{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T19:57:18Z","timestamp":1773691038630,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/gatesopenres.14300.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000}},{"DOI":"10.12688\/gatesopenres.14300.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000}}],"reference-count":64,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V031112\/1"],"award-info":[{"award-number":["MR\/V031112\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/T008709\/1"],"award-info":[{"award-number":["BB\/T008709\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["gatesopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Gates Open Res"],"abstract":"<ns4:p>\n                    Background The global prevalence of diseases transmitted by\n                    <ns4:italic>Aedes aegypti<\/ns4:italic>\n                    mosquitoes, such as dengue, Zika and Yellow Fever, is increasing, but development of promising new mosquito control technologies could reverse this trend. Target Product Profiles (TPPs) and Preferred Product Characteristics (PPCs) documents issued by the World Health Organization can guide the research and development pathways of new products and product combinations transitioning from proof of concept to operational use. Methods We used high resolution global maps of the case and economic burden of dengue to derive programmatic cost targets to support a TPP for\n                    <ns4:italic>Wolbachia<\/ns4:italic>\n                    replacement. A compartmental entomological model was used to explore how release size, spacing and timing affect replacement speed and acceptability. To support a PPC for a hybrid suppress-then-replace approach we tested whether\n                    <ns4:italic>Wolbachia<\/ns4:italic>\n                    replacement could be achieved faster, more acceptably or at a lower cost if preceded by a mosquito suppression programme. Results We show how models can reveal trade-offs, identify quantitative thresholds and prioritise areas and intervention strategies for further development. We estimate that for\n                    <ns4:italic>Wolbachia<\/ns4:italic>\n                    replacement to be deployable in enough areas to make major contributions to reducing global dengue burden by 25% (in line with 2030 WHO targets), it must have the potential for cost to be reduced to between $7.63 and $0.24 (USD) per person protected or less. Suppression can reduce the number of\n                    <ns4:italic>Wolbachia<\/ns4:italic>\n                    mosquitoes necessary to achieve replacement fixation by up to 80%. A hybrid approach can also achieve fixation faster and potentially improve acceptability, but may not justify their cost if they require major new investments in suppression technologies. Conclusions Here we demonstrate the value dedicated modelling can provide for interdisciplinary groups of experts when developing TPPs and PPCs. These models could be used by product developers to prioritise and shape development decisions for new\n                    <ns4:italic>Wolbachia<\/ns4:italic>\n                    replacement products.\n                  <\/ns4:p>","DOI":"10.12688\/gatesopenres.14300.3","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T11:30:08Z","timestamp":1730374208000},"page":"68","update-policy":"https:\/\/doi.org\/10.12688\/gatesopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Using models and maps to inform Target Product Profiles and Preferred Product Characteristics: the example of Wolbachia 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\n<i>Posted: 14 Oct 2024<\/i>; Thank you for reviewing this manuscript. Exactly as suggested, the manuscript has now been edited throughout to remove statements indicating that a combined suppress and then release programme presents cost savings. Additionally, the outdated statement about the lack of donor-funded implementations has now been removed. We hope you now find this manuscript acceptable for publication.","URL":"https:\/\/gatesopenresearch.org\/articles\/7-68\/v3#referee-comment-3734","order":1,"name":"referee-comment-3734","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/gatesopenres.17692.r38381, Perran Ross, The University of Melbourne, Melbourne, Victoria, 08 Nov 2024, version 3, indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/7-68\/v3#referee-response-38381","order":2,"name":"referee-response-38381","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/gatesopenres.17127.r37727, Gabriela Paz-Bailey, Centers for Disease Control and Prevention, San Juan, Puerto Rico, 16 Sep 2024, version 2, 3 approved with reservations, 1 not approved","URL":"https:\/\/gatesopenresearch.org\/articles\/7-68\/v2#referee-response-37727","order":3,"name":"referee-response-37727","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Katie Tiley<\/b>; \n<i>Posted: 14 Oct 2024<\/i>; \n<i>The paper reports on a mathematical model used to inform the WHO Target Product Profile (TPP) development for&nbsp;Wolbachia&nbsp;replacement. It contributes to the literature by discussing aspects of the TPP that influence&nbsp;Wolbachia&nbsp;implementation, using dengue cost data as a proxy for willingness to pay, and highlighting areas with the greatest benefit based on disease burden. However, there are several areas where the paper could be improved:<\/i>  \n<b><i>1. <\/i><\/b>\n<i>The components of the TPP need to be explained in the background section. Some elements are mentioned later in the paper without sufficient context. Adding a table with the TPP elements and their descriptions would be helpful.<\/i> \n<b>1. <\/b>Thank you for reviewing this manuscript.\n<b> <\/b>We agree that more context on the TPP would be helpful. This is boosted by the final approved version of the TPP now being publicly available which we now reference and should provide additional detail if readers are interested. We have expanded the relevant section of the introduction to summarise the main features of the TPP:  \u201cIn early 2022 the WHO convened a Technical Advisory Group (TAG) to develop a draft TPP for Wolbachia replacement and a draft PPC for a hybrid mosquito suppression then Wolbachia replacement strategy. The TPP for Wolbachia replacement began with the development of a \u201cuse case characterisation\u201d, following which specific TPP criteria were established under the categories of product performance, product characteristics, production and delivery and intellectual property. For each of these, a minimum and preferred target was established with the former intended to inform a go \/ no go product development decision point. A combination of different types of evidence from the field, laboratory and modelling studies were used to inform these targets, with the modelling work focused on release and cost-related characteristics. The final WHO TPP was published February 2022 (World Health Organisation, 2022). TAG members decided that a core premise of the TPP and PPC was that they should closely align with the WHO\u2019s strategy and goals to control dengue globally. As such the WHO\u2019s goal to reduce dengue incidence by 25% by 2030 (2010 \u2013 2020 baseline24) provided a basis to understand the scale and range of settings in which these TPPs, PPCs and the products they ultimately produce are relevant.\u201d  \n<i>Several parameters and assumptions in the model conflict with current replacement program practices:<\/i> \n<b><i>1a.<\/i><\/b>\n<i> Most programs release adult mosquitoes daily, rather than releasing eggs every two weeks. This discrepancy likely impacts costs and time to introgression.<\/i>  \n<b>1a. <\/b>We acknowledge that the form and frequency of releases may have changed since the time this decision was made. Our focus on egg releases every two weeks was aligned with the major field evidence available at the time which was the Yogyakarta RCT (Utarini et al., 2021) which also informed other aspects of the TPP. Therefore, this choice was made to improve consistency with the available field data and consistency across different elements of the TPP. We have edited the text in the methods to emphasise this:  \u201cAn entomological Wolbachia replacement model was formulated and calibrated to the main evidence available at the time, namely the Yogyakarta RCT which comprised nine to 14 egg releases in release cups every two weeks. This approach was also chosen to maximize consistency with other elements of the TPP.\u201d  We have also added an additional limitation to the discussion: \u201cWhile we simulate egg releases once every two weeks, we acknowledge that adult releases at weekly timescales may be possible and could accelerate the time to fixation.\u201d  \n<b><i>1b.<\/i><\/b>\n<i> Costs decrease when intervening in larger areas with high population density. Dividing endemic areas into 5x5 km pixels to prioritize regions seems unrealistic. For the model to be useful, it should reflect how countries are likely to implement the strategy, prioritizing cities based on population density and dengue incidence. What is the point of having a few pixels in one country and a few in another on the priority list if implementing the strategy based on these priorities is not feasible?<\/i>  \n<b>1b.<\/b> We agree with the review that treating pixels in isolation is likely not realistic. The same point was raised by review #1 in their initial review (see 1.2.1b for comment and response). In this response we clarified that occurrence of isolated 5x5km pixels is very rare in our analysis. We summaries the treated area estimates for each 2\n<sup>nd<\/sup> administrative area and provide this in the supplementary information. Original response: \u201cThe administrative-unit summary provided in the supplement shows that 85.5% of 2nd administrative units (admin2s) have predicted release areas at or above 10km2. Among the remaining admin2s with smaller release areas all of them are in countries that also contain admin2s with larger (&gt;10km2) release areas and 66% of smaller release admin2s occur in Vietnam, Colombia, Thailand, Brazil and Mexico which would all require large release areas across their respective countries. These smaller areas could thus be considered an extension of programmes in nearby areas. Introducing restrictions on contiguity or release area will, therefore, only affect a very small number of areas and have minimal impact on the overall findings.\u201d  In this response we also acknowledge the gap between our predicted treated areas map and likely implementation area: \u201cWe recognize and agree that many additional considerations will go into which areas will ultimately be targeted for Wolbachia implementation and the resulting map is not intended to be prescriptive, but rather give an indication of the kinds of areas that would be most sensible to priorities from a net cost efficiency perspective. Even if the decision to implement occurs at administrative unit-level, not everywhere within an administrative unit will see Wolbachia releases and the pixel-level maps can be useful for informing within- administrative unit targeting subject to a set of criteria that should be locally determined. It should also be emphasized that the TPP is, by definition, for a hypothetical Wolbachia replacement product, not the current most widely-used wMel programme. This means that such considerations may differ in their importance and, as such, are beyond the scope of the TPP and the accompanying modelling analysis.\u201d  \n<b><i>2. <\/i><\/b>\n<i>The focus on the combination of suppression followed by replacement is disconnected from practical realities. There are only two places in the world with&nbsp;Wolbachia&nbsp;suppression program (Singapore and China), and these do not represent the capabilities of endemic countries. This topic is prominently featured in the background, introduction, results, and discussion. I recommend moving it to the supplemental information and including a sentence in the results directing readers to it. Presenting it so prominently could distract from the main message and might influence policy and implementation discussions inappropriately. The main challenges with mosquito control include insecticide resistance, the limited impact of ULV spraying, and the difficulty of reaching cryptic breeding sites with larvicides. Mosquito control is largely ineffective and suggesting it as a viable strategy to accelerate replacement programs is dangerous. Effectiveness of SIT and&nbsp;Wolbachia&nbsp;methods have not been demonstrated outside a few small trials or in high-resource settings like Singapore and China. Wolbachia suppression is also potentially more expensive than the six-month replacement releases. Claiming that it may reduce costs without including the costs of various suppression methods is <\/i>\n<i>misleading. Table 3 should be eliminated.<\/i>  \n<b>2.<\/b> The suppression then replacement strategies were developed for the PPC. We explicitly clarify in the Introduction that: \u201cPPCs identify broader areas of unmet need and aim to stimulate new products or product combinations that can address these needs.\u201d This work, therefore, is not intended to represent current practical realities, but rather understand under what circumstances such new strategy may be beneficial. As well as having a clear theoretical basis, this intervention combination has been suggested by multiple previous modelling studies (Hu et al., 2021; Qu et al., 2018; Yakob et al., 2008) and is therefore a plausible potentially viable strategy that should be tested. We believe that the results presented in this paper are not particularly favorable for suggesting the hybrid approach over conventional replacement and list extensive barriers that will need to be overcome for it to become a viable alternative. We don\u2019t believe removing or relegating this work to the supplementary information would remove any perceived danger as implementers could still ask about these strategies based on work in prior publications. While we agree that the results text for the hybrid strategies is longer than for conventional replacement, this reflects the additional model development and complexity more than any perceived prominence or prioritization between these options.  We do, however, agree that we can do more to differentiate the work done for the TPP and PPC and as a result, we have made a number of modifications to sections to clarify that hybrid strategies are not currently used and the caveats that would need to be addressed for it to become a practical reality.  In the introduction: \u201cWhile not currently practiced, in theory, combining a prior programme of mosquito suppression followed by Wolbachia population replacement could offer community acceptance or dengue incidence reduction advantages.\u201d  In the discussion: \u201cHybrid approaches offer one unproven but potential option for increasing speed or acceptability of Wolbachia replacement.\u201d And \u201cThe implementation of any suppression method should be accompanied by mosquito surveillance that confirms that the levels of suppression achieved are above and beyond what would have normally been achieved by the programme.\u201d  Furthermore, Figure 6 showing a seasonal analysis of hybrid suppress then release strategies has been moved to the Supplementary Materials.  Following the comments of reviewer #1 all reference to the cost savings of hybrid suppress then release programmes have been removed and we substantially modified Table 3 and the section of text where it is discussed:  \u201cBy reducing the number of Wolbachia mosquitoes released and duration of the replacement phase of the hybrid strategy, the costs of this phase could be reduced. If these levels of suppression can be achieved at a lower cost than the savings of the replacement phase, then a hybrid strategy could reduce costs overall. Here we use models to estimate these maximum costs for suppression, beyond which a replacement-only programme would be preferable. If the baseline replacement programme can meet the TPP minimum cost of $2.33 per person, then suppression would need to cost not more than $0.41 \u2013 $1.17 per person for mosquito-release suppression methods and $0.09 \u2013 0.50 per person for conventional methods (Table 3).\u201d   \n<i>Results:<\/i> \n<b><i>3a. <\/i><\/b>\n<i>The results would benefit from examples to aid interpretation. For instance, figures 2c and 2d, and throughout the results section.<\/i>  \n<b>3a. <\/b>While we appreciate the suggestion, including these is challenging due to the fact that all well-known example cities are included in all of the targeting scenarios and our desire to keep the focus at a global level (see response 4e). We have slightly modified parts fo the results where figure 3 is described: \u201cThis corresponds to 34.7% of the urban (&gt; 300 people per km2) area at risk and all major dengue-endemic cities, and just 1.7% of the total area at risk of dengue.\u201d And \u201cA full list of cities and 2nd administrative units included under each targeting scenario, the costs each will support and additional contextual information (population, density, etc) is included in the following repository: https:\/\/github.com\/katietiley\/Wolbachia_TPP_PPC.git.\u201c  \n<b><i>3b. <\/i><\/b>\n<i>Figure 1: The reduction in mosquito population has not been demonstrated in field trials. It would be important to show whether the model results can be corroborated by empirical data.<\/i>  \n<b>3b. <\/b>While we agree that measuring pre- and post-\n<i>Wolbachia<\/i> replacement mosquito population size in the field is important, we are currently not aware of any datasets where this has been robustly measured and reported. We believe this may be challenging to practically measure given the heterogeneity over time and space of mosquito populations and the variable measurement accuracy of different traps for estimating true mosquito abundance. The modest (~ 30-35%) declines in mosquito abundance that we estimate are an implicit consequence of reduced \n<i>Wolbachia<\/i> mosquito fitness, a trait that is well documented in laboratory studies and a common assumption of many modelling studies (e.g., Joubert et al., 2016; Ross &amp; Hoffmann, 2022). In comparison with these, the fitness cost we selected was a conservative estimate which, consequently, means our estimates of mosquito abundance reduction post-\n<i>Wolbachia<\/i> release are more likely to be an over-estimate. We have edited the discussion to acknowledge this: \u201cThe fitness cost of \n<i>Wolbachia<\/i> infection selected in these models was a conservative estimate and, consequently, the decline of total mosquito population equilibrium from pre- to post-\n<i>Wolbachia<\/i> release (Figure 1A,B) is likely to be an over-estimation.\u201d  \n<i>Figure 2 highlights the challenges of the pixel approach. Covering only 12.5% of the burden means that smaller areas spread further apart would need to be covered, which may not be feasible with an intervention as logistically demanding as&nbsp;Wolbachia&nbsp;replacement. This should be noted somewhere in the paper<\/i>  In the discussion we mention: \u201cIt is important to clarify that these maps should not be used prescriptively, but rather give an indication of the kinds of areas that are likely to be most cost efficient to target, with the final decision on which areas are targeted for release subject to additional operational, entomological, financial and political considerations.\u201d  \n<b><i>3c. <\/i><\/b>\n<i>Page 10, third paragraph: Explain what is meant by &quot;exacerbation issues\u201d.<\/i>  \n<b>3c. <\/b>This has been amended: \u201cHigher RRs and higher release round numbers also lead to disproportionately undesirable temporary exacerbation of the mosquito population, particularly at higher values (Figure 1A,B,D).\u201d  \n<b><i>3d. <\/i><\/b>\n<i>Table 2: The implications of the cost per person covered could be better explained in the results. Providing an example of a city with a certain population and comparing the costs of protection in areas with high versus low willingness to pay would be useful. The significance of the cost changes from 12.5% to 25% reduction is unclear.<\/i>  \n<b>3d. <\/b>We appreciate the review\u2019s implementer focussed perspective, but this was not the intended purpose of this model, or these results and we believe that discussing such exampled explicitly may lead to misinterpretation of this work. The cost targets presented in Table 2 are global targets that a Wolbachia replacement solution would need to meet to be compatible with the TPP. While it is true that for any one individual city, these targets could be higher (indicating higher willingness to pay), development of a Wolbachia replacement product at this cost point would not then achieve the TPP target of being affordable in enough areas to meet either the 12.5% or 25% global burden reduction targets. We therefore believe focussing the discussion of these results at the global level is a more appropriate summary of the model and its results.  \n<i>Discussion: <\/i> \n<b><i>4a. <\/i><\/b>\n<i>Page 17, first paragraph: In countries where Wolbachia has been implemented, releases stop when&nbsp;Wolbachia&nbsp;introgression reaches 50-60%, allowing it to continue to naturally progress to a higher prevalence. Proposing this as an alternative to current practice is wrong as it is already how it is done.<\/i>  \n<b>4a. <\/b>The aim of this sentence is to indicate an alternative use case where Wolbachia is released in a checkerboard spatial pattern where the current standard release programme is completed in 50-60% of areas and, over time, mosquito movement allows Wolbachia to spread to non-release areas to gradually build up to 90% of areas covered. This is distinct from prevalence within a single area, where we agree that the current practice is to release Wolbachia mosquitoes until population prevalence is ~50-60% then relying on cytoplasmic incompatibility to further increase prevalence to 90% after releases stop. Thank you for highlighting how the previous phrasing may be misleading. We have now edited to clarify how the alternative TPP use case differs from current practice and hope this improves interpretation: \u201cOne alternative use case, considered in the TPP, is to conduct lower intensity releases with larger distances between release sites. This would result in only around 50% of areas initially having a Wolbachia prevalence of over 90%, however over time mosquito diffusion would spread Wolbachia to all remaining areas to ensure all target areas had a Wolbachia prevalence over 90%.\u201d   \n<u>References<\/u> Hu, L., Yang, C., Hui, Y., &amp; Yu, J. (2021). Mosquito Control Based on Pesticides and Endosymbiotic Bacterium Wolbachia. Bulletin of Mathematical Biology, 83(5). https:\/\/doi.org\/10.1007\/s11538-021-00881-9 Joubert, D. A., Walker, T., Carrington, L. B., De Bruyne, J. T., Kien, D. H. T., Hoang, N. L. T., Chau, N. V. V., Iturbe-Ormaetxe, I., Simmons, C. P., &amp; O\u2019Neill, S. L. (2016). Establishment of a Wolbachia Superinfection in Aedes aegypti Mosquitoes as a Potential Approach for Future Resistance Management. PLoS Pathogens, 12(2). https:\/\/doi.org\/10.1371\/journal.ppat.1005434 Qu, Z., Xue, L., &amp; Hyman, J. M. (2018). Modeling the transmission of wolbachia in mosquitoes for controlling mosquito-borne diseases*. SIAM Journal on Applied Mathematics, 78(2), 826\u2013852. https:\/\/doi.org\/10.1137\/17M1130800 Ross, P. A., &amp; Hoffmann, A. A. (2022). Fitness costs of Wolbachia shift in locally-adapted Aedes aegypti mosquitoes. Environmental Microbiology, 24(12), 5749\u20135759. https:\/\/doi.org\/10.1111\/1462-2920.16235 Utarini, A., Indriani, C., Ahmad, R. A., Tantowijoyo, W., Arguni, E., Ansari, M. R., Supriyati, E., Wardana, D. S., Meitika, Y., Ernesia, I., Nurhayati, I., Prabowo, E., Andari, B., Green, B. R., Hodgson, L., Cutcher, Z., Ranc&egrave;s, E., Ryan, P. A., O\u2019Neill, S. L., \u2026 Simmons, C. P. (2021). Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue. New England Journal of Medicine, 384(23), 2177\u20132186. https:\/\/doi.org\/10.1056\/nejmoa2030243 World Health Organisation. (2022). TPP Wolbachia Aedes aegypti population replacement. https:\/\/cdn.who.int\/media\/docs\/default-source\/ntds\/vector-ecology-mangement\/tpp-wolbachia-infected-aedes-aegypti-population-replacement-intervention.pdf?sfvrsn=5296c1dc_3 Yakob, L., Alphey, L., &amp; Bonsall, M. B. (2008). Aedes aegypti control: The concomitant role of competition, space and transgenic technologies. Journal of Applied Ecology, 45(4), 1258\u20131265. https:\/\/doi.org\/10.1111\/j.1365-2664.2008.01498.x","URL":"https:\/\/gatesopenresearch.org\/articles\/7-68\/v3#referee-comment-3736","order":4,"name":"referee-comment-3736","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/gatesopenres.17127.r37731, Asha Mary Abraham, Christian Medical College, Vellore, 30 Sep 2024, version 2, 3 approved with reservations, 1 not approved","URL":"https:\/\/gatesopenresearch.org\/articles\/7-68\/v2#referee-response-37731","order":5,"name":"referee-response-37731","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Katie Tiley<\/b>; \n<i>Posted: 14 Oct 2024<\/i>; Thank you for reviewing this manuscript, we have addressed each of your comments.  \n<b><i>1.<\/i><\/b>\n<i> The economic model: the comment that cost savings from the hybrid programmes offer savings over replacement alone programmes is misleading since the cost of the additional suppressive methods has to be included in addition to replacement.<\/i> \n<b>Response:<\/b> In response to another reviewer\u2019s suggestion, the manuscript has now been edited throughout to remove statements indicating that a combined suppress and then release programme presents cost savings.  \n<b><i>2. <\/i><\/b>\n<i>For large developing countries like&nbsp;India, even the lowest cost per person protected&nbsp;in the predicted range works out to an enormous sum across the large population. It may actually prove more cost-effective to evaluate newer vaccines for dengue (with more specific neutralising antibody production and hence, less ADE activity) as has currently begun.<\/i> \n<b>Response:<\/b> We agree that total programme costs can appear large when scaled up over populous countries. For clarity, our approach does not project scaling up \n<i>Wolbachia <\/i>to cover every area in India or elsewhere, but instead targets \n<i>Wolbachia<\/i> to a subset of high burden areas, which can help to decrease costs. We do acknowledge, however, that other methods of dengue control will likely be important in reaching the WHO 2030 goals, including vaccines, particularly in areas where \n<i>Wolbachia<\/i> implementation may be challenging or less cost effective. We have edited the discussion to clarify this: \u201cIn practice, commercial considerations\u2026will limit the rate of uptake and the ultimate scale of deployment achieved. In areas where \n<i>Wolbachia<\/i> implementation may be challenging or less cost effective, other methods of dengue control, including vaccines, will likely be important in reaching the WHO 2030 goals.\u201d  \n<b><i>3.<\/i><\/b>\n<i> Regarding the environmental model, can weather data from Rio de Janeiro be applicable to other countries in the tropics?<\/i> \n<b>Response:&nbsp;<\/b>While the economic modelling components of our analysis were geographically explicit, the mosquito population dynamics model was intended to represent a more generalisable dengue-endemic setting with distinct wet and dry seasons that drive mosquito population dynamics. Rio de Janeiro has a typical meteorological profile of a dengue-endemic region with distinct wet and dry seasons. Basing our generic model on this typical seasonal profile allowed us to explore the effects of distinct seasonal changes on \n<i>Wolbachia<\/i> release ratio and other hybrid scenarios. The results of this analysis are now found in Supplementary Figure 7.  We hope you now find this manuscript acceptable for publication.","URL":"https:\/\/gatesopenresearch.org\/articles\/7-68\/v3#referee-comment-3735","order":6,"name":"referee-comment-3735","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Bill & Melinda Gates Foundation [OPP1183567] and UK Medical Research Council Career Development Award [MR\/V031112\/1] assigned to OJB.\nBiotechnology & Biological Sciences Research Council [BB\/T008709\/1] assigned to KT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":7,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}