PONE-D-21-38330Naturally acquired antibodies against 7 Streptococcus pneumoniae serotypes in Indigenous and non-Indigenous adultsPLOS ONE

Dear Dr. Ulanova,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. During the revision process, please focus on addressing the comments related to study design, including the selection of serotypes, and data analysis and presentation.  Also, if there is a way to provide functional information regarding the antibody response it would be greatly appreciated.

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"We would like to thank all the participants who donated their serum for the study. We are indebted to our collaborators, especially the health care providers at Indigenous Health Access Centers and First Nations community members who kindly helped us with collecting samples, with our special thanks to Annette Schroeter, Connee Badiuk, Anita Cameron, Cynthia Price, Wayne Hyacinthe, Karen Fobister, Rekha Netto, Sherisse McLaughlin, Trudy Jacobs, and Lori Sinclair.  We also thank Hanan Alsarmi for collecting the healthy Thunder Bay participant samples as well as Twyla Biluk (Thunder Bay 55 Plus Centre) for assistance with recruitment of healthy Thunder Bay participants. We thank Angele Desbiens-Forget, Brenda Huska (Northern Ontario School of Medicine) and Amanda Bakke for technical help.

Funding was provided by Mitacs Accelerate with contribution by Bruce Power, Northern Ontario Academic Medicine Association, Pfizer, and NOSM (Summer Medical Student Research Awards)."

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competing interests: Marina Ulanova received research funding from Pfizer through a

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an original and thought-provoking paper. Indigenous populations of non-vaccinated adults had higher levels of IgG and IgA to all pneumococcal serotypes tested than did non-Indigenous adults (Tables 2A and 2C). Antibody levels were unrelated to age.

The following specific suggestions might help with the clarity of the presentation.

What were the vaccination rates in infants and children in the Indigenous vs non-Indigenous populations at the time of the study?

The authors address well the principal question that the reader will, have, namely, why the antibody that is more prevalent in the population fails to provide protection:

“However, high burden of chronic diseases and immunocompromising conditions, along with unfavourable socioeconomic conditions, are important factors predisposing Indigenous people to invasive bacterial disease [35, 65]. As Indigenous Canadians have high burden of obesity, diabetes, circulatory diseases, chronic kidney disease, and cancer, this suggests that an increased IPD rate in Indigenous adults is due to the increased prevalence of risk factors rather than lack of natural immune defenses [66].”

These important points are summarized well in the conclusion.

I think, however, that better terminology in the preceding paragraph would be: “…rather than lack of anticapsular antibody.” There are other natural defenses, including those related to comorbidities, so this sentence should be rephrased. The authors also might add that some studies have shown that all antibody measured by ELISA is equally protective (Musher, Johnson and Watson Infect Immun 1990; Romero-Steiner et al Clin Infect Dis 1999).

Reviewer #2: This study by Gaultier and colleagues report the naturally-acquired pneumococcal serotype-specific antibody levels among Canadian indigenous adult populations compared with non-indigenous adults. They measured serum IgG, IgM and IgA to 7 serotypes contained in PCV13 and PPV23. This is a nicely written manuscript that adds to the evidence around the immune profiles among indigenous populations globally to try and understand the basis for their increased susceptibility to pneumococcal carriage and disease.

I have a few queries and suggestions for the authors to consider:

1. What was the rationale for selecting those 7 serotypes in particular? Only serotype 3 is a non-PCV13 type and is usually associated with lower responses. Have the authors considered extending the range of serotypes for examination to gain a better idea of the responses in these groups? Particularly since they state that 72% of IPD was caused by non-PCV13 types.

2. Many of the demographic information was obtained by self-declaration, including pneumococcal vaccination history and health status. How reliable do the authors think this is since we know the indigenous groups often have a higher proportion of co-morbidities that can effect immune responses?

3. In terms of the analysis, I think reporting GMCs is OK but for the IgG response, it would be good to also include the proportion >1.0ug/ml or >1.3ug/ml as this is what is often used to determine an adequate or protective response (even if not in the context of PPV23 vaccination). This might help with the interpretation of the data.

4. As the authors noted, the biological role of the IgA response observed needs further investigation. The values are very low so it would be helpful to have some discussion around this in terms of how this might provide protection.

5. The manuscript would greatly benefit from some analysis of functional antibody, whether by avidity or opsonophagcytosis since this would provide a better insight into whether these responses are truly protective among indigenous populations.

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Reviewer #1: Yes: Daniel M. Musher MD, Distinguished Service Professor of Medicine, Baylor College of Medicine

Reviewer #2: No

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Naturally acquired antibodies against 7 Streptococcus pneumoniae serotypes in Indigenous and non-Indigenous adults

PONE-D-21-38330R1

Dear Dr. Ulanova,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Victor C Huber

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have addressed the comments sufficiently and the manuscript is acceptable for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No