Increase in prevalence of Streptococcus pneumoniae serogroup 24 in children upon introducing 13-valent pneumococcal conjugate vaccine in Japan
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After introducing the 13-valent pneumococcal conjugate vaccine (PCV13) for children, a change in the prevalence of different Streptococcus pneumoniae serotypes that cause invasive pneumococcal diseases (IPDs) has been observed. The prevalence of vaccine serotypes has decreased and that of non-vaccine serotypes has increased. Currently, serogroup 24 has become one of the major non-vaccine serotypes causing IPDs in children in Japan. The aim of this study was to characterize clinical and genomic features of S. pneumoniae serogroup 24 strains isolated from sterile body sites in Japanese children. Serotyping, multi-locus sequence typing and genomic analysis of capsular polysaccharides of 61 strains of serogroup 24 were performed from 2015 to 2021. Among the 61 strains, 36, 23 and two belonged to serotypes 24F, 24B and 24C, respectively. The 24F sequence type (ST) 2572 and 24B ST 2572 were the major serotypes and sequence types observed from 2015 to 2019. By contrast, 24F ST 162 and 24B ST 2754 were the two major serotypes and sequence types observed after 2020. Two strains of serotype 24C were detected for the first time in Japan. Sequence analysis of the abpA gene, which plays a role in the synthesis of capsular polysaccharides in S. pneumoniae , was performed to distinguish different strains of serogroup 24. After the introduction of PCV13 in Japan, serogroup 24 has become one of the most prevalent non-vaccine serotypes causing IPDs in children. This serogroup has not been targeted in the next-generation pneumococcal conjugate vaccines. Therefore, monitoring of S. pneumoniae serogroup 24 that causes IPDs in children is essential.
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The work presented is clear and the arguments well formed. This is a study that would be of interest to the field and community.
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Dear Dr Ishiwada Thank you for submitting your paper to Access Microbiology. Your manuscript has now been reviewed and I would like you to address their comments, in line with the provided reports at the end of this email. The reviewers and I agree that whilst your work on epidemiological and genetic characterisation of serogroup 24 pneumococcal isolates, provides a valuable addition to the existing literature and is of interest to readers of Access Microbiology. However some major changes have been suggested by the reviewers on the details of the methods provided and on the presentation/interpretation of the results that will improve the readability of the manuscript and the reproducibility fo the data. I would like you to consider, where appropriate, those comments and address them in a revision. Furthermore, given the open access …
Dear Dr Ishiwada Thank you for submitting your paper to Access Microbiology. Your manuscript has now been reviewed and I would like you to address their comments, in line with the provided reports at the end of this email. The reviewers and I agree that whilst your work on epidemiological and genetic characterisation of serogroup 24 pneumococcal isolates, provides a valuable addition to the existing literature and is of interest to readers of Access Microbiology. However some major changes have been suggested by the reviewers on the details of the methods provided and on the presentation/interpretation of the results that will improve the readability of the manuscript and the reproducibility fo the data. I would like you to consider, where appropriate, those comments and address them in a revision. Furthermore, given the open access policy of Access Microbiology, I would kindly ask to consider the possibility to make the data that support this study available on a public database.
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Comments to Author
Methodologically this is mainly simple and clearly explained. My main methodological questions are about the sampling. The Chiba sample seems to be complete. I am less sure of the extent to which the wider survey of samples across Japan is representative or may be biased. This could be in terms of differential sampling across the time period, the selected clinical - demographic population, and subtype. Here the description "samples from other prefectures were obtained from clinicians on request" does not give much idea. It would be good to be more explicit on this and the extent to which this may have biased the pattern across years, subtype or patient demography or clinical picture. If this is likely then features such as counts over time may be better restricted to the Chiba prefecture sample or at …
Comments to Author
Methodologically this is mainly simple and clearly explained. My main methodological questions are about the sampling. The Chiba sample seems to be complete. I am less sure of the extent to which the wider survey of samples across Japan is representative or may be biased. This could be in terms of differential sampling across the time period, the selected clinical - demographic population, and subtype. Here the description "samples from other prefectures were obtained from clinicians on request" does not give much idea. It would be good to be more explicit on this and the extent to which this may have biased the pattern across years, subtype or patient demography or clinical picture. If this is likely then features such as counts over time may be better restricted to the Chiba prefecture sample or at least for this to be visible in presentation and discussion of results across these dimensions. The other sampling issue is the overall timeframe. The title "Increase in prevalence of Streptococcus pneumoniae serogroup 24 in children upon introducing 13-valent pneumococcal conjugate vaccine in Japan" would lead me to expect as ample comparing afterwards with before. However the vaccination was introduced in 2010 (7 valent) and 2013 (13 valent) but the sample extends forward from 2015. At least for the 7 valent this was very late in terms of the main carriage group for most S. pneumoniae being your children with quite extensive coverage in place for this population before 2015. The rationale for this sampling period vs what might be expected and inferred from the title is not discussed or mentioned in limitations. The data summary statement notes that "No data was generated during this research." This seems to conflict with a description of methods to generate data and the data then presented in results as part of this research. There is also no statement on depositing of the data generated. Part of the usefulness of this research is for these data to be curated and accessible to other researchers and this should be assured and described. Presentation of results The paper generally presents data clearly. In comparing the sequences in table 2 the main findings to me look to be that (i) ST162 has many differences shared across all ST162 isolates and not present in the other STs., (ii) there is a lot of diversity within ST2572 serotype 24B, the recently emerged (or at least identified) serotype 24C is present across at least sequence types. I think that it would be useful to pull out these themes in the results descriptions and discussion. Also (Line 237 : "…point mutations were detected in the abpA sequences of all the 24B ST 2754 strains,…") sounds to me as though describing a range of mutations but Table 2 appears to show a single shared difference across 24B ST 5724 vs the reference sequence used in the paper. As above - ther emay be a reason to present the Chiba prefecture results as a population sample and other isolates not as a representative population sample subject to how this process of sampling more widely was conducted. MINOR DETAILS Line 55 : This serogroup has not targeted by …. This serogroup has not been targeted in … Line 77 : reading.. leading.. Also "S. pneumoniae is one of the (l)eading causes of invasive pneumococcal diseases (IPDs)" does not make sense as by definition it is the only cause of invasive pneumococcal diseases. Line 107: …various… …from various… Line 173-175 I am not sure what is referred to in the BLAST search in the first of the two sentences across lines 175-177. The second sentence is following the methods description of comparing the cps among a subset of amplifies and sequenced isolates. The first one appears to be comparing all isolates, although only a subset were sequenced. Or this may be a reference to a BLAST search of isolates on public databases? It would be good to make this clear, including a statement in the methods to anticipate this aspect of the results. "The BLAST search results revealed that the cps loci (except the abpA gene sequences) of all the serogroup 24 strains shared 100% identity. The cps loci (except the abpA gene sequences) of all the175 five tested strains of 24F ST 2572 and 24B ST 2572 were identical." Line 232: "serotyp0e" "serotype" Discussion - There is some discussion of external publication as regards the increase in non-vaccine serotypes being widely observed in other countries post vaccination, and some detail on ST-serotype distributions in some other datasets. The emergence of serotype 24 C is set in the international context. However a fuller comparison of the dynamics of serotype 24 generally in other countries post vaccination is missing and I think a gap. Subject to any journal space limitations expanding this aspect of the introduction/ discussion would be useful. The proposed mechanism for generation of variation is highly speculative but is only presented as a "possibility" in line with this speculative and sketchy nature.
Please rate the manuscript for methodological rigour
Satisfactory
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
The authors present an epidemiological/capsular polysaccharide genetic analysis of serogroup 24 pneumococcal isolates from cases of invasive disease in Japan between 2015 and 2021. They demonstrate a switch in dominance of 24F to 24B, a loss of ST 2572 24F, the discovery of 24C for the first time in Japan and finally a potential clonal expansion of a capsular switch event involving 24B ST2754. Serogroup 24 is important in the context of pneumococcal disease and the authors are right to examine the epidemiology against a backdrop of PCV implementation. Methodological rigour, reproducibility and availability of underlying data The methods used are generally ok. However, there are several gaps in the methodology descriptions that would make reproduction difficult and therefore need to be addressed. 1. …
Comments to Author
The authors present an epidemiological/capsular polysaccharide genetic analysis of serogroup 24 pneumococcal isolates from cases of invasive disease in Japan between 2015 and 2021. They demonstrate a switch in dominance of 24F to 24B, a loss of ST 2572 24F, the discovery of 24C for the first time in Japan and finally a potential clonal expansion of a capsular switch event involving 24B ST2754. Serogroup 24 is important in the context of pneumococcal disease and the authors are right to examine the epidemiology against a backdrop of PCV implementation. Methodological rigour, reproducibility and availability of underlying data The methods used are generally ok. However, there are several gaps in the methodology descriptions that would make reproduction difficult and therefore need to be addressed. 1. The age distribution of cases is not clear. I would argue that 15-year-olds are better described as adolescents and not children and would urge the authors to reflect on this and alter. 2. For those unfamiliar with the study locations, it would be good to give a brief overview of the prefecture in terms of location and population, and the sites these isolates came from. 3. It is not clear how many isolates came from other prefectures. Please clarify. 4. You should indicate how many pneumococcal isolates were available in total from which these 61 were taken. That would give an indication of the overall prevalence of serogroup 24 as a cause of IPD relative to other serotypes. 5. The descriptions of the methods need improving. For example, was it Columbia Blood Agar? If so, what was the manufacturer. How was optochin sensitivity assessed? Manufacturer of discs? 6. You also need to give the PCR reaction conditions (primer concentrations, mastermix, thermocycler used and cycling conditions). This also applies to cps sequencing (where you should also supply the name of the sequencing instrument used and where it was done. 7. Line 174: Blast is mentioned here but there is no mention in the methods section. Presentation of results 1. Line 143-144. The optochin sensitivity and lytA PCRs do not confirm serogroup. 2. Line 144. Please can the authors clarify how in the methods it states that 61 serogroup isolates were acquired and here you state that it was 31, is this just a typo? 3. Figure 1. I do not have an issue with presenting counts however you should also present proportion as this figure does not illustrate whether overall IPD has remained constant over this period. Also, Y axis needs to be clearer. 4. The authors should consider a table of case demographics, or perhaps a figure showing when cases (by age) were isolated. 5. Line 174-175. It's not clear why you tested all cps loci and then a subset of five. This requires clarifying. 6. Please put the detail that all 24F ST2572 abpA were identical into Table 2. 7. Perhaps the information in Table 2 would be better communicated alongside a Figure. How the style and organization of the paper communicates and represents key findings The overall structure and organisation of the paper works for the data being presented. Literature analysis or discussion 1. I don't believe ST2754 has been previously associated with 24B and I think this potential capsule switch requires further discussion. 2. Line 190: Whilst serogroup 24 might be rare in adults in Japan it nevertheless was reported in France (just as an example, Ouldali et al., Lancet ID, 2020). This should be reflected in the discussion. 3. Line 196: I'm not sure I follow here. You state that most isolates had specific STs which suggests some did not? Can you clarify please. 4. Line 233-239: is the heterogeneity of abpA in 24B ST2754 common? I think this needs expanding as a discussion point. 5. The 'limitations' section of the study requires expanding. AMR data would have been useful, and achievable. Whilst more challenging and costly the lack of genomic resolution of lineages, i.e., GPSCs, does make contextualisation difficult. Any other relevant comments Line 75: Gram should be capitalised Line 77: re-word, there are no other causes of IPD other than pneumococci Line 81: Specify that this is in adults Line 90: There is more to this reference than is given in this introduction. For the reader it would be useful to expand to highlight the GPSC narrative of these findings. Line 96-97: This implies that this has not been described previously, whereas it has. Perhaps rephrase to indicate this is a description of isolates from a specific geographic area. Line 118: Please cite the Jolley et al., 2018 paper in Wellcome Open Research for pubMLST. Line 207 (and elsewhere): please replace bacteria with pneumococci Line 232: typo with Serotype
Please rate the manuscript for methodological rigour
Satisfactory
Please rate the quality of the presentation and structure of the manuscript
Satisfactory
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes