Eleventh meeting of the WHO Vector Control Advisory Group: meeting report, Geneva, 11-13 November 2019

Eleventh meeting of the WHO Vector Control Advisory Group MEETING REPORT Geneva, 11–13 November 2019

Eleventh meeting of the WHO Vector Control Advisory Group MEETING REPORT Geneva, 11–13 November 2019 Eleventh meeting of the WHO Vector Control Advisory Group ISBN 978-92-4-000075-9 (electronic version) ISBN 978-92-4-000076-6 (print version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Eleventh meeting of the WHO Vector Control Advisory Group. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third- party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. This publication contains the report of the WHO Vector Control Advisory Group and does not necessarily represent the decisions or policies of WHO. iiiEleventh meeting of the WHO Vector Control Advisory Group CONTENTS Background 1 Open session 1 Opening remarks 1 Outcomes of the WHO Strategic Advisory Group on Malaria Eradication 2 Updates: summary of discussions 2 Open discussion on VCAG processes 5 Closed session 5 Endectocides 5 Piperonyl butoxide-impregnated net study in Uganda: review of statistical analysis plan 9 Spatial repellents 10 Lethal house lures 13 Wolbachia suppression 16 Prequalification evaluation of vector control products 19 New interventions pathway – categorization and terminology 19 Aedes-specific interventions: evidence requirements in the context of integrated vector management 20 Group discussion: VCAG operations, processes, feedback 20 References 21 Annex 1. Agenda 24 Annex 2. List of participants 26 Annex 3. Declarations of interest 28

1Eleventh meeting of the WHO Vector Control Advisory Group BACKGROUND The WHO Vector Control Advisory Group (VCAG) serves as an advisory body to WHO on new tools, technologies and approaches – collectively referred to as “interventions” – for the control of vectors of malaria, dengue and other vector-borne diseases. VCAG is managed by the WHO Global Malaria Programme (GMP), the WHO department of Control of Neglected Tropical Diseases (NTD) and the WHO Prequalification Team for vector control products (PQT-VC). The specific functions of VCAG are: • to provide guidance to product developers, innovators and researchers on the generation of epidemiological data and study designs to enable assessment of the public health value of new vector control interventions; • to assess the public health value of new vector interventions submitted to WHO; and • to provide advice to WHO, for submission to the Malaria Policy Advisory Committee (MPAC) and the Strategic and Technical Advisory Group for neglected tropical diseases (STAG), on the public health value of new interventions. VCAG experts, innovators (referred to as “applicants”) and other stakeholders met in Geneva on 11–13 November 2019 for the 11th VCAG meeting. The agenda is reproduced in Annex 1. Ten VCAG members were joined by five temporary advisors and a prequalification assessor. The open session was attended by the VCAG (including temporary advisors), applicants and product developers, WHO staff from GMP, NTD and PQT-VC and other stakeholders, including representatives of donor and procurement agencies. A WebEx link was provided for participants who participated in the open session remotely. The closed meeting was attended only by VCAG members, temporary advisors, WHO Secretariat and relevant parties. The participants are listed in Annex 2. OPEN SESSION The declarations of interest of participants were reviewed by the WHO Secretariat, in accordance with WHO policy and procedures, and relevant interests were disclosed. The declarations are presented in Annex 3. Opening remarks Dr Pedro Alonso, Director, GMP, thanked the experts for devoting their time and knowledge to support WHO with the assessment of public health value of novel vector control interventions. He noted that the fight against malaria continues to be challenging, with insecticide resistance being one of several key challenges. Within this context there is a need for continued research on and development of new interventions for vector control. Dr Mwele Malecela, Director, NTD, welcomed and thanked the VCAG members for their contributions to public health. She updated the group on the NTD Roadmap, 2021–2030. The roadmap, in which effective vector control plays a vital role, sets ambitious but realistic global targets to tackle 20 NTDs by 2030. She also noted that the fight against vector-borne diseases must be integrated in terms of both interventions and sectors. 2 Eleventh meeting of the WHO Vector Control Advisory Group In that context, she highlighted the importance of partnership among the three WHO departments involved (GMP, NTD and PQT) to meet the goal of saving lives through vector control measures. Emer Cooke, Director, Regulation of Medicines and other Health Technologies, observed that it is an exciting time to be working in vector control. WHO’s Prequalification department has many years of experience in the regulation of health products. This experience as well as the now established evaluation process for vector control products, will be important in meeting the challenge of providing access to new and innovative vector control interventions, such as genetically modified mosquitoes. The prequalification system is adapting to meet such submissions, with the aim to help and not hinder access to these innovations. Outcomes of the WHO Strategic Advisory Group on Malaria Eradication Dr Pedro Alonso presented on the outcomes of the Strategic Advisory Group on Malaria Eradication, which was formed in 2016 to advise WHO on future scenarios for malaria, including whether eradication is feasible. The Group, composed of scientists and public health experts from around the world, conducted a 3-year study of trends and projections of the factors and determinants that underpin malaria. They affirmed that eradication is a goal worth pursuing, as it is likely to save millions of lives and billions of dollars. It noted, however, that with the currently available tools, we are far from a malaria-free world. The Group called for more investment in research and development of new tools and approaches to fight malaria, stronger universal health coverage to ensure that everyone can access the services they need, stronger community engagement and better surveillance linked to subnational, national and regional strategies for a more targeted malaria response (1). Updates: summary of discussions Anna Bowman, VCAG Project Manager, started her presentation by contextualizing the work of VCAG. She noted that WHO’s legitimacy and technical authority lie in its rigorous adherence to systematic use of evidence as the basis for all policy (2). In this context, VCAG plays an important role in both supporting the generation of evidence and reviewing it. It was noted that VCAG’s core function, to assess the public health value of new vector control interventions, has remained the same since its inception; however, the scope of the group’s work has changed. VCAG’s Terms of Reference have been updated to focus its role on supporting the generation of epidemiological evidence. It is no longer within the remit of VCAG to provide guidance on economic feasibility, efficacy, and user acceptability, for example; this is now considered by respective disease departments. Ms Bowman, shared the results from the implementation of the VCAG Improvement Plan. The Improvement Plan was developed in 2018, drawing on feedback from an independent assessment by the Boston Consulting Group, funded by the Bill & Melinda Gates Foundation. The Improvement Plan was presented to VCAG during the open session of its 8th meeting. Key achievements of implementing this plan include: • The roles and responsibilities of the departments involved in the vector control evaluation process have been defined. • VCAG Terms of References have been updated to clarify the role of VCAG and how this relates to the work of the prequalification team. 3Eleventh meeting of the WHO Vector Control Advisory Group • Standard operating procedures have been developed to clarify VCAG processes. • The expertise in VCAG has been diversified to include experts in gene drive, regulatory processes and product development. • Feedback loops have been established to provide VCAG members, applicants and other stakeholders means to provide feedback on the functioning of VCAG to the WHO Secretariat, including during sessions of VCAG meetings. • Off-cycle reviews have been introduced to improve the timeliness of feedback. • Communications have been improved through a new VCAG website, regular updates on VCAG provided through the vector control mailing list, provision of WebEx during open sessions of VCAG meetings for virtual participation, and greater transparency, with regular updating of a list of interventions under VCAG review (4). Since the meeting in May 2019, further improvements have been made, including the development of an information sheet, with input from applicants, on the interventions under VCAG review (5). Pre-meeting calls between working group members were organized to ensure that all the experts had the necessary background information. Finally, a teleconference was organized with new VCAG members and experts to provide an in-depth introduction to VCAG. In terms of next steps in the evolution of VCAG, there are plans to update and harmonize current documents on the evaluation of vector control interventions (“The evaluation process for vector control products” (6) and “How to design of vector control efficacy trials” (7)) and to align them with the revised GMP policy-making process (8). It is presently planned to achieve this through the release of a document on the norms and standards underpinning vector control policy making. Currently, there are 16 intervention classes under VCAG review (9). Epidemiological trials are planned or are under way for 12 out of 16 intervention classes. Marion Law, Group Lead, PQT-VC, summarized the activities of PQT-VC to support assessment of safe, efficacious and high-quality vector control products. Two assessor sessions were held in 2019 (in Dakar, Senegal, and Hanoi, Viet Nam), which included reviews of submissions, labels and protocols as requested. During the meeting in Dakar, the assessors also contributed to development of a regulatory framework for gene drive vector control products, started work on a safety review of DDT, as requested by the GMP, and reviewed data requirements and testing methods. They also had a field trip to testing facilities for indoor residual spray products in Senegal. The assessors session in Hanoi reviewed a number of new submissions for prequalification of various product types, including insecticide treated nets (ITNs), indoor residual sprays and larvicides. Change submissions and protocol reviews were also evaluated. In addition to the evaluation of submissions, work continued on a number of operational policies, re-evaluation of specific older chemistries and the regulatory framework for gene drive mosquitoes. The session also included a visit to a ITN manufacturing facility. During the same week, PQT-VC participated in a regulatory workshop for countries in the Asia–Pacific region. The 16th FAO/WHO Joint Meeting on Pesticide Specifications (JMPS) was held in June 2019, at which 19 WHO specifications were evaluated and adopted. Several issues related to the specifications for LLINs were reviewed and approved, and the manual will be revised accordingly. The JMPS work plan for 2020 has been initiated, and 25 submissions have been received. 4 Eleventh meeting of the WHO Vector Control Advisory Group Prequalification inspectors have completed all initial inspections of facilities for the manufacture of ITN. A number of follow-up inspections have also been completed, with more scheduled. With the completion of these inspections, the focus will now be on facilities for the manufacture of other types of vector control products, such as indoor residual spray. Dr Jan Kolaczinski, Coordinator, GMP Entomology and Vector Control, informed participants about the invasion and spread of Anopheles stephensi into East Africa and the WHO response. An. stephensi, a highly competent vector of Plasmodium falciparum and P. vivax, is an efficient vector of urban malaria in some parts of the world. Until 2011, its reported distribution was confined to certain countries in South-East Asia and large parts of the Arabian Peninsula. The vector has since been reported in Djibouti (2012), Ethiopia (2016), Sri Lanka (2017) and most recently from the Republic of the Sudan (2019). WHO considers the spread of An. stephensi to be a major potential threat to malaria control and elimination in Africa and southern Asia. In response to this threat WHO developed a ‘Vector Alert’ that was posted online in August 2019 to urge WHO Member States and their implementing partners in and around the Horn of Africa, Sudan and surrounding areas, and Sri Lanka to take immediate action (10). WHO has also prepared a data reporting sheet and has updated the Malaria Threats Map to illustrate current and new reports of An. stephensi distribution / invasion (allowing flexibility to incorporate other invasive anopheline species) (11). Assessment of new vector control interventions, including genetically modified mosquitoes, will be important in finding ways to control An. stephensi and to eliminate it from recently invaded areas. Dr Raman Velayudhan, Coordinator, NTD Vector Ecology and Management, briefed the open session on the NTD Roadmap and the Global Strategy for Dengue Prevention and Control 2021–2030. The Roadmap is a high-level strategy that sets the direction for the fight against NTDs, serves as an aid to policy and advocacy and will align the work of stakeholders over the next decade. The roadmap was developed through consultation and feedback from countries, donors, partners and experts. The aim of the Global Strategy for Dengue Prevention and Control 2021–2030, to be published in 2020, is to reduce the global burden of dengue, with the following draft objectives: • to build capacity in countries to detect, prevent and respond to dengue outbreaks; • to reduce preventable dengue deaths to zero; and • to reduce the burden of disease in countries and reduce incidence by 25% (12). The technical elements of the Global Strategy remain largely unchanged from the previous one (13). The foundations of the Strategy are capacity-building and programme management, advocacy among all stakeholders and strong political commitment, including legislative support and basic and applied research. Dr Rajpal Yadav, NTD Vector Ecology and Management, described the interim results of a WHO multi-centre laboratory study to develop test protocols and determine discriminating concentrations of insecticides for monitoring resistance in Anopheles and Aedes spp. mosquitoes. The test protocols are being updated because there is a lack of validated insecticide discriminating concentrations of older compounds for Anopheles, Aedes and Culex spp., in addition to gaps for compounds in new classes. There are also a lack of adequate protocols for testing resistance to compounds with new modes of action (e.g. clothianidin and chlorfenapyr). A follow-up expert consultation will be held in 2020, after which the updated discriminating concentrations of insecticides for monitoring resistance in Anopheles and Aedes spp. mosquitoes will be published by WHO. 5Eleventh meeting of the WHO Vector Control Advisory Group Open discussion on VCAG processes Salim Abdulla, VCAG co-chair, led an open discussion on VCAG processes. The following points were raised: • It was highlighted that applicants could propose topics or questions for discussion during the open session. For example, topics could include aspects of study design and/or sharing of lessons learnt from developing and implementing epidemiological trials. • It was noted by an applicant that VCAG no longer ascribes a “step” to describe what stage an intervention is in the WHO Evaluation Process for new vector control tools. Now, the status of products is described in narrative form using language consistent with data generation in other scientific fields. • Applicants welcomed the availability of WebEx during open sessions and noted that off-cycle reviews are a valuable addition. One applicant asked whether VCAG feedback could be communicated formally to applicants before the meeting report was published. The WHO Secretariat noted that the timeline for publication of the meeting report has been significantly shortened and that no other formal communication of VCAG deliberations is foreseen. The published meeting report will continue to serve as the source of formal feedback from VCAG. CLOSED SESSION Endectocides Background The objective of the “broad one health endectocide-based malaria intervention in Africa” (BOHEMIA) project is to determine the efficacy of ivermectin given by mass drug administration to humans and to humans plus livestock to reduce residual transmission of malaria. The rationale is that mosquito blood meals containing a sufficiently high concentration of ivermectin increase mosquito mortality and may also have additional sublethal effects that impact vector populations (e.g. reductions in mosquito fertility and fecundity). The project is testing this strategy in Mozambique and the United Republic of Tanzania. The target livestock species is pigs in Mozambique and cattle in the United Republic of Tanzania. Trials are planned for 2021–2022, with final results anticipated for 2023. Updates At this meeting, the applicants submitted a point-by-point response to feedback provided by VCAG at 10th meeting (May 2019) and a draft efficacy and safety protocol (v0.7) for planned epidemiological trials. The BOHEMIA project consists of a combination of studies organized around a central community prevention drug trial and four sub-studies (social science, entomology, health economics and animal health, and environmental impact), each of which will have a protocol. In addition to the main efficacy and safety protocol, the applicants submitted the following appendices: • summary of trials and other studies to support the proposed human oral ivermectin dose of 400 µg/kg; • a report on modelling the impact of ivermectin mass drug administration on malaria incidence and prevalence; 6 Eleventh meeting of the WHO Vector Control Advisory Group • a summary of evidence for the potential impact of ivermectin on resistance in other (non-malarial) human parasites; • justification of the target whole blood concentration of ivermectin proposed for the trials, which is based on previous studies in An. arabiensis and An. gambiae; • a summary of studies of the pharmacokinetics of ivermectin in pigs and cattle, with emphasis on the duration for which concentrations remain above the target whole blood concentration; and • a draft community engagement plan for each site. The applicants provided additional points of clarification following the meeting that addressed: 1) the duration of the human + livestock arm; 2) the extent to which migratory cattle are incorporated into the livestock coverage estimate; 3) synthesis of livestock ivermectin pharmacokinetic studies; and 4) the blood matrix (whole blood or plasma) used to set the target ivermectin dose for humans and livestock. In the updated protocol, two arms (groups of clusters) will be randomized in year 1 to receive (a) ivermectin in humans or (b) control (i.e. albendazole), and all areas will be subject to enhanced passive surveillance for malaria. In year 2, the above-mentioned interventions will continue, and a third arm will be introduced consisting of ivermectin in humans and livestock (see Fig. 1). Fig. 1. Treatment arms in the BOHEMIA project in Mozambique and the United Republic of Tanzania Year Arm A Arm B Arm C 1 Ivermectin to humans Control (albendazole) 2 Ivermectin to humans Control (albendazole) Ivermectin to humans + livestock Summary of discussions The applicant indicated that the epidemiological trial protocol is still under development and that they are seeking further feedback from VCAG to finalize it before submission for ethics approval. VCAG noted that most of the points raised about the trial design at previous meeting had been largely addressed in the updated submission (v0.7), and that the trial design is now more orthodox. The following points were discussed and/or clarified following the meeting: • The applicants clarified that, in terms of WHO preferred product characteristics for endectocides (14), their efficacy end-point was “minimally acceptable” rather than “desired”. • The applicants made a case for use of an active control drug, which has a deworming effect similar to ivermectin. • The applicants clarified the dosing regimes, indicating they will use 1 × 400 µg/kg monthly for 3 months. • The statistical power of the trial was estimated under scenarios in which parameters such as incidence are affected by drought, flooding, conflict, withdrawal of consent and a lower-than-expected effect of ivermectin. It was noted that in terms of follow-up, a duration of only 6 months, as stated in version 7Eleventh meeting of the WHO Vector Control Advisory Group 0.7 of the protocol, is assumed in the power analysis even though the total follow-up will be 6 months in each of 2 years. This is because of the intent to power the study to make comparisons within each study year. • The applicants confirmed they are confident of being able to source ivermectin of the necessary quality and safety for the trial. • The applicants clarified the overall approach and analyses to support the proposed ivermectin dosimetry for humans and livestock. They also clarified that they intend to use whole blood for their analyses of ivermectin pharmacokinetics, as this best represents the exposure matrix for the mosquitoes. The applicant also clarified that they are assuming that whole-blood concentrations are approximately 70% of corresponding plasma concentrations. • VCAG noted that the revised study design for the human intervention ensures an assessment that covers at least 2 years. On the other hand, the combined human and livestock intervention is 1 year and would not meet the current VCAG recommendation for a 2-year trial duration. The applicants explained that a) they are allowing an additional year of preparation for the combined human–livestock intervention, which is more complex, and b) each year of the intervention is powered separately. VCAG noted that data gained from the evaluation of use of ivermectin in humans and livestock over 1 year may provide useful baseline data for continuing studies. • The applicant clarified that the possibility of migratory cattle in the study area was incorporated in their planning for the Tanzanian trial, as reflected by the estimate that 60–70% of cattle would be covered in the study design. • VCAG noted the plans for interim analysis in the current protocol and encouraged the applicants to refer to VCAG’s guidance on “Conditions for early terminations of trials” in the report of the 8th meeting (15). Conclusions Overall, the supporting documentation, including a letter of clarification following the meeting, and discussions with the applicants constituted well-substantiated responses to the points raised by VCAG at its 10th meeting. • VCAG noted that the method for the sample size calculation is explained in detail in the protocol and is suitable. In terms of the parameters used in this analysis, the stated value of the between-cluster coefficient of variation is backed up by existing data from one site. VCAG noted that the applicants made a strong case for why the stated effect size of 20% is realistic. • VCAG concluded that the applicants had clarified and enhanced their synthesis and interpretation of mosquito toxicity data, and human and livestock pharmacokinetics studies to support the preparation of their protocol. The materials and references provided to VCAG clarify how the target plasma and whole blood concentrations for both humans and livestock were derived, as well as pharmacokinetic/dynamic analyses to support the selection of dosing regimens for humans (400 µg/kg orally once per month for 3 months) and livestock (200 µg/kg by injection once per month for 3 months). • VCAG noted that, at its 10th meeting (May 2019), the applicants referred to a study of ivermectin pharmacokinetics in zebu Gobra (Bos indicus), a West African cattle breed, as support for the proposed livestock dosing regimen; however, they provided no supporting documentation for similar kinetics in cattle breeds in eastern and southern Africa. Ndong et al. (16) reported that physiological differences among breeds may influence the pharmacokinetics of ivermectin. In the report of the 10th VCAG meeting, the applicants referenced pharmacokinetics 8 Eleventh meeting of the WHO Vector Control Advisory Group in swine, but the data were not provided. In the documents submitted for the 11th VCAG meeting, additional pharmacokinetics data for cattle (e.g. Holstein and Belgian blue) and swine were provided. Although these data were not quantitatively integrated to evaluate the extent to which the 200 µg/kg dosing regime is broadly applicable to a variety of cattle breeds and swine, the dose appears reasonable based on a qualitative comparison of the pharmacokinetics studies. • As noted in the 10th VCAG meeting report, caution is warranted in the use of albendazole in the control arm of the study until its impact on the target vector species is known. Although this drug is not anticipated to impact vector survival, the applicants are acting on a recommendation of the 10th VCAG meeting to test this hypothesis. • VCAG welcomed the outline of the community engagement plan, which provides a good foundation for specific steps in community engagement. Recommendations • Future versions of the epidemiological trial protocol should include the rationale for conducting the combined human–livestock intervention for only 1 year. • As mentioned above, the sample size at each site was calculated in version 0.7 of the protocol for each year separately, based on 6 months’ follow-up, for 80% power. The primary analysis should be over the whole duration of the study (2 years). The expected power – which will be more than 80% – for this analysis should be calculated and stated for the current sample size (without changing the current design of two 6-month periods). Also, although one of the existing scenarios (flooding) involves changing the coefficient of variation, the incidence also changes at the same time under this scenario. Hence, it would be worthwhile to include scenarios in which only the coefficient of variation changes. Also, it would be worthwhile to include scenarios that include dilution of the main comparison due to any effect of albendazole on mosquitoes. • The description of the statistical analysis in the protocol should be more specific, e.g. in terms of what method will be used for the primary analysis and what, if any, variables are to be adjusted for. In due course, a separate and more detailed statistical analysis plan (SAP) should be developed and submitted to VCAG. For the previous point, it should also be clarified that the main analysis will be of the complete 2-year period. • In the protocol, the applicants should clarify whether the project covers one trial or two (protocol V0.7 is not consistent in this regard). • The protocol would benefit from a clearer and more specific case definition. For example, two different rapid diagnostic tests will be used, and the applicant should explain how the case definition depends on different possible combinations of results. • The protocol should specify how the secondary ectoparasite end-points will be assessed, particularly the specimens to be collected and timing, including any baseline. • The protocol should clarify that ivermectin concentrations in whole blood are being used in the pharmacokinetics analyses and that this matrix is used to set the human and livestock doses. It should also be clarified that it was assumed that whole-blood concentrations represent approximately 70% of plasma concentrations to facilitate extrapolation of supporting study results based on plasma or whole blood concentrations. 9Eleventh meeting of the WHO Vector Control Advisory Group Piperonyl butoxide-impregnated net study in Uganda: review of statistical analysis plan Background At the 9th VCAG meeting, Dr Samuel Gonahasa, Infectious Diseases Research Collaboration, and Professor Janet Hemingway, Liverpool School of Tropical Medicine, presented a cluster randomized trial being conducted to measure the impact of ITNs with and without piperonyl butoxide (PBO) on malaria indicators in Uganda (17). The aim of the study is to determine whether parasite prevalence is lower in intervention clusters (health sub-districts randomized to receive PBO nets) than in control clusters (those randomized to conventional nets) in eastern and western Uganda. The study was expected to be conducted from January 2017 to December 2019. The study includes 104 health sub-districts or clusters in 48 districts. The primary objective is to evaluate the impact of combination ITNs with PBO (Permanet 3.0, Olyset Plus) as compared to ITNs without PBO (Permanet 2.0, Olyset Net) on parasite prevalence. The primary outcome is prevalence of asexual parasitaemia in children aged 2–10 years measured by microscopy (thick blood smears) at baseline and 6, 12, 18 and 25 months after distribution. The secondary outcomes relate to prevalence of moderate/severe anemia in children < 5 years, ITN coverage (ownership, adequate coverage, use), and indoor-resting vector density at baseline and at 6, 12, 18 and 25 months. ITN assessment (integrity, insecticide content, bio-efficacy) will be done at 12 and 25 months. Nets were distributed between March 2017 and March 2018. The community survey includes an average of two children per household, for an estimated total of 10 400 children (50 households in the 104 clusters in each round of surveys), which would allow detection “of a maximum parasite prevalence of 33% in the intervention arm, assuming parasite prevalence in the control arm of 40%” (18). Update In accordance with VCAG’s request to review the analytical protocol and SAP at its 9th meeting, the applicant provided a SAP before the 11th meeting. The applicants were unable to attend the 11th meeting, and this report serves to convey the results of VCAG’s review of the SAP to the applicant. Analyses for the primary (parasite prevalence) and secondary outcomes will be conducted using both a per protocol (the primary approach) and intention-to-treat. For the per protocol analysis, clusters will be analysed according to the nets actually distributed in a target area and received by the target groups based on data from the 6-month follow-up survey. A cut-off for dominant net within a target area of > 75% for the four net types included in the study will be applied to include clusters in the analysis. For the intention-to-treat analysis, clusters will be analysed according to the nets allocated to specific target areas, without accounting for the fact that the specific net type may not have been received by the intended beneficiaries. Conclusions • VCAG notes that the SAP is well designed, robust and appropriate to demonstrate the objective of a 17% reduction in parasite prevalence in clusters with PBO nets as compared with clusters with standard nets without PBO. • As recommended at the 9th VCAG meeting, the applicants have published the SAP and trial design (19). • VCAG would welcome a presentation of the study results by the applicants at a future meeting once the trial is completed and data have been analysed. This step will be essential for WHO to consider revision of the conditional policy recommendation for pyrethroid–PBO nets issued in 2017 (20). 10 Eleventh meeting of the WHO Vector Control Advisory Group • VCAG noted inconsistency in the timing of the planned data analyses. In section 1.4 of the SAP, the “document details the planned analyses for the randomized comparison of the study arms (PBO vs non-PBO) for the PBO trial, including the 6, 12, and 18-month follow-up surveys, and the net bioefficacy assessment planned for the 12-month timepoint”. While, in section 3.1, the SAP states “The evaluation includes cross-sectional community surveys (at baseline, 6, 12, 18 and 25 months after distribution), entomological surveillance, and assessment of net bio-efficacy at 12 and 25 months”. Recommendations • VCAG recommends that the inconsistencies noted in the SAP be clarified. VCAG recommends that the analysis should include the 25-month end-points, as this aligns with VCAG’s general recommendation that interventions should be tested over 2 consecutive years. • Considering the statistical methods, the applicants propose to conduct both per- protocol and intention-to-treat analysis. Since it is not general practice to make the per-protocol analysis to be the primary one, VCAG recommends that this approach be further justified when the results are reported. Spatial repellents Background Spatial repellents are designed to interrupt human–vector contact through vector behaviour modification induced by airborne chemicals, potentially offering protection from the bites of vectors and nuisance pests. The spatial repellent intervention proposed is a transfluthrin-based passive emanator produced by SC Johnson. It is designed to release the volatile pyrethroid into the air and prevent human–vector contact in the treated space. The intervention targets Anopheles, Aedes and Culex spp. mosquitoes, with claims to protect all age groups and populations in countries endemic for mosquito-borne diseases from daytime, early-evening or late-night biting by mosquitoes in enclosed and semi-enclosed structures. Deployment of the spatial repellent product in enclosed and semi-enclosed spaces is intended to reduce human pathogen transmission. Epidemiological trials have been completed on Sumba Island, Indonesia, and in Iquitos, Peru, to generate data to allow VCAG’s assessment of the product’s public health value against infection with malaria and Aedes-borne viruses, respectively. At the 10th VCAG meeting the applicant had shared results from the Indonesian trial (21). Updates Before the 11th meeting, the applicants submitted a study protocol for a planned trial in Mali and an accompanying SAP for VCAG’s review. In addition, they provided updates on the status of the analysis of the Peru trial results, a preprint describing the results of the trial in Indonesia presented at the 10th VCAG meeting and updates on the planned trials in Kenya and Sri Lanka. Summary of discussion VCAG recognizes that good progress has been made, including efforts to get the results of the Indonesia trial published. Furthermore, the applicant provided an update on the status of the analysis of results from the Peru trial, for which laboratory sample processing for Zika virus is ongoing. The applicants confirmed that an updated protocol for a study in Sri Lanka and the accompanying SAP will be submitted in May 2020 after analysis of the primary results of the randomized controlled trial (RCT) in Peru. The analysis will allow additional refinements of the protocol for the trial in Sri Lanka based on outcomes obtained in Peru. 11Eleventh meeting of the WHO Vector Control Advisory Group The applicants updated VCAG about preparations for the trial in Kenya. Members of the Data and Safety Monitoring Board have been identified, ethical approval has been acquired, regulatory assurance reviews are under way, shipment of the product is planned, villages have been mapped and geocoded, and clusters have been delineated. The trial is planned to start in February 2020. The study protocol for the trial in Mali was shared with VCAG and discussed. The primary objective of the study is to evaluate the protective efficacy of spatial repellent against the first-time malaria infection. It will evaluate the epidemiological impact of spatial repellents in a single cohort (aged 6 months to 15 years). It is planned to be a 24-month trial with 60 clusters (30 clusters per arm). The two arms will receive spatial repellents or placebo. Baseline data will be collected for 6 months before the study. For evaluation of the primary objective, 23 households (assuming 35% loss to follow-up) will have bi-weekly malaria check-ups (scheduled and passive). It was noted that the product is a pyrethroid, to which there is widespread resistance in Mali. The applicant confirmed that entomological studies have been conducted that demonstrate that even in places with pyrethroid resistance, spatial repellents have been observed to have a repellency effect on mosquitoes (22). VCAG noted that there is a relatively low use of ITNs in the proposed trial site. Ideally, high coverage of ITNs would be established in all clusters throughout the trial period, including at baseline, to reduce the risk of an imbalance in background interventions between study arms that could affect the outcomes of the evaluation. If this is not possible, care should be taken to balance background intervention coverage between the treatment arms. The protocol for the study in Mali does not include a formal assessment of diversion, unlike the Kenya trial. However, the infrastructure, including mapping of the whole study area and use of health facilities to obtain information, nevertheless offers an opportunity to explore indication of any major diversionary effects outside the intervention clusters. Conclusions • VCAG commends the applicants for continued good progress in the development of the spatial repellent products. • VCAG considers that the proposed site for the RCT in Mali satisfies the requirements for a sufficiently diverse geographical site for a second trial in Africa. • The protocol and SAP for the trial in Mali are endorsed conditionally, subject to corrections provided in the recommendation below. • VCAG clarified that the social science component of the proposed trials in Kenya and Mali is beyond their mandate to review, but VCAG would appreciate being informed of the results of this work. It will provide context for interpretation of the epidemiological and entomological results. Recommendations VCAG strongly supports the continuing evaluation of spatial repellents against Aedes- (Sri Lanka) and Anopheles-transmitted diseases (Kenya and Mali). VCAG also encourages timely implementation of the proposed trial in Sri Lanka, which will be of great value for consolidating the evidence base for policy formulation. 12 Eleventh meeting of the WHO Vector Control Advisory Group VCAG requests that the following changes be made to the protocol and SAP of the trial in Mali and that the revised documents containing the major changes are shared with VCAG. For the protocol, the major recommended changes are as follows. • Provide a clear definition of clusters: Villages are mentioned as the unit of randomization, but there is no description of how many villages there are, or the number and distribution of compounds among households within the villages. • Explain the distribution of villages relative to health facilities, which will serve as the primary points of data collection. Clarify the plan of stratification or matching for cluster randomization in the final protocol. • The protocol indicates that insecticide resistance will be measured by bioassays for permethrin. VCAG recommends also incorporating bioassays using transfluthrin as this is the active ingredient used in the spatial repellent product. Minor points for clarification or correction that do not require further review by VCAG, are as follows. • Clarify the main modality of data collection to be used in the field and in health facilities, i.e. paper-based or electronic devices (phones and tablets). • Provide specific information on the environmental covariates to be collected alongside the entomological and epidemiological sampling. For the SAP, the major recommended changes are as follows. • The proposed statistical model for the primary analysis (section 7.1) is complicated and the description difficult to follow. VCAG recommends that the investigators review the SAP to ensure that the description is clear and that there is a clear rationale for the various covariate adjustments. Detailed comments follow. • VCAG is concerned that the model for the primary analysis, which includes both cluster-level random effects and cluster-level covariates, seems likely to face issues with collinearities between parameters and consequent identifiability. No rationale is given for including cluster-level covariates (e.g. population size). • Calendar time appears to be taken into account in the model for primary efficacy only by its effect on the baseline hazard (i.e. on the hazard that applies at reference levels of the covariates). There should be a description of how the temporal pattern of incidence and of intervention effects will be explored, particularly as use of time-to-first infection as the primary outcome may mean that there is little time-at-risk in the second year of the study. • In section 6 on recurrent detection of infections over short time intervals, it is indicated that “the positive diagnoses that cannot be treated as new infections should not be recoded as negative”. The investigators should confirm that their procedure adheres to the basic principle that any observations for which there is no possibility of a new infection should be excluded from the time-at-risk and hence from both numerators and denominators. • There is insufficient detail to understand the proposed supplementary analysis of human biting rates (e.g. how this is “adjusted” for when people are outdoors or when using an ITN). 13Eleventh meeting of the WHO Vector Control Advisory Group • The SAP indicates that associations between malaria hazard rate and all the entomological outcomes will be explored in a model that also includes a covariate for “intervention”. If the aim is to predict epidemiological parameters from entomological parameters, the intervention effect should not be included in the model, as there should be co-linearity between the intervention and the entomological effects. Minor points for clarification or corrections which don’t need further review by VCAG are as follows. • It is unclear whether a separate analysis will be performed for each Anopheles species, and it is not clear how many species are present in the study area. The objectives appear to imply that the analysis will be for all Anophelines combined. VCAG suggest that separate analyses be conducted for each major vector. • The 6-month baseline data collection should coincide with the start of the malaria transmission season. • Provide necessary definitions (e.g. definition of solicited and non-solicited versus attribution of causality). • Check for consistency between the protocol and the SAP in the number of clusters in the different assessments and which objectives are primary, secondary, exploratory or other. • Compile documentation on other malaria control interventions in the study area, and harmonize the mechanism of data collection, i.e. when spatial repellent devices are retrieved (monthly or at monthly health facility visits). Lethal house lures Background Eave tubes target indoor-biting mosquitoes, specifically Anophelines, that enter houses through the eaves (open areas between the roof and walls) and transmit human malaria parasites. Eave tubes aim to reduce mosquito entry into houses by killing host- seeking mosquitoes and thereby lowering the risk of malaria transmission, if they are deployed at sufficient coverage. Eave tubes are plastic tubes containing a mesh with a static coating that holds powder- formulated insecticides and are intended for installation in the eaves of houses. The tubes funnel the indoor human-scented air outwards, making the house a lethal lure for host-seeking mosquitoes. They have been field tested as a stand-alone tool and in conjunction with household screening, including closure of windows, eaves and other mosquito entry points with the aim to maximize their attraction and efficacy to Anophelines. The efficacy of this combined intervention against clinical episodes of malaria has been evaluated in a randomized controlled trial in Côte d’Ivoire. The 2-year study started in April 2017, and the results were presented at the 11th VCAG meeting. During the 7th VCAG meeting, it had been recommended that a second RCT be conducted in a different geographical setting to assess the public health value of eave tubes, as WHO requires at least two trials with epidemiological end-points to inform the development of a policy recommendation. At the 8th VCAG meeting, the applicants discussed designs for a second RCT. 14 Eleventh meeting of the WHO Vector Control Advisory Group Updates The applicants presented detailed results of their epidemiological trial in Côte d’Ivoire, which showed a substantial impact on malaria of a combined intervention of eave tubes and household screening. The applicants also reported on a recently published semi-field study (23), which indicated that eave tubes alone (no screening) had a substantial impact on entomological outcomes and that treated eave tubes can reduce mosquito entry even when windows remain open which suggests that eave tubes might not need to be combined with household screening to have an impact on malaria transmission. The applicants also reported on another recently published semi-field study that “confirms that a well-screened structure can effectively block mosquito entry, providing personal protection at the household level. The addition of insecticide-treated tubes at eave height turns the house (in this case experimental huts) into a lethal house lure and this additional mortality could contribute to control at the community level assuming high coverage of the intervention” (24). The applicants requested feedback on the planned next steps in conducting a cluster factorial design field trial in the United Republic of Tanzania, with four arms: 1. bednets only 2. eave tubes only 3. household screening only 4. eave tubes and household screening Summary of discussions VCAG commended the applicants on the exemplary trial which showed clear evidence of an epidemiological impact on clinical malaria. In response to specific questions posed by the applicant, VCAG provided the following feedback. Do the Côte d’Ivoire RCT results validate a public health impact (malaria) of eave tubes? VCAG confirmed that the results of the Côte d’Ivoire trial contribute substantially to the evidence base on eave tubes and house screening but leave open the question of how well either of these interventions perform on their own. VCAG reiterates their previous statement that evidence will be required from at least two epidemiological trials before a WHO recommendation for eave tubes as a malaria control intervention can be considered (25). VCAG strongly supports continued evaluation of the potential epidemiological impact of this tool. Once data from at least one additional epidemiological trial are available, WHO will review the available evidence including both epidemiological and entomological results. What are the next steps towards a WHO recommendation? WHO requires results from at least two trials in different geographical settings. As stated in the 8th VCAG meeting report, the second trial should be sufficiently powered to show an epidemiological effect in a different setting to support generalization of the results (25). The applicants provided an outline of a second factorial design RCT trial of eave tubes with and without household screening to be carried out in the United Republic of Tanzania. This builds on the recommendations made by VCAG at its 8th meeting, that a second trial of this intervention in East Africa would meet the requirements for a suitable trial site, providing the malaria prevalence is appropriate (25). The next step 15Eleventh meeting of the WHO Vector Control Advisory Group towards a WHO recommendation is to share a draft of the detailed protocol of the second study for review by VCAG. Can a different insecticide be used on the inserts? VCAG reiterates the statement made in its 8th meeting report that the active ingredient used for the eave tubes insert and the formulation of the netting could be changed for future trials (25). It is recommended that the new inserts be formulated from active ingredients currently used in WHO- recommended (i.e. prequalified) vector control products to ensure that the intrinsic insecticidal properties are known and that technical materials are sourced from WHO- recommended manufacturers with specifications for these materials. Further data supporting the entomological efficacy end-points of any second-generation products should be collected during the proposed trials following WHO guidance. Which nets should be used (standard, PBO or other)? VCAG recommends that net choice be based on the appropriate standard of care for the study area, ensuring that the same net type is used across all arms. Can prevalence be the main outcome, with passive incidence as the secondary outcome? VCAG noted that, as indicated in the report of the 8th VCAG meeting, the greater expense and complexity of measuring incidence provides a strong argument for considering prevalence as the primary outcome, depending on the possibilities for ascertainment of infection and disease (25). If prevalence is used as the primary trial outcome, data should also be collected on incidence of disease by trial arm and on rates of health care-seeking to check if the intervention induces behavioural change. Can results from this trial be sufficient for a recommendation of eave tubes alone (if impact is shown)? VCAG reiterated that two completed trials are the minimum required by VCAG to assess public health value and to make a recommendation to WHO. The design and outcomes of the second trial will likely affect the type and wording of a WHO recommendation. VCAG was asked to comment on calculation of the entomological inoculation rate. VCAG agreed that the assumption that sporozoite positivity is negligible in nulliparous mosquitoes is appropriate. With regard to insecticide resistance, VCAG reiterated the point made at its 8th meeting that data on insecticide resistance in the study setting(s) should be collected according to WHO protocols for resistance monitoring. These data are needed to contribute towards an understanding of the efficacy of eave tubes against resistant mosquitoes in a specific local context. The applicants confirmed that the insecticide resistance monitoring data collected in the Côte d’Ivoire trial will be submitted to VCAG as soon as the analyses have been completed. Conclusions • VCAG confirms that the results of the trial in Côte d’Ivoire contribute substantially to the evidence base on eave tubes and house screening but it leaves open the question of how either of these interventions perform on their own. • VCAG agrees with the investigators that it is important to understand the ways in which eave tubes and household screening interact. The results of the semi-field studies suggest that eave tubes have substantial effects, irrespective of whether the house is screened, however this has not yet been tested in an epidemiological trial. The proposal to carry out a four-arm factorial design trial is an appropriate 16 Eleventh meeting of the WHO Vector Control Advisory Group way of generating convincing evidence on this. An important consideration for the factorial design trial is that it have sufficient power to distinguish whether eave tubes are efficacious irrespective of household screening, or whether their epidemiological effect is conditional on presence of household screening. Recommendations • VCAG recommends continued evaluation of the potential epidemiological impact of this tool and once data from at least one additional epidemiological trial are available, WHO will be able to review the available evidence including both epidemiological and entomological results. Wolbachia suppression Background “Wolbachia suppression” refers generally to an insect control strategy involving the release of insects infected with an intracellular bacterium, Wolbachia spp., that interferes with their reproduction under some conditions. In the case of Ae. aegypti control, the strategy entails releasing laboratory-reared male mosquitoes infected with Wolbachia bacteria into the field. When infected males mate with Ae. aegypti females in the target population that are not infected with Wolbachia, the females lay nonviable eggs, because of a phenomenon known as “cytoplasmic incompatibility”. Repeated releases of Wolbachia-infected male Ae. aegypti at certain frequencies and scales can lead to significant reductions in the target population size. The applicants are proposing to test this intervention in a large-scale epidemiological trial in Puerto Rico. It is hypothesized that release of Wolbachia-infected male Ae. aegypti at the planned trial site will be sufficient to reduce the density of Ae. aegypti adults in target vector populations to a level at which the incidence of human infections and disease caused by dengue, chikungunya and Zika viruses are reduced. The intervention will be considered successful if the incidence of arboviral infection is reduced by 50% in residents of intervention clusters relative to those in control clusters. A trial is being conducted by Communities Organized to Prevent Arboviruses (COPA), a collaboration between the Ponce Health Sciences University, the Puerto Rico Vector Control Unit, the US Centers for Disease Control and Prevention and the citizens of Puerto Rico. The intervention involves the production and release of Wolbachia-infected male Ae. aegypti in intervention clusters and will be implemented by the Debug Project of Verily Life Sciences Inc. Verily Life Sciences Inc. are developing and testing mass- rearing and sex-sorting technologies for mosquitoes that will enable them to produce the Wolbachia-infected males at the scale and frequency required for this project. The intervention will be implemented by Verily Life Sciences Inc. and the Puerto Rico Vector Control Unit. COPA is planning to evaluate the epidemiological impact of this intervention in a cluster-randomized control trial in Ponce, Puerto Rico, involving annual follow-ups of an established cohort of about 3800 residents in 38 clusters (19 with and 19 without the Wolbachia suppression intervention). The intervention will involve repeated releases of male Ae. aegypti mosquitoes infected with W. pipientis bacteria in the selected clusters. At least 100 Wolbachia-infected male mosquitoes per household or approximately 1.5 million males per week (given approximately 15 000 households in intervention clusters) will be released initially in intervention clusters and subsequent releases will attempt to maintain an “over-flooding” ratio of at least 7:1 (7 Wolbachia-infected males per uninfected male in the target population). The applicants met with VCAG for the first time at the 11th meeting to introduce their intervention and seek feedback on plans for the upcoming trial. 17Eleventh meeting of the WHO Vector Control Advisory Group Summary of discussions Although this was the first meeting for these applicants, their intervention has been in development for a number of years. The applicants presented information on the intervention and details of the proposed cluster RCT in Puerto Rico. VCAG discussions and feedback to the applicants were separated into comments related to the entomological and epidemiological components of the planned trial, as described below. Entomological components • VCAG was impressed by the sophistication of the mosquito rearing and sex- sorting processes. The applicants described field trials for entomological end- points that demonstrated the applicant’s ability to produce, sort and release Wolbachia-infected mosquitoes at frequencies and scales that can result in significant reductions in mosquito densities in small urban test plots. • Determination and optimization of the overflooding ratio and how it would be monitored in the trial were discussed. • VCAG noted that autocidal gravid ovitraps are being considered for mosquito surveillance in the trial. These traps are also being reviewed by VCAG for consideration as an intervention in their own right. The applicants responded that these traps are unlikely to impact mosquito population size at the density proposed for use in the trial. • VCAG asked whether there was possible interference from other interventions in the study area. The applicants reported that no other interventions against mosquito-borne diseases are currently being conducted, nor were any implemented during the recent outbreak of Zika virus disease. The possibility of interference from other interventions hence seems unlikely. • The applicants proposed testing mosquitoes for viruses during the intervention, but the exact approach is still being determined. There was discussion about the difficulty of detecting sufficient quantities of virus-infected mosquitoes in the trial because of the proposed timing and frequency of mosquito collection from traps (the length of which would probably result in significant virus degradation) and the paucity of infected mosquitoes, even in high-transmission settings. • VCAG expressed concern that the applicants might not have time to obtain the appropriate permits for mosquito releases before the proposed trial start date; however, several contingency plans appear to be in place to accommodate any issues. • The applicants explained the reason for the 150-m buffer zone proposed between clusters, which has been used in similar trials as well as in “mark, release, recapture” studies conducted by the applicants at other locations. Epidemiological components • Various aspects of the power calculations were discussed, including the age distribution of participants, the incidence rate, annual variations in transmission intensity and the effect size. In particular: • The proposed age range of participants will likely have a large fraction of older, immune individuals (or individuals whose infections cannot be detected with serology). The incidence rate used in the sample 18 Eleventh meeting of the WHO Vector Control Advisory Group size calculations may therefore not be appropriate for the entire trial population. The applicants are currently collecting serological data that should be able to inform this issue. • There is, historically, large year-to-year variation in the transmission intensity of all arboviruses. This may be an issue if there are numerous years during the trial that are lower than average. If possible, it might be optimal to consider a fourth year of the trial if there is an indication of lower-than-average transmission over the first few years of the trial. • The applicant indicated a few changes to the trial design since its submission (e.g. from a matched pair design to a stratified randomization design). • The applicants raised further concern about human movement between clusters of alternate arms of the trial. Although this sort of information would not be included in an intent-to-treat analysis of the primary end-point, it could be accounted for in secondary analyses. Conclusions • VCAG acknowledges the effort the applicants have made in developing and optimizing their intervention and the associated evaluation of its impact against the targeted vector-borne diseases. The intervention is considered to have considerable potential, and VCAG looks forward to further supporting the applicant through the WHO evaluation process. • VCAG identified a few issues that may result in the statistical power of the trial being lower than anticipated. Specific recommendations that may help to address this issue are provided below (see recommendations section). • The applicant asked whether the intervention could be considered in the same class as other sterile male releases. Their primary question here was if VCAG thought there was potential to combine results from epidemiological trials across similar interventions to satisfy the requirements of VCAG and of WHO. VCAG considers that any decision on this subject of the intervention class would be premature (26). Recommendations 1. VCAG recommends that the applicant share an updated protocol with the Group before the start of the trial if they wish to receive further feedback on the final design. Given the proposed start date of the trial (before the next VCAG meeting), VCAG could conduct an off-cycle review of the updated trial protocol, if the criteria for off-cycle review are met (27). 2. VCAG recommends that the applicants reconsider the age distribution of their trial population and their serological history with respect to arboviruses, given the concern about serological detection of infections. Specifically, VCAG recommends incorporating age-specific seroprevalence data collected recently by the applicants or other incidence data to assess the plausibility of the 3% incidence value used in the power calculations. 3. VCAG recommends that the applicants reconsider the effect size. Given the likelihood that participants will not spend 100% of their time in their cluster (or any cluster), the 50% effect size may be too large. 4. VCAG recommends that the applicants prepare a contingency plan if there are signals, such as those referenced in recommendations 2 and 3 above, that their trial is underpowered. 19Eleventh meeting of the WHO Vector Control Advisory Group 5. VCAG recommends that the applicants provide information on: • the site-specific effectiveness of male acoustic sound traps relative to other standard methods for estimating Ae. aegypti population density, • details of the ‘mark, release, recapture’ studies used to estimate the dispersal of Wolbachia-infected males and • the relative fitness of released mosquitoes compared to wild-type mosquitoes. 6. VCAG recommends that the applicants prepare alternative monitoring plans that could be used if the effectiveness of male acoustic sound traps proves to be inadequate. 7. VCAG recommends that, given the importance of overflooding, methods to determine and monitor overflooding ratios be calibrated to Puerto Rico to maximize the chances of success. Prequalification evaluation of vector control products Marion Law, Group Lead, PQT-VC, presented the process for prequalification evaluation of vector control products. She described aspects of the process, including the evaluation approach, the prequalification pathway, the format of the submission dossier (modular) and the data and information required for each module, as well as the approaches used to analyse data, document results and make a final decision. Dossiers are assessed by prequalification assessors at bi-annual meetings. The assessors are product chemists, toxicologists, entomologists and medicines prequalification assessors. New interventions pathway – categorization and terminology Dr Jan Kolaczinski, Coordinator, GMP Entomology and Vector Control (EVC), presented on behalf of the WHO Secretariat on issues related to the categorization of intervention types and classes. Under the current evaluation process the Pre-Submission Coordination Committee (PCC) review the pre-submission packages to determine whether: a) the product has potential for use in disease control programmes; and b) the product falls within an established product class (28). As new tools come into the new intervention pathway it is necessary, in some instances, to revise the categorization of intervention types and/or classes because the current categories do not accommodate all of the submissions received by WHO. As part of the process to update the Norms, Standards and Process underpinning WHO Vector Control Policy Recommendations there will be a comprehensive review of the categorization. One specific issue which the WHO Secretariat sought input on was for the categorization of paints or other products that are painted onto an entire wall or part of a wall. They cannot be categorized as indoor residual sprays, as they are not sprayed. One option is to create a new intervention type called “indoor wall treatments” or “indoor residual wall treatments” which accommodates paints and indoor residual sprays. This intervention type could be divided into the following intervention classes: 1) treatment of whole indoor surfaces with insecticide by spraying or paint, and 2) selective application of insecticide to only parts of indoor walls. VCAG agreed that this sounded reasonable in principle. In addition, it was agreed that the WHO Secretariat would involve VCAG in the comprehensive review of the intervention types and classes. There was some discussion on how to generate evidence on vector control interventions whose primary impact is personal protection for use in the development of policy recommendations. It was agreed that the WHO Secretariat would engage further with VCAG on this issue. 20 Eleventh meeting of the WHO Vector Control Advisory Group Aedes-specific interventions: evidence requirements in the context of integrated vector management Dr Audrey Lenhart, US Centers for Disease Control and Prevention, led a discussion on Aedes-specific interventions and the evidence requirements in the context of integrated vector management. She framed the discussion by noting that most of the Aedes- focused interventions will never function as ‘stand-alone’ interventions, and therefore it would be difficult and impractical to evaluate such interventions alone. The group discussed various trial designs and noted that, while RCTs are the gold standard, VCAG has stated in “How to design vector control efficacy trials” (29) that it will consider non- randomized trials with a control, such as before-and-after studies, cohort studies, case–control studies, cross-sectional studies, time-series or interrupted time-series on a case by case basis. Applicants should propose the most appropriate trial design for an intervention, and, as there is no finite list of approaches suitable for all interventions, VCAG is willing to consider novel approaches to trial design. The group also discussed the step–wedge-like design for studies of the release of sterile insects. More work is required to define an optimal strategy for such releases. The WHO Secretariat noted that there are plans for a consultation on trial design, including designs used in fields other than vector control. The WHO Secretariat plan to include VCAG in these discussions. In terms of next steps, VCAG will continue their discussion and research into novel trial design approaches. Group discussion: VCAG operations, processes, feedback VCAG members discussed ways to make interactions with applicants more efficient and effective. VCAG will continue to revise their processes in order to improve them. 21Eleventh meeting of the WHO Vector Control Advisory Group REFERENCES 1. WHO Strategic Advisory Group on Malaria Eradication. Malaria eradication: benefits, future scenarios and feasibility. Executive summary. Geneva: World Health Organization; 2019 (WHO/CDS/GMP/2019.10). https://www.who.int/publications-detail/strategic-advisory-group-malaria-eradication-executive- summary. 2. Twelfth General Programme of Work 2014–2019: Not merely the absence of disease. World Health Organization 2014 https://apps.who.int/iris/bitstream/handle/10665/112792/GPW_2014-2019_eng.pdf, p. 19. 3. Standard operating procedures for Vector Control Advisory Group (VCAG) applicants (revised July 2019). World Health Organization 2019. (https://apps.who.int/iris/bitstream/handle/10665/274450/WHO-CDS- VCAG-2018.02-eng.pdf) 4. Standard operating procedures for Vector Control Advisory Group (VCAG) applicants (revised July 2019). World Health Organization 2019. (https://apps.who.int/iris/bitstream/handle/10665/274451/WHO-CDS- VCAG-2018.03-eng.pdf) 5. New tools, technologies and approaches for vector control. World Health Organization. (https://www.who.int/vector-control/vcag/new-interventions/en/, accessed November 2019). 6. The evaluation process for vector control products. Information note. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/bitstream/handle/10665/255644/WHO-HTM-GMP-2017.13-eng.pdf, accessed November 2019). 7. How to design vector control efficacy trials. Guidance on phase III vector control field trial design (Provided by the Vector Control Advisory Group). Geneva: World Health Organization; 2017. (https://www.who.int/neglected_diseases/vector_ecology/resources/WHO_HTM_NTD_VEM_2017.03/en/, accessed November 2019). 8. Malaria policy pathway overview. Geneva: World Health Organization; 2019 (https://www.who.int/ malaria/policy/en/, accessed November 2019). 9. Overview of intervention classes and prototype/products under VCAG review for assessment of public health value. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/bitstream/ handle/10665/274451/WHO-CDS-VCAG-2018.03-eng.pdf, accessed November 2019). 10. Vector alert: Anopheles stephensi invasion and spread. Geneva: World Health Organization, 26 August 2019. (https://www.who.int/publications-detail/vector-alert-anopheles-stephensi-invasion-and- spread) 11. Malaria Threats Map. World Health Organization. https://apps.who.int/malaria/maps/threats/. 12. With 2010–2020 levels as baseline. 13. Global strategy for dengue prevention and control 2012-2020. Geneva: World Health Organization 2012. (https://apps.who.int/iris/bitstream/handle/10665/75303/9789241504034_eng.pdf) 14. WHO preferred product characteristics: endectocide for malaria transmission control. Geneva: World Health Organization; 2017 (WHO/HTM/GMP/2017.10). No longer online. 15. Eighth meeting of the WHO Vector Control Advisory Group. Geneva: World Health Organization, 2018. (https://www.who.int/vector-control/publications/eighth-vcag-meeting-report/en/, p. 7). 16. Ndong TB, Kane Y, Ba M, Sane I, Sutra J, Alvinerie M. Pharmacokinetics of ivermectin in zebu Gobra (Bos indicus). Vet Parasitol. 2005;128(1–2):169–173. 17. Ninth meeting of the WHO Vector Control Advisory Group. Geneva: World Health Organization, 2018. (https://www.who.int/vector-control/publications/ninth-vcag-meeting-report/en/). 18. Uganda PBO Study Statistical Analysis Plan, Version 1.0, October 2019 19. Staedke SG, Kamya MR, Dorsey G, Maiteki-Sebuguzi C, Gonahasa S, Yeka A, et al. LLIN Evaluation in Uganda Project (LLINEUP) – Impact of long-lasting insecticidal nets with, and without, piperonyl butoxide on malaria indicators in Uganda: study protocol for a cluster-randomised trial. Trials. 2019;20(1):321. 20. Conditions for deployment of mosquito nets treated with a pyrethroid and piperonyl butoxide Geneva: World Health Organization; 2017 (https://apps.who.int/iris/bitstream/handle/10665/258939/WHO-HTM- GMP-2017.17-eng.pdf, accessed November 2019). 21. Tenth meeting of the WHO Vector Control Advisory Group. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/bitstream/handle/10665/326584/WHO-CDS-VCAG-2019.02-eng.pdf). 22 Eleventh meeting of the WHO Vector Control Advisory Group 22. Bibbs CS, Bloomquist JR, Hahn DA, Kaufman PE, Xue RD. Gone in 60 seconds: Sub-lethal effects of metofluthrin vapors on behavior and fitness of resistant and field strains of Aedes aegypti (Diptera: Culicidae). J Med Entomol. 2019;56(4):1087–94; Horstmann S, Sonneck R. Contact bioassays with phenoxybenzyl and tetrafluorobenzyl pyrethroids against target-site and metabolic resistant mosquitoes. PLoS One. 2016;11(3):e0149738; Kawada H, Nakazawa S, Shimabukuro K, Ohashi K, Kambewa EA, Pemba DF. Effect of metofluthrin-impregnated spatial repellent devices in combination with new long-lasting insecticidal nets (Olyset® Plus) on pyrethroid-resistant malaria vectors and malaria prevalence – field trial in south-eastern Malawi. Jpn J Infect Dis. 2019; doi: 10.7883/yoken.JJID.2019.311. 23. Barreaux AMG, Brou N, Koffi AA, N’Guessan R, Oumbouke WA, Tia IZ, et al. Semi-field studies to better understand the impact of eave tubes on mosquito mortality and behaviour. Malaria J. 2018;17:306. 24. Barreaux AMG, Oumbouke WA, Tia IZ, Brou N, Koffi AA, N’Guessan R, et al, Semi-field evaluation of the cumulative effects of a “lethal house lure” on malaria mosquito mortality. Malaria J. 2019;18:298. 25. Eighth meeting of the WHO Vector Control Advisory Group. Geneva: World Health Organization, 2018. (https://www.who.int/vector-control/publications/eighth-vcag-meeting-report/en/, p. 23). 26. WHO indicated later in the meeting that they are undertaking a comprehensive review of the intervention classes and types and will consider this intervention in the review. 27. Standard operating procedures for Vector Control Advisory Group applicants (https://apps.who.int/iris/ bitstream/handle/10665/274450/WHO-CDS-VCAG-2018.02-eng.pdf page 4) 28. The evaluation process for vector control products [information note]. Geneva: World Health Organization; 2017 (http://apps.who.int/iris/bitstream/handle/10665/255644/WHO-HTM-GMP-2017.13- eng.pdf). 29. How to design vector control efficacy trials: guidance on phase III vector control field trial design. Geneva: World Health Organization; 2017 (https://www.who.int/neglected_diseases/vector_ecology/resources/ WHO_HTM_NTD_VEM_2017.03/en/). 23Eleventh meeting of the WHO Vector Control Advisory Group ANNEX 1. AGENDA MONDAY, 11 NOVEMBER 2019 Session 1: Introductory session 09:00–09:30 Opening of meeting • Opening remarks • Introductions 9:30–9:45 Introductory remarks by VCAG members Session 2: Open session 9:45–9:50 Declarations of interest 9:50–10:15 Outcomes of the WHO Strategic Advisory Group on Malaria Eradication 10:15–10:45 Updates • VCAG update • PQT VC update • GMP update, relevant outcomes from the Malaria Policy Advisory Committee 11:00–11:30 NTD update, relevant outcomes from the Strategic and Technical Advisory Group and update on insecticide discriminating concentrations 11:30–12.00 Open discussion on VCAG processes by all participants Session 3: Interactions with applicants 13:00–15:00 Endectocides – review of protocol Chair of session: Neal Alexander Applicant presentation (30 min) Questions and answers (15 min) Closed discussion (40 min) Feedback (35 min) 15:30–16:00 PBO nets. SAP review – Uganda study Chair of session: Fabrice Chandre 16.00–16.45 Prequalification evaluation of vector control products 16:45–17:00 Summary of day 1 24 Eleventh meeting of the WHO Vector Control Advisory Group TUESDAY, 12 NOVEMBER 2019 9:00–11:00 Spatial repellents – review of protocol Chair of session: Salim Abdulla Applicant presentation (30 min) Questions and answers (15 min) Closed discussion (40 min) Feedback (35 min) 11:30–13:30 Lethal house lures – review of results Chair of session: Thomas Smith Applicant presentation (30 min) Questions and answers (15 min) Closed discussion (40 min) Feedback (35 min) 14:30–16:30 Wolbachia suppression – review of protocol Chair of session: Robert Reiner Applicant presentation (40 min) Questions and answers (15 min) Closed discussion (30 min) Feedback (35 min) 16:45–17:30 Working sessions to draft recommendations. Discussion 17:30–17:45 Summary of day 2 WEDNESDAY, 13 NOVEMBER 2019 Session 4. Discussion 9:00–9:45 Terminology for new interventions pathway 9.45–10.15 Aedes-specific interventions – evidence requirements in the context of integrated vector management 10.15–10:30 Group discussion – VCAG operations, processes, feedback Session 5: Discussion and drafting of recommendations 11:00–12:30 Draft recommendations (working groups) 13:30–15:00 Plenary sessions to review draft recommendations (continued) 15:15–16:00 Plenary sessions to review draft recommendations 16:00–16:15 Close of meeting 25Eleventh meeting of the WHO Vector Control Advisory Group ANNEX 2. LIST OF PARTICIPANTS MEMBERS Co-Chairs Salim ABDULLA Ifakara Health Institute, Ifakara, United Republic of Tanzania Heather FERGUSON University of Glasgow, Glasgow, United Kingdom VCAG experts Neal ALEXANDER Centro Internacional de Entrenamiento et Investigaciones Médicas (CIDEIM), Cali, Colombia and London School of Hygiene and Tropical Medicine, London, United Kingdom Kalpana BARUAH National Vector Borne Disease Control Programme, Ministry of Health and Family Welfare, New Delhi, India Steven BRADBURY Iowa State University, Iowa, USA Fabrice CHANDRE Institute for Research for Development, Montpellier, France Audrey LENHART Centers for Disease Control and Prevention, Atlanta (GA), USA David O’BROCHTA Foundation for the National Institutes of Health, North Bethesda (MD), USA Robert REINER University of Washington, Seattle (WA), USA Thomas SMITH Swiss Tropical Institute, Basel, Switzerland TEMPORARY ADVISERS Camilla BEECH Cambea Consulting Ltd, Reading, England Mamadou Brahima COULIBALY University of Sciences, Techniques and Technologies, Bamako, Mali Alfred TIONO National Centre for Research and Training in Malaria, Ouagadougou, Burkina Faso Alia ZAYED Cairo University, Cairo, Egypt Tongyan ZHAO Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China PARTICIPANTS Endectocides Carlos CHACCOUR ISGlobal, Spain Regina RABINOVICH ISGlobal, Spain Lethal house lures Jackie COOK London School of Hygiene and Tropical Medicine, United Kingdom Marit FARENHORST In2Care, Netherlands Anne OSINGA In2Care, Netherlands Spatial repellents Nicole L. ACHEE Notre Dame University, USA John P. GRIECO Notre Dame University, USA Maria DAHN (remotely) Notre Dame University, USA Wolbachia suppression Jacob CRAWFORD Verily, USA Sara MITCHELL Verily, USA Gabriela PAZ-BAILEY Centers for Disease Control and Prevention, USA 26 Eleventh meeting of the WHO Vector Control Advisory Group Nigel SNOAD Verily, USA Steve WATERMAN Centers for Disease Control and Prevention, USA OBSERVERS Katerina GALUZZO Unitaid, Switzerland Kate KOLACZINSKI Global Fund to Fight AIDS, Tuberculosis and Malaria, Switzerland Dave MALONE Bill & Melinda Gates Foundation, USA REMOTE PARTICIPANTS Chandel BRISWALTER Syngenta Crop Protection AG Nick BROWN A to Z Textile Mills Ltd Elisa MARTELLO University of Nottingham Fu HAILI Yorkool Jo LEONARDI-BEE University of Nottingham Leilia DORE Clinton Health Access Initiative Maria DAHN Notre Dame University Susanne STUTZ BASF Joseph ZVOUSHOMA Clinton Health Access Initiative Denis ESCOBAR Universidad Nacional Autónoma de Honduras Derric NIMMO IVCC Edward THOMSEN ISTMED Peter RYAN World Mosquito Programme Sarah DEWHIRST London School of Hygiene and Tropical Medicine Shelia OGOMA Clinton Health Access Initiative WHO SECRETARIAT, GENEVA Global Malaria Programme Pedro ALONSO Director Jan KOLACZINSKI Coordinator, Entomology and Vector Control Anna BOWMAN VCAG Project Manager, Entomology and Vector Control Department of Control of Neglected Tropical Diseases Mwelecele MALACELA Director Raman VELAYUDHAN Coordinator, Vector Ecology and Management Rajpal YADAV Scientist, Vector Ecology and Management Lauren CARRINGTON Consultant, Vector Ecology and Management Regulation of Medicines and other Health Technologies Emer COOKE Director Philip COYNE Prequalification Review Team, World Health Organization Deusdedit MUBANGIZI Coordinator, Prequalification Marion LAW Team Lead, Prequalification Team, Vector Control Group Dominic SCHULER Technical Officer, Prequalification Team, Vector Control Group Jeannette MARTINEZ Entomologist, Prequalification Team, Vector Control Group 27Eleventh meeting of the WHO Vector Control Advisory Group ANNEX 3. DECLARATIONS OF INTEREST All VCAG members and invited experts completed forms for declarations of interests for WHO experts before the meeting. The VCAG secretariat assessed the interests declared by the experts and, with the exception of those described below, found that they were not directly related to the topics under discussion at the meeting. It was therefore decided that those experts could participate in the meeting, subject to disclosure of their interests at that time. The following interests were declared and assessed as related to topics under discussion at the meeting. The disclosed interests did not warrant full exclusion but rather partial participation. The conclusions and mitigating actions are described below. Dr Neal Alexander (Centro Internacional de Entrenamiento et Investigaciones Médicas and London School of Hygiene and Tropical Medicine) sits on the Data and Safety Monitoring Board for Spatial Repellents. Conclusion: Dr Alexander did not participate in the VCAG review group for spatial repellents; however, he participated in discussions on the topic with the whole group. Dr Mamadou Coulibaly (University of Sciences, Techniques and Technologies, Bamako, Mali) declared a conflict of interest with regard to spatial repellents. Conclusion: Dr Coulibaly did not have access to related documentation or participate in discussions or in the drafting and finalization of the recommendations on spatial repellents. Dr Robert Reiner (Institute for Health Metrics and Evaluation, USA) declared a conflict of interest with regard to spatial repellents. Conclusion: Dr Reiner did not have access to related documentation or participate in discussions or in the drafting and finalization of the recommendations on spatial repellents. FOR FURTHER INFORMATION PLEASE CONTACT: Vector Control Advisory Group World Health Organization 20 Avenue Appia CH-1211 Geneva 27 Switzerland vcag@who.int www.who.int/vector-control/vcag