# INTRODUCTION Background
Malaria continues to cause unacceptably high levels of disease and death, as documented in successive editions of the World malaria report. According to the latest report, there were an estimated 247 million cases and 619 000 deaths globally in 2021. Malaria is preventable and treatable, and the global priority is to reduce the burden of disease and death while retaining the long-term vision of malaria eradication. Here, we present the WHO Guidelines for malaria developed by the WHO Global Malaria Programme as a comprehensive and inclusive resource for advice on malaria.
The Global technical strategy for malaria 2016-2030  (GTS) provides an overarching framework to guide malaria control and elimination efforts. Adopted by the World Health Assembly in May 2015 and update adopted in May 2021, the Strategy defines goals, milestones and targets on the path to a world free of malaria (Table 1). The goals focus attention on the need to both reduce morbidity and mortality, and to progressively eliminate malaria from countries that had malaria transmission in 2015. The GTS presents a framework through which the goals can be achieved (Figure 1).

# Table 1. Goals, milestones and targets for the Global technical strategy for malaria 2016-2030
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
The GTS  states that it is essential for malaria programmes to '"ensure access to malaria prevention, diagnosis and treatment as part of universal health coverage"' (Fig. 1, -Pillar 1). Universal health coverage (UHC) means that all individuals and communities receive the health services they need without suffering financial hardship. It includes the full spectrum of essential, quality health services, from health promotion to prevention, treatment, rehabilitation and palliative care. For malaria, WHO has recommended a range of interventions -namely, vector control, chemoprevention, diagnostic testing and treatment -to reduce transmission and prevent morbidity and mortality. A UHC approach means ensuring that individuals and communities are covered by the appropriate mix of these interventions, based on local context, to control and ultimately eliminate malaria. The second pillar of the GTS urges all countries to accelerate efforts towards elimination and attainment of a malaria-free status. Progress towards elimination is a continuous process and not a set of independent stages. Countries, subnational areas and communities are situated at different points along the malaria transmission continuum. Malaria transmission intensity varies within a country or area, as does the level of investment, biological determinants, environmental factors, strength of health systems and social, demographic, political and economic factors. Strategies will need to be tailored to the local setting by taking into account the local context and epidemiology of malaria.
The principal objective of national malaria programmes (NMPs) is to combine a selection of these interventions into packages that are tailored to achieve sustainable and equitable impact in a given setting. To decide upon the appropriate intervention package and allocation of resources that will achieve this objective and contribute to UHC, programmes should use a process that combines the analysis of impact and value for money with extensive stakeholder engagement and discussion. The process should be informed by past and current malaria transmission intensity and incidence data; contextual vulnerability related to the human host, parasites, vectors, and past and present intervention coverage; acceptability; and equality of access and use (including analysis of financial barriers and how to address them). When the objective is elimination, a similar process is undertaken, although the types of interventions and value for money analysis will be different than in high-burden settings.
Following progressive reductions in malaria burden between 2000 and 2015, progress stalled. By 2017, the world was off track to achieve the malaria morbidity and mortality reduction targets. In response, a revitalization effort called "High burden to high impact (HBHI)" was launched in 2018. This approach focuses attention on how to get back on track: garnering political will to reduce the toll of malaria; using strategic information to drive impact; developing better guidance, policies and strategies; and improving coordination of support for national malaria responses. Although the impetus for articulating these key activities was the need to get back on track to achieve the GTS morbidity and mortality targets, these activities apply equally well to all malaria-endemic countries and to ensure continued progress towards the GTS elimination goals.
These consolidated WHO Guidelines for malaria aim to provide the latest evidence-based recommendations in one reference to support countries in their efforts to reduce and ultimately eliminate malaria. The objectives of the Guidelines are:
- to provide evidence-based and context-sensitive recommendations on the appropriate choice(s) for malaria prevention (vector control, preventive chemotherapies and the vaccine), case management (diagnosis and treatment) across all transmission settings and interventions in the final phase of elimination and prevention of re-establishment; - to support the development by WHO Member States of evidence-based national malaria policies for prevention and case management across all transmission settings; - to encourage the use of local data to inform subnational stratification to maximize the impact of available resources; and - to inform the research agenda to enable updates to the Guidelines by identifying gaps in evidence that constrain the development of guidance or weaken current recommendations.

# Evidence base
These Guidelines are based on the synthesis of the available evidence on the health effects of interventions, and the grading of the certainty of that evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The synthesized and graded evidence on the health effects of interventions, as well as any evidence on contextual factors, is used to develop an evidence-to-decision (EtD) framework for each recommendation. The judgement on the different factors in the EtD framework (including the certainty of evidence) facilitates the determination of the strength and direction of each recommendation.
Expert input is important for the interpretation of the evidence, and the development of guidance may rely on expert opinion, particularly in areas where the evidence is currently weak, scarce or absent. For example, the vector control recommendations presented in the Guidelines are based on a consideration of the evidence gained from randomized controlled trials (RCTs) and other types of trials and studies, as well as the technical knowledge and experience of the GDG and External Review Group involved in the standard guideline development process. Details of how evidence is considered are presented in Section 8: Methods. Details of contributors for specific recommendations are presented in Section 10: Contributors and interests.

# Target audience
The primary audience for these Guidelines is policy-makers in ministries of health and the managers of NMPs in endemic countries. The Guidelines may also be of interest to health care practitioners, environmental health service professionals, procurement agencies, the private sector, and civil society groups. The Guidelines are also intended for use by international development partners, donors and funding agencies in order to support decision-making on allocation of resources for interventions and procurement of appropriate malaria control products. In addition, the Guidelines are intended to guide researchers, research funders and those interested in the outcomes of research to address the evidence gaps that are constraining the development of guidance or weakening current recommendations.

# Equity, gender and human rights
The right to enjoy the highest attainable standard of physical and mental health (commonly referred to as the right to health) is enshrined in several international human rights treaties, regional agreements, and national constitutions and laws. Member States have minimum "core" obligations that include "the prevention, treatment and control of epidemic, endemic, occupational and other diseases".
Yet, gender-based discrimination, human rights violations, and inequities related to social, economic, environmental, commercial and political determinants of health deprive billions of people around the world of their right to enjoy the highest attainable standard of health and well-being. It is of great concern that, over the past few years, health inequities have been exacerbated by the impacts of the ongoing and interlinked crises of the coronavirus disease (COVID- 19), conflict, climate change, food insecurity and the global economy.
Too many people are missing out on the interventions they need to keep them healthy, including interventions to prevent and treat malaria. According to a WHO report malaria, TB and HIV/AIDS are diseases that predominantly impact the chronically disadvantaged. While the magnitude and extent of health inequalities remain poorly understood, it is clear that certain population groups have persistently higher disease mortality and morbidity and more limited access to life-saving interventions. The report documents that the poorest, least educated and rural groups are less likely to seek care for children with fever.
In most countries, Member States have not adequately identified and addressed social and structural barriers to health, or taken action to ensure gender equality, equity and human rights. Communities are often excluded from health decision-making, even though people are entitled to active, free and meaningful participation in decisions that directly affect them, such as the design, implementation and monitoring of health interventions.
Participation increases ownership and helps to ensure that policies and programmes are responsive to the needs of the people they are intended to benefit.
The existing inequities are barriers to achieving global and national goals and targets on malaria. Successful implementation of malaria control interventions should, therefore, be viewed through a human rights and health equity lens. This means fully acknowledging the importance of engaging people in the design and delivery of health and care systems to meet their needs, and empowering them to make informed decisions about their health and take action.
As many of the malaria interventions are reliant on broader health care delivery platforms, a rights-based approach is required to ensure that quality health services and programmes are available, accessible and acceptable to all those in need, including nomadic populations, individuals with disabilities, out-of-school youth, and those living in sparsely populated and underserved areas far from health services and schools.
National programmes should address inequity concerns by monitoring the coverage of recommended interventions among individuals in identified risk categories and targeting those most at risk. Health inequities and barriers to health need to be systematically identified and addressed by Member States and other stakeholders through gender-responsive, equitable and human rights-based health systems, with a focus on individuals and groups experiencing intersecting forms of discrimination, marginalization and/or social exclusion.
Malaria is a life-threatening disease caused by the infection of red blood cells with protozoan parasites of the genus Plasmodium that are transmitted to people through the bites of infected female Anopheles mosquitoes. Four species of Plasmodium (P. falciparum, P. vivax, P. malariae and P. ovale) most commonly infect humans. P. falciparum and P. vivax are the most prevalent species and P. falciparum is the most dangerous. A fifth species, P. knowlesi (a species of Plasmodium that primarily infects non-human primates) is increasingly being reported in humans inhabiting forested regions of some countries of South-East Asia and the Western Pacific regions, and in particular on the island of Borneo.

# Malaria transmission, acquisition of immunity, and clinical manifestations of disease
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
The intensity of transmission depends on factors related to the parasite, the vector, the human host and the environment. Transmission tends to be more intense in places where the mosquito lifespan is longer and where the females prefer to bite humans rather than other animals. The survival and longevity of female mosquitoes is of critical importance in malaria transmission, as the malaria parasite generally requires a period of 7-10 days to develop inside the mosquito into a form that is infective to humans. Female mosquito longevity is dependent on intrinsic, genetic factors, as well as on environmental factors including temperature and humidity. The strong human-biting habit of the African vector species is one of the reasons why approximately 90% of the world's malaria cases occur in Africa.
Transmission intensity is usually assessed as the incidence of cases or the prevalence of infection. Most countries have information on the annual parasite incidence (number of new parasitologically confirmed malaria cases per 1000 population per year) from routine surveillance and/or on the parasite prevalence from surveys, often conducted during or just after periods of peak transmission.
The following categories of transmission intensity are indicative and meant to provide an adaptable framework in which each country can conduct a stratification exercise to classify geographical units according to local malaria transmission.
- Areas of high transmission are characterized by an annual parasite incidence of 450 or more cases per 1000 population and a P. falciparum prevalence rate of 35%. - Moderate transmission areas have an annual parasite incidence of 250-450 cases per 1000 population and a prevalence of P. falciparum/P. vivax malaria of 10-35%. - Areas of low transmission have an annual parasite incidence of 100-250 cases per 1000 population and a prevalence of P. falciparum/P. vivax of 1-10%. It should be noted that the incidence of cases or infections is a more useful measure in geographical units in which the prevalence is low, given the difficulty of measuring prevalence accurately at low levels. - Very low transmission areas have an annual parasite incidence of  0 but < 1%.
The relation between parasite incidence, parasite prevalence and the number of cases presenting to health facilities per week can be estimated using models. Differences in transmission from one area to another may be due to geographical characteristics, such as altitude, temperature, humidity, rainfall patterns, proximity to water bodies, land use, vector species and distribution, sociodemographic characteristics, access to antimalarial treatment, and coverage with vector control. In most endemic areas, seasonal patterns of transmission are observed, with high transmission during part of the year. Both the intensity and timing of transmission are important considerations in designing elimination strategies.
The manifestation of clinical disease depends strongly on the background level of acquired protective immunity, which is a consequence of the pattern and intensity of malaria transmission in the area of residence. In areas of moderate to high transmission, partial immunity to clinical disease and a reduced risk of developing severe malaria are acquired in early childhood. The pattern of acquired immunity is similar across the Sahel subregion, where malaria transmission is intense only during the three-or four-month rainy season and low at other times. In both these situations, clinical disease is confined mainly to young children, who may develop high parasite densities that can progress rapidly to severe malaria. By contrast, in these settings, adolescents and adults are partially immune and suffer clinical disease much less frequently, although they are often infected with low bloodparasite densities. Immunity is modified in pregnancy and gradually lost, at least partially, when individuals move out of the endemic areas for prolonged periods (e.g. a year or more).
In areas of low and very low transmission, as found in much of Asia, Latin America and other malaria-endemic areas, the transmission fluctuates widely by season, year, and over relatively small distances. P. vivax is an important cause of malaria in these regions. This generally low transmission delays acquisition of immunity, so that adults and children alike suffer from acute clinical malaria, with a significant risk for progression to severe malaria if left untreated. Epidemics may occur in these low or very low transmission areas when the inoculation rate increases rapidly because of a sudden increase in vectorial capacity. Epidemics may result in a very high incidence across all age groups, which can overwhelm health services.
In moderate and high transmission areas with sustained high coverage of vector control and access to treatment, reduced exposure to malaria infection may change the population structure of acquired immunity to reflect that found in low or very low transmission areas, resulting in a corresponding change in the clinical epidemiology of malaria and an increasing risk of epidemics if control measures are not sustained.

# Recommendations and supporting implementation guidance
Evidence-informed recommendations are a critical component to support the development of national malaria strategic plans; they are intended to communicate "what to do". A second critical element is the strategic use of local data. This informs an understanding of the contextual diversity within each malariaendemic country. Local data provide an understanding of the different types of settings -or strata -within each country. This is an essential prerequisite to identify the optimal mix of interventions and the best means to deliver them in the different subnational strata.
The Global Malaria Programme is working with countries to strengthen the generation and use of local information for stratification, the definition of optimal mixes of interventions, and the rational, safe and ethical prioritization of resources to maximize impact. Local data are also essential to understand the impact of the strategies deployed, providing opportunities to further refine sub-national strategies and inform global knowledge.
WHO also develops implementation guidance such as operational and field manuals to support the "how" aspect of delivering the recommended tools and strategies. Operational manuals and other WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) guidance hold practical information for increasing the target population's access to interventions. These documents are referenced and linked to these Guidelines. The Global Malaria Programme is working to align this implementation guidance with the recommendations in the WHO Guidelines for malaria. However, where there are inconsistencies, the Guidelines should be the default resource for national decisions. Countries may use the implementation guidance to define ways in which a recommendation can be implemented effectively -for example, intermittent preventive treatment for malaria in pregnancy could be implemented through antenatal care and/or community distribution. The intention of the guidance is to enable delivery, not to prescribe exactly how it should be done.

# Strategic information to tailor programmatic response and selection of interventions
As malaria control improves, malaria transmission and risk become increasingly heterogeneous, both between and within countries.
Thus, a "one-size-fits all" approach to programme decisions on intervention selection becomes inefficient. The situation requires stratification of the country at subnational levels according to past, present and future malaria risk, the structure and function of the health system, and other contextual factors. Stratification provides a rational basis to identify context-specific packages of interventions to target specific populations in the different subnational strata. Local data are essential to complete stratification and to inform the selection of the optimal mixes of interventions to maximize impact. Given that resource constraints usually limit the implementation of all desirable interventions in all areas of malaria risk, a prioritization exercise must also be conducted to ensure that resource allocation also optimizes intervention mixes and resultant impact. Guidance on these activities is available in Section 7: Surveillance.
The choice of interventions in each stratum should be informed by WHO's recommendations. However, given the complexities of malaria, with heterogeneity of risk and the unique contexts that every programme has to consider, global guidance is not intended and should not be used to provide prescriptive guidance on what should be done in every situation. These Guidelines signal a paradigm shift towards a problem-solving approach using local data to identify recommendations that are relevant at a country level and based on local context, defining stratumspecific packages of interventions that optimize impact and are prioritized for resource allocation. This shift moves away from overly prescriptive recommendations and will clearly distinguish evidence-informed recommendations from contextual considerations. The contextual considerations at national and subnational levels will inform how recommendations should be applied and strategies that may increase access for the target population.
Accurate stratification of malaria transmission intensity is essential for effective targeting of interventions. As countries progress towards elimination, finer scale mapping is required, and stratification should be more specific, ideally at the level of localities or health facility catchment areas . As transmission intensity is progressively reduced, stratification needs to include vulnerability and receptivity to malaria, i.e. the risk for importation of malaria cases and the inherent potential of the vector-human ecosystem to transmit malaria.
These Guidelines provide a framework within which NMPs and their implementing partners may adopt and adapt the recommendations for use. Good quality surveillance data can also feed into this process by providing the granular local information needed to inform and evaluate national programme decisions (see Section 7: Surveillance). Where the boundaries of current knowledge are pushed, it is particularly important to ensure adequate attention to monitoring and evaluation. The information generated can then feed into updated guidance.
Nearly half of the world's population is at risk of malaria. In areas with high malaria transmission, young children and pregnant women are particularly vulnerable to malaria infection and death. Since 2000, expanded access to WHO-recommended malaria prevention tools and strategies -including effective vector control and the use of preventive chemotherapies -has had a major impact in reducing the global burden of this disease.

# Vector control Background
The consolidated Guidelines incorporate: i) recommendations based on systematic reviews of the available evidence on the effectiveness of vector control interventions conducted since the launch of the Guidelines; and ii) existing WHO recommendations developed previously. The Guidelines commence by providing general recommendations on malaria vector control, followed by more specific recommendations on individual interventions and good practice statements on their deployment. The interventions are divided into categories of those recommended for large-scale deployment and those recommended as supplementary. Interventions that are recommended for large-scale deployment are those that have demonstrated public health value, i.e. have proven protective efficacy to reduce or prevent infection and/or disease in humans at the individual level, community level or both, and that are broadly applicable for populations at risk of malaria in most epidemiological and ecological settings. Malaria vector control interventions recommended for large-scale deployment are: i) ITNs that are prequalified by WHO, which in many settings WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) continue to be pyrethroid-only long-lasting insecticidal nets (LLINs); and ii) indoor residual spraying (IRS) with a product prequalified by WHO. Specific product choices within these broad intervention types should be informed by insecticide resistance data for the target area(s) and other information compiled during sub-national prioritization exercises. Once optimal coverage with one of these interventions has been achieved, supplementary interventions may be considered for deployment depending on the specifics of the population, situation or setting. These include personal protection measures that have a primary use-pattern of protecting individual users, although they may have some as yet unproven impact when deployed at the community level.

# Vectors, their behaviour and distribution
Malaria is transmitted through the bites of infective female Anopheles mosquitoes. Of the more than 400 different species of Anopheles mosquitoes, only around 40 are malaria vectors of major importance. Anopheles mosquitoes lay their eggs in water.
The eggs hatch to produce larvae, which undergo several moults before emerging from the pupal stage as adult mosquitoes. Different species of Anopheles mosquitoes have their own preferred aquatic habitats; for example, some prefer small, shallow collections of fresh water such as puddles and animal hoof prints, whereas others prefer large, open water bodies including lakes, swamps and rice fields.
Both male and female mosquitoes feed on plant nectar, but it is just the female mosquitoes that feed on blood as they require protein to develop their eggs. Different mosquito species demonstrate preferences for feeding on animals (zoophily) or on humans (anthropophily); however, these preferences are not absolute, and females may take a blood meal from non-preferred hosts when these are present in the area. Different hosts may be more or less attractive to mosquitoes than others. Several factors have been implicated in the attraction of female mosquitoes to a host, including exhaled carbon dioxide, lactic acid, host odours, warmth and moisture. Blood-feeding can take place inside human habitations (endophagy) or outdoors (exophagy), depending on the mosquito species. has implications for the selection and effectiveness of vector control interventions.
Female Anopheles mosquitoes blood feed predominantly at night, although some species may bite during the day in heavily shaded conditions, and some exhibit a peak in biting activity in the early evening or early morning. The blood-feeding preferences (zoophily/anthropophily, endophagy/exophagy) as well as the interplay between the peak biting time of Anopheles vectors and the activity and sleeping patterns of the human hosts has important consequences for malaria transmission and the choice of appropriate vector control interventions.
After blood-feeding, female mosquitoes rest in order to digest the blood meal and mature their eggs. Female mosquitoes may rest indoors (endophily) or outdoors (exophily), and this depends on innate species preferences as well as the availability of suitable resting sites in the local environment. The mosquitoes' choice of post-feeding resting site also has major implications for the selection of control interventions.
It is important to note that while an individual species of Anopheles will characteristically exhibit certain biting and resting behaviours, these are not absolute; subpopulations and individuals may exhibit different behaviours depending on a combination of intrinsic genetic factors, availability of preferred hosts and availability of suitable resting sites. Environmental and climatic factors, including rainfall, moonlight, wind speed, etc., as well as the deployment of vector control interventions can all influence biting and resting behaviours.
Accurate species identification is crucial for all studies and surveillance activities on field populations of vectors. Many of the vectors belong to species complexes and require advanced molecular analyses for species identification, necessitating appropriate laboratory resources. Without accurate species identification, the data collected on behaviour, distribution and infection rates will have limited use for decision-making by control programmes.

# Background and rationale for vector control
The role of arthropods in the transmission of diseases to humans was first elucidated in the late 19th and early 20th centuries. Since effective vaccines or drugs were not always available for the prevention or treatment of these diseases, control of transmission often had to rely principally on control of the vector. Early control activities included the screening of houses, the use of mosquito nets, the drainage or filling of swamps and other water bodies used by insects for breeding, and the application of oil or Paris green to breeding places. Following the discovery of the insecticidal properties of dichlorodiphenyltrichloroethane (DDT) in the 1940s and subsequent discovery of other insecticides, the focus of malaria vector control shifted to the deployment of insecticides to target both the larval and adult stages of mosquito vectors.
Nowadays, it is well established that effective vector control programmes can make a major contribution to advancing human and economic development. Aside from direct health benefits, reductions in vector-borne diseases enable greater productivity and growth, reduce household poverty, increase equity and women's empowerment, and strengthen health systems. Despite the clear evidence in broad support of vector control efforts, the major vector-borne diseases combined still account for around 17% of the estimated global burden of communicable diseases, claiming more than 700 000 lives every year.
Recognizing the great potential to enhance efforts in this area, WHO led the development of the Global vector control response 2017-2030 which is outlined in the subsequent section.
Between 2000 and 2015, the infection prevalence of Plasmodium falciparum in endemic Africa was halved and the incidence of clinical disease fell by 40%. Malaria control interventions averted an estimated 663 million (credible interval (CI) 542-753 million) clinical cases in Africa, with ITNs making the largest contribution (68% of cases averted). Indoor residual spraying (IRS) contributed an estimated 13% (11-16%), with a larger proportional contribution where intervention coverage was high.

# Global vector control response 2017-2030
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
The vision of WHO and the broader infectious diseases community is a world free of human suffering from vector-borne diseases. In 2017, the World Health Assembly welcomed the Global vector control response 2017-2030  (GVCR) and adopted a resolution to promote an integrated approach to the control of vector-borne diseases. The approach builds on the concept of integrated vector management (IVM), but with renewed focus on improved human capacity, strengthened infrastructure and systems, improved surveillance, and better coordination and integrated action across sectors and diseases. Development programmes, including, for example, irrigated agriculture, hydroelectric dam construction, road building, forest clearance, housing development and industrial expansion, all have the potential to influence vector-borne diseases, offering the opportunity for intersectoral collaboration and the adoption of strategies other than those based on insecticides.
The ultimate aim of the GVCR is to reduce the burden and threat of vector-borne diseases through effective, locally adapted, sustainable vector control in full alignment with Sustainable Development Goal 3.3: to end epidemics of malaria by 2030.
Effective and sustainable vector control is achievable only with sufficient human resources, an enabling infrastructure and a functional health system. As recommended under the GVCR, national programmes should lead a vector control needs assessment across the relevant sectors  to help appraise current capacity, define the requisite capacity to conduct proposed activities, identify opportunities for improved efficiency in vector control delivery, and guide resource mobilization to implement the national strategic plan.

# Prevention, mitigation and management of insecticide resistance
Widespread and increasing insecticide resistance poses a threat to effective malaria vector control. Failure to mitigate and manage insecticide resistance is likely to result in an increased burden of disease, potentially reversing some of the substantial gains made in controlling malaria over the last decade.
WHO maintains a global insecticide resistance database and an online mapping tool that consolidate information on the status of the insecticide susceptibility of Anopheles mosquitoes in malaria-endemic countries. The latest data reveal that almost 90% of the malaria-endemic countries reporting insecticide resistance have detected resistance of their vectors to at least one insecticide class. Globally, resistance to pyrethroids is widespread, having been detected in at least one malaria vector in 68% of the sites for which data were available. Resistance to organochlorines was reported in 64% of the sites. Resistance to carbamates and organophosphates was less prevalent, detected in 34% and 28% of the sites that reported monitoring data, respectively.
To date, there is no evidence of operational failure of vector control programmes as a direct result of increasing frequency of pyrethroid resistance . Based on past experience, however, it is likely that operational failure will eventually occur if effective insecticide resistance management (IRM) strategies are not designed and implemented. Ideally, such strategies should be implemented early to prevent the spread and increase in the intensity of resistance. The overarching concepts of such resistance management strategies were outlined in the Global plan for insecticide resistance management in malaria vectors (GPIRM) in 2012.
Guidance on monitoring of insecticide resistance, interpretation of test results and implications for decision-making are given in the WHO Test procedures for monitoring insecticide resistance in malaria vector mosquitoes  and in the Framework for a national plan for monitoring and the management of insecticide resistance in malaria vectors. When deciding whether adjustments to the national malaria strategic plan are required in a given area, at least the following must be considered for that locality:
- current and past transmission levels;
- current and past interventions deployed, including the coverage, usage and duration of efficacy; - the insecticide resistance profile of the main vector species (including resistance intensity and resistance mechanisms); and - other entomological information including vector species distribution, abundance and other bionomic data.
The susceptibility of mosquitoes to insecticides and determination of the species-specific presence, intensity and mechanisms of resistance in vector populations can be used to guide the selection of the most appropriate insecticidal products to deploy. Generally, if mosquitoes are found to be resistant to an insecticide, insecticides with a different mode of action should be deployed. However, there are reports of mosquitoes having differential susceptibility to insecticides within the same class, and questions have been raised about the level of crossresistance between pyrethroid products. The Global Fund to Fight AIDS, Tuberculosis and Malaria recently commissioned a review of the interpretation of insecticide resistance assays when selecting insecticidal products.The review aimed to answer the question: In areas where pyrethroid resistance exists, but mosquitoes of the same population differ in their susceptibility to different pyrethroids, should programmes consider selecting one pyrethroid over another in order to manage insecticide resistance? Based on a review of evidence from molecular, laboratory and field data, the authors concluded that differences between adult mosquito mortalities in pyrethroid insecticide resistance assays are not indicative of a true or operationally relevant difference in the potential performance of pyrethroids currently in common use (deltamethrin, permethrin, -cypermethrin and -cyhalothrin). Consequently, switching between pyrethroid insecticides (to improve intervention efficacy) should not be used as a means of managing insecticide resistance. This finding supports WHO's past and present position. Given that pyrethroid resistance in mosquitoes is widespread, WHO encourages the development and continued evaluation of nets treated with alternative insecticides.
Key technical principles for addressing insecticide resistance are as follows:
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
- Insecticides should be deployed with care and deliberation in order to reduce unnecessary selection pressure and maximize impact on disease. National malaria programmes (NMPs) should consider whether they are using insecticides judiciously, carefully and with discrimination, and if there is a clear epidemiological benefit. - Vector control programmes should avoid using a single class of insecticide everywhere and over consecutive years. Whenever possible, vector control programmes should diversify from pyrethroids to preserve their effectiveness. Although pyrethroids will continue to be used for ITNs in the near term, they should not generally be deployed for IRS in areas with pyrethroid ITNs, whether alone or combined with insecticides from a different class.
- IRM principles and methods should be incorporated into all vector control programmes, not as an option, but as a core component of programme design. - NMPs should engage with the agricultural sector to coordinate insecticide use, with the aim of avoiding use of the same classes of insecticide for both crop protection and public health within the same geographical area. - Routine monitoring of insecticide resistance is essential to inform the selection and deployment of insecticides. - The additional costs of deploying new vector control tools as part of a comprehensive IRM response should be balanced against the potential long-term public health impact. Where feasible, formal economic evaluation is encouraged to investigate the likely incremental costs and effectiveness of potential IRM approaches, relative to feasible alternatives, for a given context.
Historically, the most common way insecticides have been deployed to control malaria vectors has been through "sequential use". In essence, this is when a single insecticide class is used continuously or repeatedly until resistance has rendered it less effective or ineffective, after which a switch is made to an insecticide with a different mode of action to which there is no (or less) resistance. In theory, this may allow for an eventual switch back to the original insecticide class if resistance decreases to the point that it is no longer detectable by means of bioassays.
The agricultural industry has had some success in managing resistance by using different insecticides over space and time.
Similar approaches have been proposed with the aim of preventing or delaying the spread and increase of resistance by removing selection pressure or by killing resistant mosquitoes. These strategies include mixtures of insecticides, mosaic spraying, rotations of insecticides and deployment of multiple interventions in combination.
- Mixtures are co-formulations that combine two or more insecticides with different modes of action. Effective deployment of a mixture requires the presence of resistance to all insecticides in the mixture to be rare, so that any individual mosquito that survives exposure to one insecticide is highly likely to be killed by the other insecticide or insecticides. Ideally, all insecticides in a mixture should have a similar residual life and remain bioavailable over time; in practice, this is difficult to achieve, particularly for vector control products that are meant to last for a number of years, such as long-lasting insecticidal nets (LLINs). An ITN product containing a pyrethroid and a pyrrole insecticide and another containing a pyrethroid and a juvenile hormone mimic have been developed and prequalified by WHO. Trials are ongoing to assess the epidemiological impact of these products after which their public health value will be assessed in order to develop any WHO recommendation. A mixture of a pyrethroid and a neonicotinoid insecticide for IRS has been prequalified by WHO.
- Rotations involve switching between insecticides with different modes of action at pre-set time intervals, irrespective of resistance frequencies. The theory is that resistance frequencies will decline (or at least not increase) during the period of non-deployment of insecticides with a specific mode of action. - Mosaics involve the deployment of insecticides with different modes of action in neighbouring geographical areas. The optimal spatial scale (size of areas) for mosaics has yet to be determined, and rotations are generally considered to be more practical and feasible. - Combinations expose the vector population to two classes of insecticides with differing modes of action through the co-deployment of different interventions in the same place, such as ITNs co-deployed with non-pyrethroid IRS (where both are at high coverage; see recommendation under section 4.1.2).
For malaria vector control, however, there is still little evidence of the success of these strategies and no consensus on the best IRM approach or approaches to apply in a given situation. Success of a particular approach will likely depend on mosquito genetics, behaviour and population dynamics, and the chemical nature of the insecticides and their formulation. A 2013 review of experimental and modelling studies on insecticide, pesticide and drug resistance concluded that mixtures generally lead to the slowest evolution of resistance. However, more recently, an exploration of overlaps between agriculture and public health found that -owing to caveats and case specificity -there is only weak evidence of one IRM approach being better than another, and that the standard practice of using insecticides until resistance emerges before switching to an alternative (i.e. sequential use) may be equally effective under certain circumstances. More data, both from research and programmatic operations, are needed to compare resistance management approaches in the field  and to improve understanding of the biological mechanisms that are likely to favour different approaches in different situations .

# Evidence-based planning
To achieve optimal impact against malaria, control measures must be suitable for the geographic area (based on vector bionomics) and, well targeted and deployed at sufficient coverage. Without an evidence base or sufficient capacity to deploy interventions appropriately, resources may be used suboptimally. Given the heavy reliance on insecticidal interventions -primarily ITNs and IRS -the impacts on the environment and insecticide resistance of local vectors are key considerations in vector control planning and implementation. The inappropriate deployment of insecticides both in agriculture and in public health programmes has the potential to result in avoidable insecticide contamination of the environment and/or development of insecticide resistance of local vectors. Ideally, IRM practices should be implemented as part of routine operations, rather than waiting for resistance to spread or increase and for control failure to be suspected or confirmed. A pragmatic approach must be taken that seeks to select appropriate vector control interventions based on the insecticide resistance profile of the major malaria vectors in the target area.
To outline how resistance will be monitored and managed, NMPs should develop and implement national plans in accordance with the WHO Framework for a national plan for monitoring and management of insecticide resistance in malaria vectors.
Detailed information on insecticide resistance monitoring methods and on how to use the data to inform the selection of appropriate interventions will be provided in the revised WHO Test procedures of monitoring insecticide resistance in malaria vectors, anticipated to be published in 2022. Further information on insecticide resistance monitoring and, more broadly, on entomological surveillance is included in the WHO Malaria surveillance, monitoring & evaluation: a reference manual, which outlines priority data across different transmission settings.
IRM plans should be revisited regularly to consider new information, and to integrate new interventions once they have been supported by WHO recommendations and prequalified.

# Vector control across different malaria transmission settings
Access to effective vector control interventions will need to be maintained in the majority of countries and locations where malaria control has been effective. This includes settings with ongoing malaria transmission, as well as those in which transmission has been interrupted but in which some level of receptivity and vulnerability remains. Malaria elimination is defined as the interruption of local transmission (reduction to zero incidence of indigenous cases) of a specified malaria parasite species in a defined geographical area as a result of deliberate intervention activities. Following elimination, continued measures to prevent re-establishment of transmission are usually required. Interventions are no longer required once eradication has been achieved. Malaria eradication is defined as the permanent reduction to zero of the worldwide incidence of infection caused by all human malaria parasite species as a result of deliberate activities.

# Residual transmission
WHO acknowledges that malaria can persist despite high coverage of antimalarial interventions, including in areas with optimal access to and use of ITNs or with high IRS coverage. This persistence of malaria transmission following the implementation in time and space of a widely effective malaria programme is referred to as residual transmission. Residual transmission occurs as a result of a combination of human and vector behaviours, for example, when people reside in or visit forest areas or do not sleep in protected houses, or when local mosquito vector species exhibit one or more behaviours that enable them to avoid vector control interventions, such as biting outside early in the evening before people have retired indoors and/or resting outdoors. The sources and risk of residual transmission may, therefore, vary by location, time and the existing components of the current malaria programme.
In some settings, supplementary interventions may be used in addition to ITNs or IRS to further reduce transmission.
Recommendations on larviciding with chemical or biological insecticides and the use of house screening are outlined in a subsequent chapter. Supplementary interventions should be implemented in accordance with the principles outlined in the Global vector control response 2017-2030.
Residual transmission can be difficult to measure, as is the specific impact of supplementary tools on this component of ongoing transmission. Standardized methods for quantifying and characterizing this component of transmission are required in order to evaluate the effectiveness of single or combined interventions in addressing this biological challenge to malaria prevention, control and elimination.
There is an urgent need for greatly improved knowledge of the bionomics of the mosquitoes responsible for maintaining local transmission. New interventions and strategies should be evaluated against these vectors in order to effectively address residual transmission. While this knowledge is being gained and interventions are being developed, NMPs must prioritize the effective implementation of current interventions to reduce transmission to the lowest level possible. At the same time, they should collaborate with academic or research institutions to generate local evidence on the magnitude of the problem of residual transmission of malaria, including information on human and vector behaviours, and the effectiveness of existing and novel interventions.

# Acceptability, participation and ethical considerations
Community participation in the implementation of vector control interventions often takes the form of "instruction" or "information", with decisions about the need for interventions being made at international and national levels. Taking into account communities' views on the recommended interventions may promote acceptance and adherence to the intervention. Increased levels of participation (e.g. consultation, inclusion and shared decision-making) should be included in the development and deployment of vector control interventions -from inception through to the planning and implementation stages.
WHO acknowledges that appropriate policy-making often requires explicit consideration of ethical matters in addition to scientific evidence. However, the ethical issues relevant to vector-borne disease control and research have not received the analysis necessary to further improve public health programmes. Moreover, WHO Member States lack specific guidance in this area. The Seventieth World Health Assembly  requested the Director-General "to review and provide technical guidance on the ethical aspects and issues associated with the implementation of new vector control approaches in order to develop mitigating strategies and solutions; and to undertake a WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) review of the ethical aspects and related issues associated with vector control implementation that include social determinants of health, in order to develop mitigating strategies and solutions to tackle health inequities." A scoping meeting was convened by WHO to identify the ethical issues associated with vector-borne diseases. Unique ethical issues associated with vector control that were identified include the ethics of coercive or mandated vector control, the deployment of insecticides (and growing vector resistance to insecticides), and research on and/ or deployment of new vector control technologies. Genetically modified mosquitoes are one such innovation that presents potential challenges, including how to prevent their spread beyond the intended geographical target areas and limit potential effects on the local fauna. In 2020 WHO published guidance on vector-borne disease and ethical considerations. Work is continuing the develop guidance in this area.
Equity, gender and human rights WHO advocates for optimal coverage with recommended vector control interventions. As such, malaria vector control should be implemented without discrimination on the basis of age, sex, ethnicity, religion or other characteristics. In some cases, special effort is required to reach populations that are geographically isolated or adopt a nomadic lifestyle.

# Resource implications and prioritization
In the Guidelines, resource implications and the costeffectiveness of vector control interventions have been largely addressed by drawing on a recent systematic review of the cost and cost-effectiveness of vector control interventions  and expert opinion within the GDG.
The systematic review of the cost and cost-effectiveness of vector control interventions that was used to inform the current vector control guidelines was published in 2021, as part of a broader systematic review on the cost and cost-effectiveness of malaria control interventions, drawing on evidence published between 2005 and 2018. The body of evidence on vector control interventions was based on the use of ITNs/LLINs, IRS and larval source management (LSM) mostly in sub-Saharan African countries. The review reported that, overall, WHOrecommended malaria interventions including vector control represent value for money; however, there was great variation in the costs of intervention delivery, reflecting not only differences in the actual resource use, but also the various types of costing methodologies employed. The available cost and costeffectiveness data focused largely on individual interventions and less so on packages of interventions, which are recommended for effective malaria control. The authors reported that, due to the heterogeneity of the study contexts and the way data were presented, comparative analysis of the cost-effectiveness of interventions was not possible.
The WHO Global Malaria Programme is working with partners to update the evidence review on the cost and costeffectiveness of the vector control interventions covered in the Guidelines to support future Guideline development deliberations, for example, by building and updating a database for the cost and cost-effectiveness of vector control and other malaria interventions. It is also planned that systematic reviews commissioned in the future will include a search of the literature on both the cost and cost-effectiveness of interventions under consideration as well as those previously approved.

# Interventions recommended for large-scale deployment
Interventions that are recommended for large-scale deployment in terms of malaria vector control are those that have proven protective efficacy to reduce or prevent infection and/or disease in humans and are broadly applicable for populations at risk of malaria in most epidemiological and ecological settings.
Vector control interventions applicable for all populations at risk of malaria in most epidemiological and ecological settings are: i) deployment of ITNs that are prequalified by WHO, and ii) IRS with a product prequalified by WHO. Between 2000 and 2015, 78% of the clinical malaria cases averted was attributed to insecticidal vector control, namely through the widespread scale-up of ITNs and IRS.
Programmatic targets against malaria, as detailed within national strategic plans, should be used to guide the decisionmaking process to assemble context-appropriate intervention packages. Decision-making around the intervention mix to deploy and the coverage level of each intervention needs to consider available local data to guide the stratification of interventions, the available funding, the relative costeffectiveness of available intervention options, the resources required to provide access within the broader context of universal health coverage (UHC), the feasibility of deploying the intervention(s) at the desired coverage level, and the country's strategic goal. The resulting optimal coverage of the components of an intervention package for a given geographical area will also depend on other site-specific factors such as past and present transmission intensity, past and present intervention coverage, acceptability, and equity of access/use.
For malaria vector control interventions recommended for large-scale deployment namely, ITNs and IRS, optimal coverage refers to providing populations at risk of malaria with access to ITNs coupled with health promotion to maximize use, and ensuring timely replacement; or providing these populations with regular application of IRS. Either intervention should be deployed at a level that provides the best value for money while reflecting programmatic realities. In practice, this often means quantifying commodities to provide full access by the population at risk while realizing that this will not result in 100% coverage or 100% access due to various system inefficiencies. Being cognizant of such constraints, decisionmaking should then consider other alternatives as part of the intervention package, ranging from chemoprevention to supplementary vector control, instead of pursuing the idealistic WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) goal of providing full population coverage.

# Insecticide-treated nets
For the ITN classes covered by WHO recommendations as interventions for use in protecting populations at risk of malaria, including in areas where malaria has been eliminated but the risk of reintroduction remains, WHO recommends products that have been prequalifed by WHO. WHO Member States and their procurement partners are encouraged to draw on the list of prequalified products to inform their choice of product(s).
An ITN may repel, disable and/or impact the fecundity of mosquitoes that come into contact with the insecticide on the netting material in addition to providing a physical barrier, thereby protecting the individual user. In addition, some studies have indicated that ITNs produce a "community effect", which means that when enough ITNs are being used in a community, the survival of the mosquito population as a whole is affected; this effect increases the protection against malaria for ITN users and extends protection to members of the community who do not sleep under an ITN  . However, such a community effect has not been observed in all settings . The WHO Global Malaria Programme commissioned a review to examine the evidence for a community effect and to investigate the biological mechanisms by which ITNs provide both personaland community-level protection against malaria. The review also investigated what factors may determine the presence of a community effect and moderate its intensity (Lines et al unpublished evidence).
The review concluded that a community effect does occur in the majority of settings, and that its extent is driven by a number of contextual factors. These factors include vector behaviour (particularly the extent of anthropophily, i.e. the propensity to feed on people, and endophagy, i.e. the tendency of mosquitoes to blood-feed indoors); the relative availability of human and non-human hosts in the locality; the level of ITN coverage and use in a community; the insecticide used (its residual insecticidal activity and repellency); and the resistance of the local malaria vectors, both physiological and behavioural, to the insecticide on the net.
The ITN coverage threshold for when the community effect becomes apparent depends on a large number of contextual factors. Regardless of the context-dependent starting threshold, the extent of the community-level protection increases as ITN coverage and net use in a given community increases. Because ITNs kill insecticide-susceptible mosquitoes that come into contact with the insecticide on the netting material, more mosquitoes will be killed as ITN coverage increases. This killing effect reduces both mosquito population density and mosquito longevity, resulting in fewer malaria vectors overall and a lower infectivity rate as fewer mosquitoes will survive the time it takes for the malaria parasite to develop in the mosquito. Consequently, the reduced density, age and proportion of the local mosquito population that is infective offer an additional level of protection to the community as a whole beyond the individual protection provided by ITNs.
Large-scale field trials   and transmission models   originally suggested that community coverage (i.e. the proportion of human population using an ITN with effective insecticide treatments each night) of  50% is expected to result in some level of community-wide protection. The WHO-commissioned review indicated that this area-wide protection may start to occur at lower coverage levels (Lines et al unpublished evidence). The review modelled the short-term effect of increasing ITN coverage on the EIR (infectious bites per person per year) in an area with high malaria transmission and an insecticide-susceptible, anthropophilic vector, assuming fixed human infectiousness. In the coverage range of 15% to 85%, an additional 20% increase in coverage of the human population at risk was shown to result in a reduction in malaria transmission intensity of approximately 50% (these findings are taken from the report submitted to WHO; findings may be revised if indicated by peer review). Additional ITN coverage is always beneficial in terms of providing more protection to individuals -both users and non-users of ITNs -and, conversely, any reduction in coverage may result in increased malaria transmission. However, there may be diminishing marginal returns to increasing coverage at higher levels. In terms of absolute cases of malaria averted, a reduction in malaria transmission when increasing ITN coverage from 80% to 100% may not generate the same impact as a 20% increase in coverage at lower levels of coverage; the marginal costs required to increase coverage at high levels (>80%) will also increase due to growing system inefficiencies. At the country level, these diminishing returns must be balanced against potential investments in other costeffective malaria prevention and control activities by means of a well-informed prioritization process.
Three main ITN classes are recognized by WHO as given below. With the March 2023 update to the guidelines, these classes are now formally:
- ITNs designed to kill host-seeking insecticide-susceptible mosquito populations that have demonstrated public health value compared to untreated nets and whose entomological effects consist of killing and reducing the blood-feeding of insecticide-susceptible mosquito vectors. This intervention class covers pyrethroid-only nets prequalified by WHO and conventionally treated nets that rely on periodic retreatment with a WHO prequalified self-treatment kit.
Public health value has been demonstrated for products within this class and WHO recommends use of pyrethroid-only LLINs prequalified by WHO for largescale deployment. - ITNs designed to kill host-seeking insecticide-resistant mosquitoes and for which a first-in-class product demonstrates public health value compared to the epidemiological impact of pyrethroid-only nets. This class includes nets that are treated with a pyrethroid insecticide and a synergist such as piperonyl butoxide (PBO) and nets WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) treated with insecticides other than pyrethroid-based formulations. Public health value has been demonstrated for this class and WHO has issued recommendations for deployment of pyrethroid-PBO nets and for pyrethroidchlorfenapyr nets in areas with pyrethroid-resistant mosquitoes. - ITNs designed to sterilize and/or reduce the fecundity of host-seeking insecticide-resistant mosquitoes for which a first-in-class product demonstrates public health value compared to the epidemiological impact of pyrethroidonly nets. Nets treated with pyrethroid + pyriproxyfen (an insect growth regulator), which fall into this class, are now conditionally recommended for deployment instead of pyrethroid-only LLINs.
ITNs are most effective where the principal malaria vector(s) mosquitoes bite predominantly at night after people have retired under their nets. ITNs can be used both indoors and outdoors, wherever they can be suitably hung (although hanging nets in direct sunlight should be avoided, as sunlight can affect insecticidal activity).
Indoor residual spraying IRS is the application of a residual insecticide to potential malaria vector resting surfaces, such as internal walls, eaves and ceilings of houses or structures (including domestic animal shelters), where such vectors are likely to come into contact with the insecticide. IRS with a WHO-prequalified product is recommended for large-scale deployment in most malariaendemic locations. IRS is most effective where the vector population is susceptible to the insecticide(s) being applied, where the majority of mosquitoes feed and rest indoors, and where most structures are suitable for spraying. In deciding whether to deploy IRS, programmes should consider whether achieving the target coverage of IRS is feasible.

# Humanitarian emergencies
The first priorities for malaria control in a humanitarian emergency are prompt and effective diagnosis and treatment. Deployment of ITNs and IRS have been shown to provide protection against malaria in the limited number of studies that have been carried out in the chronic phase of emergencies     (Messenger et al unpublished evidence). However, deployment of such interventions may be logistically challenging during the acute phase of a humanitarian emergency. In the following sections, recommendations regarding the deployment of ITNs and IRS are provided.
Some vector control interventions and personal protection measures have been specifically designed for deployment in emergency situations. Such interventions include insecticidetreated plastic sheeting (ITPS), which can be used to construct temporary shelters; insecticide-impregnated blankets or topsheets, which may be included in emergency relief kits provided at the outset of an emergency; repellents; and treating cattle with insecticides. For all of these interventions, a limited number of studies have evaluated their efficacy in humanitarian emergencies  (Messenger et al unpublished evidence) and, as such, the evidence base on the effectiveness of these interventions against malaria is currently insufficient to formulate recommendations.
As in more stable settings, the appropriateness and effectiveness of vector control in humanitarian emergencies will depend on:
- the malaria infection risk;
- the behaviour of the human population (e.g. mobility, where they are sleeping or being exposed to vector mosquitoes); and - the behaviours of the local vector population (e.g. indoor resting, indoor biting, early evening or night biting).
In humanitarian emergencies, further consideration must be given to whether the delivery of vector control interventions is feasible. This may depend on:
- the type of shelter available (e.g. ad hoc refuse materials, plastic sheeting, tents, more permanent housing); and - the available infrastructure, resources and human capacity to deliver vector control.

# Practical Info
The current WHO recommendation for ITNs applies only to those mosquito nets that have been prequalified by WHO and Strong recommendation for High certainty evidence

# Pyrethroid-only nets (2019)
Pyrethroid-only long-lasting insecticidal nets (LLINs) should be deployed for the prevention and control of malaria in children and adults living in areas with ongoing malaria transmission.
- WHO recommends ITNs that have been prequalified by WHO for deployment in protecting populations at risk of malaria.
- ITNs are most effective where the principal malaria vector(s) bite predominantly at night after people have retired under their nets. - ITNs can be used both indoors and outdoors, wherever they can be suitably hung (though hanging nets in direct sunlight should be avoided, as sunlight can affect insecticidal activity).
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) that contain only an insecticide of the pyrethroid class (categorized as 'pyrethroid-only LLINs').
As with all insecticide-based interventions, the insecticide resistance profile of the vectors within the area of deployment should be assessed. If pyrethroid-resistance is detected, pyrethroid-PBO ITN or pyrethroid-chlorfenapyr ITNs should be considered for distribution, and pyrethroid-pyrproxyfen ITNs may be considered, instead of pyrethroid-only nets (see the following recommendations on the other types of nets).
ITNs are generally acceptable to most communities. In many malaria-endemic countries, untreated nets were in use for many years prior to the introduction of ITNs and, even where there is not a long history of their use, they have become familiar tools for preventing mosquito bites. Individuals often appreciate the extra privacy afforded by a net, as well as its effectiveness in controlling other nuisance insects. In very hot climates, ITNs may be less acceptable, as they are perceived to reduce air flow, making it too hot to allow for a comfortable sleep. In areas where mosquito densities are low or where malaria transmission is low, individuals and communities may perceive less benefit to using nets.
When deploying ITNs, coverage must be optimized such that both personal and community-level effects are maximized and maintained in endemic settings. Post-distribution monitoring of nets is essential, reporting their durability, usage and coverage. Evaluation of the impact on vectors, such as their abundance, EIR and behaviour, and insecticide resistance status can be used to inform and guide future deployment.
Nets should be handled and disposed of appropriately to minimize risk to human and animal health and of environmental contamination. WHO recommends that old nets are not burned in the open air but are buried, preferably in non-permeable soil and away from water sources. Burning may lead to the release of dioxins, which are harmful to human health. The insecticides used on nets are toxic to aquatic organisms and so should not be disposed of in water.

# Evidence To Decision
The systematic review  reported that ITNs significantly reduce all-cause child mortality (rate ratio: 0.83; 95% CI: 0.77-0.89; high-certainty evidence), incidence of P. falciparum malaria (rate ratio: 0.55; 95% CI: 0.48-0.64; highcertainty evidence), prevalence of P. falciparum malaria (risk ratio: 0.83; 95% CI: 0.71-0.98; high-certainty evidence), and incidence of severe malaria disease (rate ratio: 0.56; 95% CI: 0.38-0.82; high-certainty evidence) compared to no nets.
No undesirable effects were identified in the systematic review. However, the panel noted that brand new nets recently removed from packaging may cause slight, transitory irritation to skin, eyes, nose, etc. Some users complain that the nets are too hot to sleep under, especially during the warmer seasons. As with any insecticide-based intervention, ITNs may also play a role in insecticide resistance development in Anopheles vectors, and there is a risk of environmental contamination with potential toxic effects on animals if nets are not handled or disposed of carefully (see section on Practical Info).

# Benefits and harms
The systematic review determined that, overall, the evidence that ITNs have an impact on malaria was high compared to no nets and compared to untreated nets.

# Certainty of the Evidence
The table below, compiled by the GDG, lists resources that should be considered for the deployment of ITNs. Note that this table does not include resource needs for product selection or assessment of impact of the intervention.
The systematic review  followed the original 2003 analysis, which included insecticide-treated curtains and ITNs together and included two studies solely evaluating insecticide-treated curtains and one study evaluating both ITNs and insecticide-treated curtains. There was no obvious heterogeneity that would lead to a subgroup analysis to examine whether the effects were different, and the results from studies evaluating insecticide-treated curtains were consistent with the results of those evaluating ITNs. The GDG drew on the analysis to make recommendations related to ITNs only.
The systematic review  reported high-certainty evidence that, compared to no nets, ITNs are effective at reducing the rate of all-cause child mortality, the rate of uncomplicated episodes of P. falciparum, the incidence rate of severe malaria episodes, and the prevalence of P. falciparum. ITNs may also reduce the prevalence of P. vivax, but here the evidence of an effect was less certain.
Compared to untreated nets, there was high certainty evidence that ITNs reduce the rate of uncomplicated episodes of P. falciparum and reduce the prevalence of P. falciparum. There was moderate certainty evidence that ITNs also reduce all-cause child mortality compared to untreated nets. The effects on the incidence of uncomplicated P. vivax episodes and P. vivax prevalence were less clear.
The systematic review did not identify any undesirable effects of pyrethroid ITNs.

# Research Needs
- Determine the impact (incidence of malaria  and/or prevalence of malaria infection), as well as potential harms and/or unintended consequences of new types of nets and insecticides in areas where resistance to pyrethroids is high. - Determine the comparative effectiveness and durability of different pyrethroid-only net types.
- Determine the effectiveness of nets in situations of residual/outdoor transmission.
- Determine the impact of ITNs in transmission 'hotspots' and elimination settings.

# Practical Info
Given that the evidence indicates that unwashed pyrethroid-PBO ITNs are more effective than pyrethroid-only LLINs in areas with pyrethroid resistance up to 25 months post-deployment, the decision on whether to switch from pyrethroid-only LLINs to pyrethroid-PBO ITNs, or another ITN product designed to provide enhanced efficacy in areas of pyrethroid resistance, should be guided by resource availability. WHO recommends that pyrethroid-PBO ITNs be used where pyrethroid resistance is confirmed using standard procedures. Given that pyrethroid-PBO nets are designed to provide improved impact against resistant mosquitoes in which pyrethroid resistance is, at least in part, conferred by a monooxygenase-based resistance mechanism, determining the presence of such resistance mechanisms in local vector populations will provide additional information to help target deployment.
In deciding whether to use potentially more expensive pyrethroid-PBO ITNs, malaria programmes should consider the impact this switch may have on vector control coverage. Deployment of pyrethroid-PBO ITNs must only be considered in situations where coverage with effective vector control (primarily ITNs or IRS) will not be reduced. The primary goal must be to ensure continued access and use of ITNs or IRS at levels that ensure optimal coverage for all people at risk of malaria as part of an intervention package. Post-distribution monitoring of nets to estimate coverage in terms of access to and use of nets and other malaria interventions is recommended.
Pyrethroid-PBO ITNs should not be considered a tool that can alone effectively manage insecticide resistance in malaria vectors. Despite the recent recommendation of other ITN classes and associate product, the development and evaluation of Conditional recommendation for Moderate certainty evidence

# Pyrethroid-PBO ITNs (2022)
Pyrethroid-PBO ITNs instead of pyrethroid-only LLINs can be deployed for the prevention and control of malaria in children and adults in areas with ongoing malaria transmission where the principal malaria vector(s) exhibit pyrethroid resistance.
The conditionality of this recommendation is largely driven by the current higher unit cost of pyrethroid-PBO ITNs compared to pyrethroid-only LLINs and therefore the uncertainty of their cost-effectiveness. Furthermore, as PBO is less wash-resistant than pyrethroids, its bioavailability declines faster over the three-year estimated life of an ITN; therefore, the added impact of pyrethroid-PBO ITNs over that of pyrethroid-only LLINs may decline over time. The evidence comes from two sites in eastern Africa with pyrethroid resistance and not from other geographies where transmission levels and vector characteristics may vary. PBO acts by inhibiting certain metabolic enzymes, primarily oxidases, and so are likely to provide greater protection than pyrethroid-only LLINs where mosquitoes display mono-oxygenase-based insecticide resistance mechanisms.
In deciding whether pyrethroid-PBO ITNs may be appropriate in their context, malaria programmes should:
- consider the deployment of pyrethroid-PBO ITNs in areas where resistance to pyrethroids in local vectors has been detected; - determine whether resources are adequate to cover the extra cost of pyrethroid-PBO ITNs, while ensuring that coverage of populations at risk of malaria is not affected; - note that WHO recommends that ITNs prequalified by WHO be selected for deployment.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) ITNs treated with non-pyrethroid insecticides and other innovative vector control interventions for deployment across all settings continues to remain a priority to provide alternatives for use in a comprehensive IRM strategy.
The systematic review reported that the washing of pyrethroid-PBO ITNs may result in lower mosquito mortality and higher blood-feeding success than the washing of pyrethroid-only LLINs. The durability of pyrethroid-PBO ITNs compared to pyrethroid-only LLINs has been questioned previously based on wash-resistance data. The added epidemiological and entomological impact of pyrethroid-PBO ITNs depends on the bioavailability and retention of PBO on/in the net. If this is reduced significantly over time and/or declines with washing, the greater impact of pyrethroid-PBO ITNs over pyrethroidonly LLINs in terms of protection against malaria may be limited to less than three years. In addition, at present, it is unknown how differences in the design/composition of pyrethroid-PBO ITNs affect their relative efficacy. A series of experimental hut trials with entomological end-points using non-inferiority designs have recently been completed with as a means to provide clarity in this respect. As part of M&E activities, data collected by programmes on net durability would provide information on the life span of pyrethroid-PBO ITNs under field conditions and hence on the period over which the additional impact is maintained.
Programmes that decide to switch from pyrethroid-only LLINs to pyrethroid-PBO ITNs based on concerns regarding continued effectiveness and/or insecticide resistance status of local vectors, should not revert back to the use of pyrethroidonly LLINs thereafter. Instead, programmes should plan for continued deployment of pyrethroid-PBO ITNs in that geographic area or develop plans for deployment of other equally or more effective new interventions once these are covered by a WHO recommendation.

# Evidence To Decision
The systematic review  included two trials  from the United Republic of Tanzania and the Republic of Uganda that compared the epidemiological impact of pyrethroid-PBO ITNs against malaria to that of pyrethroid-only LLINs. Both trials were conducted in areas with highly pyrethroid-resistant mosquitoes, defined by the review team as mosquitoes demonstrating <30% mortality in discriminating dose assays. The review provided high-to moderate-certainty evidence that malaria parasite prevalence was lower where pyrethroid-PBO nets were deployed at four time points post net distribution (4-6 months: OR: 0.74; 95% CI: 0.62-0.89, 9-12 months: OR: 0.72; 95% CI: 0.61-0.86, 16-18 months: OR: 0.88; 95% CI: 0.74-1.04, and 21-25 months: OR: 0.79; 95% CI: 0.67-0.95).
The review also reported entomological outcomes, mosquito mortality and mosquito blood-feeding success derived from experimental hut studies. In areas classified by the authors as having highly pyrethroid-resistant mosquitoes, unwashed pyrethroid-PBO ITNs were found to result in higher mosquito mortality and lower blood-feeding success compared to unwashed pyrethroid-only LLINs. Comparing washed pyrethroid-PBO ITNs to washed pyrethroid-only LLINs, however, the review reported that it was unclear whether the washed pyrethroid-PBO ITNs had a greater effect on mosquito mortality, although the washed pyrethroid-PBO ITNs did decrease the blood-feeding success of mosquitoes.
In areas defined as having moderate, low (defined by the review team as 31-60% and 61-90% mosquito mortality, respectively, in discriminating dose assays) or no pyrethroid insecticide resistance, the review did not identify any studies with epidemiological outcomes. Regarding entomological outcomes, mosquito mortality was only shown to be higher with unwashed pyrethroid-PBO ITNs compared to unwashed pyrethroid-only LLINs in those areas with moderate insecticide resistance. Little or no difference was seen in terms of mosquito mortality or blood-feeding rates when washed or unwashed pyrethroid-PBO ITNs were used in areas with low or no resistance compared to pyrethroid-only LLINs.
Given that the systematic review was limited to two studies with malaria outcomes, a number of potential effect modifiers could not be examined. However, as with pyrethroid-only LLINs, the GDG concluded that the extent of the impact of pyrethroid-PBO ITNs is likely to vary in different settings and will depend on a number of factors, such as the behaviour of the main malaria vectors and their level and mechanism(s) of insecticide resistance, the parasite prevalence in that area, and the usage of nets within a community.
The systematic review did not report any harms or unintended consequences of the intervention. However, the GDG noted that, compared to pyrethroid-only LLINs, pyrethroid-PBO ITNs may play an as yet unknown role in the development of insecticide resistance in Anopheles mosquito vectors, such as increasing selection pressure for nonoxygenase resistance mechanisms or perhaps increasing the intensity of oxygenase resistance. In the absence of empirical evidence, this potential undesirable effect was judged to be small.

# Benefits and harms
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
The systematic review assessed that the overall certainty of evidence that pyrethroid-PBO ITNs have an impact on malaria parasite prevalence was moderate.

# Certainty of the Evidence
No research was identified regarding preferences and values. The GDG judged that there was probably no important uncertainty or variability.

# Values and preferences
Similar resources, other than the cost of the ITN itself, are needed for the deployment of the different ITN products that are now available within the WHO recommended classes. (See table provided under 'Resources and other considerations' for pyrethroid-only ITNs.)
Based on the available cost data, the GDG judged that there are currently additional costs associated with deploying pyrethroid-PBO and other types of ITNs over pyrethroid-only LLINs. Due to the likely scale of ITN deployment, any additional cost per net would amount to a considerable additional budget associated with a switch away from pyrethroid-only LLINs, which would need to be met in order to maintain coverage. The GDG, however, remarked that unit costs change over time and, as they do, a review will be needed to determine whether this cost discrepancy remains. National programmes are encouraged to pay specific attention to the commodity cost, as this will also vary depending on required quantities and lead-times and will be a key ingredient to the separately developed guidance on ITN prioritization.
Apart from the higher cost of the net, the GDG identified no additional resource requirements associated with a switch from pyrethroid-only LLINs to pyrethroid-PBO ITNs. Based on experience to date, pyrethroid-PBO ITNs require similar resources to those identified for the distribution of pyrethroid-only LLINs (see table provided under "Resources and other considerations" for pyrethroid-only LLINs). It would be necessary to assess the insecticide resistance status in the principal vector(s) in the area where deployment is planned in order to determine whether pyrethroid resistance is present and thus to justify such deployment. However, regular insecticide resistance testing by means of bioassays should form part of routine programme monitoring operations and therefore should already be part of the budget. Further information justifying the use of pyrethroid-PBO ITNs could be generated using standard WHO procedures  to determine if a monooxygenase-based mechanism is at least partially involved in conferring pyrethroid resistance.
The systematic review reported that cost-effectiveness analyses comparing pyrethroid-PBO ITNs and pyrethroid-only LLINs are currently not available. The GDG concluded that the cost-effectiveness of pyrethroid-PBO ITNs compared to pyrethroid-only LLINs may vary. In areas of pyrethroid resistance, pyrethroid-PBO ITNs may have greater impact on malaria than pyrethroid-only LLINs during the period for which the PBO is bioavailable. However, PBO is less wash-resistant than pyrethroids and its bioavailability therefore declines faster over the three-year estimated life of an ITN. The added impact of pyrethroid-PBO ITNs over that of pyrethroid-only LLINs may be lost or decline considerably over time.
In addition to the issue of durability, the cost-effectiveness may also depend on a number of potential effect modifiers, such as the malaria transmission level and vector characteristics in an area. Lastly, the GDG was concerned that, given flatlined funding for malaria the procurement of pyrethroid-PBO ITNs may negatively impact programmes' ability to maintain ITN coverage of at-risk populations. Due to the current moderately higher cost of this commodity, there is a risk that existing net coverage could not be maintained if no additional funds were made available to cover the additional expenditure required to purchase the same quantity of nets as previously deployed.
The impact on the equity of using pyrethroid-PBO ITNs instead of pyrethroid-only LLINs was judged to vary by the GDG. If switching to more costly pyrethroid-PBO ITNs resulted in lower coverage of those at risk of contracting malaria with preventive tools, equity would likely be reduced. However, if the switch resulted in no reduction in coverage and
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
Pyrethroid-PBO ITNs combine pyrethroids and a synergist, which acts by inhibiting certain metabolic enzymes, primarily oxidases, within the mosquito that would otherwise detoxify or sequester insecticides before they could reach their target site in an insect. Therefore, compared to a pyrethroid-only LLIN, a pyrethroid-PBO ITNs should have an increased killing effect on malaria vectors that express elevated oxidases, which is commonly associated with pyrethroid resistance.
The systematic review  identified and included two trials both from eastern Africa, evaluating parasite prevalence in areas where pyrethroid-PBO ITNs were deployed compared to pyrethroid-only LLINs. Both trials were conducted in areas with highly pyrethroid-resistant mosquitoes, defined by the review team as mosquitoes demonstrating <30% mortality in discriminating dose assays. Parasite prevalence was reduced by approximately 20% up to 25 months after distribution. The Tanzanian trial has been extended further to establish whether this effect lasts the full duration of an LLIN's intended 36-month life span, but results are not yet publicly available.
Although the two epidemiological trials included in the review were from areas where pyrethroid resistance was determined to be high, the methods used by the authors to determine the level of resistance and the categorization of the different bands of resistance intensity were not consistent with those recommended by WHO. In many parts of Africa, as well as other parts of the world, pyrethroid resistance is becoming more prevalent and is generally increasing in intensity in the presence of continued selection pressure. The panel therefore concluded that pyrethroid-PBO ITNs are likely to offer greater protection against malaria than pyrethroid-only LLINs in most areas where pyrethroid resistance is detected and mediated by elevated oxidases, regardless of resistance intensity.
When moving from the evidence provided to a decision on the strength of the recommendation, the GDG concluded that the recommendation should be conditional rather than strong for this intervention. In the context of guideline development, a conditional recommendation reflects the lower strength of a recommendation and one for which the GDG concludes that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects, but the panel is not confident about these trade-offs. The conditionality of this recommendation was based on the fact that the available evidence was only from African sites with pyrethroid resistance, rather than from other geographies; the moderate additional benefit of deploying pyrethroid-PBO ITNs compared to pyrethroid-only LLINs; the overall moderate certainty of the results; the higher unit cost of pyrethroid-PBO ITNs compared to pyrethroid-only LLINs; and the uncertainty of costeffectiveness.

# Research Needs
WHO encourages additional high-quality research to generate further evidence on:
- the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/ unintended consequences of pyrethroid-PBO ITNs in areas where the mechanisms of resistance in vector species are not oxidase-based and in areas of lower malaria transmission intensity; - contextual factors (e.g. acceptability, feasibility, resource use, cost-effectiveness, equity, values and preferences) related to pyrethroid-PBO ITNs; - the durability of pyrethroid-PBO ITNs.
those populations who were previously provided with pyrethroid-only LLINs were then protected against malaria by a slightly more effective intervention, equity would likely increase.
No research was identified regarding the acceptability of pyrethroid-PBO ITNs. However, the GDG judged that such nets would be equally acceptable to key stakeholders, given that they are by-and-large physically the same as and used similarly to pyrethroid-only LLINs.
No research was identified regarding the feasibility of implementing pyrethroid-PBO ITNs. Nevertheless, the GDG judged that distributing such nets would be equally feasible as for pyrethroid-only LLINs.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)

# Evidence To Decision

# Practical Info
Given that pyrethroid-chlorfenapyr ITNs are designed to provide improved impact against insecticide-resistant mosquitoes, pyrethroid resistance in potential target areas should be confirmed using standard procedures as should the susceptibility of local vectors to chlorfenapyr. In any case, pyrethroid-chlorfenapyr ITNs should not be considered a tool that alone can effectively manage insecticide resistance in malaria vectors.
As with all malaria interventions, post-distribution monitoring of ITNs to estimate coverage in terms of access to and use of ITNs is recommended. WHO also recommends that programmes conduct studies of ITN survival, which includes assessments of ITN integrity, each time a campaign uses a new product such as pyrethroid-chlorfenapyr ITNs. Such studies will provide information on the product's life span under field conditions and thus enable estimation of the period over which the additional impact against malaria may be maintained. The systematic review reported that, two years after deployment, 34% of pyrethroid-chlorfenapyr ITNs were torn (defined as hole area  790 cm2) and therefore not fit for use, compared to 28% of pyrethroid-only LLINs and 43% of pyrethroid-PBO ITNs.

# Strong recommendation for Moderate certainty evidence

# Pyrethroid-chlorfenapyr ITNs vs pyrethroid-only LLINs (2023)
Pyrethroid-chlorfenapyr ITNs should be deployed instead of pyrethroid-only LLINs for prevention of malaria in adults and children in areas with pyrethroid resistance.
Note: Recommendations on deployment of pyrethroid-chlorfenapyr nets were separated into two distinct recommendations for better clarity, but share the same evidence to decision, justification, practical info and research needs. Please refer to the following section.

# Certainty of the Evidence

# Conditional recommendation for Moderate certainty evidence

# Pyrethroid-chlorfenapyr ITNs vs pyrethroid-PBO ITNs (2023)
Pyrethroid-chlorfenapyr ITNs can be deployed instead of pyrethroid-PBO ITNs for prevention of malaria in adults and children in areas with pyrethroid resistance.

# The conditionality of the recommendation to deploy pyrethroid-chlorfenapyr ITNs instead of pyrethroid-PBO ITNs is based on the GDG's judgement that the balance of desirable and undesirable effects probably favours pyrethroid-chlorfenapyr

# Evidence To Decision
Given that the systematic review  was limited to two studies with malaria outcomes, a number of potential effect modifiers could not be examined. The GDG concluded that the extent of the impact of pyrethroid-chlorfenapyr ITNs is likely to vary by setting and will depend on several factors such as intensity of malaria transmission, behaviour of the main malaria vectors, the level and mechanism(s) of insecticide resistance, and the usage of ITNs within a community. The GDG also noted that both the type and dosage of pyrethroid on the pyrethroid-only LLINs and on pyrethroid-chlorfenapyr ITNs (alphacypermethrin) differed from those on the pyrethroid-PBO ITNs (permethrin), and this may influence the impact against malaria. Furthermore, the GDG observed that the resistance mechanism of the vector population at the study site was not reported. If the pyrethroid resistance in the study was not due to P450-based mechanisms, the effect of the pyrethroid-PBO ITNs may have been underestimated, as these nets would not have offered the same level of protection than in areas where resistance is conferred, at least partly, by P450-based mechanisms.
The systematic review reported  that one trial  recorded 90 (44.1%) adverse events in the group assigned to the pyrethroid-only LLINs, 17 (8.5%) in the pyrethroid-chlorfenapyr ITN group and 17 (8.5%) in the pyrethroid-PBO ITN group. The authors also narratively reported that skin irritation was the most commonly reported adverse event; however, no adverse event was assessed as serious. While five deaths were reported in the cohort, three of these were from drowning, one was due to severe malaria and one to pneumonia; all of these deaths were judged to be unrelated to the study interventions.
The review also reported data on ITN integrity from the United Republic of Tanzania. The numbers (proportion) of torn ITNs (defined as hole area  790 cm2 and therefore not serviceable) were reported as 86 (28%) in the pyrethroidonly LLIN group, 96 (34%) in the pyrethroid-chlorfenapyr ITN group and 81 (43%) in the pyrethroid-PBO ITN group.
The GDG noted that, compared to pyrethroid-only LLINs, pyrethroid-chlorfenapyr ITNs may exert an as yet unknown selection pressure for the development of resistance to pyrrole insecticides and non-oxygenase resistance mechanisms in Anopheles mosquito vectors.
Overall, the GDG judged that the extent of undesirable effects associated with pyrethroid-chlorfenapyr ITNs was small compared to either pyrethroid-only LLINs or pyrethroid-PBO ITNs and that the overall balance of effects probably favours pyrethroid-chlorfenapyr ITNs.

# Benefits and harms
Based on the systematic review the GDG concluded that the overall certainty of evidence that pyrethroid-chlorfenapyr ITNs have an impact against malaria was moderate.

# Certainty of the Evidence
No research was identified regarding preferences and values. The GDG judged that there was probably no important uncertainty or variability associated with pyrethroid-chlorfenapyr ITNs.

# Values and preferences
Similar resources, other than commodity costs, would be needed for the deployment of pyrethroid-chlorfenapyr ITNs as those listed for pyrethroid-only LLINs. (See
Pyrethroid-chlorfenapyr ITNs combine two active ingredients: a pyrethroid and a pyrrole insecticide. They are designed to associated with a switch from pyrethroid-only LLINs to pyrethroid-chlorfenapyr ITNs, which would need to be met in order to maintain the same population coverage.
The GDG, however, remarked that unit costs change over time and often decrease as new technologies are brought to scale. As pyrethroid-chlorfenapyr ITNs are scaled up, further review will be needed to determine whether this cost difference remains. National programmes are encouraged to pay specific attention to the commodity cost, as this will also vary depending on required quantities and lead-times and will be a key ingredient to the separately developed guidance on ITN prioritization.
Insecticide resistance status of the principal vector(s) in the area where deployment is planned should be assessed to justify deployment of pyrethroid-chlorfenapyr nets. However, regular insecticide resistance testing by means of bioassays  should already be part of routine monitoring operations and programme budgets.
The systematic review reported that the study conducted in the United Republic of Tanzania  carried out cost-effectiveness analyses that compared pyrethroid-chlorfenapyr ITNs and pyrethroid-PBO ITNs to pyrethroid-only LLINs over the two-year period of the trial. Pyrethroid-chlorfenapyr ITNs were estimated to avert 152 DALYs  per 10 000 total population, while pyrethroid-PBO ITNs averted 37 DALYs  per 10 000 population. When considering the costs of malaria diagnosis and treatment, pyrethroid-chlorfenapyr ITNs were reported to be less costly (incremental cost US$ 2894  per 10 000 population) than pyrethroid-PBO ITNs (US$ 4816 from all perspectives. From societal and household perspectives, pyrethroid-chlorfenapyr ITNs would be more effective and less costly than either pyrethroid-only LLINs or pyrethroid-PBO ITNs over a two-year period. The GDG concluded that the cost-effectiveness would probably favour pyrethroid-chlorfenapyr ITNs over pyrethroid-only LLINs and pyrethroid-PBO ITNs.
The GDG was concerned that, given flatlined funding for malaria the procurement of pyrethroid-chlorfenapyr ITNs may negatively impact the ability of programmes to maintain ITN coverage of at-risk populations. Due to the current moderately higher cost of this commodity, there is a risk that programmes may not be able to maintain existing ITN coverage or coverage of other malaria interventions if no additional funds to cover the higher costs are made available. Some pragmatic prioritization guidance  has been provided with a view to supporting programmes in decision-making around the deployment of new types of nets in resource-constrained environments.
The GDG judged that the impact on the equity of using pyrethroid-chlorfenapyr ITNs instead of pyrethroid-only LLINs or pyrethroid-PBO ITNs is variable. If switching from pyrethroid-only LLINs to more costly pyrethroid-chlorfenapyr ITNs would result in lower coverage of preventive interventions for those at risk of malaria, equity may be reduced. However, if the switch resulted in no reduction in coverage (due to increased funding or price reduction) and those populations who were previously provided with pyrethroid-only LLINs were then protected from malaria by a more effective intervention, equity would likely increase.
No research was identified regarding the acceptability of pyrethroid-chlorfenapyr ITNs. However, the GDG judged that such ITNs would be acceptable to key stakeholders, given that they are largely similar to pyrethroid-only LLINs and pyrethroid-PBO ITNs in terms of their appearance, design and use, and given that they are currently available at a cost similar to that of pyrethroid-PBO ITNs.
Although no research was identified regarding the feasibility of implementing pyrethroid-chlorfenapyr ITNs, the GDG judged that deploying these ITNs would be as feasible as deploying pyrethroid-only LLINs or pyrethroid-PBO ITNs.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) kill mosquitoes that are resistant to pyrethroids and, as such, fall into the second class of ITNs recognized by WHO. Pyrrole insecticides such as chlorfenapyr disrupt adenosine 5'-triphosphate production in the mosquito's mitochondria, thereby reducing the target insects' ability to produce energy and leading to cell dysfunction and subsequent death. Pyrethroids, meanwhile, target voltage-gated sodium channels associated with the nervous system of the insect, which results in muscular paralysis and rapid death. Due to its different mode of action, chlorfenapyr is, therefore, unlikely to show any cross-resistance to standard neurotoxic insecticides such as pyrethroids. Furthermore, death of the insect may occur 24-48 hours after exposure to chlorfenapyr, in contrast to pyrethroids, which result in a more rapid kill. The different entomological mode and site of action of chlorfenapyr may reduce selection pressure for insecticide resistance. By including two active ingredients in an ITN, the likelihood of the mosquitoes being resistant to both is greatly reduced. Therefore, compared to pyrethroid-only LLINs or pyrethroid-PBO ITNs, pyrethroid-chlorfenapyr ITNs should have an increased killing effect against pyrethroid-resistant malaria vectors and thus a greater impact against malaria.
The systematic review  identified and included two trials   from eastern and western Africa evaluating the impact of pyrethroid-chlorfenapyr ITNs on incidence of clinical malaria and prevalence of malaria infection, compared to pyrethroid-only LLINs or pyrethroid-PBO ITNs. Both trials were conducted in areas with high malaria transmission (malaria infection prevalence in children under 10 years of age recorded as 20-40%) and pyrethroid-resistant mosquitoes. Compared to pyrethroid-only LLINs, incidence of clinical malaria (defined as malaria symptoms, i.e. current fever with a temperature  37.5C or fever in the past 48 hours, plus malaria parasitaemia) was reduced by approximately 55% one year after deployment of pyrethroid-chlorfenapyr ITNs and by 40% two years postdeployment. Prevalence of malaria infection (regardless of symptoms) was reduced by approximately 20% one year after deployment and by approximately 45% two years post-deployment. Compared to pyrethroid-PBO ITNs, pyrethroidchlorfenapyr ITNs had little or no effect on incidence of clinical malaria one year after their deployment. However, after two years, incidence was reduced by 35%. Prevalence of malaria infection was reduced by approximately 20% one year postdeployment and by 30% two years post-deployment. The trials in Benin and the United Republic of Tanzania are continuing and will investigate whether the protective effect lasts the full duration of an LLIN's intended 36-month life span. Results are not available yet.
When moving from the evidence provided by the systematic review to a decision as to the strength of the recommendation, the GDG concluded that there should be a strong recommendation to deploy pyrethroid-chlorfenapyr ITNs instead of pyrethroid-only LLINs in areas where malaria vectors are resistant to pyrethroids. This was due to the large effect against malaria and the high certainty that the benefits of deploying pyrethroid-chlorfenapyr ITNs instead of pyrethroid-only LLINs would outweigh any harms. However, the panel concluded that the recommendation to deploy pyrethroid-chlorfenapyr ITNs instead of pyrethroid-PBO ITNs in areas of insecticide resistance should be conditional. This was based on the fact that the available evidence was from only one trial in the United Republic of Tanzania, where intensity of malaria transmission is high and An. funestus is the primary malaria vector, which in turn limits generalizability of the findings to other geographies with different anopheline vectors and eco-epidemiological characteristics. Furthermore, deploying pyrethroid-chlorfenapyr ITNs was associated with a moderate additional benefit compared to pyrethroid-PBO ITNs two years after ITN deployment, but with little or no difference in malaria outcomes one year after deployment.

# Research Needs
WHO encourages additional high-quality research to generate further evidence on:
- the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/ unintended consequences of pyrethroid-pyriproxyfen ITNs in areas with insecticide resistance traits in the local primary vectors that differ from those of the available studies; - contextual factors (e.g. acceptability, feasibility, resource use, cost-effectiveness, equity, values and preferences) related to use of pyrethroid-chlorfenapyr ITNs; and - the durability of pyrethroid-chlorfenapyr ITNs under field conditions.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)

# Evidence To Decision

# Practical Info
Given that pyrethroid-pyriproxyfen ITNs are designed to provide improved impact against resistant mosquitoes, pyrethroid resistance in potential target areas should be confirmed using standard procedures as should susceptibility of the local vectors to pyriproxyfen. In any case, pyrethroid-pyriproxyfen ITNs should not be considered a tool that alone can effectively manage insecticide resistance in malaria vectors.
As with all malaria interventions, post-distribution monitoring of ITNs to estimate coverage in terms of access to and use of ITNs is recommended. WHO also recommends that programmes conduct studies of ITN survival each time a campaign uses a new product such as pyrethroid-pyriproxyfen ITNs, including assessment of ITN integrity. Such studies will provide information on the life span of the product under field conditions and thus enable estimation of the period over which the additional impact against malaria may be maintained. The systematic review reported that, two years after deployment, 39% of pyrethroid-pyriproxyfen ITNs were torn (defined as having a total hole area  790 cm2 and therefore assumed to be not fit for use), compared to 28% of pyrethroid-only LLINs and 43% of pyrethroid-PBO ITNs.

# Conditional recommendation for Moderate certainty evidence

# Pyrethroid-pyriproxyfen ITNs vs pyrethroid-only LLINs (2023)
Pyrethroid-pyriproxyfen ITNs can be deployed instead of pyrethroid-only LLINs for prevention of malaria in adults and children in areas with pyrethroid resistance.
The conditionality of the recommendation to deploy pyrethroid-pyriproxyfen ITNs instead of pyrethroid-only LLINs is based on the GDG's concerns that the available evidence indicates poor cost-effectiveness of pyrethroid-pyriproxyfen ITNs compared to pyrethroid-only LLINs and that the extra resources currently required to purchase these ITNs may negatively impact on coverage and equity.
In deciding whether pyrethroid-pyriproxyfen ITNs should be deployed instead of pyrethroid-only LLINs, malaria programmes should:
- determine whether resources are adequate to cover the extra cost compared to pyrethroid-only LLINs, while ensuring optimal coverage of populations at risk of malaria; - generate additional information or conduct analyses with the aim of maximizing impact through targeted deployment (e.g. stratification of malaria risk, assessment of the characteristics of local vectors, such as pyrethroid resistance mechanisms); and - note that WHO recommends that ITNs prequalified by WHO be selected for deployment.
Note: Recommendations on deployment of pyrethroid-pyriproxifen nets were separated into two distinct recommendations for better clarity, but share the same evidence to decision, justification, practical info and research needs. Please refer to the following section.

# Certainty of the Evidence

# Conditional recommendation against Moderate certainty evidence

# Pyrethroid-pyriproxyfen ITNs vs pyrethroid-PBO ITNs (2023)
Pyrethroid-pyriproxyfen ITNs are not recommended for deployment over pyrethroid-PBO ITNs for prevention of malaria in adults and children in areas with pyrethroid resistance.

# The conditionality of the recommendation against the deployment of pyrethroid-pyriproxyfen ITNs instead of pyrethroid-PBO ITNs is based on the GDG's judgement that the balance of effects favours pyrethroid-PBO

# Evidence To Decision
Given that the systematic review was limited to three studies with malaria outcomes, a number of potential effect modifiers could not be examined. The GDG concluded that the extent of the impact of pyrethroid-pyriproxyfen ITNs is likely to vary by setting and will depend on several factors, such as intensity of malaria transmission, behaviour of the main malaria vectors, the level and mechanism(s) of insecticide resistance, and the usage of ITNs within a community. The GDG also noted that, across the studies, different pyrethroids (either permethrin or alphacypermethrin) were used in the ITNs and the impact on malaria may vary by the pyrethroid used. However, the panel's overall judgement was that the anticipated desirable effects of pyrethroid-pyriproxyfen ITNs compared to pyrethroid-only LLINs would be moderate. Compared to pyrethroid-PBO ITNs, the GDG considered the benefits to be minor.
The trial from the United Republic of Tanzania  included in the systematic review reported 90 (44.1%) adverse events in the pyrethroid-only LLIN group, 80 (38.8%) in the pyrethroid-pyriproxyfen ITN group and 17 (8.5%) in the pyrethroid-PBO ITN group. The authors also narratively reported that skin irritation was the most commonly reported adverse event; however, no adverse event was assessed as serious. While five deaths were reported in the cohort, three of these were from drowning, one was due to severe malaria and one was due to pneumonia; all deaths were judged to be unrelated to the study interventions.
The review also reported data from the same trial  on ITN integrity. The numbers (proportion) of ITNs that were torn (defined as hole area  790 cm2) were reported as 86 (28%) in the pyrethroid-only LLIN group, 109 (39%) in the pyrethroid-pyriproxyfen ITN group and 81 (43%) in the pyrethroid-PBO ITN group.
Overall, the GDG judged the magnitude of undesirable effects associated with pyrethroid-pyriproxyfen ITNs to be small compared to pyrethroid-only LLINs. However, compared to pyrethroid-PBO ITNs, the undesirable effects were judged to be large. Overall, the GDG concluded that, compared to pyrethroid-only LLINs, the balance of effects probably favours pyrethroid-pyriproxyfen ITNs, but when comparing pyrethroid-pyriproxyfen ITNs to pyrethroid-PBO ITNs, the balance of effects was judged to favour the comparator, namely pyrethroid-PBO ITNs.

# Benefits and harms
Based on the systematic review, the GDG concluded that the overall certainty of evidence that pyrethroid-pyriproxyfen ITNs have an impact against malaria was moderate, compared to both pyrethroid-only LLINs and pyrethroid-PBO ITNs.

# Certainty of the Evidence
No research was identified regarding preferences and values. The GDG judged that there was probably no important uncertainty or variability associated with pyrethroid-pyriproxyfen ITNs.

# Values and preferences
Apart from the higher commodity cost of pyrethroid-pyriproxyfen ITNs, similar resources would be needed for their deployment as those listed for pyrethroid-only LLINs. (See table provided under "Resources and other considerations" for pyrethroid-only LLINs.)
Based on cost data reported by the study in the United Republic of Tanzania pyrethroid-pyriproxyfen ITNs were estimated to cost US$ 3.68 per ITN, while pyrethroid-only LLINs and pyrethroid-PBO ITNs were estimated to cost US$ 2.07 and US$ 2.98 per ITN, respectively. Based on these data, the GDG judged that there are currently moderate additional costs associated with deploying pyrethroid-pyriproxyfen ITNs instead of pyrethroid-PBO ITNs. Based on the likely scale of ITN deployment, this moderate additional cost per ITN could amount to considerable additional costs associated with a switch to pyrethroid-pyriproxyfen ITNs, which would need to be met to maintain the same population coverage. The GDG, however, remarked that unit costs change over time and often decrease as new technologies are brought to scale. As pyrethroid-pyriproxyfen ITNs are scaled up, further review will be needed to determine whether this cost difference remains. National programmes are encouraged to pay specific attention to the commodity cost, as this will also vary depending on required quantities and lead-times and will be a key ingredient to the separately developed guidance on ITN prioritization.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
Pyrethroid-pyriproxyfen ITNs combine a pyrethroid insecticide and an insect growth regulator (IGR). The two ingredients have different entomological effects. The pyrethroid insecticide rapidly kills mosquitoes by targeting voltage-gated sodium channels associated with the nervous system of the insect. The IGR is a hormone mimic that does not directly kill insects, but disrupts their growth and reproduction. Mosquitoes that are not killed by the pyrethroid may be sterilized and/or have their fecundity reduced, thereby preventing multiplication of the insecticide-resistant mosquitoes. Pyriproxyfen has also shown some impact on a mosquito's life span. Pyrethroid-pyriproxyfen ITNs, therefore, fall into the third class of ITNs recognized by WHO, which consists of ITNs primarily designed to sterilize and/or reduce the fecundity of insecticideresistant mosquitoes. It is unlikely that mosquitoes exposed to ITNs that combine a pyrethroid and an IGR will be resistant to both active ingredients due to their different modes of action and limited to no selection pressure exerted so far for pyriproxyfen resistance. As such, pyrethroid-pyriproxyfen ITNs could have a greater impact against malaria than pyrethroidonly LLINs in areas with pyrethroid-resistant malaria vectors.
The systematic review  identified and included three trials   from western and To justify the deployment of pyrethroid-pyriproxyfen nets, the insecticide resistance status of the principal vector(s) in the area where deployment is planned should be assessed. However, regular insecticide resistance testing by means of bioassays  should already be part of routine monitoring operations and programme budgets.
The systematic review reported that the study conducted in the United Republic of Tanzania  carried out cost-effectiveness analyses comparing pyrethroid-pyriproxyfen ITNs and pyrethroid-PBO ITNs with pyrethroid-only LLINs over the two-year period of the trial. Pyrethroid-pyriproxyfen ITNs were estimated to incur 9 DALYs  per 10 000 total population, while pyrethroid-PBO ITNs averted 37 DALYs  per 10 000 population. When considering the costs of malaria diagnosis and treatment, pyrethroid-pyriproxyfen ITNs were reported to be the more costly (incremental cost US$ 9621  per 10 000 population), whereas pyrethroid-PBO ITNs were less costly (US$ 4816 from all perspectives. The GDG concluded that the cost-effectiveness would probably favour pyrethroid-only LLINs or pyrethroid-PBO ITNs over pyrethroid-pyriproxyfen ITNs.
The GDG was concerned that, given flatlined funding for malaria the procurement of pyrethroid-pyriproxyfen ITNs may negatively impact the ability of programmes to maintain ITN coverage of at-risk populations while not improving impact. Due to the current moderately higher cost of this commodity, there is a risk that programmes may not be able to maintain existing ITN coverage or coverage of other malaria interventions if no additional funds to cover the additional costs are made available. Some pragmatic prioritization guidance  has been provided with a view to supporting programmes in decision-making around the deployment of new types of nets in resource-constrained environments.
The GDG judged that the impact on the equity of using pyrethroid-pyriproxyfen ITNs instead of pyrethroid-only LLINs or pyrethroid-PBO ITNs would vary. If switching from either of these types of nets to more costly pyrethroidpyriproxyfen ITNs resulted in lower coverage of preventive interventions for those at risk of malaria, equity may be reduced. However, if the switch resulted in no reduction in coverage (due to increased funding or a price reduction) and those populations who were previously provided with potentially less effective pyrethroid-only LLINs were then protected from malaria by a potentially slightly more effective intervention, equity may increase.
No research was identified regarding the acceptability of pyrethroid-pyriproxyfen ITNs. However, the GDG judged that such ITNs would be acceptable to key stakeholders, given that they are largely similar to pyrethroid-only LLINs and pyrethroid-PBO ITNs in terms of their appearance, design and use.
Although no research was identified regarding the feasibility of implementing pyrethroid-pyriproxyfen ITNs, the GDG judged that deploying such ITNs would be as feasible as deploying pyrethroid-only LLINs or pyrethroid-PBO ITNs.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) eastern Africa, evaluating the impact of pyrethroid-pyriproxyfen ITNs on incidence of clinical malaria and prevalence of malaria infection, compared to either pyrethroid-only LLINs or pyrethroid-PBO ITNs. All trials were conducted in areas of high malaria transmission (malaria infection prevalence in children under 10 years of age recorded by the trials as 20-40% and as 50-70% in children under 5) and pyrethroid-resistant mosquitoes. Compared to pyrethroid-only LLINs, incidence of clinical malaria (defined as malaria symptoms, i.e. current fever of temperature  375C or fever in the past 48 hours, plus malaria parasitaemia) decreased by approximately 20% one year after deployment of pyrethroid-pyriproxyfen ITNs and by 15% two years post-deployment. Prevalence of malaria infection (regardless of symptoms) was reduced by approximately 30% one year post-deployment and by approximately 20% two years post-deployment. Compared with pyrethroid PBO ITNs, the use of pyrethroid-pyriproxyfen ITNs, the use of pyrethroid-pyriproxyfen ITNs was associated with a two-fold higher incidence of clinical malaria one year after ITN deployment, with a slightly increased or no effect on incidence two years post-deployment. There was no effect on prevalence of malaria infection one or two years post-deployment. The trial in Benin is continuing and will investigate whether the impact against malaria varies for the full duration (36-month life span) of an LLIN. Results are not available yet.
The GDG concluded on a conditional recommendation to deploy pyrethroid-pyriproxyfen ITNs instead of pyrethroid-only LLINs in areas where malaria vectors are resistant to pyrethroids. The recommendation for deployment was based on the moderate effect against malaria and the GDG's judgement that the benefits probably outweighed any harms of deploying pyrethroid-pyriproxyfen ITNs instead of pyrethroid-only LLINs. The conditionality, however, was stipulated based on the panel conclusion that pyrethroid-pyriproxyfen ITNs were less cost-effective than pyrethroid-only LLINs and, due to the higher unit cost of pyrethroid-pyriproxyfen ITNs, extra resources would be required to replace pyrethroid-only LLINs with these dual active ingredient ITNs. Unless additional resources are provided, a switch to pyrethroid-pyriproxyfen ITNs would result in reduced coverage of populations at risk of malaria, thereby negatively affecting coverage and equity.
The panel conditionally recommended against the deployment of pyrethroid-pyriproxyfen ITNs instead of pyrethroid-PBO ITNs in areas of insecticide resistance. This decision was based on the lack of evidence of pyrethroid-pyriproxyfen ITNs having a greater impact against malaria compared to pyrethroid-PBO ITNs; the balance of effects favours pyrethroid-PBO ITNs over pyrethroid-pyriproxyfen ITNs. Based on these results and the current unit costs of pyrethroid-pyriproxyfen ITNs, pyrethroid-PBO ITNs are currently more cost-effective. Extra resources would be required while there would be no benefit of deploying pyrethroid-pyriproxyfen ITNs instead of pyrethroid-PBO ITNs, and, in the absence of additional resources, this would result in reduced coverage of malaria interventions for populations at risk of malaria, thereby negatively affecting equity. The GDG also acknowledged that the available evidence on the efficacy of pyrethroid-pyriproxyfen ITNs compared to pyrethroid-PBO ITNs was from only one trial conducted in the United Republic of Tanzania, where malaria transmission is high and An. funestus is the primary malaria vector, which in turn limits generalizability of the findings to other geographies with different anopheline vectors and eco-epidemiological characteristics.

# Research Needs
WHO encourages additional high-quality research to generate further evidence on:
- the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/ unintended consequences of pyrethroid-pyriproxyfen ITNs in areas with insecticide resistance traits in the local primary vectors that differ from those of the available studies; - contextual factors (e.g. acceptability, feasibility, resource use, cost-effectiveness, equity, values and preferences) related to use of pyrethroid-pyriproxyfen ITNs; - the durability of pyrethroid-pyriproxyfen ITNs over the expected life span of an LLIN (three years).

# Strong recommendation for High certainty evidence

# Insecticide-treated nets: Humanitarian emergency setting (2022)
Insecticide-treated nets (ITNs) should be deployed for the prevention and control of malaria in children and adults in areas with ongoing malaria transmission affected by a humanitarian emergency.

# This recommendation is limited to classes of ITNs currently recommended by WHO.
As with ITNs deployed in more stable settings, WHO recommends that ITNs that are prequalified by WHO be selected for use in humanitarian emergencies.
When considering deployment of ITNs in humanitarian emergencies, the infrastructure, access, logistical capacity and resources available must be taken into account, as these may influence the feasibility and cost of procuring and deploying nets.

# Practical Info
In deciding whether to deploy ITNs in emergency settings, consideration must be given to whether ITNs are appropriate for that setting, taking into account vector characteristics, human behaviour and available infrastructure. ITNs are most effective where the principal malaria vector(s) bite predominantly at night after people have retired under their nets and where the mosquitoes are susceptible to the insecticides used to treat the nets. Data will need to be collected to assess whether these criteria are met. There may be more limited capacity to gather such data in humanitarian emergencies than in more stable settings. In addition to assessing whether ITNs are appropriate, consideration of the feasibility of deploying nets in a particular emergency setting is important. Depending on the infrastructure, access, logistical capacity and resources available, procuring and distributing nets may be more challenging than in more stable settings. Instability in such settings may challenge long-term planning and so result in shorter lead times and consequently higher costs. It is also important to determine whether the shelters or housing structures in such settings are suitable for hanging a net. In some situations, the structure may have nowhere to hang a net or it may be too small to adequately accommodate a net.
Other considerations for the deployment, monitoring and evaluation of nets apply equally to emergency and non-emergency settings. Please consult the practical information under the WHO recommendations for the different ITN classes. However, as for collecting data to assess whether nets are suitable in an area, the feasibility and capacity to regularly collect information for M&E in emergency settings must be assessed.

# Evidence To Decision
The systematic review  (Messenger et al unpublished evidence) assessed the epidemiological impact of pyrethroid-only LLINs against malaria compared to no nets in areas affected by humanitarian emergencies in the chronic phase -in the Republic of Union of Myanmar, on the Myanmar-Thailand border and in the Islamic Republic of Pakistan    ; no studies were found from areas in the acute phase of an emergency. The review presented evidence that pyrethroid-only LLINs were associated with reduced P. falciparum parasite incidence (rate ratio: 0.55; 95% CI: 0.37-0.79; four studies; high-certainty evidence) and P. falciparum parasite prevalence (rate ratio: 0.60; 95% CI: 0.40-0.88); two studies; high-certainty evidence) compared to no nets. Deployment of pyrethroid-only LLINs was reported to probably result in reduced P. vivax parasite incidence (rate ratio: 0.69; 95% CI: 0.51-0.94; three studies; moderate-certainty evidence). Little or no difference was seen in P. vivax parasite prevalence (risk ratio: 1.00; 95% CI: 0.75-1.34; two studies; low-certainty evidence).
The systematic review did not report any unintended consequences of the intervention. However, the GDG noted that the potential undesirable effects identified for the use of ITNs in stable settings are also likely to apply in humanitarian emergencies. The GDG also noted that if nets are deployed in settings where the population is accommodated in tents or small houses (structures that are commonly shelters in emergency settings), uptake and use may be limited because the restricted space may not allow the net to be hung easily and the net may encroach on the space required for other household activities. The GDG judged these potential undesirable effects to be minimal.
Although the studies included in the systematic review were limited to the use of pyrethroid-only LLINs, the likely benefits extend to other types of ITNs that are recommended by WHO for large-scale deployment in more stable settings (e.g. pyrethroid-PBO nets). The GDG judged the balance of benefits and harms to favour the use of ITNs that have been recommended for use in more stable settings to prevent and control malaria in humanitarian emergency settings.

# Benefits and harms
The systematic review assessed that the overall certainty of the evidence that pyrethroid-only LLINs ha ve s an impact on malaria in humanitarian emergency settings was high.

# Certainty of the Evidence
No research was identified regarding preferences and values. The GDG judged that there was probably no important uncertainty or variability.

# Values and preferences
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
The systematic review  (Messenger et al unpublished findings) compared pyrethroid-only LLINs to no nets in terms of malaria outcomes in areas affected by humanitarian emergencies. The review concluded that deploying pyrethroid-only LLINs was associated with reductions in P. falciparum parasite incidence, P. falciparum parasite prevalence and P. vivax parasite incidence compared to no nets. It was unclear whether pyrethroid-only LLINs reduced P. vivax parasite prevalence in these settings. The included studies were all from emergencies in the chronic phase in Asia -in the Republic of Union of Myanmar, on the Myanmar-Thailand border, and in the Islamic Republic of Pakistan. Deploying nets in the acute stage of an emergency may differ from deploying nets once some infrastructure has been established, due to numerous logistical challenges. Humanitarian emergencies in other parts of the world may differ in terms of the available capacity, infrastructure, community behaviour and acceptance.
Based on cost data published in 2021 the median economic cost of ITNs was US$ 1.39 per person protected per year, drawing on data from non-emergency settings. The GDG noted that the cost of deploying nets in humanitarian emergency settings may be higher than in stable settings for a number of reasons. First, the cost of transporting nets may increase, particularly for locations that are difficult to access. Second, in some emergency settings, there may be a need to establish human capacity for net delivery, which could incur further cost. Finally, given the nature of emergency settings, the necessity for immediate deployment of interventions may require shorter lead times for procurement, resulting in higher costs of the commodity. The GDG judged that deploying ITNs would therefore involve moderate costs and cost more than deploying ITNs in stable settings.
A review of the cost and cost-effectiveness of malaria control interventions  in more stable settings reported that the cost-effectiveness of ITNs compared to no ITNs was US$ 5.85 per episode averted, US$ 1281.97 per death averted, and US$ 44.51 per disability-adjusted life year (DALY) averted. The GDG noted that the cost-effectiveness of deploying pyrethroid-only LLINs may depend largely on the setting: the cost-effectiveness may vary with the infrastructure in the setting and available capacity, as well as the malaria transmission level in the area of deployment. The GDG judged that, while there may be some upfront costs to deliver nets in such settings, given the associated benefits to protecting such vulnerable populations, deploying pyrethroid-only LLINs would be cost-effective compared to no nets.
Providing ITNs to populations in areas with ongoing malaria transmission affected by humanitarian emergencies was judged by the GDG to result in increased equity, as populations in these settings are at increased risk of malaria infection.
No research was identified regarding the acceptability of pyrethroid-only LLINs in emergency settings. Nevertheless, the GDG judged that ITNs would be acceptable to key stakeholders, given that they are generally well accepted in more stable settings. The acceptability may improve further over time as users see the benefit to protecting themselves from malaria.
No research was identified regarding the feasibility of implementing pyrethroid-only LLINs in humanitarian emergency settings. The GDG judged that distributing ITNs would be feasible, but consideration would need to be given to whether:
- the sleeping structures in the setting are amenable to having nets installed; - nets can be procured in time and within the given budget; - there is sufficient human capacity to deliver nets in the emergency setting; and - there are sufficient resources available to cover potential extra costs to access the population, particularly hard-toreach populations and those affected by conflict.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
Given that the systematic review only identified and included four trials, a number of potential effect modifiers could not be examined. However, as for pyrethroid-only LLINs deployed in more stable settings, the impact of nets may vary depending on, for example, the behaviour of the mosquito species, the level and mechanism(s) of insecticide resistance, parasite prevalence, and net usage by the population.
While the review included studies that only examined the impact of pyrethroid-only LLINs, other ITNs recommended by WHO in more stable settings are likely to have a similar balance of benefits and harms to those deployed in humanitarian emergencies. Important considerations regarding resource needs, acceptability and feasibility when deploying pyrethroidonly LLINs in emergency settings should largely apply to other WHO-recommended ITNs. Based on the review findings and these considerations, the GDG judged that the desirable effects of deploying WHO-recommended ITNs, not just pyrethroidonly LLINs, in humanitarian emergencies compared to no nets would outweigh the undesirable effects. Based on the high certainty of the findings from emergency settings and the feasibility, acceptability and cost-effectiveness of ITNs in more stable settings, the panel felt that the recommendation should be classified as strong.

# Research Needs
WHO encourages funding of high-quality research to generate further evidence on:
- the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/ unintended consequences of ITNs in the acute phase of humanitarian emergencies (where logistics and priorities may differ); and - contextual factors (i.e. acceptability, feasibility, resource use, cost-effectiveness, equity, values and preferences) related to products from the different ITN classes covered by a WHO recommendation deployed in humanitarian emergencies.

# Practical Info
To achieve and maintain optimal ITN coverage, countries should apply a combination of mass free net distribution through campaigns and continuous distribution through multiple channels, in particular through ANC clinics and the EPI. Mass campaigns are the only proven cost-effective way to rapidly achieve high and equitable coverage. Complementary continuous distribution channels are also required because coverage gaps can start to appear almost immediately postcampaign due to net deterioration, loss of nets, and population growth.
Mass campaigns should distribute one ITN for every two persons at risk of malaria. However, for procurement purposes, the calculation to determine the number of ITNs required needs to be adjusted at the population level, since many households have an odd number of members. Therefore, a ratio of one ITN for every 1.8 persons in the target population should be used to estimate ITN requirements, unless data to inform a different quantification ratio are available. In places where the most recent population census is more than five years old, countries can consider including a buffer (e.g. adding 10% after the 1.8 ratio has been applied) or using data from previous ITN campaigns to justify an alternative buffer amount. Campaigns should also normally be repeated every three years, unless available empirical evidence justifies the use of a longer or shorter interval between campaigns. In addition to these data-driven decisions, a shorter distribution interval may be justified during humanitarian emergencies, as the resulting increase in population movement may leave populations uncovered by vector control, potentially increasing their risk of infection as and the risk of epidemics.
Continuous distribution through ANC and EPI channels should remain functional before, during and after mass distribution campaigns. In determining the optimal mix of ITN delivery mechanisms to ensure optimal coverage and maximized efficiency, consideration should be given to the required number of nets, the cost per net distributed and coverage over time. For example, during mass distribution campaign years, other delivery schemes may need to be altered to avoid-over supply of ITNs.

# Good practice statement

# Achieving and maintaining optimal coverage with ITNs for malaria prevention and control (2019)
To achieve and maintain optimal ITN coverage, countries should apply mass free net distribution through campaigns, combined with other locally appropriate delivery mechanisms such as continuous distribution using antenatal care (ANC) clinics and the Expanded Programme on Immunization (EPI).
Recipients of ITNs should be advised (through appropriate communication strategies) to continue using their nets beyond the three-year expected lifespan, irrespective of the condition and age of the net, until a replacement net is available.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
"Top-up" campaigns (i.e. ITN distributions that take into account existing nets in households and provide each household only with the additional number of nets needed to bring it up to the target number) are not recommended. Substantial field experience has shown that accurate quantification for such campaigns is generally not feasible and the cost of accounting for existing nets outweighs the benefits.
There should be a single national ITN plan and policy that includes both continuous and campaign distribution strategies. This should be developed and implemented under the leadership of the NMP, based on an analysis of local opportunities and constraints, and identification of a combination of distribution channels with which to achieve optimal coverage and minimize gaps. This unified plan should include a comprehensive net quantification and gap analysis for all public sector ITN distribution channels. As much as possible, the plan should include major ITN contributions by the private sector.
Therefore, in addition to mass campaigns, the distribution strategy could include:
- ANC, EPI and other child health clinics: These should be considered high-priority continuous ITN distribution channels in countries where these services are used by a large proportion of the population at risk of malaria, as occurs in much of sub-Saharan Africa. - Schools, faith-and community-based networks, and agricultural and food-security support schemes: These can also be explored as channels for ITN distribution in countries where such approaches are feasible and equitable. Investigating the potential use of these distribution channels in complex emergencies is particularly important. - Occupation-related distribution channels: In some settings, particularly in Asia, the risk of malaria may be strongly associated with specific occupations (e.g. plantation and farm workers and their families, miners, soldiers and forest workers). In these settings, opportunities for distribution through channels such as private sector employers, workplace programmes and farmers' organizations may be explored. - Private or commercial sector channels: These can be important channels for supplementing free ITN distribution through public sector channels. Access to ITNs can also be expanded by facilitating the exchange of vouchers or coupons provided through public sector channels for a free or subsidized ITN at participating retail outlets. ITN products distributed through the private sector should be regulated by the national registrar of pesticides in order to ensure that product quality is in line with WHO recommendations.
The procurement of ITNs with attributes that are more costly (e.g. nets of conical shape) is not recommended for countries in sub-Saharan Africa, unless nationally representative data clearly show that the use of ITNs with particular attributes increases significantly among populations at risk of malaria. To build an evidence base to support the purchase of more costly nets, investigation into the population's preferences and whether adhering to those preferences translates into increased use of ITNs may also be warranted, particularly in situations where standard nets are unlikely to suit the lifestyle of specific population groups at risk of malaria, such as may be the case for nomadic populations.
The life spans of ITNs can vary widely among individual nets used within a single household or community, as well as among nets used in different settings. This makes it difficult to plan the rate or frequency at which replacement nets need to be procured and delivered. All malaria programmes that have undertaken medium-to large-scale ITN distributions should conduct ITN durability monitoring in line with available guidance to inform appropriate replacement intervals. Where there is evidence that ITNs are not being adequately cared for or used, programmes should design and implement BCC activities aimed at improving these behaviours.
In countries where untreated nets are widely available, NMPs should promote access to ITNs. Strategies for treating untreated nets can also be considered, for example, by supporting access to insecticide treatment kits.
As NMPs implement different mixes of distribution methods in different geographic areas, there will be a need to accurately track ITN coverage at subnational levels. Subnational responses should be triggered if coverage falls below programmatic targets. Tracking should differentiate among the contributions of various delivery channels to overall ITN coverage.
Countries should generate data on defined standard indicators of coverage and access rates in order to ascertain whether optimal coverage has been achieved and maintained. The data should also inform changes in implementation in order to improve performance and progress towards the achievement of programmatic targets. Currently, the three basic survey indicators are: i) the proportion of households with at least one ITN; ii) the proportion of the population with access to an ITN within their household; and iii) the proportion of the population reporting having slept under an ITN the previous night (by age gender and access to ITN).
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
In December 2017, WHO published updated recommendations on Achieving and maintaining universal coverage with LLINs for malaria control. These recommendations were developed and revised based on expert opinion through broad consultation, including multiple rounds of reviews by the Malaria Policy Advisory Group (MPAG). Under the section on "practical information", these recommendations have been summarized and slightly revised to clarify that these recommendations are not specific to LLINs, but apply to ITNs in general.

# Practical Info
It is important to determine whether the environmental benefits outweigh the costs when identifying the best disposal option for old ITNs and their packaging. For malaria programmes in most endemic countries, there are limited options for dealing with ITN collection. Recycling is not currently a practical option in most malaria-endemic countries (with some exceptions for countries with a well-developed plastics industry). High-temperature incineration is likely to be logistically difficult and expensive in most settings. In practice, when malaria programmes have retained or collected packaging material in the process of distributing ITNs, it has mostly been burned in the open air. This method of disposal may lead to the release of dioxins, which are harmful to human health.
If such plastic material (with packaging an issue at the point of distribution and old ITNs an intermittent issue at household level when the net is no longer in use) is left in the community, it is likely to be re-used in a variety of ways. While the insecticide exposure entailed by this kind of re-use has yet to be fully studied, the expected negative health and environmental impacts of leaving the waste in the community are considered to be less than amassing it in one location and/ or burning it in the open air.
Since the material from nets represents only a small proportion of total plastic consumption, it will often be more efficient for old ITNs to be dealt with as part of larger and more general solid-waste programmes. National environment management authorities have an obligation to consider and plan for what happens to old ITNs and packaging materials in the environment in collaboration with other relevant partners.
Currently, ITNs and the vast majority of their packaging (bags and baling materials) are made of non-biodegradable plastics.The large-scale deployment of ITNs has given rise to questions as to the most appropriate and cost-effective way to deal with the resulting plastic waste, particularly given that most endemic countries do not currently have the resources to manage ITN collection and waste disposal programmes.
A pilot study was conducted to examine patterns of ITN usage and disposal in three African countries (the Republic of Kenya, the Republic of Madagascar and United Republic of Tanzania). Findings of this pilot study, along with other background information were used to generate recommendations through the WHO Vector Control Technical Expert Group (VCTEG) and MPAG on best practices with respect to managing waste.
The following are the main findings from the pilot study and other background material:
- ITNs entering domestic use in Africa each year contribute approximately 100 000 tonnes of plastic and represent a per capita rate of plastic consumption of 200g per year. This is substantial in absolute terms; however, it constitutes only approximately 1% to 5% of the total plastic consumption in Africa and thus is small compared to other sources of plastic Good practice statement

# Management of old ITNs (2019)
Old ITNs should only be collected where there is assurance that: i) communities are not left without nets, i.e. new ITNs are distributed to replace old ones; and ii) there is a suitable and sustainable plan in place for safe disposal of the collected material.
If ITNs and their packaging (bags and baling materials) are collected, the best option for disposal is high-temperature incineration. They should not be burned in the open air. In the absence of appropriate facilities, they should be buried away from water sources and preferably in non-permeable soil.
Recipients of ITNs should be advised (through appropriate communication strategies) not to dispose of their nets in any water body, as the residual insecticide on the net can be toxic to aquatic organisms (especially fish).
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
and other forms of plastic consumption. - The plastic from ITNs is treated with a small amount of pyrethroid insecticide (less than 1% per unit mass for most products), and plastic packaging is therefore considered a pesticide product/container. - Old ITNs and other nets may be used for a variety of alternative purposes, usually due to the perceived ineffectiveness of the net, loss of net physical integrity or presence of another net. - ITNs that no longer serve a purpose are generally disposed of at the community level along with other household waste by discarding them in the environment, burning them in the open, or placing them into pits. - ITN collection was not implemented on a large scale or sustained in any of the pilot study countries. It may be feasible to recycle ITNs, but it is not practical or cost-effective at this point, as there would need to be specialized adaptation and upgrading of recycling facilities before insecticide-contaminated materials could be included in this process. - Two important and potentially hazardous practices are: i) routinely removing ITNs from bags at the point of distribution and burning discarded bags and old ITNs, which can produce highly toxic fumes including dioxins, and ii) discarding old ITNs and their packaging in water, as they may contain high concentrations of residual insecticides that are toxic to aquatic organisms, particularly fish. - Insecticide-treated plastics can be incinerated safely in high-temperature furnaces, but suitable facilities are lacking in most countries. Burial away from water sources and preferably in non-permeable soil is an appropriate method to dispose of net bags and old ITNs in the absence of a suitable high-temperature incinerator. - In most countries, ministries of environment (national environment management authorities) are responsible for setting up and enforcing laws/regulations to manage plastic waste broadly. Although some countries have established procedures for dealing with pesticide-contaminated plastics, it is unrealistic to expect NMPs to single-handedly address the problem of managing waste from ITNs. Environmental regulations; leadership and guidance from national environmental authorities; and oversight from international agencies, such as the United Nations Environment Programme, are all necessary.

# Practical Info
IRS is considered an appropriate intervention where:
- the majority of the vector population tends to feed and rest indoors;
- people mainly sleep indoors at night; - the malaria transmission pattern is such that the population can be protected by one or two rounds of IRS per year;
- the majority of structures are suitable for spraying.
When selecting insecticides to be used for IRS, it is important to investigate the resistance profile of the local vectors in order to select insecticides to which the vectors are susceptible.
Insecticide formulations currently used for IRS fall into five major insecticide classes with three modes of action, based on their primary target site in the vector. WHO-prequalified products have been assessed for their safety, quality and entomological efficacy, which includes evaluation of their mortality effect on mosquitoes when applied to a range of interior surfaces of dwellings found in malaria-endemic areas.

# Sodium channel modulators
Strong recommendation for Low certainty evidence

# Indoor residual spraying (2019)
IRS should be deployed for the prevention and control of malaria in children and adults living in areas with ongoing malaria transmission.
WHO recommends that WHO-prequalified insecticidal products be selected for IRS use and that these be selected based on the insecticide susceptibility of the local malaria vector(s). IRS is considered an appropriate intervention where:
- the majority of the vector population feeds and rests indoors;
- people mainly sleep indoors at night; - the malaria transmission pattern is such that the population can be protected by one or two rounds of IRS per year; and - the majority of structures are suitable for spraying.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
- Pyrethroids: alphacypermethrin, deltamethrin, lambda-cyhalothrin, etofenprox, bifenthrin - Organochlorines (e.g. DDT): No prequalified product available

# Acetylcholinesterase inhibitors
- Organophosphates: malathion, fenitrothion, pirimiphos-methyl - Carbamates: bendiocarb, propoxur

# Nicotinic acetylcholine receptor competitive modulators
- Neonicotinoids: clothianidin IRS products using four of these insecticide classes have been prequalified by WHO; as of August 2020, there were no organochlorine IRS formulations prequalified, including DDT. This means that no DDT product has been assessed by WHO for its efficacy, safety and quality for vector control, and no inspection of manufacturing sites has been conducted. Unlike the other four classes covered by WHO's recommendation for IRS, DDT has been classified as a persistent organic pollutant.
As such, its production and use are strictly restricted by an international agreement known as the Stockholm Convention on Persistent Organic Pollutants. The Convention's objective is to protect both human health and the environment from persistent organic pollutants. When the Stockholm Convention was established in 2004, it provided an exemption for the production and use of DDT for disease vector control, mainly because of the absence of equally effective and efficient alternatives at the time. The recent expansion of products available for IRS and overall expansion of vector control interventions has provided additional options.
WHO actively supports the promotion of chemical safety and, together with the United Nations Environment Programme, shares a common commitment to the global goal of reducing and eventually eliminating the use of DDT, while minimizing the burden of vector-borne diseases. DDT use for malaria vector control has declined over the years and WHO supports continuation of this trend.
In some areas, the use of DDT may be warranted. The decision to use DDT for malaria vector control needs to be based on a detailed analysis that considers all other potential options for vector control and provides clear reasoning for choosing DDT over the other options. WHO considers DDT to be a last resort, not a first choice. If DDT is selected, it should be used under strict control measures and only for the intended purpose. Its use requires that the conditions set by the Stockholm Convention be met. Effective use and safe storage of DDT rely on compliance with well-established and well-enforced rules and regulations in accordance with national guidelines and following WHO technical guidance provided in the WHO Operational manual for IRS for malaria transmission, control and elimination. Where DDT is deployed, it is essential for adequate resources and technical support to be in place to ensure the sound management of this persistent organic pollutant.
Countries that are using DDT for malaria vector control need to regularly (at least once every two years) reassess whether there is a justified continued need for DDT. The outcome of such assessment should be reported to the WHO Global Malaria Programme and to the Secretariat of the Stockholm Convention as part of the formal reporting process.
When selecting products and formulations, residual efficacy needs to continue for at least three months after the application of the insecticide to the substrate (usually cement, mud or wood). Insecticides are available in various formulations to increase their longevity on different surfaces.
Community acceptance of IRS is critical to the programme's success, particularly as it requires householders to grant permission for spray teams to enter their house. It also involves disruption to the household, requiring householders to remove personal items from their house prior to spraying. Furthermore, some insecticide formulations leave unsightly residue on sprayed surfaces. Repeated, frequent spraying of houses over extended periods can lead to refusal by householders. Reduced acceptance has been an impediment to effective IRS implementation in various parts of the world. It is therefore important to develop information, education and communication (IEC) strategies to keep the community informed and to ensure full support and cooperation.
In areas with ongoing malaria transmission, optimal coverage of IRS should be maintained. Implementation of the intervention should take place prior to the onset of the peak transmission season. Following application of the insecticide(s), it is important to monitor the residual activity.
The WHO Operational manual for IRS for malaria transmission, control and elimination  aims to assist malaria programme managers, entomologists and public health officers in designing, implementing and sustaining high-quality IRS programmes.

# Evidence To Decision
The systematic review  reported that IRS may reduce malaria incidence (risk ratio : 0.12; 95% CI: 0.04-0.31; one study; low-certainty evidence) and parasite prevalence (RR: 0.24; 95% CI: 0.17-0.34; one study; low-certainty evidence) compared to no IRS. The GDG noted that evidence from the programmatic implementation of IRS over many years has reported reductions in all-cause child mortality, malaria mortality, P. falciparum incidence and prevalence, and incidence of severe disease compared to no IRS. No undesirable effects were identified in the systematic review. However, IRS may play an as yet undetermined role in insecticide resistance development in Anopheles vectors.

# Benefits and harms
The systematic review assessed that the overall certainty of the evidence that IRS has an impact on malaria was low.

# Certainty of the Evidence
The table below, compiled by the GDG lists resources that should be considered for the deployment of IRS. Note that this table does not include resource needs for product selection or assessment of impact of the intervention.
When carried out correctly, IRS has historically been shown to be a powerful intervention to reduce adult mosquito vector density and longevity and, therefore, to reduce malaria transmission. However, despite its long tradition and the large body of associated operational experience, few randomized controlled trials (RCTs) have been conducted on IRS. Therefore, the availability of data suitable for use in the meta-analysis was limited  and the certainty of evidence reported by the systematic review was low. The GDG considered that despite the low certainty of the evidence, a strong recommendation for the intervention is warranted based on the fact that a number of implementation trials and programmatic data have demonstrated impact against malaria. The GDG considered that this body of evidence, when viewed as a whole, provides higher certainty evidence (compared to the evidence from the systematic review) of the effectiveness of IRS as a malaria prevention and control intervention. The GDG judged that, based on the systematic review comparing IRS and ITNs, ITNs are an equally effective alternative intervention in areas where local vectors are susceptible to the insecticides being used.
- Insecticide-contaminated residues and packaging must be transported from remote clean-up sites under an environmentally compliant transport plan often using small trucks. An updated systematic review of data on IRS interventions from recent studies, RCTs and other designs is being undertaken to further support this recommendation or modify it as appropriate.

# Research Needs
- Generate further evidence on the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms and/or unintended consequences of IRS. - Determine the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/unintended consequences of IRS in urbanized areas with changing housing designs. - Determine the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/unintended consequences of IRS using new insecticides in areas where mosquitoes are resistant to currently deployed insecticides. - Determine the impact (incidence of malaria  and/or prevalence of malaria infection) of IRS in areas with different mosquito behaviours (such as in areas with outdoor transmission). - Given the relatively high cost of implementing IRS, especially in the context of growing insecticide resistance and when delivering IRS in more remote areas, there is a need to investigate new approaches to delivering IRS to increase the cost-effectiveness of this intervention.

# Practical Info
In deciding whether to deploy IRS in emergency settings, as in more stable settings, consideration must be given to whether IRS is a suitable intervention for that setting, taking into account vector characteristics, human behaviour and available infrastructure. IRS is considered an appropriate intervention where the majority of the vector population feeds and rests indoors; the vectors are susceptible to the insecticide that is being deployed; people mainly sleep indoors at night; the majority of structures are suitable for spraying; and where high enough coverage can be achieved to provide communitylevel protection. Data will need to be collected to assess whether these criteria are met. Data on vector composition, density, behaviour and insecticide susceptibility prior to deploying IRS not only provide information as to whether IRS is suitable in that setting, but also provide baseline information against which changes can be detected and monitored. Combined with data on coverage, this information can be used to gauge the effectiveness and efficiency of IRS. However, there may be more limited capacity to regularly gather such data in humanitarian emergencies than in more stable settings. Data are also required on the structures present in humanitarian emergencies to assess whether they are amenable to IRS. Open-sided structures or those with surfaces constructed from materials that impact the residual nature of the spray may not be suitable.
Initiating any IRS programme requires a well-defined management system to be established with dedicated human, logistical, transport and financial resources. Programmes and implementing partners should consider whether the logistical needs Conditional recommendation for Very low certainty evidence

# Indoor residual spraying: Humanitarian emergency setting (2022)
IRS can be deployed for the prevention and control of malaria in children and adults in areas with ongoing malaria transmission affected by a humanitarian emergency.

# The conditionality of this recommendation is largely driven by the very low certainty of the evidence that IRS reduces malaria in such settings and due to concerns around feasibility and cost.
When deciding whether IRS may be appropriate for prevention and control of malaria in humanitarian emergency settings, programmes should consider:
- whether the structures are suitable for spraying. Some shelters provided in emergency settings may not be suitable for application of insecticides, such as open-sided structures and those built from materials that affect the residual nature of the insecticides; - whether the target coverage of IRS can be feasibly achieved in the setting; - whether there are sufficient resources to cover the relatively high costs associated with an IRS programme. In such settings, transport of commodities to hard-to-reach areas, coupled with the need to quickly procure items and establish human capacity to deliver the intervention, is likely to incur higher costs than when deploying IRS in more stable settings.
As with the deployment of IRS in more stable settings, WHO recommends that WHO-prequalified insecticides be selected for IRS use in humanitarian emergencies. It is important to ensure that the vector population is susceptible to the insecticide selected for spraying.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
(acquisition of commodities and equipment, recruitment of personnel and transport) can be met in emergency situations with the available resources within the given timeframe. Timeliness is a key factor in obtaining the maximum benefits from IRS; the spray should be applied over the shortest period of time just prior to the onset of the transmission season. As with ITNs, instability in humanitarian emergencies may reduce the options for long-term planning, resulting in shorter lead times for establishing a programme and acquiring supplies and equipment than in more stable settings. If commodities and personnel have to be sourced at short notice, procurement costs may be higher. Costs may also increase if more expensive means of transport are required for deployment in more remote, less accessible areas or those affected by conflict.
As with more stable settings, ensuring optimal coverage to provide community-level protection is critical. To support this community acceptance of IRS is essential. Given that in some humanitarian emergencies, the local language may differ to that of the affected population, consideration should be given to whether messaging needs to be adapted.

# Evidence To Decision
The systematic review  (Messenger et al unpublished evidence) assessed the epidemiological impact of IRS against malaria compared to no IRS in areas affected by humanitarian emergencies in the chronic phase; no studies were found from areas in the acute phase of an emergency. One RCT was carried out in the Republic of the Sudan  and two controlled before-after studies and one cross-sectional study were conducted in the Islamic Republic of Pakistan . While the incidence of P. falciparum was lower with IRS, only one observational study contributed to this evidence (rate ratio: 0.57; 95% CI: 0.53-0.61; very low-certainty evidence). There was little to no difference in P. falciparum parasite prevalence between arms (rate ratio: 1.31; 95% CI: 0.91-1.88; one study; low-certainty evidence). P. vivax parasite incidence was lower compared to no IRS (rate ratio: 0.51; 95% CI: 0.49-0.52; one study; very lowcertainty evidence); however, only one observational study was included. Little or no difference was seen in P. vivax parasite prevalence between arms (OR: 0.74; 95% CI: 0.25-2.14; two studies; very low-certainty evidence).
The GDG judged that the extent of the desirable effects of IRS compared to no IRS is likely to vary depending on a number of factors. Many of these factors also apply to more stable settings: IRS works best when the majority of vectors rest indoors and are susceptible to the insecticides used; where people sleep indoors; where the population is not nomadic; and where the structures are sprayable and not too scattered. The suitability of structures for spraying is an important factor to consider in emergency settings. Tents are often used to provide emergency shelter and not all tent material will allow the application of the insecticide by spraying; in some areas, structures are open-sided. It may be that IRS is more appropriate in the chronic phase of an emergency than in the acute phase due to the type of shelter, infrastructure and human capacity likely to have been established by this later stage.
The systematic review did not report any unintended consequences of the intervention. However, the GDG noted that undesirable effects may be similar to those that may arise when deploying IRS in non-emergency settings (see "Evidence to decision" section of the recommendation for IRS). These undesirable effects were judged by the GDG to be minimal.
The GDG judged the balance of benefits and harms to probably favour the use of IRS against malaria compared to no IRS in humanitarian emergency settings.

# Benefits and harms
The systematic review assessed the overall certainty of evidence that IRS has an impact on malaria in humanitarian emergency settings to be very low.

# Very low

# Certainty of the Evidence
No research was identified regarding preferences and values. The GDG judged that there was probably no important uncertainty or variability.

# Values and preferences
The resources needed for IRS in humanitarian emergencies are, at a minimum, the same as those needed for delivery of
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)
The systematic review  (Messenger et al unpublished evidence) included four studies conducted in the Islamic Republic of Pakistan and The Republic of the Sudan that compared IRS versus no IRS on malaria outcomes in areas affected by humanitarian emergencies. The review included only one observational study showing that P. falciparum was reduced, but the certainty of evidence was considered to be very low. One RCT showed no effect of IRS on P. falciparum parasite prevalence (low-certainty evidence). IRS was reported to reduce both P. vivax parasite incidence and prevalence based on two observational studies, but the certainty of evidence was assessed to be very low. All studies were conducted during the IRS in more stable settings (see "Resources and other considerations" table, section 4.1.1), but the overall cost is likely to be higher due to the various logistical issues noted below. Based on cost data published in 2021  the median economic cost per person protected per year was estimated to be US$ 5.70 in stable settings. As in stable settings, establishing an IRS programme in an area for the first time requires a great amount of resources. In emergency settings, increased costs are assumed to be associated with transporting commodities and personnel to areas where access is limited by geography or conflict, the fact that shorter lead times for procurement generally result in higher cost of goods, and the need to quickly establish capacity (recruitment and training of personnel, establishment of operation sites, i.e. stores, soak pits, and wash areas) to protect the at-risk population and avoid a potential malaria epidemic. The GDG therefore judged that deploying IRS in such settings would likely involve high costs.
Data from a review of the cost and cost-effectiveness of malaria control interventions deployed in stable settings  reported that the cost-effectiveness of IRS compared to no IRS was US$ 840.44 per death averted and US$ 25.16 per DALY averted. The GDG noted that the cost-effectiveness of deploying IRS is likely to vary depending on the malaria transmission level in the area of deployment and other contextual factors. However, the GDG judged that IRS is likely to be cost-effective compared to no IRS, given the benefits of protecting vulnerable populations from malaria in such settings.
Providing IRS to populations in areas with ongoing malaria transmission affected by humanitarian emergencies was judged by the GDG to result in increased equity by providing the most vulnerable with an effective malaria prevention intervention
No research was identified regarding the acceptability of IRS in emergency settings. Despite the lack of evidence, the GDG judged that IRS is likely to be acceptable to key stakeholders, given that IRS is generally accepted in more stable settings.
No evidence was included in the systematic review and no studies were identified by the GDG regarding the feasibility of implementing IRS in humanitarian emergency settings.
The GDG judged that the feasibility of IRS would vary, likely depending on whether:
- the structures in such settings are amenable to being sprayed; open-sided structures and certain surface materials would not be suitable for spraying; - commodities can be acquired and skilled personnel recruited with the resources available within the given timeframe; - access to the population is feasible, which may involve higher costs than in more stable settings.
The GDG noted that IRS may be more feasible in the chronic phase of a humanitarian emergency, when shelter, general infrastructure and human resources are better established than in the acute stages. In the acute phase of an emergency, there may be other competing demands on resources and overall capacity.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) chronic phase of the emergency. Deploying IRS in the acute stage of an emergency may differ from employing IRS once some infrastructure has been established, due to numerous logistical challenges.
Given that the systematic review only identified and included four studies, a number of potential effect modifiers could not be examined, and the generalizability of the findings was limited. Humanitarian emergencies in other parts of the world may differ in terms of available capacity, infrastructure, community behaviour and acceptance. As for many vector control interventions, the impact of IRS may vary in different settings depending on a number of factors, such as the behaviour of the mosquito species, the level and mechanism(s) of insecticide resistance in vectors, parasite prevalence, and coverage of IRS in the population. As with deploying IRS in more stable settings, IRS will only be effective where vectors rest primarily indoors and mosquitoes are susceptible to the insecticide being deployed.
The review findings provided little evidence of an impact on malaria outcomes in humanitarian emergencies. Given the effectiveness of IRS programmes in reducing malaria burden in more stable settings, however, the GDG judged that the desirable effects of deploying IRS compared to no IRS in humanitarian emergencies would likely outweigh the undesirable effects. Given the low certainty of the evidence, the panel felt that the recommendation should be classified as conditional. Considerations of feasibility and the cost and cost-effectiveness of implementing IRS in such settings were viewed by the GDG as important. In humanitarian emergencies, the shelters provided may not be amenable to spraying and there may be higher costs associated with deploying IRS in such settings than in more stable ones.

# Research Needs
WHO encourages funding of high-quality research to generate further evidence on:
- the impact (incidence of malaria  and/or prevalence of malaria infection) and potential harms/ unintended consequences of IRS in the acute phase of humanitarian emergencies (where logistics and priorities may differ); - contextual factors (i.e. acceptability, feasibility, resource use, cost-effectiveness, equity, values and preferences) related to IRS deployed in humanitarian emergencies.

# Co-deploying ITNs and IRS Practical Info
Given the resource constraints across malaria-endemic countries, the deployment of a second vector control intervention on top of optimal coverage with an existing one should only be considered as part of a broader prioritization analysis aimed at achieving maximum impact with the available resources. In many settings, a switch from ITNs to IRS or vice versa, rather than their combination, is likely to be the only financially feasible option. Deployment of either intervention needs to ensure optimal coverage of populations at risk of malaria and ensure they are delivered to a high standard. Further guidance on best practices for ensuring high-quality deployment of interventions is provided in the WHO Indoor residual spraying: An operational manual for IRS for malaria transmission, control and elimination  and in the Alliance for Malaria Prevention toolkit.

# Conditional recommendation against Moderate certainty evidence

# Prioritize optimal coverage with either ITNs or IRS over combination (2019)
The co-deployment of ITNs and IRS is not recommended for prevention and control of malaria in children and adults in areas with ongoing malaria transmission. Priority should be given to delivering either ITNs or IRS at optimal coverage and to a high standard, rather than introducing the second intervention as a means to compensate for deficiencies in the implementation of the first intervention.
In settings where optimal ITN coverage, as specified in the strategic plan, has been achieved and where ITNs remain effective, additionally implementing IRS may have limited utility in reducing malaria morbidity and mortality. Given the resource constraints across malaria endemic countries, it is recommended that effort be focused on good-quality implementation of either ITNs or IRS, rather than deploying both in the same area. However, the combination of these interventions may be considered for resistance prevention, mitigation or management should sufficient resources be available.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)

# Evidence To Decision Justification
The systematic review published in 2019  on the deployment of IRS in combination with ITNs (specifically pyrethroidonly LLINs) provided evidence that, in settings where there is optimal coverage with ITNs and where these remain effective, IRS may have limited utility in reducing malaria morbidity and mortality. WHO guidance was developed accordingly to emphasize the need for good-quality implementation of either ITNs or IRS, rather than deploying both in the same area. However, the co-deployment of these interventions may be considered for resistance prevention, mitigation or management should sufficient resources be available Insecticide resistance threatens the effectiveness of insecticidal interventions and hence is a key consideration in determining which vector control interventions to select to ensure maximum impact. One approach to the prevention, mitigation and management of vector insecticide resistance is the co-deployment (or combination) of interventions with different insecticides (see Section 4.1 on "Prevention, mitigation and management of insecticide resistance"). Therefore, WHO guidance developed based on the systematic review  differentiates between the effect of combined interventions on malaria morbidity and mortality versus the utility of this approach in a resistance management strategy.
A summary of the conclusions (with minor updates for clarity) used to develop the above recommendations is as follows:
- In settings with high ITN coverage where ITNs remain effective, IRS may have limited utility in reducing malaria morbidity and mortality. However, IRS may be implemented as part of an IRM strategy in areas where ITNs are in use. - Malaria control and elimination programmes should prioritize the delivery of ITNs or IRS at optimal coverage and to a high standard, rather than introducing the second intervention as a means to compensate for deficiencies in the implementation of the first intervention. - If ITNs and IRS are to be deployed together in the same geographical location, IRS should be conducted with a nonpyrethroid insecticide. - Evidence is needed to determine the effectiveness of combining IRS and ITNs in malaria transmission foci, including in low transmission settings. Evidence is also needed from different eco-epidemiological settings outside of Africa. - All programmes in any transmission setting that decide to prioritize the combined deployment of ITNs and IRS over other potential use of their financial resources should include a rigorous programme of M&E (e.g. a stepped wedge introduction of the combination) in order to confirm whether the additional inputs are having the desired impact. Countries that are already using both interventions should similarly undertake an evaluation of the effectiveness of the combination versus either ITNs or IRS alone. - The approach of co-deploying interventions for resistance management was developed largely based on experience with agricultural pest management, and the evidence base from public health remains weak.
- No benefit of adding IRS to areas where pyrethroid-only ITNs are being used was identified in systematic review.
- In areas of confirmed pyrethroid resistance, IRS with a non-pyrethroid insecticide may increase effectiveness against malaria. - No undesirable effects were identified in systematic review. However, the cost of combining two interventions will significantly increase commodity and operational costs.

# Benefits and harms
The certainty of evidence identified in the systematic review showing no benefit to adding IRS in situations where ITNs are already being used was graded as moderate.

# Certainty of the Evidence
- The degree of pyrethroid resistance and its impact on the effectiveness of pyrethroid-only ITNs should be considered. - The status of vector resistance to the proposed IRS active ingredient needs to be known.
- In resource-constrained situations, it is unlikely to be financially feasible to deploy both ITNs and IRS.

# Resources and other considerations

# Practical Info
Financial considerations such as cost and cost-effectiveness are major drivers of decision-making, and the selection of malaria vector control interventions and determination of their coverage should thus be embedded in a prioritization process that considers the cost and effectiveness of all available malaria interventions and aims at achieving maximum impact with the available resources. Evaluations of the relative cost and cost-effectiveness of ITNs and IRS are ongoing to inform revision of the guidelines.
ITNs can provide both personal and community-level protection when nets are deployed at the community rather than individual level, with the aim of providing sufficient nets to cover all household inhabitants. Similarly, IRS will have a greater effect on mosquito populations and therefore transmission if deployed at high coverage. It is therefore important to maximize access to ITNs or IRS in communities that are at risk of malaria. This will involve quantification of needs to enable access for all household inhabitants when placing procurement orders and putting in place appropriate delivery structures. For malaria vector control interventions recommended for large-scale deployment, namely ITNs and IRS, optimal coverage refers to providing populations at risk of malaria with access to ITNs coupled with health promotion to maximize use and ensuring timely replacement; or providing these populations with regular application of IRS. Either intervention should be deployed at a level that provides the best value for money while reflecting programmatic realities. In practice, this often means quantifying commodities to provide full access by the population at risk, while realizing that this will not result in 100% coverage or 100% access due to various system inefficiencies. Being cognizant of such constraints, decision-making should then consider other alternatives as part of the intervention package, ranging from chemoprevention to supplementary vector control, instead of pursuing the idealistic goal of providing full population coverage.
In terms of the relative effectiveness of IRS compared to pyrethroid-only ITNs, a systematic review published in 2010  reported low-certainty evidence that, in areas of intense malaria transmission, IRS may be associated with lower malaria incidence, but no effect was evident for parasite prevalence. In areas of unstable transmission, ITNs may be associated with lower malaria incidence and prevalence; however, the certainty of evidence was determined to be very low. The panel therefore could not provide a definitive conclusion on the comparative effectiveness of these interventions. WHO currently views these two interventions as being equally effective ways of delivering an insecticide. The actual effectiveness in reducing the burden of malaria is dependent on the insecticide(s) used on the ITN or applied by IRS. Decisions on whether to deploy IRS or ITNs need to be informed by a number of factors, such as data on insecticide resistance, past and present experience of using interventions (including feasibility of deployment and acceptability and use by end-users), vector behaviours and the current options available within the context. Given these various considerations, the wide range of different contexts and the lack of correlation between insecticide resistance data assessed using bioassays and the actual effectiveness of an insecticidal intervention in controlling vectors, no general recommendation to guide the selection of ITNs over IRS can be made.

# Good practice statement

# Access to ITNs or IRS at optimal coverage levels (2019)
Access to effective vector control using ITNs or IRS at optimal coverage levels should be ensured for all populations at risk of malaria in most epidemiological and ecological settings.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO)

# Practical Info
Access to effective vector control interventions will need to be maintained in the majority of countries and locations where malaria control has been effective. This includes settings with ongoing malaria transmission, as well as those in which transmission has been interrupted but some level of receptivity and importation risk remains. Malaria elimination is defined as the interruption of local transmission (reduction to zero incidence of indigenous cases) of a specified malaria parasite species in a defined geographical area as a result of deliberate intervention activities. Following elimination, continued measures to prevent re-establishment of transmission are usually required. Interventions are no longer required once eradication has been achieved. Malaria eradication is defined as the permanent reduction to zero of the worldwide incidence of infection caused by all human malaria parasite species as a result of deliberate activities.
There is a critical need for all countries with ongoing malaria transmission, and in particular those approaching elimination, to build and maintain strong capacity in disease and entomological surveillance and health systems. The capacity to detect and respond to possible resurgences with appropriate vector control relies on having the necessary entomological information (i.e. susceptibility status of vectors to insecticides, as well as their biting and resting preferences). Such capacity is also required for the detailed assessment of malariogenic potential, which is a pre-condition for determining whether vector control can be scaled back (or focalized).
If areas where transmission has been interrupted are identified, the decision to scale back vector control should be based on a detailed analysis that includes assessment of the receptivity and importation risk of the area, as well as an assessment of the active disease surveillance system, and capacity for case management and vector control response.
A comprehensive review of historical evidence and mathematical simulation modelling undertaken for WHO in 2015 indicated that the scale-back of malaria vector control was associated with a high probability of malaria resurgence, including for most scenarios in areas where malaria transmission was very low or had been interrupted. Both the historical review and the simulation modelling clearly indicated that the risk of resurgence was significantly greater at higher EIRs and case importation rates, and lower coverage of active case detection and case management.
Once transmission has been reduced to very low levels approaching elimination, ensuring optimal access to vector control for at-risk populations remains a priority, even though the size and demographics of the at-risk populations may change as malaria transmission is reduced.
As malaria incidence falls and elimination is approached, increasing heterogeneity in transmission will result in foci with ongoing transmission in which vector control may need to be optimized and enhanced. Such foci may be the result of particularly high vectorial capacity, lapsed prevention and treatment services, changes in parasites that make the current strategies less effective, or reintroduction of malaria parasites by the movement of infected people or infected mosquitoes. Monitoring the coverage, quality and impact of vector control interventions is essential to maintain the effectiveness of control. Guidance on entomological surveillance across the continuum from control to elimination is provided elsewhere.
Once elimination has been achieved, vector control may need to be continued by targeting defined at-risk populations to prevent reintroduction or re-establishment of local transmission.
It is acknowledged that malaria transmission can persist following the implementation of a widely effective malaria programme. The sources and risks of residual transmission may vary by location, time and the existing components of the current malaria programme. This variation is potentially due to a combination of both mosquito and human behaviours, such as when people live in or visit forest areas or do not sleep in protected houses, or when local mosquito vector species bite and/or rest outdoors and thereby avoid contact with IRS or ITNs/LLINs.
Once elimination has been achieved, optimal vector control coverage should be maintained in receptive areas where there is

# Good practice statement

# No scale-back in areas with ongoing local malaria transmission (2019)
In areas with ongoing local malaria transmission (irrespective of both the pre-intervention and current level of transmission), vector control interventions should not be scaled back. Ensuring access to effective malaria vector control at optimal levels for all inhabitants of such areas should be pursued and maintained.
WHO Guidelines for malaria -14 March 2023 -World Health Organization (WHO) a substantial risk of reintroduction.