Influenza Vaccination in Children During the First Two Seasons of Routine Vaccination Programs (2023–24 and 2024–25) in Central Catalonia, Spain: A Retrospective Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Manuscript ID: ijerph-4015025

Type: Article

Title: Influenza vaccination in children during the first two seasons of routine vaccination programmes (2023-24 and 2024-25) in Central Catalonia, Spain

Authors: Sílvia Burgaya-Subirana , Mònica Balaguer * , Laia Sola Reguant , Anna Ruiz-Comellas

A brief summary

The manuscript explores the issue of influenza vaccination coverage among the pediatric population within a specific region of Spain. Influenza vaccination represents a key public health intervention, particularly when its effectiveness is assessed within a defined target population, which constitutes the principal strength and distinctive feature of this study. Nevertheless, notwithstanding the study’s innovative approach, substantial revisions are required to enhance the overall scientific quality and clarity of the manuscript. Detailed comments are provided below:

 

Line 49: Please specify the incidence rate for both observation years.

Line 65-66: Please clarify precisely which complications are being referred to, i.e., what is meant by "high-risk pathology."

In general, the terminology in the Introduction section should be carefully reviewed and standardized. Terms such as “flu” and “influenza” are used interchangeably throughout the text; please select one term and use it consistently.

Results:

For each reported percentage, please provide the corresponding absolute number (N) (see Lines 134, 135, 136, etc.).

The tables presented are quite lengthy and complex. Consider either shortening the textual descriptions of the tables or simplifying the tables themselves by presenting only the most important and statistically significant results. There is no need for repetition.

Additionally, I suggest that Table 2 and Table 6 be split into two separate tables each (i.e., separate tables for each observed cohort: children from 6 to 59 months and children between 5 and 14 years), as this would significantly improve clarity and facilitate interpretation.

The quality of English is, in places, exceptionally poor, to the extent that it is difficult to understand the authors’ intended meaning.

Discussion:

This section must be strengthened with additional data on vaccination policies and coverage rates in other countries, especially neighboring European countries. It would also be beneficial to reference additional local studies and compare their findings with those obtained in the present study, thereby further enriching this section.

Furthermore, it would be advisable to present the limitations and recommendations for future research as separate subheadings. In general, a more detailed discussion of the study's limitations and shortcomings would be beneficial.

Lines 359-453: The reference formatting lacks consistency. Please carefully review all references to ensure complete adherence to the journal’s author guidelines.

English: The manuscript would benefit from further language and style refinement. Utilizing a professional English-language editing service is recommended.

Comments on the Quality of English Language

The manuscript would benefit from further language and style refinement. Utilizing a professional English-language editing service is needed and recommended.

Author Response

 

1. Line 49: Please specify the incidence rate for both observation years.

Thank you for your comment. Now, It is line 72: We have included the follow sentence: “In Spain, the highest incidence rate for influenza in the 2021-22 and 2022-23 seasons was observed in the 0- to 4-year-old group (1,500 cases and 1,100 cases per 100,000 inhabitants respectively), followed by the 5- to 14-year-old group (400 cases and 1,000 cases per 100,000 inhabitants respectively).”

2. Line 65-66: Please clarify precisely which complications are being referred to, i.e., what is meant by "high-risk pathology."

Thank you for your comment. We have added a table clarifying wich are considered de high-risk pathology. It is table 1.

Table 1. High-risk pathology that Catalan Department of Health considered as indications for receiving the influenza vaccine in children older than 6 months up to the 2022/23 season.

 

High-risk pathology for Influenza Vaccination in Children

Chronic cardiovascular, neurological or respiratory diseases (including hypertension, asthma, bronchopulmonary dysplasia and cystic fibrosis). Diabetes mellitus. Morbid obesity: body mass index (BMI)≥ 35 in adolescents and ≥ 3 standard deviations in children. Chronic kidney disease and nephrotic syndrome. Haemoglobinopathies and anaemia. Haemophilia and other clotting disorders, chronic bleeding disorders, recipients of blood products and multiple transfusions. Asplenia or severe splenic dysfunction. Chronic liver disease. Severe neuromuscular diseases. Immunosuppression (including primary immunodeficiencies and those caused by HIV infection), drugs (including eculizumab treatment), or in transplant recipients and associated deficiencies. Cancer and malignant blood diseases. Cochlear implant or awaiting implant. Cerebrospinal fluid fistula. Coeliac disease. Chronic inflammatory disease. Disorders and diseases that entail cognitive dysfunction: Down’s syndrome, etc. Children and adolescents receiving prolonged treatment with acetylsalicylic acid, due to the possibility of developing Reye’s syndrome after influenza. Long-term institutionalised children. Children between 6 months and 2 years old with a history of prematurity, born at less than 32 weeks gestation.

 

3. In general, the terminology in the Introduction section should be carefully reviewed and standardized. Terms such as “flu” and “influenza” are used interchangeably throughout the text; please select one term and use it consistently.

Thank you for your comment. We have changed “flu” to “infuenza”. And we have changed the introduction:

Influenza is a very common infection in children and has a large impact on public health [1,2]. It is caused by orthomixovirus influenza A, B, or C. Viruses A and B are the causes of annual epidemics, and the A virus has caused global pandemics. Although most of the time the symptoms are mild (sudden catarrhal onset with high fever, cough, mucus, and myalgia), it can sometimes have complications and serious symptoms [2-4]. The World Health Organization (WHO) estimates that every year 1 billion people get influenza of which 3-5 million have serious symptoms and the number of deaths from respiratory disease related to this infection is between 290,00-650,000[3]. It has been shown that the paediatric population is the most affected by this infection and is the main transmitter of the virus [4-5]. In line of these findings, in Spain, the highest incidence rate for influenza in the 2021-22 and 2022-23 seasons was observed in the 0- to 4-year-old group (1,500 cases and 1,100 cases per 100,000 inhabitants respectively), followed by the 5- to 14-year-old group (400 cases and 1,000 cases per 100,000 inhabitants respectively) [6-7]. Hospitalizations for influenza in the same period were highest in elderly people, followed by the 0 to 4-year-old group [6,7]. Therefore, children under 5 years of age are the most susceptible to influenza and the most vulnerable to serious infection [8]. Vaccination is considered one of the best ways to prevent influenza and can reduce the duration of hospital admissions and the risk of severe cases and deaths [5-9]. Several studies have shown that influenza vaccination at the paediatric age cannot only protect children, but also the entire community, and contributes to reducing the incidence of influenza in the general population [10-12]. Despite this evidence, childhood influenza vaccination coverage in Spain is very low [5,13-20].

In Spain (and, therefore, in Catalonia) until the 2022-23 season, paediatric influenza vaccination was recommended for all children over 6 months of age with any high-risk pathology for complications [Table 1][21,22], but from the 2023-24 season, and following the recommendations of the Spanish Ministry of Health and the WHO, they were extended to all children under 5 years of age and any children over this age with risk factors [23-25]. The influenza vaccine has become part of the routine vaccination calendar.

 

Table 1. High-risk pathology that Catalan Department of Health considered as indications for receiving the influenza vaccine in children older than 6 months up to the 2022/23 season.

 

High-risk pathology for Influenza Vaccination in Children

Chronic cardiovascular, neurological or respiratory diseases (including hypertension, asthma, bronchopulmonary dysplasia and cystic fibrosis). Diabetes mellitus. Morbid obesity: body mass index (BMI)≥ 35 in adolescents and ≥ 3 standard deviations in children. Chronic kidney disease and nephrotic syndrome. Haemoglobinopathies and anaemia. Haemophilia and other clotting disorders, chronic bleeding disorders, recipients of blood products and multiple transfusions. Asplenia or severe splenic dysfunction. Chronic liver disease. Severe neuromuscular diseases. Immunosuppression (including primary immunodeficiencies and those caused by HIV infection), drugs (including eculizumab treatment), or in transplant recipients and associated deficiencies. Cancer and malignant blood diseases. Cochlear implant or awaiting implant. Cerebrospinal fluid fistula. Coeliac disease. Chronic inflammatory disease. Disorders and diseases that entail cognitive dysfunction: Down’s syndrome, etc. Children and adolescents receiving prolonged treatment with acetylsalicylic acid, due to the possibility of developing Reye’s syndrome after influenza. Long-term institutionalised children. Children between 6 months and 2 years old with a history of prematurity, born at less than 32 weeks gestation.

 

The objectives of this study are to evaluate the coverage and adherence to childhood influenza vaccination in Central Catalonia during the first two seasons (2023-24 and 2024-25) of routine childhood influenza vaccination, and to identify the factors associated with influenza vaccination both in children under 5 years of age, and in children aged 5 to 14 years who had risk factors.

Results:

4. For each reported percentage, please provide the corresponding absolute number (N) (see Lines 134, 135, 136, etc.).

Thank you for your comment. It has been added the absolute number for each reported percentage as you can see: “A total of 39,987 children were studied. 53.3% (21,330) were male. 40% (16,003) were between 6 months and 2 years old. 69.7% (27,875) lived in a rural or semi-urban area and 80.7% (26,696) were of Spanish origin.79 1% (31,621) had not been vaccinated in either of the two seasons evaluated”.

5. The tables presented are quite lengthy and complex. Consider either shortening the textual descriptions of the tables or simplifying the tables themselves by presenting only the most important and statistically significant results. There is no need for repetition.

Thank you for your comment. The tables 2,3,4,8 and 9 have been shortened. The variables “sex”, “ rurality” and “country of origin” have been removed because they are described in the text.

6. Additionally, I suggest that Table 2 and Table 6 be split into two separate tables each (i.e., separate tables for each observed cohort: children from 6 to 59 months and children between 5 and 14 years), as this would significantly improve clarity and facilitate interpretation.

Thank you for your comment. Table 2 and 6 has been separated into two tables for each cohort: children from 6 to 59 months and children between 5 to 14 years. Now are tables 3,4, 8 and 9.

7. The quality of English is, in places, exceptionally poor, to the extent that it is difficult to understand the authors’ intended meaning.

Thank you for your comment. English has been improved.

Discussion:

8. This section must be strengthened with additional data on vaccination policies and coverage rates in other countries, especially neighboring European countries. It would also be beneficial to reference additional local studies and compare their findings with those obtained in the present study, thereby further enriching this section.

Thank you for your comment. The text has been changed taking into account your suggestions. This is the text:

Seasonal influenza represents a significant public health burden, and vaccination is the most effective strategy for preventing influenza infection [1,2,5,9]. Children are the main transmitters of the virus; therefore, more than 70 countries have implemented seasonal influenza vaccination programs for pediatric populations. However, differences exist between countries regarding the age groups included in routine vaccination schedules. For example, the United Kingdom has vaccinated children aged 2 to 16 years against influenza since the 2013–2014 season, whereas Finland introduced influenza vaccination for children aged 6 to 36 months in 2007 and extended routine vaccination to children up to 6 years of age in 2015 [26–28].

In Spain, and consequently in Catalonia, until the 2022–2023 season, influenza vaccination was recommended only for children aged 6 months and older with underlying risk conditions [21,22]. From the 2023–2024 season onward, influenza vaccination was expanded to include all children aged 6 to 59 months [23,25].In this way, influenza vaccination was considered routine in children of this age group. In older children (5-14 years) the vaccine continued to be administered only in those who had some underlying pathology [23]. This measure was applied following the recommendations of the Spanish Ministry of Health [23,25].

The data provided by our study indicate that, despite the application of this new measure, childhood influenza vaccination coverage (6 months to 14 years) remains very low: 18.1% and 19.3% for the 2023-24 and 2024-25 seasons respectively. As for influenza vaccination in the range of 6 to 59 months, coverage was 19.1% during the 2023-24 season and 26.8% during the 2024-205 season.

Other local studies in Spain have shown that Galicia was the community with the most vaccination, with vaccine coverage of 55.8%, followed by Murcia (51.1%) and Andalusia (45.8%). Ceuta was the community with the lowest vaccination rates, with a coverage of 2.9%. Throughout Catalonia, influenza vaccination coverage was observed at 24.4% [29-31]. It should be noted that these data, provided by the Ministry of Health, only include children aged 1 to 5 years (leaving out children aged 6 to 11 months) so that our coverage is closer to the total figures recorded throughout the Catalan region. As for the 2024–25 season, official coverage figures at the state level have not yet been published for comparison, but a coverage of 58,6% has been registered this season in Andalusia for children from 6 to 59 months [32].

The reason for this heterogeneity between territories seems to be due to different vaccination campaigns to carried out in different autonomous communities [31]. For example, in Murcia and Andalusia, vaccinations took place in schools, while in Galicia a mass vaccination campaign was promoted for a specific weekend in designated locations with longer vaccination shifts, imitating the COVID-19 vaccination campaign [32-34].

Another possible cause of the low coverage of influenza vaccination in children in our territory is the lack of promotional campaigns for influenza vaccination among health professionals. Several studies have shown that the main cause of influenza vaccination in children is advice from their paediatrician [9,35-40].

At the European level, influenza vaccination coverage varies considerably across countries. During the 2023–2024 season, the United Kingdom reported an influenza vaccination coverage of 50%. In Finland, coverage was 41% among children under 2 years of age and 29% among children aged 2 to 6 years. Denmark, which introduced universal influenza vaccination for children aged 2 to 6 years in the 2020–2021 season, reported a coverage rate of 22% [26–28,41]

However, it should be noted that in the present study we observed an increase in influenza vaccination during the 2024-25 season of 7.7% in the group of 6 to 59 months compared to the previous season, so that we believe that once routine vaccination programs are more rooted in the territory, families will have more confidence in the initiative. This increase in coverage between seasons is also seen Andalusia where we see an increase between the two seasons of 12.8% [42].

It should be noted that this represents a substantial increase in coverage within the universally recommended group. In contrast, vaccination coverage among the risk-based target population (children with comorbidities) did not increase, underscoring the importance of universal vaccination strategies. Indeed, several studies have demonstrated that universal vaccination is the most cost-effective approach to reducing the overall burden of influenza at the population level [43–50].

Adherence to influenza vaccination during the last two flu seasons is very low. Only 17% of children have been vaccinated consecutively in the 2023-24 and 2024–25 seasons. At the Spanish level there is no study that analyzes this data for the last two seasons has been found, therefore we cannot compare whether our region is above or below the Spanish average. In a study carried out by our group in the 5 seasons prior to routine influenza vaccination programs in children under 5 years of age in Central Catalonia, we found influenza vaccination an adherence of 21.6% in two seasons, a figure similar to our current results [14]. With this data we can say that the extension of influenza vaccination to children under 5 years of age has not led to an improvement in adherence. However, we would have to wait and see the trend in the coming seasons.

In relation to the variables associated with vaccination, our study shows that the male sex is more likely to be vaccinated than the female in the group of 6 to 59 months. In a study of Catalonia in 2015, Gonzalez R et al. also observed that gender was significantly associated with vaccination, but appears not to be corroborated by most authors, so we do not consider it clinically relevant[13].

Regarding parent education, we have observed that both in the group of younger children (6 to 59 months) and in the group of 5- to 14-year-olds, parents with a higher educational level vaccinate more, probably because they have more information about influenza vaccination and the possible consequences of complications in case of an infection.

Non-native children are vaccinated more often than Spanish children. This result is similar to studies conducted in previous campaigns [13, 14]. In a study conducted in Murcia during the 2022-23 campaign, Pérez Martin J et al. found that there were no differences in influenza vaccination according to the children's country of origin, but the parents' country of origin did have a difference. The reasons for this phenomenon can probably be explained for cultural reasons, but more studies would be needed to reach a definitive conclusion.

The positive association between the number of risk factors and influenza vaccination, already described above [13,14], is quite logical. The higher the number of risk factors, the more likely it is to experience complications from influenza.

Finally, certain underlying conditions such as diabetes, asthma, heart disease, nephropathies and hepatopathies and hemoglobinopathies and clotting disorders are also positively associated with influenza vaccination in children from 6 to 59 months.

Note that in the 5 to 14-year-old age group, obesity is negatively associated with influenza vaccination; children with obesity are not vaccinated for the flu probably because of their poor perception of illness. This is in line with a previous study conducted by our group [14].

 

4.2. Limitations and strengths

The main limitation presented by our study is that the data are obtained from the ICS database, therefore children vaccinated in other health providers would have been excluded from the study. However, the ICS is the main healthcare provider in Catalonia and therefore, we believe that the data analyzed are representative of our population.

Another limitation of this study is the potential presence of incomplete data inherent to the use of medical and administrative databases. Specifically, information on parental educational attainment was missing for approximately half of the study population. This lack of completeness may have limited the ability to fully assess the association between parental education level and influenza vaccination uptake in children. However, given the large sample size and the population-based nature of the database, we believe that the overall findings remain robust and representative of the study population.

The main strength of our research is that this is one of the few studies that analyzes the factors associated with influenza vaccination in children under 5 years of age after the implementation of routine influenza vaccination program in Spain. Another strength of the study is the sample size, as we present a sample of almost 40,000 children.

 

4.3 Futures Research

A possible future line of research could be the effect of the implementation of new campaigns to promote vaccination between the population and health professionals to try to increase coverage of influenza vaccination in children, especially in the 6 to 59 month age group.

9. Furthermore, it would be advisable to present the limitations and recommendations for future research as separate subheadings. In general, a more detailed discussion of the study's limitations and shortcomings would be beneficial.

Thank you for your comment. A subtitle for limitations and for recommendations for future research has been included.

The limitations of the study has been changed to the next text:

The main limitation presented by our study is that the data are obtained from the ICS database, therefore children vaccinated in other health providers would have been excluded from the study. However, the ICS is the main healthcare provider in Catalonia and therefore, we believe that the data analyzed are representative of our population.

Another limitation of this study is the potential presence of incomplete data inherent to the use of medical and administrative databases. Specifically, information on parental educational attainment was missing for approximately half of the study population. This lack of completeness may have limited the ability to fully assess the association between parental education level and influenza vaccination uptake in children. However, given the large sample size and the population-based nature of the database, we believe that the overall findings remain robust and representative of the study population.

The main strength of our research is that this is one of the few studies that analyzes the factors associated with influenza vaccination in children under 5 years of age after the implementation of routine influenza vaccination program in Spain. Another strength of the study is the sample size, as we present a sample of almost 40,000 children.

 

10. Lines 359-453: The reference formatting lacks consistency. Please carefully . review all references to ensure complete adherence to the journal’s author guidelines.

Thank you for your comment. The references has been reviewed:

11. English: The manuscript would benefit from further language and style refinement. Utilizing a professional English-language editing service is recommended.

Thank you for your comment. English has been improved with an English-Spanish translator.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The investigators report an ERC-approved study of influenza vaccine coverage among children (all children 6-59-months and children 5-14-years with a comorbidity, n=39,987) in Spain during the first two influenza seasons in which there was a government recommendation (2023/24 and 2024/25 seasons) for influenza vaccination of children, and to identify risk factors associated with influenza vaccination of target children. The design was a retrospective cohort study with data sourced from Catalan Institute of Health. They found that 21% of all subjects were vaccinated both seasons, and 19% and 27% of 6-59-month-olds were vaccinated the first and second seasons and 18% and 18% of older children with comorbidities were vaccinated, by season. They found several factors that were associated with vaccination. They concluded that “Coverage and adherence to influenza vaccination in childhood are very low, despite the implementation of a routine influenza vaccination programme.”

Young children and children with comorbidities are recommended by WHO to receive influenza vaccination. Spain introduced influenza vaccination for young children and children with comorbidities. Vaccines only work when given, so coverage and adherence to the recommendation is important. The use of a health data platform for obtaining vaccination data, demographics, and medical data is appropriate and efficient, providing that the records are complete. The manuscript is reasonably well written. The strengths and limitations are stated. The conclusions are supported by the data presented.

I have some comments and suggestions to improve the manuscript.

STROBE guidelines recommend putting the study design in the title of the manuscript/article. The authors should do so.

The authors’ conclusion is based on the evidence presented. However, I think that they could have also concluded that coverage increased (from 19% to 27%) for the universally-recommended group (6-59-month-olds) during the two-year study, but did not increase for the risk-based target population (with comorbidities). This would allow the authors to contrast a universal vs a risk-based recommendation and to highlight a significant increase in coverage for the universally-recommended group.

Lines 80-82 – The subjects were 6-59 months and 5-14-years with a comorbidity, which the authors say are “all children eligible for the influenza vaccination during the 2023-24 and 2024-25 seasons.”  However, it is not clear how any child less than one year of age could be eligible for two influenza vaccination seasons. Also, some older children may have had a comorbidity one year but not the other year. This raises the question about how the denominators were calculated for each of the coverage measures. The authors should describe the numerators and denominators for each of the outcome calculations in sufficient detail for study replication by another researcher.

In Table 1 title (and line 108 and line 139), “... susceptible to influenza vaccination during the 2023-24 and 2024-25 seasons,” it is not clear what susceptible to influenza vaccination means. Does it mean eligible for influenza vaccination?

In Table 1, it is not clear what the “i” means in “1,2 i 3”.

Table 2 gives column percents, but row percents would be more informative for the reader, since row percent equates to coverage.

In Table 2, the p-value of “<0.000” doesn’t make mathematical sense. Perhaps authors could say <0.001.

Lines 322-325 (limitations) – another limitation is the risk of incomplete data in the medical/administrative database. For example, about half of subjects’ parents do not have information on educational attainment listed.

Line 57 – The sentence “... contributes to reducing the incidence of influenza in the general population [9-12]”is about indirect protection of off-target populations, but reference 9 is about vaccine hesitancy, not herd immunity. Authors should check to see if reference 9 is correct. Refs 10-12 are relevant.

The writing is clear enough to follow, but there are some typos that should be corrected when proofing the manuscript so that it meets journal standards for English.

 

 

Author Response

1. STROBE guidelines recommend putting the study design in the title of the manuscript/article. The authors should do so.

Thank you for your comment. The title has been changed to “Influenza vaccination in children during the first two seasons of routine vaccination programmes (2023-24 and 2024-25) in Central Catalonia, Spain. A retrospective study.”

2. The authors’ conclusion is based on the evidence presented. However, I think that they could have also concluded that coverage increased (from 19% to 27%) for the universally-recommended group (6-59-month-olds) during the two-year study, but did not increase for the risk-based target population (with comorbidities). This would allow the authors to contrast a universal vs a risk-based recommendation and to highlight a significant increase in coverage for the universally-recommended group.

Thank you for your comment. The conclusions have been changed taking into account your suggestions.This is the text: 

Influenza vaccination coverage and adherence among children in Central Catalonia remain low overall, despite the introduction of a routine influenza vaccination programme for children aged 6–59 months from the 2023–2024 season onwards. However, a significant increase in vaccination coverage was observed in this universally recommended age group, rising from approximately 19% in the first season to nearly 27% in the second season. In contrast, vaccination coverage among children aged 5–14 years targeted through a risk-based recommendation remained low and showed no meaningful increase between seasons. These findings highlight a differential impact of universal versus risk-based influenza vaccination strategies, suggesting that universal recommendations may be more effective in improving coverage in paediatric populations. Factors associated with influenza vaccination in children aged 6–59 months included immigrant origin, urban residence, the presence of multiple risk factors, and specific underlying chronic conditions. Continued efforts are needed to strengthen influenza vaccination programmes, particularly among children targeted through risk-based strategies, to improve both coverage and adherence.

3. Lines 80-82 – The subjects were 6-59 months and 5-14-years with a comorbidity, which the authors say are “all children eligible for the influenza vaccination during the 2023-24 and 2024-25 seasons.”  However, it is not clear how any child less than one year of age could be eligible for two influenza vaccination seasons. Also, some older children may have had a comorbidity one year but not the other year. This raises the question about how the denominators were calculated for each of the coverage measures. The authors should describe the numerators and denominators for each of the outcome calculations in sufficient detail for study replication by another researcher.

Thank you for your comment. We have added a paragraph to clarify how the numerators and denominators were defined for each season. "For each influenza season, vaccination coverage denominators were defined as all children who met the eligibility criteria at that specific season (children aged 6–59 months and children aged 5–14 years with underlying conditions). Eligibility was assessed independently for each season; therefore, children could be included in one or both seasons depending on their age and comorbidity status at each seasonal time point. Children younger than 12 months could only contribute to one season, and children with underlying conditions were included only in seasons in which the comorbidity was present. Numerators were defined as the number of eligible children who received the influenza vaccine during the corresponding season."

4. In Table 1 title (and line 108 and line 139), “... susceptible to influenza vaccination during the 2023-24 and 2024-25 seasons,” it is not clear what susceptible to influenza vaccination means. Does it mean eligible for influenza vaccination?

Thank you for your comment. We agree that the term “susceptible” was ambiguous in this context. It has been replaced with “eligible for influenza vaccination” in the title of Table 2 and in lines 108 and 139 to better reflect that these children met the criteria for influenza vaccination during the 2023–2024 and 2024–2025 seasons.

5. In Table 1, it is not clear what the “i” means in “1,2 i 3”.

We are so sorry. It has been a mistake. “i” means “and”. It has been corrected. 

6. Table 2 gives column percents, but row percents would be more informative for the reader, since row percent equates to coverage.

We thank the reviewer for the comment and for the suggestion to present row percentages. However, we believe that Table 2 (now 3 and 4)  as presented in the original manuscript offers several methodological and interpretative advantages over the proposed alternative format, particularly in relation to the aims of the study.

1. Direct comparability between vaccinated and unvaccinated groups
Table 2 allows a direct and simultaneous comparison between vaccinated and unvaccinated children, stratified by age group (<5 years and 5–14 years), and includes the corresponding p values. This structure facilitates the clear identification of statistically significant differences between groups, which is essential for understanding the factors associated with influenza vaccination in each age category.

In contrast, the alternative table mainly presents within-row percentage distributions, which, although informative, make cross-group reading and direct comparison between vaccinated and unvaccinated children within each variable more difficult.

2. Consistency with subsequent bivariate and multivariate analyses
Table 2 is designed to be fully consistent with the bivariate analyses that are subsequently expanded in the multivariate logistic regression models (Table 6 of the manuscript). Variables are presented using the same classification criteria, thereby facilitating methodological and narrative continuity throughout the Results section.

3. Clarity for clinical and epidemiological interpretation
One of the main objectives of the study is to identify factors associated with influenza vaccination. Table 2 presents this information in a clinically and epidemiologically interpretable manner, explicitly showing which characteristics (country of origin, rurality, number of risk factors, and specific underlying conditions) differentiate vaccinated from unvaccinated children within each age group.

For these reasons, we consider that Table 2 in its current format is better suited to meet the objectives of the study, while maintaining methodological coherence, interpretative clarity, and statistical comparability. Nevertheless, we appreciate the reviewer’s suggestion, which prompted a careful re-evaluation of the presentation of our results.

 

 

7. In Table 2, the p-value of “<0.000” doesn’t make mathematical sense. Perhaps authors could say <0.001.

We are so sorry. It has been a mistake. It has been changed to < 0.001. 

8. Lines 322-325 (limitations) – another limitation is the risk of incomplete data in the medical/administrative database. For example, about half of subjects’ parents do not have information on educational attainment listed.

Thank you for your comment. We agree that the use of medical/administrative databases may involve a risk of incomplete data. Accordingly, we have added this issue to the Limitations section:

"Another limitation of this study is the potential presence of incomplete data inherent to the use of medical and administrative databases. Specifically, information on parental educational attainment was missing for approximately half of the study population. This lack of completeness may have limited the ability to fully assess the association between parental education level and influenza vaccination uptake in children. However, given the large sample size and the population-based nature of the database, we believe that the overall findings remain robust and representative of the study population."

9. Line 57 – The sentence “... contributes to reducing the incidence of influenza in the general population [9-12]”is about indirect protection of off-target populations, but reference 9 is about vaccine hesitancy, not herd immunity. Authors should check to see if reference 9 is correct. Refs 10-12 are relevant.

We are so sorry. It has been a mistake. We have changed the reference to [10-12]. 

10. The writing is clear enough to follow, but there are some typos that should be corrected when proofing the manuscript so that it meets journal standards for English.

The english has been improved. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

in introduction: Correct citation formatting inconsistencies (e.g., “[1.2]” → “[1,2]”).

• Improve the transition between paragraphs 45–50 and 59–65, where the text shifts abruptly from general information to the Spanish context.

• Avoid repeating the idea that “coverage is low” too many times; one strong statement is enough.

in methods: 

• In the “Variables” section, clarify whether parental education is self-reported or extracted from registries.

• Standardize terminology:

  • “basic pathologies” → “underlying conditions”

  • “miscellanea” → “miscellaneous conditions”

• In the rural/urban definition, consider citing the administrative or statistical criteria used, if available.

in results: 

• Several paragraphs start with “As for…”  vary with “Regarding…”, “In the subgroup…”, etc.

in discussion

• Some sentences are long and could be split for better readability (particularly paragraphs 246–260).

• The concept “coverage is very low” is repeated frequently; consider reducing redundancy.

• Add 1–2 sentences emphasizing the public health relevance of pediatric influenza to strengthen the discussion.

in Conclusions

• Soften the expression “despite the introduction of a routine influenza vaccination programme” to “despite the recent introduction…”.

• The sentence “being an immigrant…” can be rephrased more neutrally:
  to “non-native origin was associated with higher vaccination rates.”

in References:

 

• • Standardize all DOIs to “https://doi.org/...”

  • Check accessibility and update status for references 26–32 (some are websites).

Comments on the Quality of English Language

 

• Avoid minor typos (e.g., “vaccuming” → “vaccination”).

• Standardize terminology: use “influenza vaccination” rather than “anti-flu vaccination.”

• Remove unnecessary commas (e.g., “a figure very similar to our current results” → “a figure similar to our current results”).

• Standardize decimal formatting in percentages.

Author Response

 

1. In introduction: Correct citation formatting inconsistencies (e.g., “[1.2]” → “[1,2]”).

 

We are so sorry. It has been a mistake. It has been corrected.

 

2. Improve the transition between paragraphs 45–50 and 59–65, where the text shifts abruptly from general information to the Spanish context.

Thank you for your comment. A connector with the two paragraphs has been added.

This is the new text:

 

The World Health Organization (WHO) estimates that the annual influenza epidemic causes 1 billion infections, 3-5 million cases of severe disease and 290,00-650,000 deaths [3]. It has been shown that the paediatric population is the most affected by this infection and is the main transmitter of the virus [4-5]. In line of this findings, in Spain, the highest incidence rate for influenza in the 2021-22 and 2022-23 seasons was observed in the 0- to 4-year-old group (1,500 cases and 1,100 cases per 100,000 inhabitants respectively), followed by the 5- to 14-year-old group (400 cases and 1,000 cases per 100,000 inhabitants respectively) [6-7].

 

3. Avoid repeating the idea that “coverage is low” too many times; one strong statement is enough.

Thank you for your comment. A part of the text has been removed and a strong statement has been written.

In methods: 

4. In the “Variables” section, clarify whether parental education is self-reported or extracted from registries.

Thank you for your comment. The compilation of “parental education” has been clarified in the “variables” section. The variable “parental education" has been extracted from registries.

 

5. Standardize terminology:

1. “basic pathologies” → “underlying conditions”

We are so sorry. The word “basic pathologies” has been changed to “underlying conditions”.

 

2. “miscellanea” → “miscellaneous conditions”

We are so sorry. The word “miscellena" has been changed into “miscellaneous conditions”.

 

6. In the rural/urban definition, consider citing the administrative or statistical criteria used, if available.

To classify the place of residence in rural or urban, the number of inhabitants of each population was considered. An area is considered rural or semi-urban if it has less than 10,000 inhabitants and urban if it has more than 10,000.

In results:  

7. Several paragraphs start with “As for…”  vary with “Regarding…”, “In the subgroup…”, etc.

We are so sorry. The beginning of the different paragraphs has been changed based on your suggestions.

In discussion:

8. Some sentences are long and could be split for better readability (particularly paragraphs 246–260).

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Seasonal influenza represents a significant public health burden, and vaccination is the most effective strategy for preventing influenza infection [1,2,5,9]. Children are the main transmitters of the virus; therefore, more than 70 countries have implemented seasonal influenza vaccination programs for pediatric populations. However, differences exist between countries regarding the age groups included in routine vaccination schedules. For example, the United Kingdom has vaccinated children aged 2 to 16 years against influenza since the 2013–2014 season, whereas Finland introduced influenza vaccination for children aged 6 to 36 months in 2007 and extended routine vaccination to children up to 6 years of age in 2015 [26–28].

In Spain, and consequently in Catalonia, until the 2022–2023 season, influenza vaccination was recommended only for children aged 6 months and older with underlying risk conditions [21,22]. From the 2023–2024 season onward, influenza vaccination was expanded to include all children aged 6 to 59 months [23,25].In this way, influenza vaccination was considered routine in children of this age group. In older children (5-14 years) the vaccine continued to be administered only in those who had some underlying pathology [23]. This measure was applied following the recommendations of the Spanish Ministry of Health [23,25].

The data provided by our study indicate that, despite the application of this new measure, childhood influenza vaccination coverage (6 months to 14 years) remains very low: 18.1% and 19.3% for the 2023-24 and 2024-25 seasons respectively. As for influenza vaccination in the range of 6 to 59 months, coverage was 19.1% during the 2023-24 season and 26.8% during the 2024-205 season.

Other local studies in Spain have shown that Galicia was the community with the most vaccination, with vaccine coverage of 55.8%, followed by Murcia (51.1%) and Andalusia (45.8%). Ceuta was the community with the lowest vaccination rates, with a coverage of 2.9%. Throughout Catalonia, influenza vaccination coverage was observed at 24.4% [29-31]. It should be noted that these data, provided by the Ministry of Health, only include children aged 1 to 5 years (leaving out children aged 6 to 11 months) so that our coverage is closer to the total figures recorded throughout the Catalan region. As for the 2024–25 season, official coverage figures at the state level have not yet been published for comparison, but a coverage of 58,6% has been registered this season in Andalusia for children from 6 to 59 months [32].

The reason for this heterogeneity between territories seems to be due to different vaccination campaigns to carried out in different autonomous communities [31]. For example, in Murcia and Andalusia, vaccinations took place in schools, while in Galicia a mass vaccination campaign was promoted for a specific weekend in designated locations with longer vaccination shifts, imitating the COVID-19 vaccination campaign [32-34].

Another possible cause of the low coverage of influenza vaccination in children in our territory is the lack of promotional campaigns for influenza vaccination among health professionals. Several studies have shown that the main cause of influenza vaccination in children is advice from their paediatrician [9,35-40].

At the European level, influenza vaccination coverage varies considerably across countries. During the 2023–2024 season, the United Kingdom reported an influenza vaccination coverage of 50%. In Finland, coverage was 41% among children under 2 years of age and 29% among children aged 2 to 6 years. Denmark, which introduced universal influenza vaccination for children aged 2 to 6 years in the 2020–2021 season, reported a coverage rate of 22% [26–28,41]

However, it should be noted that in the present study we observed an increase in influenza vaccination during the 2024-25 season of 7.7% in the group of 6 to 59 months compared to the previous season, so that we believe that once routine vaccination programs are more rooted in the territory, families will have more confidence in the initiative. This increase in coverage between seasons is also seen Andalusia where we see an increase between the two seasons of 12.8% [42].

It should be noted that this represents a substantial increase in coverage within the universally recommended group. In contrast, vaccination coverage among the risk-based target population (children with comorbidities) did not increase, underscoring the importance of universal vaccination strategies. Indeed, several studies have demonstrated that universal vaccination is the most cost-effective approach to reducing the overall burden of influenza at the population level [43–50].

Adherence to influenza vaccination during the last two flu seasons is very low. Only 17% of children have been vaccinated consecutively in the 2023-24 and 2024–25 seasons. At the Spanish level there is no study that analyzes this data for the last two seasons has been found, therefore we cannot compare whether our region is above or below the Spanish average. In a study carried out by our group in the 5 seasons prior to routine influenza vaccination programs in children under 5 years of age in Central Catalonia, we found influenza vaccination an adherence of 21.6% in two seasons, a figure similar to our current results [14]. With this data we can say that the extension of influenza vaccination to children under 5 years of age has not led to an improvement in adherence. However, we would have to wait and see the trend in the coming seasons.

In relation to the variables associated with vaccination, our study shows that the male sex is more likely to be vaccinated than the female in the group of 6 to 59 months. In a study of Catalonia in 2015, Gonzalez R et al. also observed that gender was significantly associated with vaccination, but appears not to be corroborated by most authors, so we do not consider it clinically relevant[13].

Regarding parent education, we have observed that both in the group of younger children (6 to 59 months) and in the group of 5- to 14-year-olds, parents with a higher educational level vaccinate more, probably because they have more information about influenza vaccination and the possible consequences of complications in case of an infection.

Non-native children are vaccinated more often than Spanish children. This result is similar to studies conducted in previous campaigns [13, 14]. In a study conducted in Murcia during the 2022-23 campaign, Pérez Martin J et al. found that there were no differences in influenza vaccination according to the children's country of origin, but the parents' country of origin did have a difference. The reasons for this phenomenon can probably be explained for cultural reasons, but more studies would be needed to reach a definitive conclusion.

The positive association between the number of risk factors and influenza vaccination, already described above [13,14], is quite logical. The higher the number of risk factors, the more likely it is to experience complications from influenza.

Finally, certain underlying conditions such as diabetes, asthma, heart disease, nephropathies and hepatopathies and hemoglobinopathies and clotting disorders are also positively associated with influenza vaccination in children from 6 to 59 months.

Note that in the 5 to 14-year-old age group, obesity is negatively associated with influenza vaccination; children with obesity are not vaccinated for the flu probably because of their poor perception of illness. This is in line with a previous study conducted by our group [14].

 

4.2. Limitations and strengths

The main limitation presented by our study is that the data are obtained from the ICS database, therefore children vaccinated in other health providers would have been excluded from the study. However, the ICS is the main healthcare provider in Catalonia and therefore, we believe that the data analyzed are representative of our population.

Another limitation of this study is the potential presence of incomplete data inherent to the use of medical and administrative databases. Specifically, information on parental educational attainment was missing for approximately half of the study population. This lack of completeness may have limited the ability to fully assess the association between parental education level and influenza vaccination uptake in children. However, given the large sample size and the population-based nature of the database, we believe that the overall findings remain robust and representative of the study population.

The main strength of our research is that this is one of the few studies that analyzes the factors associated with influenza vaccination in children under 5 years of age after the implementation of routine influenza vaccination program in Spain. Another strength of the study is the sample size, as we present a sample of almost 40,000 children.

 

4.3 Futures Research

A possible future line of research could be the effect of the implementation of new campaigns to promote vaccination between the population and health professionals to try to increase coverage of influenza vaccination in children, especially in the 6 to 59 month age group.

 

 

 

 

9. The concept “coverage is very low” is repeated frequently; consider reducing redundancy.

 

Thank you for your comment. We agree that the repeated use of the expression “coverage is very low” was redundant. The manuscript has been revised to reduce repetition by retaining a single clear statement of this finding and using alternative, synonymous expressions throughout the text to improve readability while preserving the intended meaning.

 

 

10. Add 1–2 sentences emphasizing the public health relevance of pediatric influenza to strengthen the discussion.

Thank you for your comment. We have revised the Discussion section to include additional sentences highlighting the public health relevance of pediatric influenza, emphasizing its role in community transmission and the importance of improving vaccination coverage to reduce the overall disease burden.

"Seasonal influenza represents a major public health burden, and vaccination is the most effective strategy for preventing influenza [1,2,5,9]. Children are key drivers of virus transmission; consequently, more than 70 countries have implemented seasonal influenza vaccination programs targeting pediatric populations."

In conclusion:

11. Soften the expression “despite the introduction of a routine influenza vaccination programme” to “despite the recent introduction…”.

Thank you for your comment. The sentence has been reformulated taking into account your suggestion.

 

12. The sentence “being an immigrant…” can be rephrased more neutrally:
    to “non-native origin was associated with higher vaccination rates.”

Thank you for your comment. The sentence has been reformulated taking into a account your suggestion.

In references:

13. Standardize all DOIs to “https://doi.org/...”

 

Thank you for your comment. All DOIs has been standardized.

 

14. Check accessibility and update status for references 26–32 (some are websites).

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Comments on the Quality of English Language

 

15. Avoid minor typos (e.g., “vaccuming” → “vaccination”).

We are so sorry. It has been corrected.

 

16. Standardize terminology: use “influenza vaccination” rather than “anti-flu vaccination.”

 

We are so sorry. It has been corrected.

 

17. Remove unnecessary commas (e.g., “a figure very similar to our current results” → “a figure similar to our current results”).

Thank you for your comment. The unnecessary commas has been removed.

 

18. Standardize decimal formatting in percentages.

Thank you for your comment. The decimal formatting in percentages has been standardized.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

 

It was a pleasure to be appointed to review the research article entitled “Influenza vaccination in children during the first two seasons of routine vaccination programmes (2023-24 and 2024-25) in  Central Catalonia, Spain” by Sílvia Burgaya-Subirana , Mònica Balaguer, Laia Sola and Anna Ruiz-Comellas.

The article is offering a valuable and well-structured discussion on the assessment of the coverage and adherence of influenza vaccination in childhood during the two seasons of a influenza vaccination programme along with identification of the factors associated with influenza vaccination in all children under 5 years of age and 5 to 14 years of age with risk factors.

The manuscript is written clearly and concisely and, after review, it may be considered for publication in the present form.

Author Response

The reviewer had no suggestions. We are grateful for your feedback on our article. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I do not have any further comments or suggestions for improvement.