The Effect of Aligning Childhood Influenza Vaccination with Specific Well-Visits in a Primary Care Institution in Singapore

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article written by Goh Z. et al., entitled "The effect of aligning childhood Influenza vaccination with specific well-visits in a primary care institution in Singapore" is well presented and easy to understand.

It is a retrospective database study aiming to evaluate the effect of aligning childhood Influenza vaccination to coincide with specific well-visits in the primary care setting in Singapore country. Methodology is very clear and coherent to the objectives of the study and obtained results.

Authors highlighted in this study that the aligning childhood influenza vaccination increases the number of young children who receive and complete their influenza vaccination and at an earlier age. They demonstrated that this aligning proved to be a highly effective strategy for improving immunization coverage in a primary care setting.

The scientific information among this study is interesting for vaccination policy within the country.  The article is suitable for publication after minor revisions. Revisions should be made among different sections:

• The abstract: this section should be more detailed, and conclusions should be more developed and not limited to a simple one...
• Material and Methods: This section should be shorted and only important information regarding especially cohorts and methodology analysis should be only included.

Sections 2.1.1, 2.1.2 and 2.1.3 should be integrated in one section which is the most appropriate section 2.2

Authors should include in this section the ethical statement regarding research conduct

• Figure 3 of Results section should demonstrate the statistical signification of values. Please improve the quality of the figure also...

Author Response

Comment 1: The abstract: this section should be more detailed, and conclusions should be more developed and not limited to a simple one.

Response 1: We agree and have revised the abstract accordingly. Revision made on page 1, lines 23-25. “Aligning influenza vaccination with specific well-visits substantially improves uptake, completion rates, and timeliness of vaccination, demonstrating a scalable system-level strategy to enhance immunization coverage in primary care.”

Comment 2: Material and Methods: This section should be shorted and only important information regarding especially cohorts and methodology analysis should be only included. Sections 2.1.1, 2.1.2 and 2.1.3 should be integrated in one section which is the most appropriate section 2.2.

Response 2: We agree and have made the following revisions: We revised Sections 2.1 and 2.4 to include only important information regarding methodology analysis and data handling. Revisions made on pages 2-4, lines 82-131 and page 5, lines 152-161.

Comment 3: Authors should include in this section the ethical statement regarding research conduct.

Response 3: We have included ethical consideration in Section 2.6. Revision made on page 5, lines 180-181. “Ethical review was waived as this study involved analysis of de-identified data in accordance with institutional guidelines.”

Comment 4: Figure 3 of Results section should demonstrate the statistical signification of values. Please improve the quality of the figure also.

Response 4: We have improved the quality of Figures 1, 2, and 3. Revision of Figures 1 and 2 also include the following amendments: Separate MMR and Varicella vaccines are administered as Dose 1 (instead of the combined vaccine MMRV) and PCV13 booster is administered at 15 months (instead of 12 months). Revised Figure 1 on Page 3, lines 95-102, Revised Figure 2 on Page 4, lines 108-111. Figure 3 is revised to reflect the statistical significance of the values and included further explanation in the caption. Revised Figure 3 on page 8, lines 238-245.

Reviewer 2 Report

Comments and Suggestions for Authors

In the study by Ziying Goh and co-authors, an extensive retrospective analysis was performed comparing two vaccination schedules for children aged 6-12 months against influenza in Singapore. In one cohort of analyzed patients, a routine vaccination approach was used that was not tied to a specific well visit to a medical facility. In another cohort, an alternative schedule of two dose flu vaccination synchronized with specific well-visit touch points to administer other vaccines from the Singapore National Childhood Immunisation Schedule was used. According to the authors, this optimized schedule made it possible to dramatically (seventeen-fold) increase the coverage of the children's population with influenza vaccination and thereby reduce the risks associated with the flu.

In general, the authors presented convincing statistically reliable results, which do not raise doubts about the validity of their conclusions. I have a few comments on the text of the article.

1. When talking about vaccinating children against influenza, the authors do not specify which type (or types) of vaccines from which manufacturer were used in their study. To date, there are a number of regulatory approved influenza vaccines on the global market, including on various technological platforms (inactivated split vaccines, live attenuated vaccines, mRNA vaccines), therefore, adding this information to the methodological part of the article would be extremely significant.
2. In my opinion, it is necessary to clarify exactly how the simultaneous vaccination with two vaccines was carried out in one visit? Have two injections been performed in anatomically different areas of the body, which is standard practice in such cases?
3. Synchronization of children's flu vaccination with the administration of another vaccine is obviously not just a modification of the vaccination schedule, but also a fundamentally different effect on the immune system of children associated with the simultaneous administration of a significantly larger set of antigens. In the article, the authors focus solely on expanding the level of vaccination coverage, but such two vaccines exposure raises concerns due to additional risks of possible interference of the injected vaccine antigens. Are there any data available on possible undesirable side effects with an optimized vaccination regimen, as well as on the efficacy of the immune protection achieved in this way?
4. As far as I know, any modification of the approved vaccination schedule is essentially a new medical manipulation that requires a wide clinical research and appropriate regulatory permission. In my opinion, it is necessary to mention in the article what are the regulatory and legal bases of the modified visit-aligned schedule?

Author Response

Comment 1: When talking about vaccinating children against influenza, the authors do not specify which type (or types) of vaccines from which manufacturer were used in their study. To date, there are a number of regulatory approved influenza vaccines on the global market, including on various technological platforms (inactivated split vaccines, live attenuated vaccines, mRNA vaccines), therefore, adding this information to the methodological part of the article would be extremely significant.

Response 1: We agree that this is important information and have added details to the Methods section. The influenza vaccines used in this study were non-live inactivated influenza vaccines routinely supplied within public primary care institutions in Singapore, including Vaxigrip (Sanofi Pasteur) and Influvac (Abbott Biologicals). These are split-virion inactivated influenza vaccines administered via the intramuscular route, in accordance with national guidelines. Revision made to Materials and Methods Section 2.1 on page 4, lines 91-92. “In Singapore, inactivated influenza vaccines routinely supplied in public primary care institutions are administered via the intramuscular route.”

Comment 2: In my opinion, it is necessary to clarify exactly how the simultaneous vaccination with two vaccines was carried out in one visit? Have two injections been performed in anatomically different areas of the body, which is standard practice in such cases?

Response 2: We have clarified this in the Methods section. When more than one injectable vaccine was administered at the same visit, injections were given intramuscularly at anatomically separate sites, typically in different limbs. In situations where more than one injection was administered in the same limb, injection sites were spaced at least 2.5 cm apart, in accordance with ACIP recommendations to facilitate identification of local adverse reactions. Revision made on page 2, lines 85-89. “When more than one injectable vaccine was administered at a single visit, injections were given at anatomically separate sites, typically in different limbs. In situations where more than one injection was required in the same limb, injection sites were spaced at least 2.5 cm apart to facilitate differentiation of local reactions, in accordance with recommended practice.”

Comment 3: Synchronization of children's flu vaccination with the administration of another vaccine is obviously not just a modification of the vaccination schedule, but also a fundamentally different effect on the immune system of children associated with the simultaneous administration of a significantly larger set of antigens. In the article, the authors focus solely on expanding the level of vaccination coverage, but such two vaccines exposure raises concerns due to additional risks of possible interference of the injected vaccine antigens. Are there any data available on possible undesirable side effects with an optimized vaccination regimen, as well as on the efficacy of the immune protection achieved in this way?

Response 3: We acknowledge the importance of this consideration. The co-administration of influenza vaccines with other routine childhood vaccines is supported by available evidence and regulatory product information. According to product inserts for both influenza vaccines and co-administered vaccines, concurrent administration does not adversely affect immunogenicity or safety profiles. In our study, vaccines were administered in accordance with approved indications, minimum intervals, and established immunization practices. No safety signals or adverse trends were identified in routine clinical use during the study period.  

Comment 4: As far as I know, any modification of the approved vaccination schedule is essentially a new medical manipulation that requires a wide clinical research and appropriate regulatory permission. In my opinion, it is necessary to mention in the article what are the regulatory and legal bases of the modified visit-aligned schedule?

Response 4: We thank the reviewer for highlighting this important point. We have added clarification in the Methods. The visit-aligned schedule did not involve any deviation from approved vaccine indications. Vaccines were administered within the minimum ages and intervals specified in product regulations in Singapore. Influenza vaccination is recommended from 6 months of age, and the timing of doses in our intervention adhered to these requirements. The intervention represents an operational alignment of vaccine delivery with routine well-child visits rather than a modification of vaccine indications or schedules. The approach was discussed with senior clinical experts, including a Pediatric Infectious Diseases specialist who chairs the national expert committee on immunization practices that advises the Ministry of Health, Singapore. We also acknowledged the specialist at the end of our paper for her input. Revisions made on page 4, lines 118-121. “The design of the schedule was informed by clinical consensus and discussed with senior subject matter experts, including a Pediatric Infectious Diseases specialist involved in national immunization policy development.”

Reviewer 3 Report

Comments and Suggestions for Authors

Goh et al. demonstrated through an interrupted time series study that bundling the pediatric influenza vaccine with 6- and 7-month well-child visits can significantly increase vaccination and completion rates and result in earlier vaccination ages. The manuscript is of scientific significance; however, the following issues need to be addressed before publication:

1. Reasons for non-vaccination were not collected; therefore, the core barriers among the remaining unvaccinated children cannot be clearly identified.
2. This is a single-center study; is replicability assured across different healthcare systems and regions?
3. The contingency plan for vaccine shortages was only described in text, and its actual implementation rate and effectiveness were not quantitatively evaluated.
4. How were the acceptability data obtained from healthcare professionals and parents?
5. What is the rationale for fixing the interval between the two doses to 4 weeks? Does this meet the individualized needs of children's immune development?
6. Why was the strategy of limiting each visit to two shots chosen?
7. The cost-effectiveness of this model in terms of manpower and time has not been evaluated in the long term.
8. The readability of all figures is poor; it is recommended that all figures be optimized.
9. The quality of the Discussion and Conclusions sections is poor and does not reflect the research significance of this study. They must be rewritten.

Author Response

Comment 1: Reasons for non-vaccination were not collected; therefore, the core barriers among the remaining unvaccinated children cannot be clearly identified.

Response 1: We agree and have stated this as a limitation of our study under Discussion. Revisions made on page 9, lines 293-295. “Furthermore, data regarding specific reasons for non-uptake, such as parental refusal, vaccine hesitancy, or acute medical deferrals, were not captured in our dataset.”

Comment 2: This is a single-center study; is replicability assured across different healthcare systems and regions?

Response 2: Our study is done across ten public primary care clinics within a regional healthcare system. Although conducted within a single healthcare cluster, this study included data from ten polyclinics serving a large and diverse population. The care model and workflow are comparable across public primary care institutions in Singapore, which supports the broader applicability of our findings. Revisions made on page 9, lines 286-291. “As a single-healthcare cluster study, the generalizability of findings to other settings with different primary care models may vary. However, this study included data from ten polyclinics within the cluster, serving a large and diverse population. The care model and workflow are comparable across public primary care institutions in Singapore, which supports the broader applicability of our findings.”

Comment 3: The contingency plan for vaccine shortages was only described in text, and its actual implementation rate and effectiveness were not quantitatively evaluated.

Response 3: We recognize this limitation and have included it as a limitation under Discussion. Revisions made on page 9, lines 301-303. “Although a contingency protocol was implemented to manage vaccine supply interruptions, its activation frequency and effectiveness were not systematically captured and therefore could not be evaluated.”

Comment 4: How were the acceptability data obtained from healthcare professionals and parents?

Response 4: We acknowledge that while feasibility and effectiveness of this intervention was demonstrated, acceptability not formally measured. Acceptability was not formally assessed using structured instruments. However, the successful implementation across ten clinics without disruption to routine workflows and sustained uptake suggests a high degree of operational feasibility. Future studies should incorporate formal evaluation of both provider and parental acceptability. Revisions made on page 9, lines 295-296 “In addition, acceptability among healthcare providers and parents was not formally assessed using structured instruments.”, and page 9 lines 307-312. “Future studies should evaluate the economic and operational impact of this approach, including its effects on consultation time, staffing requirements, and cost per fully vaccinated child, explore parental and provider perspectives, identify residual barriers, the long-term impact on reducing influenza-related pediatric hospitalizations and morbidity and assess the scalability of this model across diverse healthcare settings.”

Comment 5: What is the rationale for fixing the interval between the two doses to 4 weeks? Does this meet the individualized needs of children's immune development?

Response 5: The 4-week interval between doses follows established immunization guidelines and represents the minimum interval required for children under 9 years receiving their first influenza vaccination series, balancing immunogenicity with timely completion. Revisions made on page 4 lines 113-114 and references made to CDC ACIP Recommendations on spacing intervals. “Influenza vaccine-naïve children require two doses administered at least four weeks apart for optimal immunogenicity [9, 10].”

Comment 6: Why was the strategy of limiting each visit to two shots chosen?

Response 6: The decision to limit each visit to a maximum of two injections reflects a pragmatic alignment with both parental and provider preferences rather than a strict clinical requirement. Revisions on page 9, lines 271-279. “Although there is no defined upper limit to the number of injectable vaccines that can be safely administered in a single visit [9], studies have shown that both caregivers and healthcare providers are more comfortable with one to two injections per visit [14,16]. Concerns regarding multiple injections are consistently reported and include perceived pain, risk of adverse events, and the overall burden on the child. Importantly, provider perceptions of parental concern may influence clinical practice, with evidence suggesting that providers may defer recommended vaccinations when they anticipate resistance to multiple injections, potentially leading to delays or incomplete immunization [15].”

Comment 7: The cost-effectiveness of this model in terms of manpower and time has not been evaluated in the long term.

Response 7: We acknowledge this and have included in Discussion. Revision on page 9-10, lines 304-312. “The long-term cost-effectiveness of this model in terms of manpower utilization and clinic time was not evaluated. However, the substantial improvement in vaccination uptake and earlier completion of the primary series suggests potential downstream benefits, including reduced influenza-related healthcare utilization. Future studies should evaluate the economic and operational impact of this approach, including its effects on consultation time, staffing requirements, and cost per fully vaccinated child, explore parental and provider perspectives, identify residual barriers, the long-term impact on reducing influenza-related pediatric hospitalizations and morbidity and assess the scalability of this model across diverse healthcare settings.”

Comment 8: The readability of all figures is poor; it is recommended that all figures be optimized.

Response 8: We have revised Figure 1 on page 3, lines 95-102, Figure 2 on page 4, lines 108-111, Figure 3 on page 8, line 238-245 to improve readability. Revision of Figures 1 and 2 also include the following amendments: Separate MMR and Varicella vaccines are administered as Dose 1 (instead of the combined vaccine MMRV), MMRV is administered as Dose 2. And PCV13 booster is administered at 15 months (instead of 12 months).

Comment 9: The quality of the Discussion and Conclusions sections is poor and does not reflect the research significance of this study. They must be rewritten.

Response 9: We have revised the Discussion and Conclusions sections.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I thank the authors for responding to my comments and for their efforts to correct the manuscript. I have no additional questions, in my opinion, the article can be published in its current form.

Reviewer 3 Report

Comments and Suggestions for Authors

The author made great modifications, which greatly improved the quality of the manuscript, and it is recommended to publish the manuscript.