PONE-D-22-01362

Quantifying Heterogeneities in Arbovirus Transmission: A Prospective Longitudinal Study of Dengue and Zika Viruses in Iquitos, Peru

PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: N/A

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Reviewer #1: Yes

Reviewer #2: No

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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: The project is very ambitious, well written and with a very experienced team. I believe it has a good chance of making great contributions to the knowledge of dengue. It must undergo a small English review before being published.

Reviewer #2: In this paper the authors describe an ambitious and comprehensive five-year program of work in Iquitos, Peru, that builds on two previous decades of dengue research in the city by the lead authors, and was designed to fill knowledge gaps in understanding the full spectrum of dengue virus infection outcomes and how these influence DENV transmission dynamics. The research program comprised integrated workstreams examining human-to-mosquito infectiousness, subjective and objective measurements of disease severity and quality of life measures, household cluster investigations to identify inapparent infections and understand spatial patterns of transmission, and analyses of the interaction of infectiousness and disease severity with human mobility, all unpinned by a combination of community-based active surveillance and clinic-based passive surveillance to detect and enrol viraemic dengue patients of all disease severities. The significance of this research program, and the quality and importance of the research findings it has produced, is not in question. What is not as clear as it could be, however, is the overall intention and the execution of this paper itself. Some relatively minor changes to the framing of the manuscript should help to resolve this, as suggested below.

Major comments

1. From the outset, starting with the title itself, it is not clear to the reader whether the focus of the paper is on i) reporting the structure, methodology and significance of the research program, ii) primary reporting of research findings, vs iii) a synthesis or review of research findings that have already been published. Throughout, the manuscript jumps between the first and third of these, but overall seems to be primarily focused on communicating the strengths of the research program's structure and methods, and the resulting synergies between the workstreams. This disconnect is most apparent in the closing sentence of the introduction, the closing paragraph of the 'Significance' section, and the closing paragraph of the manuscript, where the authors refer to expectations and hopes that the results "will have public health and basic science implications" and "will reveal new perspectives on processes in transmission of DENV...and provide key missing information for improving the design of dengue prevention strategies". This language is confusing as it implies that the research is yet to be conducted and the results are not yet known.

Given that a lot of the research findings have already been produced and published, it would be more meaningful to comment on what some of the public health and basic science implications of the key findings actually are.

Or alternatively (and more simply) the authors could make it explicit early on and throughout that results of this research have previously been published (with citations), and that the objective of this paper is to give a holistic view of the structure and methodology of the integrated research program, and how its design and implementation facilitated the achievement of the research objectives. In this case, the authors should reframe the introduction and conclusion of the paper to focus primarily on the methodological strengths of the integrated research program (as done in the penultimate paragraph of the paper) to address the knowledge gaps in dengue transmission and control, without focusing so heavily on the significance of the research findings themselves - since these findings aren't made known to the reader.

2. The title doesn't clearly communicate the scope of the paper, rather it presumably reflects the title of the research protocol. A more informative title would be something along the lines of 'An integrated program of entomological, epidemiological and clinical research to understand heterogeneities in arbovirus transmission in Iquitos, Peru'.

3. The abstract describes the objectives and activities of the Iquitos research program, and creates the impression that research findings will be presented herein. Instead the abstract should reflect the objective, scope and conclusions of this paper, i.e. including an overview of the research methodology but with a focus on the significance of the integrated projects and cores, and what has been achieved through this program.

Minor comments

- Page 5, line 164: The failure of dengue control programs has also been attributed to the lack of an evidence base for their effective implementation, generated through robust study designs with epidemiological endpoints (Wilson et al 2015; Bowman et al 2016)

- Page 15, line 420: the mosquito direct feeding experiments should be described in text here with reference to Figure 3, or a citation given for where these direct feeding experimental methods have been described previously.

- Page 16, Figure 3: the abbreviation FFA (and probably also RT-PCR) needs to be defined in the figure legend

- Page 20, line 544: there is a citation [3] here that is non-sequential with other citations.

- Page 20, line 548: this paragraph should have a new subheading reflecting its focus on highlighting synergies between the program workstreams (not 'Analysis plan and data integration', as it currently falls under).

- Page 20, line 549: P01 program is not familiar terminology for many readers. 'Research program' instead?

- Page 20, line 554: 'were also be used' - wording needs fixing

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Reviewer #1: Yes: LUCIANO PAMPLONA DE GOES CAVALCANTI

Reviewer #2: No

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Quantifying heterogeneities in arbovirus transmission: Description of the rational and methodology for a prospective longitudinal study of dengue and Zika virus transmission in Iquitos, Peru (2014-2019)

PONE-D-22-01362R1

Dear Dr. Morrison,

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,

Luciano Andrade Moreira, PhD

Academic Editor

PLOS ONE

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