PNTD-D-24-01300

Impact of a multi-pronged cholera intervention in an endemic setting

PLOS Neglected Tropical Diseases

Dear Dr. Blake,

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Joseph M. Vinetz

Section Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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Reviewers' Comments:

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

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Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

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Reviewer #1: The objectives of the study are clearly articulated.

I think that several additional analyses are necessary to the importance of the environmental reservoir and the high level of population immunity estimated in this study. Further details are provided in the general comments below.

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Results

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Reviewer #1: Results are clearly presented.

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Conclusions

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Reviewer #1: The conclusions could be better supported with some additional analyses as described in my general comments below.

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Editorial and Data Presentation Modifications?

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Reviewer #1: (No Response)

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Summary and General Comments

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Reviewer #1: This study uses mathematical modeling to assess the impact of vaccination and WASH improvement campaigns in a cholera endemic setting in eastern DRC, and also uses the model to assess the potential impact of optimal intervention strategies. The model is also used to assess the relative importance of direct transmission vs. indirect transmission via a contaminated environmental reservoir. The estimated impact of the vaccination campaign was relatively small, in large part because the model estimates that a large fraction of the population was immune prior to the outbreak. My main concern is that there is no serological or other evidence that would support this estimate, and if this estimate is off due to factors not considered in the model (heterogeneity in exposure, risk, etc) then the estimates of both the impact of vaccination and the relative importance of the environmental reservoir might be incorrect.

One possible check would be to compare the age-specific population immunity and incidence that would be estimated using a catalytic model with the other model inputs/outputs (FOI and rate of immune waning). How does this compare to estimates of the FOI from a catalytic model fit to the age-specific case data?

As an alternative to high levels of complete immunity, there may be varying levels of partial immunity from prior infection/exposure with new exposures leading to asymptomatic infections with immune boosting (e.g., King et al. 2008 Nature) and lower levels of shedding. It might be useful to model this possibility, with vaccine providing additional protection beyond naturally-derived immunity. In lines 372-377 you mention the duration of immunity from challenge studies, but the infection of naive individuals in these studies might not represent the infections or "incidence rate" observed in the cited Bangladesh study of vibriocidal titers.

Having a single environmental reservoir for the entire population might also overestimate its contribution to transmission. Metapopulation modeling was mentioned in the introduction, so it would be useful to understand if was considered here and if not, why not? Particularly given that data from this outbreak in Kalemie was previously used to show that risk of infection was higher within 200m of a previous case (Azman et al. 2018 JID), suggesting that the environmental risk varies spatially (or direct transmission is more common than estimated here).

From line 130 ("...northern part of the city laying pipes...") it sounds like the WASH intervention was more narrowly geographically targeted. Is this assumption correct, and if so could the model be subdivided in a way that would incorporate this difference?

Minor comments

1. It would be helpful to have a table with parameter descriptions in the main text for easy reference

2. In the Results and/or 1st paragraph of the Intro it would be helpful to also present the cases averted by vaccination and WASH as a % of total cases in the absence of either intervention. The raw numbers seem high relative to the number of observed cases, but I assume that is because you also estimate a large fraction of infections/cases were unreported?

3. While the counterfactual simulations of incidence under interventions that completely prevent contamination or exposure of the environment are nice examples of the potential power of improving access to clean water and sanitation, real-world WASH interventions rarely have impacts as large as those estimated here. It might be useful to also see the impact of interventions with reductions in contamination and/or exposure that are reflectively of some previous interventions

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Reviewer #1: No

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Dear Dr. Blake,

We are pleased to inform you that your manuscript 'Impact of a multi-pronged cholera intervention in an endemic setting' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Joseph M. Vinetz

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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