accelerated immune response enables viral replication to be controlled at an earlier stage and at a lower level, thereby directly reducing the degree of viremia and limiting tissue damage [19,20]. This mechanism provides a plausible explanation for the findings in our study: vaccinated children exhibited lower peak body temperature, shorter time to fever resolution, and fewer systemic inflammatory symptoms such as myalgia. Furthermore, influenza virus infection can compromise the respiratory mucosal barrier and suppress innate immunity, increasing the risk of secondary bacterial complications such as pneumonia and otitis media [21,22,23,24]. By curbing viral replication, alleviating epithelial damage, and mitigating inflammatory cytokine release, vaccination helps preserve the defensive function of the respiratory tract, thereby lowering the risk of secondary bacterial infection. This offers a coherent pathophysiological explanation for the observed reductions in antibiotic use and hospitalization rates in the vaccinated group.

It is important to consider the findings of this study in light of the predominant circulating influenza subtype. During the study period, A(H1N1)pdm09 was the overwhelmingly dominant strain in southern China, with A(H3N2) and B/Victoria detected only sporadically. Previous studies have demonstrated that vaccine effectiveness against influenza can vary substantially by subtype, with generally higher effectiveness against A(H1N1)pdm09 and influenza B compared with A(H3N2). The disease-modifying effect of vaccination observed in our cohort therefore primarily reflects the vaccine’s impact against A(H1N1)pdm09 infection. Whether similar attenuation would be observed during seasons dominated by A(H3N2)—a subtype associated with greater antigenic drift and historically lower vaccine effectiveness—warrants further investigation. We have accordingly added the predominant circulating subtype information to the Methods section and discussed this caveat in the limitations [12,25].

This study has several limitations. As a prospective study, unmeasured confounding may exist, including “healthy vaccinee bias” and recall bias in vaccination history. Second, specific vaccination dates were unavailable, precluding assessment of the vaccination-to-onset interval during which immunity may wane. Third, all vaccinated children received inactivated influenza vaccine, but trivalent versus quadrivalent formulations and strain-mismatch data were not collected. Fourth, only binary vaccination status was recorded, preventing distinction between primary vaccinees and previously primed children. Fifth, milder breakthrough infections in vaccinated children may not have presented for care, potentially overestimating severity in this group; healthcare-seeking among unvaccinated children may likewise vary with unmeasured socioeconomic and literacy factors. Sixth, “Preschool education” was defined as preschool enrollment, but older siblings’ school attendance—a known household transmission vector—was not assessed, leaving residual exposure confounding. Finally, A(H1N1)pdm09 was the predominant circulating subtype during the study period, accounting for >94% of detections in southern China in the 2024–2025 season, the small numbers of A(H3N2) and B/Victoria cases precluded subtype-stratified analysis of vaccine effectiveness against disease severity. The single-center design may limit generalizability. Future multi-center studies with detailed vaccination history, household exposure data, and strain-matching information are warranted.

This study demonstrates that influenza vaccination can alleviate clinical symptoms, reduce the risks of hospitalization and antibiotic use, and decrease healthcare resource consumption among children with community-acquired influenza. These findings strongly support the ongoing public health strategy of promoting and expanding influenza vaccination in children as a key measure for seasonal influenza prevention and control.