COVID-19 Epidemiology, Immunity, and Vaccine Development in Children: A Review

Round 1

Reviewer 1 Report

Comment:

This review is a comprehensive overview of the complexities of COVID-19 epidemiology, immunity, and vaccine development in children. The link between these three major topics lapses at times. The authors give detailed and important information on pediatric COVID-19 associated with the omicron variants and raise concern that the COVID-19 burden is increasing as of March 2022 among children and adolescents- (21 percent of all COVID-19 cases worldwide occur in populations <20 years of age).

COVID-19 Vaccine clinical trials require at least six months to properly follow up and assess the clinical endpoints of respiratory symptoms, disease severity, and hospitalization. Until recently, the COVID-19 vaccines have largely been administered to the elderly population and adults. The infections by VOCs alpha, beta, and delta variants have involved COVID-19 illness with severe symptoms and hospitalization. The rapid emergence of highly transmissible omicron variants especially in adult breakthrough infections having mild or no symptoms has left little space and attention to the course of omicron variant infection and COVID-19 illness in children and adolescents. The emergency use authorization (EUA) for administering COVID-19 mRNA vaccines to children <5 years of age, has in part hindered timely comparison of COVID-19 vaccination responses among children versus young adult populations. Due to the milder symptoms associated with the omicron variant, the vaccine trials in children may require revision of the clinical efficacy, immunogenicity, and safety and include assessment of neutralizing antibodies.

MIS-C is rare in children and so far severe COVID-19 disease is highly uncommon among SARS CoV-2 infected children. There is no evidence to suggest under-reporting of severe Pediatric COVID-19. The review could benefit from more insights on the benefits and pitfalls of COVID-19 vaccine development in children and a sub-chapter that summarizes “the lessons learned”.

Introduction

There are numerous errors in English grammar and syntax making the text difficult to follow. The term “young people” throughout is ambiguous. The recommendation is to replace it with adolescents. i.e. age >12 <20 throughout.

The term “real-world data” is not defined. Presumably, it refers to the vaccine performance assessed by the data gathered from many independent sources in heterogeneous populations in contrast to the trial data obtained for the purpose of FDA/EMEA submission and regulatory approval.

lines 36-39 contain many non-sequiturs and flaws in sentence structure “multisystem inflammatory syndrome can affect either Child (MIS-C) or young people adolescents (MISA)-C) [4, 5] whereas long-term COVID-19 and COVID-19-associated sequelae are most common among adolescents [6, 7]. The age-adjusted hospitalization rates coinciding with the COVID-19the  wave caused by the omicron variants reveal disproportionate hospitalization among children <5 years compared with other age groups [ref needed for this claim].

lines 41-47 are confusing, The text lacks clarity and needs major re-writing.

lines 69-71. What is the reason for COVID-19-associated hospitalization rates increasing 5-fold In young pre-school children <4 years age (3 per 100K in Nov 2021 to 16 per 100K during 1st omicron wave Jan 2022) ? The mild symptoms with omicron variants allowed the parents to take their children to the hospital. Parents in the earlier period of the delta variant were too ill in lockdown and stayed home with the children?

lines 81-96 must be simplified to explain the Clinical Manifestations of pediatrics versus adults. Figure 2 should be renamed Figure 1 and moved to the position after the text.

In adults, the infections by SARS CoV-2 omicron variants BA.1, BA.2, BA.3, and BA.4 are usually mild or asymptomatic and usually do not involve loss of smell or taste and show significantly fewer lower respiratory complications compared to delta variant. The trend may not hold for BA.5? These points should be highlighted in Figure 1.

Line 95. “croup rate” is pediatric terminology not well known to most readers of the Journal. Laryngotracheobronchitis or airway obstruction may be more appropriate here.

lines 125 to 185. The sections need rewriting and the sentences consolidated to highlight the SARS CoV-2 transmission and immune responses in children and to explain how children differ from adults...

3. Pediatric COVID-19 Vaccine Development – the content in this section of the review should be given greater priority and carefully rewritten.

line 187 As of July 5th, 2022, 168 COVID-19 vaccines are in clinical trials and 198 vaccines are undergoing preclinical development. Thirty seven COVID-19 vaccines received licenses or EUA. (delete  1 regulatory authority)

lines 189-190 are grammatically incorrect- they use past and present tense in the same sentence!

Table 1 entire presentation is incoherent and must be redone. Header “Details” contains an overflow of text “Characteristic” is not aligned- needs to be reformatted in one column.

Table 2. same issues as Table 1.

lines 200-383

3.1. Pediatric Clinical Trials

3.1.1. Immunogenicity and Vaccine Efficacy

3.1.3. Safety

3.2 Real World Evidence (NO logic in the sequence of section headers)

3.3. myocarditis and Pericarditis are special side effects that belong to Safety, not a separate header too much text and not well reviewed.

4. Conclusions line 388 DELETE Figure 2. summarizes current knowledge on COVID-19 characteristics and vaccination in children and young people. Begin here. “Despite the inclusion of children and young people in vaccine recommendations….”.

DELETE lines 395 and 396. “The increasing proportion of COVID-19 cases and rising hospitalization rates in unvaccinated pediatric populations associated with highly transmissible variants that pediatric COVID-19 vaccination will be critical for future pandemic control”. The statements already in the introduction- are repetitious and add little substance to the conclusion.

Add section “Take Home Messages”

Author Response

REVIEWER 1

This review is a comprehensive overview of the complexities of COVID-19 epidemiology, immunity, and vaccine development in children. The link between these three major topics lapses at times. The authors give detailed and important information on pediatric COVID-19 associated with the omicron variants and raise concern that the COVID-19 burden is increasing as of March 2022 among children and adolescents- (21 percent of all COVID-19 cases worldwide occur in populations <20 years of age).

COVID-19 Vaccine clinical trials require at least six months to properly follow up and assess the clinical endpoints of respiratory symptoms, disease severity, and hospitalization. Until recently, the COVID-19 vaccines have largely been administered to the elderly population and adults. The infections by VOCs alpha, beta, and delta variants have involved COVID-19 illness with severe symptoms and hospitalization. The rapid emergence of highly transmissible omicron variants especially in adult breakthrough infections having mild or no symptoms has left little space and attention to the course of omicron variant infection and COVID-19 illness in children and adolescents. The emergency use authorization (EAU) for administering COVID-19 mRNA vaccines to children <5 years of age, has in part hindered timely comparison of COVID-19 vaccination responses among children versus young adult populations. Due to the milder symptoms associated with the micron variant, the vaccine trials in children may require revision of the clinical efficacy, immunogenicity, and safety and include assessment of neutralizing antibodies.

MIS-C is rare in children and so far severe COVID-19 disease is highly uncommon among SARS CoV-2 infected children. There is no evidence to suggest under-reporting of severe Pediatric COVID-19. The review could benefit from more insights on the benefits and pitfalls of COVID-19 vaccine development in children and a sub-chapter that summarizes “the lessons learned”.

Response: We appreciate this summary and assessment.

 

Introduction

There are numerous errors in English grammar and syntax making the text difficult to follow.

Response: We apologize and have amended the text in various places to address grammatical and syntax errors and to improve readability.

 

The term “young people” throughout is ambiguous. The recommendation is to replace it with adolescents. i.e. age >12 <20 throughout.

Response: The following text (changes indicated by yellow highlighting) was added to clarify the ages of the population being reviewed: “We review the epidemiology of COVID-19 in children, adolescents, and young people up to 20 years of age,…” Adolescents has been used to replace young people where appropriate.

 

The term “real-world data” is not defined. Presumably, it refers to the vaccine performance assessed by data gathered from many independent sources in heterogeneous populations in contrast to the trial data obtained for the purpose of FDA/EMEA submission and regulatory approval.

Response: The definition of real-world data has been added: “real-world evidence (RWE) is clinical evidence regarding the use of a medical product and its associated benefits or risks, derived from the analysis of data from heterogenous sources such as electronic health records (EHRs), health insurance claims, product and disease registries , and patient-generated data including in-home use settings; RWE can be developed through different study designs or analyses such as randomized trials, pragmatic trials, and prospective or retrospective observational studies [66].”

 

lines 36-39 contain many non-sequiturs and flaws in sentence structure “multisystem inflammatory syndrome can affect either Child (MIS-C) or young people adolescents (MISA)-C) [4,5] whereas long-term COVID-19 and COVID-19-associated sequelae are most common among adolescents [6,7]. The age-adjusted hospitalization rates coinciding with the COVID-19 the wave caused by the omicron variants reveal disproportionate hospitalization among children <5 years compared with other age groups [ref needed for this claim].

Response: The revised text now reads (changes indicated by yellow highlighting): “Also, children and adolescents may experience multisystem inflammatory syndrome (MIS-C) [4, 5] and other long-term COVID-19‒associated sequelae [6, 7]. Analyses of hospitalization rates during the Omicron variant wave revealed disproportionate number of hospitalizations among children and adolescents, particularly those aged <5 years, compared with other age groups [8-10].” Relevant references have been added to support the observation.

 

lines 41-47 are confusing. The text lacks clarity and needs major rewriting.

Response: The text has been amended (changes indicated by yellow highlighting) to make it easier to read: “Because of the dynamic nature of COVID-19 and rapidly emerging data, comprehensive evaluation of SARS-CoV-2 infection and COVID-19 vaccination in children and adolescents is beneficial. We review the epidemiology of COVID-19 in children, adolescents, and young people up to 20 years of age, as well as clinical manifestations, transmission, and immune response. Current knowledge of COVID-19 characteristics and vaccination in children and adolescents is summarized in Figure 1 and discussed in more detail below. We also review clinical trial and real-world data for the various available COVID-19 vaccines, and vaccination recommendations for pediatric populations. In general, we have focused on evidence from larger studies where possible to enable more reliable and representative inferences among a large and rapidly growing body of disparate research.”

 

lines 67-71. What is the reason for COVID-19-associated hospitalization rates increasing 5-fold In young pre-school children <4 years age (3 per 100K in Nov 2021 to 16 per 100K during 1st omicron wave Jan 2022) ? The mild symptoms with omicron variants allowed parents to take their children to the hospital. Parents in earlier period of delta variant were too ill in lockdown and stayed home with the children?

Response: To address this question, the following text (changes indicated by yellow highlighting) has been added: “In 0‒4-year-olds in the United States, COVID-19‒associated hospitalization rates remained <3/100,000 through November 2021, but peaked at 16.2/100,000 in January 2022 during the Omicron wave [8, 15]. For children <5 years of age, COVID-19 vaccination was recommended, and vaccines became available only in June 2022 [19]; therefore, it is reasonable to infer that the increase in hospitalizations in this age group in January 2022 was caused by a highly transmissible variant, Omicron, circulating among an unvaccinated sub-population. This inference is supported by CDC analyses of COVID-19 epidemiology during Omicron predominance until June 2022 that showed that children aged 6 months–4 years were at risk of severe illness from COVID-19. More than 50% of hospitalized children in this age group had no underlying conditions. COVID-19–associated hospitalization severity among 6 months–4-year-olds was similar to or greater than older children and adolescents, and the COVID-19 hospitalization burden among 6 months–4-year-olds was similar to or exceeded that of other pediatric vaccine preventable diseases [20].”

 

lines 81-96 must be simplified to explain the Clinical Manifestations of pediatrics versus adults.

Response: The text has been simplified (changes indicated by yellow highlighting) and the text discussing differences in children and adults separated into a distinct paragraph that now reads “Common COVID-19 presenting symptoms differ between pediatric and adult populations (Figure 1). Data from systematic reviews showed that children and adolescents with SARS-CoV-2 infection exhibited symptoms consistent with acute respiratory infections, including fever and cough in up to 60% of individuals and high fevers in up to one-third of children [17,20]. Compared with adults, children more commonly presented with extra-respiratory symptoms, particularly diarrhea (9%) and vomiting (7%).”

 

Figure 2 should be renamed Figure 1 and moved to the position after the text.

Response: In response to the reviewer’s suggestion, the figure now appears immediately after the introduction and the following text (changes indicated by yellow highlighting) has been added: “Current knowledge of COVID-19 characteristics and vaccination in children and adolescents is summarized in Figure 1 and discussed in more detail below.” Furthermore, the figure has been cited at relevant locations within the manuscript.

 

In adults, the infections by SARS CoV-2 omicron variants BA.1, BA.2, BA.3, and BA.4 are usually mild or asymptomatic and usually do not involve loss of smell or taste and show significantly fewer lower respiratory complications compared to delta variant. The trend may not hold for BA.5? These points should be highlighted in Figure 1.

Response: Unfortunately, we were unable to identify published data in children to support the reviewer’s speculation, and no changes could be made in response to this comment.

 

Line 95. “croup rate” is pediatric terminology not well known to most readers of the Journal. Laryngotracheobronchitis or airway obstruction may be more appropriate here.

Response: Thank you for highlighting this; the definition has been added: “Pediatric COVID-19 symptoms may vary with emerging variants; in particular, croup rates (ie, laryngotracheobronchitis or airway obstruction) have markedly increased in connection with the initial Omicron wave [22].”

 

lines 125 to 185. The sections need rewriting and the sentences consolidated to highlight the SARS CoV-2 transmission and immune responses in children and to explain how children differ from adults…

Response: We have rewritten both the Transmission (Section 2.3) and Immune Response (Section 2.4) sections to improve coherence and readability. The revised text now reads as follows:

 

2.3 Transmission

SARS-CoV-2 transmission appears to be influenced by a variety of factors in the infected person, such as presence and type of symptoms, nature and duration of exposure, variant, and viral load [28]. Studies from 2020 with ancestral SARS-CoV-2 and before the identification of variants of concern have shown that viral load dynamics can differ between children and adults. A Swiss study (n=8027) identified a modest positive correlation between age and viral load at diagnosis – pediatric age groups exhibited steeper increases in nasopharynx (NP) viral load the first day after symptom onset versus adults, but viral shedding patterns appeared similar across age groups [29]. A separate analysis (March‒June 2020; n=68) showed that the duration of viral shedding and median time to clearance post-infection was significantly longer among 6‒15-year-old participants (median, 44 days) compared with 16‒22-year-old participants (median, 18 days), while 0‒5-year-olds (median, 22 days) did not differ significantly from either older age group; in addition, median time to detect neutralizing antibodies did not differ across the three age groups [30]. Viral RNA concentration is a surrogate for the presence of infectious virus and can remain high for many days after culture-competent viral isolation is no longer successful [31]. However, culture-competent SARS-CoV-2 was isolated from 52% (12 of 23) of NP samples of <16-year-old children infected with SARS-CoV-2 [32]. Taken together, the prolonged presence of virus in the nasopharyngeal passages of children after infection with SARS-CoV-2 suggests that they may have a tenable role in transmission; however, it is unclear if the persistence of viral genome correlates with transmissibility [30].

Household studies enable a better assessment of transmission. Reviews of studies from the early pandemic phase (published by August‒October 2020) indicated that household and cluster index cases were not commonly attributed to children [33, 34], although that may be ascribed to closing of in-person learning and extracurricular activities [35]. However, outbreaks occurring in settings frequented by children and adolescents (eg, sporting events, schools) and other transmission studies have shown that this population can also transmit SARS-CoV-2 [35] (Figure 1). A review of data published during December 2019‒June 2020 indicated that children were less likely than adults to transmit SARS-CoV-2 to household members (8 vs 205 of 213 clusters) [33]. A Canadian study of 6280 households with a pediatric index COVID-19 case (June‒December 2020) indicated a higher likelihood of younger versus older children to transmit SARS-CoV-2 [36]; however, adolescents may have greater overall transmission due to comparatively increased social interaction [35]. SARS-CoV-2 transmission among children and adolescents has likely increased with the predominance of highly transmissible variants [35].

 

2.4 Immune Response

COVID-19 epidemiology and clinical manifestations differ significantly between children and adults, a pattern that has remained consistent across the emerging SARS-CoV-2 variants (Figure S1) [37]. Adult COVID-19 patients exhibit respiratory symptoms and can progressively deteriorate to acute respiratory distress syndrome, while children infected with SARS-CoV-2 tend not to exhibit respiratory illness but can suffer from MIS-C, a rare and life-threatening severe COVID-19 complication [38]. Potentially relevant immunologic parameters include comparatively lower levels of reduced accumulated endothelial dysfunction and related comorbidities, lack of immunosenescence associated with reduced viral clearance, reduced angiotensin-converting enzyme-2 (ACE2) expression, and higher lymphocyte and cytotoxic T-cell counts among children (Figure 1) [37, 39].

Studies have attempted to characterize the difference in immune mediators between children and adults, though no edifying patterns have emerged so far. In one US study (November 2020‒January 2021) of individuals presenting to the emergency department with SARS-CoV-2 infection, significantly higher levels of cytokines, including interferon-gamma (IFN-γ), IFN-alpha-2 (IFN-α2), interleukin-1-beta (IL-1β), IL-8, and IFN-γ–inducible protein 10 were detected in nasopharyngeal samples collected from children (n=12) compared with adults (n=27) [40]. Gene expression levels corresponding to CD4, CD8A, and CD20 were also higher in the pediatric samples, further suggesting a more robust initial cellular immune response among children (Figure 1), but the total immunoglobulin G (IgG) and IgA antibody levels did not differ between age groups. On the other hand, a separate study (March‒June 2020; n=79) found that among adult COVID-19 patients, spike-specific IgG, IgM, and IgA antibody levels increased with disease severity and were significantly higher compared with levels in pediatric patients with MIS-C; antibody levels were similar among children with and without MIS-C [41]. Furthermore, anti-nucleoprotein IgG plasma levels and neutralizing antibodies were significantly lower in children than in adults, regardless of their MIS-C status [41]. Examining SARS-CoV-2–specific immune responses by age group (April‒August 2020) found that serum IgG levels negatively correlated with age among ≤18-year-olds (n=85), but a reverse trend was observed among adults (n=3648); among ≤24-year-olds (n=126), neutralizing antibody levels also negatively correlated with age [42].

Studies have also evaluated whether pre-existing immunity to common circulating human coronaviruses (HCoVs) may account for the observed age-related differences in immune responses to SARS-CoV-2 infection. In one study that examined HCoV-reactive antibody cross-reactivity with SARS-CoV-2 spike protein, 302 uninfected adults showed low (5%; n=16) cross-reactivity compared with children 6–16 years old (62%; n=43); the authors speculated that these differences reflected comparatively higher pediatric HCoV infection rates and may potentially affect disease severity and transmission patterns of COVID-19 [43].

 

3. Pediatric COVID-19 Vaccine Development – the content in this section of the review should be given greater priority and carefully rewritten.

Response: In response to Reviewer comments, we have rewritten this section to simplify the language and to improve coherence and readability. We’ve made greater reference to Figure 2 that graphically explains the various authorizations/approvals and licenses and the timeline.

The revised text now reads as follows:

 

3. Pediatric COVID-19 Vaccine Development

As of July 5, 2022, 168 and 198 vaccines were in clinical or preclinical development, respectively. Thirty- seven COVID-19 vaccines received licensure or emergency use authorization (EUA) [44, 45]. Vaccines were initially tested in adults and subsequent studies have included progressively younger populations (Figure 1). Vaccines studied in pediatric populations include 2 mRNA vaccines, BNT162b2 and mRNA-1273, and the inactivated CoronaVac and BBIBP-CorV vaccines (Table 1 [46-50]). BNT162b2 was initially authorized in the United States and in the European Union in ≥16-year-olds as a 2-dose 30-µg primary series (Figure 2 [46, 47, 51-57]) [54, 58], followed by 12‒15-year-olds, and a booster dose authorization in the United States for ≥12-year-olds [52, 54]. The 2-dose 30-µg primary series is now fully licensed in the United States for ≥16-year-olds [54]. For the pediatric age group, a 2-dose 10-µg BNT162b2 primary series in 5–11-year-olds and a 3-dose 3-µg BNT162b2 primary series in 6-month−4-year-olds have been authorized in the United States and the European Union, respectively [53, 54, 57]. A 2-dose 100-µg mRNA-1273 series is licensed in the United States for vaccination of ≥18-year-olds [59] and in the European Union in ≥12-year-olds [60]. For the pediatric age group, 6−11-year-olds, a 2-dose 50-µg series is licensed in the European Union [60]. In the United States, a 2-dose mRNA-1273 series for children 6−11-years-old (50 µg) and 6 months−5-years-old (25 µg) has been authorized [61]. CoronaVac and BBIBP-CorV are in early-stage clinical trials in children [49, 50] and have received Emergency Use Listing from the WHO for adult vaccination using a 2-dose series [62, 63].

 

line 187 As of July 5th, 2022, 168 COVID-19 vaccines are in clinical trials and 198 vaccines are undergoing preclinical development. Thirty seven COVID-19 vaccines received licenses or EUA. (delete ≥1 regulatory authority)

Response: This text has been revised as suggested.

 

lines 189-190 are grammatically incorrect- they use past and present tense in the same sentence!

Response: The sentence has been amended to: “Vaccines were initially tested in adults and subsequent studies have included progressively younger populations (Figure 1).”

 

Table 1 entire presentation is incoherent and must be redone. Header “Details” contains an overflow of text “Characteristic” is not aligned- needs to be reformatted in one column.

Response: We believe that there may have been a problem with the formatting in the manuscript copy sent by the journal to reviewers as the information in the original table was aligned in distinct columns. To address reviewer comments, we changed the formatting of Table 1. Changes include:

• Vaccine subsections within the table were removed
• Third column containing the vaccine name was added
• Studies were rearranged into distinct categories (“infants, children, and adolescents”, “adolescents”, “children”, “infants”), and the age group studied in each trial was added within each profile
• Table font size was reduced

 

Table 2. same issues as Table 1.

Response: Similar to Table 1, we believe that there may have been a problem with the formatting in the manuscript copy sent by the journal to reviewers as the information in the original table was aligned in distinct columns.

To address reviewer comments, we have changed the formatting of Table 2. Changes include:

• Bolded the vaccination types in the first column
• Added text indicating where the stated organizations provided no recommendations (rather than leaving a cell blank)

 

lines 200-383

3.1 Pediatric Clinical Trials

3.1.1 Immunogenicity and Vaccine Efficacy

3.1.3 Safety

3.2 Real World Evidence (NO logic in the sequence of section headers)

Response: We have checked the manuscript and the sections were numbered correctly. No changes have been made in response to this comment.

 

3.3 myocarditis and Pericarditis are special side effects that belong to Safety, not a separate header too much text and not well reviewed.

Response: Thank you for your suggestion. The previous section on "Safety” is specific to safety data from clinical trials only (i.e., it is a subsection [3.1.2] of Section 3.1 on Pediatric Clinical Trials), whereas the section in “Myocarditis and Pericarditis” reviews all data on this very important adverse event.

For greater clarity, we have renamed the subsections within the “Pediatric Clinical Trials” section to “Clinical Trial Data on Immunogenicity and Vaccine Efficacy” [p19/para1/line2] and “Clinical Trial Safety Data”. Also, the following subheadings have been introduced within the “Real-World Evidence” Section: “3.2.1 Real-World Effectiveness”, “3.2.2 Real-Word Safety”, and “3.2.3 Myocarditis and Pericarditis”.

 

4. Conclusions line 388 DELETE Figure 2. summarizes current knowledge on COVID-19 characteristics and vaccination in children and young people. Begin here “Despite the inclusions of children and young people in vaccine recommendations…”.

Response: The sentence has been moved to the Introduction.

 

DELETE lines 395 and 396. “The increasing proportion of COVID-19 cases and rising hospitalization rates in unvaccinated pediatric populations associated with highly transmissible variants that pediatric COVID-19 vaccination will be critical for future pandemic control”. The statements already in the introduction- are repetitious and add little substance to the conclusion.

Response: The sentence has been deleted.

 

Add section “Take Home Messages”

Response: Thank you for the suggestion. Indeed, the take-home messages are summarized in Figure 1, and in response to the Reviewer’s suggestion, we have now placed the figure earlier in the manuscript to elevate its prominence.

Reviewer 2 Report

Thank you for the invitation.  I have read this manuscript with great interest and found it timely and relevant during the ongoing pandemic. The authors have summarized the recent advancements in COVID-19 among the pediatric population. This manuscript covers all pivotal aspects. However, I would like to suggest including parenteral vaccine hesitancy towards COVID-19 in this document, as it is an evolving issue during the current phase of immunization against SARS-CoV-2. The information on the current status of parenteral vaccine hesitancy will provide a future direction for research and policy development.

Author Response

REVIEWER 2

Thank you for the invitation. I have read this manuscript with great interest and found it timely during the ongoing pandemic. The authors have summarized the recent advancements in COVID-19 among the pediatric population. This manuscript covers all pivotal aspects. However, I would like to suggest including parenteral vaccine hesitancy towards COVID-19 in this document as it is an evolving issue during the current phase of immunization against SARS-CoV-2. The information on the current status of parenteral vaccine hesitancy will provide a future direction for research and policy development

Response: Thank you for the suggestion. Section 3.4 has been added to address parental hesitancy.

 

EDITORS’ COMMENTS

Thank you again for your manuscript submission:

 

1. Please note that author names, affiliations, and e-mail could not be changed if the paper is accepted, so please check it carefully when revising your manuscript.

Response: All author details have been checked and updated as necessary.

 

You are welcome to provide a Graphical Abstract (GA) or a Video Abstract (VA) for this paper, which would help increase the publicity of the paper.

Response: Thank you for the suggestion, but we will not be adding a GA or VA to the paper.

 

2. Could you please fill out the Disclosure of Potential Conflicts of Interest form in the attachment? Please note that this COI form should be hand-signed by all authors.

Response: The Disclosure of Potential Conflicts of Interest form has been provided with the resubmission.

 

(I) Please check that all references are relevant to the contents of the manuscript.

Response: The bibliography has been checked and we can confirm that all included references are relevant to the contents of the manuscript.

 

(II) Any revisions to the manuscript should be marked up using the “Track Changes” function if you are using MS Word/LaTeX, such that any changes can be easily viewed by the editors and reviewers.

Response: All changes have been made in Tracked changes.

 

(III) Please provide a cover letter to explain, point by point, the details of the revisions to the manuscript and your responses to the referees’ comments.

Response: This has been provided.

 

(IV) If you found it impossible to address certain comments in the review reports, please include an explanation in your rebuttal.

Response: Explanations have been provided of all changes made or reasons given where we felt that changes should not be made.

 

(V) The revised version will be sent to the editors and reviewers.

Response: Noted.

 

If one of the referees has suggested that your manuscript should undergo extensive English revisions, please address this issue during revision.

Response: This has been done where required.

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Proofread and consider shortening the amount of text and the extensive details in Tables. 

Author Response

The manuscript has been professionally proofread. Edits are tracked to the version downloaded from this site. 

The author team carefully considered the reviewer's suggestion to reduce the text/details in the tables. We believe that the tables include distinct study details and data that are pertinent to the manuscript but are not included in the manuscript text. During our review of the research literature we did not find any publication or source wherein such information was handily summarized in the form of tables like the ones we have compiled. Therefore, we believe that these tabulated data in the context of a narrative review would be useful for the readers. As such, we respectfully submit that the tables be retained as is.