Tuesday 5 January 2021

Studying the control of Mosquito-borne diseases in the Bijagós Archipelago, Guinea-Bissau.

Vector-borne diseases contribute significantly to the global burden of disease and remain a threat to over 80% of the world’s population. The pathogens responsible for these infections are transmitted by Mosquitoes, Black Flies, Sand Flies, Ticks and other Arthropods, the control of which is the principal method available for controlling many Vector-borne diseases. Vector control aims to limit the transmission of pathogens by reducing or eliminating Human contact with the vector. The tools available for vector control include both chemical and non-chemical approaches that target either larval or adult stages. Insecticide-treated nets and indoor residual spraying have been the mainstay of Malaria control. However, recent decades have witnessed the development of novel interventions that approach the challenge of eliminating vector contact through the use of novel compounds for existing interventions, mass drug administration of ivermectin, genetic modification and the introduction of Bacteria that reduce or modify the vector population.

The importance of developing new tools has been emphasised since 2017 as evidence emerged that the global response to Malaria had stalled. Malaria cases were found to have increased in several countries, and this was coupled with an increasing threat of Aedes-borne diseases. The global spread of Dengue and Chikungunya Viruses, as well as outbreaks of Zika Virus disease and Yellow Fever, clearly highlight the challenges faced with Vector-borne diseases worldwide.

The World Health Organization’s Global Vector Control Response strategy aims at strengthening vector control as a fundamental approach to preventing disease and responding to outbreaks and has two foundational elements, to enhance vector control capacity and capability, and to increase basic applied research and innovation. Included in these foundations is a requirement to improve the evidence base of the impact of vector control interventions on infection and Human disease, which is generally weak beyond the core interventions used for the control of Malaria. Relatively few field studies have been performed with some interventions, and these have often been poorly designed and conducted. As a consequence, their outcomes are difficult to interpret and may give misleading results. There remains an urgent need to understand the efficacy of current interventions, and to measure the field suitability and performance of new interventions.

Randomised controlled trials provide the least biased and most robust estimate of an intervention’s efficacy, although it is important to note that not all questions in vector control can be answered with randomised controlled trials, and other study designs, including observational studies, should be considered by investigators. For example, a 2018 study led by Immo Kleinschmidt used a prospective, observational cohort study design to investigate whether insecticide resistance was associated with a loss of effectiveness of long-lasting insecticidal nets. Other study designs may be more suitable where there is already strong evidence that an intervention works; it would be unethical to use a control arm that required study populations to use no insecticide-treated nets or indoor residual spraying.

Where randomised controlled trials are appropriate and can be conducted well, the allocation to treatment and control groups in a random fashion is expected to provide no systematic differences between groups that could be caused by confounding variables. Mosquito trials typically involve area-wide, rather than individual, interventions, so their effects must be measured at community, or cluster, level. However, in order to be able to provide evidence of efficacy, the study must carefully consider cluster size and cluster separation. The movement of people also needs to be considered, since it can contaminate the study results, generally giving bias in the direction of the null result.

Avoidance of contamination is one of the primary reasons for using a cluster randomisation design for field trials. One of the main strategies for reducing contamination is to choose clusters for the trial that are well separated. Rural communities, which are often selected for such studies, have the benefit of being geographically dispersed, with less mixture of populations expected than in urban areas. Natural barriers, such as rivers or swamps, can also effectively increase the separation of clusters and prevent the mixture of populations. An extension of this concept is to base intervention studies, such as cluster-randomised trials, on islands.
Population movement is a major driver for infectious disease transmission and is known to have a significant role in the spatial spread of some diseases. The outbreak of Ebola in West Africa from 2014 to 2016 is an important recent example, but others include vector-borne diseases. Dengue, transmitted by Aedes Mosquitoes, is recognised as the most rapidly spreading Mosquito-borne disease worldwide and is so intimately linked with population movement that mobile phone-based mobility estimates have been shown to predict the geographic spread and timing of epidemics in some settings.

In addition to affecting disease transmission, the movement of populations can impact disease control and elimination strategies. First, where healthcare provision is based around mass drug administration, high population coverage is crucial to success. Elimination strategies, in particular, demand that high levels of coverage are attained. The movement of people may mean that some individuals are missed, coverage targets are not met, or there is re-introduction of disease. 

Despite islands increasingly becoming part of global systems of migration and flows of resources, the movement of people to and from isolated islands is expected to be moderate compared with movement in mainland settings and, therefore, benefit the study of vector-borne diseases and other infectious diseases. Where studies are being conducted to assess the efficacy of an intervention, such as through cluster-randomised trials, the movement of individuals between clusters could lead to dilution of the intervention’s effects. Careful study design is needed to counter these issues. In the case of mobile interventions such as insecticide-treated clothing or mass drug administration of an endectocide, a type of systemic insecticide that has activity against both endo-parasites and ecto-parasites, substantial movement of treated individuals into control-group clusters could result in a reduction in the local mosquito population and an underestimate of the impact of the intervention. Conversely, in the trial of a repellent, those wearing repellents may divert Mosquitoes to unprotected individuals and in this situation inflate the apparent effect of the intervention. By conducting intervention studies on islands, these effects may be minimised.

The movement of vector populations is a further complication for intervention studies and is anothermotive for the use of islands. The dispersal range of Anopheles gambiae Mosquitoes has been estimated through mark–release–recapture experiments to be less than 7 km, and more commonly in the range of 0.5–1 km. This means that, if intervention clusters are considerably closer together, there is more opportunity for contamination. Experiments in which labelled Anopheles gambiae were released from a Gambian village have shown that, while the majority of recaught Mosquitoes remained in the same village, there was also the movement of Mosquitoes to neighbouring villages situated 1–1.4 km away. This suggested that movement could seriously affect the entomological evaluation of vector control programmes, such as studies with insecticide-treated nets, in areas where treated and untreated villages were interspersed.

The restriction of movement of Mosquito populations is particularly important for studies with genetically modified Mosquitoes. The concern here is not just with assessing the impact of the intervention, which might be to use transgenes to suppress a local Mosquito population or replace it with a population that is refractory to the development of pathogens, but one of mitigating risks. Genetically modified strains are designed to be competitive against wild populations, and it would be difficult to halt the spread of transgenes from a self-propagating, genetically modified Mosquito population if some unanticipated negative side effects were identified following their release. As a result, it was recommended that the first field trials of genetically modified Mosquitoes be carried out with individuals that are genetically sterile, and that the release site is geographically isolated, so that there is a negligible risk of spread of Mosquitoes from any accidental release. Oceanic or lacustrine islands are natural choices for such field sites and have been considered as release sites that would allow the success and risks associated with genetic modification of Anopheles gambiae to be assessed.

Isolated riverine islands were selected for a field trial aimed at the suppression of insular Aedes albopictus populations through releases of irradiated male Mosquitoes that also carried a transinfected Wolbachia strain incompatible with local females. Several million factory-reared adult males were released in residential areas of islands in Nansha and Panyu Districts in Guangzhou, the city with the highest Dengue transmission rate in China, and resulted in near elimination of field populations. Before release, the Mosquitoes were irradiated with an X-ray dose known to effectively sterilise females but to not negatively affect male competitiveness. Wolbachia is maternally inherited; accidental release of fertile females may, therefore, result in the unintended invasion of the novel Wolbachia strain in the local population and would render any future male releases carrying the strain ineffectual. The Nansha and Panyu District islands are relatively isolated. Although there is evidence of passive Mosquito dispersal along with Human transportation networks, nearby islands provided control sites for means of comparison. Here, as elsewhere, islands have allowed for the precise monitoring of vector population suppression with limited interference from outside populations.

Rusinga Island in Lake Victoria, western Kenya, provides another example of the use of islands for the evaluation of vector control interventions. The island was used in a stepped wedge cluster-randomised trials to investigate the use of mass Mosquito trapping for Malaria control. The island is connected to the mainland via a causeway, which is used for transport to the larger town of Mbita, where there is one of the two medical clinics that serve Rusinga Island. The island is a contained area, and, therefore, considered ideal for the use of a stepped wedge trial design. However, the island’s proximity to the mainland, and its dependency on mainland infrastructure, may result in contamination from mainland vector populations. There are more remote islands in Lake Victoria, including Mageta, Magare and Ngodhe islands, which may be less likely to experience vector movements from the mainland.

While there are clear benefits of working on islands, such environments also present challenges to intervention studies. Island groups in remote settings have obvious logistical limitations, making it difficult for study teams and equipment to travel to and between study locations, and this can add study costs, which are often considerable for cluster-randomised trials.

To adequately establish the effect of intervention through cluster-randomised trials, it is crucial to ensure adequate numbers of clusters to satisfy the study design. However, the number of islands in an archipelago may restrict options for clustering, and indeed, where a study requires a certain number of individuals, the population sizes on some islands be a limiting factor.

Sample size estimates must consider the possibility of within-cluster correlation as a result of between-cluster variability. For example, the availability of breeding sites for vectors, or differences in access to healthcare, may mean that there are differences in rates of infectious disease between clusters. To ensure that study outcomes can be accurately observed, any heterogeneity between clusters must be taken into account when designing cluster-randomised trials. Where there is a high degree of correlation in the outcome, whereby some clusters report low levels of disease prevalence and others much higher, it is more difficult to demonstrate an intervention effect without a very large number of clusters. Studies of Malaria prevalence suggest that for cluster-randomised trials it may be necessary to assume high between-cluster variability when estimating realistic sample sizes.

A further consideration for conducting research studies in an island setting is the ability to translate findings to other settings. The question of external validity asks whether the results obtained in a trial may be generalised to other settings, which may differ from the study setting with respect to characteristics that influence the outcome, and whether the results have been affected by particular geographical, temporal, socio-economic and ethnical factors that may not be present at other study sites. Island populations may have different cultures and traditions, and can even differ genetically from those in other areas owing to genetic drift or differences in ancestral populations, potentially resulting in an effect modification. It is conceivable that an intervention involving an island population would have different outcomes when implemented elsewhere. This holds for both Human and vector populations. For instance, a glycine–serine mutation in the acetylcholinesterase (ace) gene that confers high levels of resistance to carbamates and organophosphates was not found to be present in Anopheles gambiae from Bioko Island, 30 miles off the coast of Cameroon where bendiocarb resistance has been documented. This indicates that there is little gene flow between Bioko Island and the nearest mainland populations. Insecticide treatments that are effective in controlling Mosquito populations on Bioko might have limited effect in other areas. It is, therefore, important that the results of any efficacy studies are considered in the context of their settings. For these reasons, the World Health Organization Vector Control Advisory Group requires data from at least two well-conducted randomised controlled trials in different and complementary entomological settings, ideally covering two transmission seasons, to accept new first-in-class products for vector control. While this can help ensure that products reaching the marketplace have public health value in more than one setting, it requires the use of more than one island group for intervention studies.

Islandswere selected for the first interventions using Release of Insects carrying a Dominant Lethal gene Mosquitoes. Approximately 3.3 million engineered male Aedes aegypti were released in a 23-week period in 2010 in a field site on Grand Cayman, an island in the Caribbean. Monitoring of ovitraps at the release sites and a control site indicated strong population suppression in the treated area during the last seven weeks of the release period. This positive outcome and successful demonstration of population suppression provided encouragement for Release of Insects carrying a Dominant Lethal gene Mosquitoes and genetic control strategies in general for population suppression. The island study was followed by sustained field releases in a suburb of Juazeiro, Bahia, Brazil. While reductions seen in ovitrap indices, compared with the adjacent no-release control area, were similar to those estimated in the Cayman trials, results from a large-scale release in Piracicaba have not been published in academic journals. Challenges in producing sufficient numbers of transgenic Mosquitoes can limit the number released per hectare and thus make it difficult to replicate successes in larger areas.

The control of Arboviral diseases through the use of Wolbachia also requires the mass-rearing and release of Mosquitoes. Wolbachia can reduce Mosquito competence for a variety of RNA Viruses, including Dengue and Chikungunya. Many Wolbachia strains induce a sperm–egg inviability known as cytoplasmic incompatibility that provides female carriers with relative reproductive advantage, allowing the Wolbachia strain to invade naive Insect populations. The reproductive advantage conferred by cytoplasmic incompatibility increases with Wolbachia population frequency, although Wolbachia infection is also often accompanied by deleterious effects on some life-history traits. This combination of frequency-dependent fitness advantages and frequency-independent costs results in an invasion threshold, below the threshold the Wolbachia strain will tend to be lost from a population, but if the threshold is surpassed, the Wolbachia strain will tend to spread. It is, therefore, important that Mosquito releases are sufficient to exceed the threshold frequency. In the case of the wMel Wolbachia infection in Aedes aegypti, it is estimated that the frequency of wMel must reach 20–30% in the population for successful invasion. The rate at which Wolbachia spreads through a population depends on the distance Mosquitoes disperse and the cost of Wolbachia infection, which are likely to be affected by environmental conditions. Indeed, different rates of spreading have been observed at different release sites in Cairns, Australia. Importantly, the ability of Wolbachia to become established can be affected by the isolation of the population. If an Aedes population is not isolated, a relatively small population of infected Mosquitoes can be swamped by immigrants from surrounding Wolbachia-free populations, and the influx is expected to push the prevalence of Wolbachia below the invasion threshold. There is, therefore, the assumption that an intervention will perform differently on an island from in a mainland setting, and theoretical models have been developed to guide programmes that deploy Wolbachia for the purposes of vector control.

In a paper published in the journal Philosophical Transactions of the Royal Society Series B: Biological Sciences on 28 December 2020, Robert Jones of the Department of Disease Control and the Arthropod Control Product Test Centre at the London School of Hygene & Tropical Medicine, Elizabeth Pretorius, also of the Department of Disease Control at the London School of Hygene & Tropical Medicine, Thomas Ant of the Centre for Virus Research at the University of Glasgow, John Bradley of the Medical Research Council International Statistics and Epidemiology Group, Anna Last of the Department of Clinical Research at the London School of Hygiene & Tropical Medicine, and James Logan, again of the Department of Disease Control and the Arthropod Control Product Test Centre at the London School of Hygene & Tropical Medicine, explore the benefits and challenges of conducting intervention studies on islands and introduce the Bijagós archipelago of Guinea-Bissau as a potential study site for interventions intended to control vector-borne diseases.
A unique setting for investigations of infectious disease epidemiology and the efficacy of control interventions is offered by the Bijagós Archipelago of West Africa. The archipelago, made up of 88 islands, is situated within an area of approximately 13 000 km² in the Atlantic Ocean, off the coast of Guinea-Bissau. Collectively, the islands cover 900 km², with the farthest being less than 100 km from the mainland. Eighteen of the islands are permanently inhabited, with an estimated population of around 24 000 people. Many of the others are reserved for seasonal agricultural use. The islands host a diversity of ecosystems from mangroves to forests, and provide habitats for a range of Arthropod vectors of disease.
Bijagós Archipelago, situated off the Atlantic coast of Guinea-Bissau. Inset shows position of Guinea-Bissau on the coast of West Africa. Jones et al. (2020).

The Bijagós Archipelago is endemic for Plasmodium falciparum Malaria and records the highest prevalence (more than 30 confirmed cases per 100 population) in Guinea-Bissau. Standard malaria control interventions implemented on the Bijagós Archipelago by the National Malaria Control Programme include insecticide-treated nets, intermittent preventive treatment in pregnancy, and case diagnosis and treatment with artemisinin-based combination therapy (artemether–lumefantrine). There are no current plans for scale-up of additional Malaria control measures on the islands, so there is an excellent opportunity to conduct interventional studies to reduce Malaria transmission in these communities using novel cost-effective approaches.

Previous studies of the archipelago have monitored Human activity and surveyed Mosquito populations. Using indoor adult light traps and larval dipping at potential breeding sites, Jones et al. characterised vectors likely to be responsible for the majority of Malaria transmission. The island of Bubaque was found to maintain both wet- and dry-season Anopheles gambiae sensu lato (members of the Anopheles gambiae species complex, which contains at least seven morphologically indistinguishable species of Mosquitoes) populations, with Anopheles gambiae sensu stricto (members of the genetically distinct species Anopheles gambiae) being the primary wet season vector, and the salt water-tolerant species Anopheles melas likely to be responsible for the majority of dry-season transmission. Anopheles melas is relatively rare, but can breed year-round in the island’s abundant littoral habitats and mangrove swamps, and thus, as in other coastal areas, maintain a relatively constant dry-season population. By contrast, Anopheles gambiae sensu stricto and Anopheles coluzzii populations on Bubaque decline as the freshwater habitats that support their breeding become scarce. 

The entomological surveys on the archipelago report that Anopheles gambiae sensu stricto and Anopheles coluzzii reside in sympatry and exist as hybrid forms. These hybrids are found at much higher frequencies than are observed elsewhere in Africa. A moderate degree of resistance to α-cypermethrin, but full susceptibility to permethrin, has been recorded. Both kdr and metabolic resistance mechanisms were detected, which could compromise current control methods that rely on insecticide-treated bed nets. 

The movement of people within and between a subset of the Bijagós islands was the subject of a study by Sophie Durrans, Anna Last, Hamadou Boiro, Adriana Goncalves, David Mabey, and Katie Greenland, which showed that, although there was likely less migration than on the mainland owing to their geographical remoteness, the movement was a common feature of island life for men and women alike. While this was a relatively small study, it showed that typical reasons for travel included subsistence activities, family events, income-generating activities, cultural festivities and healthcare. These movements often occurred erratically all-year-round, with the exception of seasonal travel within and between islands for agricultural purposes. Understanding the patterns of movement is important for tailoring and increasing the reach of public health interventions, and this analysis of the Bijogo population will facilitate future studies on the islands. Temporal movement and migration within the island communities can be mapped and monitored during trials, but there are also opportunities to measure epidemiological outcomes through active detection of disease cases in sentinel cohort populations, as has been used for vector control studies in other settings.

A previous study evaluated the suitability of the Bijagós Archipelago as a potential field site for the release of genetically modified Anopheles gambiae. Given the broad geographical distribution of Anopheles gambiae species, there are surprisingly few islands where these Mosquitoes are active in Malaria transmission and where there is a sufficient geographical distance between clusters to ensure isolation. The study collected Mosquitoes from a single site on three of the 88 islands, analysing 208 Mosquitoes, in comparison with 998 Mosquitoes collected and analysed from the Comoro Islands. However, despite the distance of the Bijagós islands from mainland Guinea-Bissau, there was no evidence of genetic sub-division between island and mainland sites, which suggests that there is some degree of ‘island hopping’ on the archipelago. As a result of this evidence, the authors concluded that the Bijagós archipelago was not sufficiently isolated for the release of transgenic strains and found the island of Grande Comore in the Indian Ocean to be a more suitable site for trials with genetically modified strains. Further, the presence of both Anopheles coluzzii and Anopheles gambiae sensu stricto on the Bijagós islands, and evidence of hybridisation between them, would complicate the implementation of an isolated genetically modified Mosquito trial on the archipelago.

A feature that was not relevant to the release of engineered Mosquitoes, but is highly beneficial for other studies, is the presence of more than one island. The Comoro Archipelago constitutes just four islands, while the Bijagós Archipelago counts 18 inhabited islands, opening considerable opportunities for clustering of intervention and control arms in a cluster-randomised trial.

The Bijagós Archipelago offers a setting for the evaluation of other vector control tools. However, it remains important to take potential contamination between clusters into consideration. If different islands of the archipelago were to serve as different clusters, mosquitoes originating on a control-group island that disperse to a treatment island, either through the inadvertent movement of Mosquitoes with local boat traffic or by wind-assisted flight, could, as with Human population movement, interfere with the interpretation of the impact of the intervention. Such impacts are expected to be smaller in island settings than in areas without such physical barriers, but they can be anticipated and minimised through study design.

To help minimise contamination, buffer zones can be designated within clusters. If buffer zones are used, each island is split into an inner core area and an outer buffer zone. The intervention is delivered to the whole island, but measurements are only taken in the core area. The advantage is that contamination can be reduced because it is more likely to occur in the buffer zone where no measurements are taken. A balance must be struck when deciding on the size of the buffer: the bigger the buffer the less contamination will occur in the core area, but the core area must be big enough to ensure a sufficiently large sample can be taken to maintain statistical power. The use of buffer zones, and their size, should consider the average distance travelled by Mosquitoes and the amount of migration of local Human populations. Such zones were used in the first randomized trial to provide evidence that indoor residual spraying, when used in combination with insecticide-treated nets, can give significant added protection against Malarial infection compared with insecticide-treated nets use alone.

It is essential that any randomised trial is sufficiently powered to detect a meaningful difference between the two arms. For a cluster-randomised trial, the principal factors that determine power are: the number of clusters, the number of individuals measured in each cluster, the underlying prevalence/incidence of the endpoint, the difference between the two arms in the endpoint, and the variation between the clusters in the endpoint. A previous cluster-randomised trial that investigated the effect of ivermectin mass drug administration on Malaria only had eight clusters and was probably very underpowered. A less appreciated consequence of using too few clusters is that some statistical models commonly used for the analysis of cluster-randomised trials will not perform well and may lead to increased type 1 errors. The Bijagós Archipelago’s 18 available inhabited islands woul allow a medium-sized, two-armed, cluster-randomised trial to take place there and the sample size should be sufficient for many disease outcomes. For example, for a trial of the use of ivermectin on the archipelago, using data collected from previous studies, we estimate there will be over 90% power to detect a difference of 5 versus 10% Malaria prevalence in the intervention and control arms, respectively.

Stratified randomisation is often used in cluster-randomised trials to increase power. Clusters that are similar in some way are grouped into strata. Analysis is carried out within strata, and the similarity of clusters within each stratum reduces between-cluster variation and, hence, increases power. Care must be taken when deciding which variable(s) are used for stratification. If clusters are stratified on the basis of variables that are not associated with the study endpoint, then power may in fact be reduced. Which variables are strong predictors of endpoints will be specific to the disease in question; for vector-borne diseases, ecological variables related to the Mosquito’s life cycle may be appropriate. A common stratification variable that is appropriate in a wide variety of circumstances is a cluster-level baseline measure of disease prevalence of incidence.

In the Bijagós Archipelago, should more than 18 clusters, representing the number of inhabited islands, be needed in a cluster-randomised trial, islands must be split wherever possible following the above considerations. For example, the island of Caravela has a population numbering more than 4200 people. There are population centres on the north, south and western parts of the island, separated by at least 5 km of sea or land. The island could be split into two or more clusters. The clusters on an island could form a stratum for randomisation, with one population centre being selected, at random, for assignment to the treatment arm and the other assigned to the control arm. This would allow for more clusters to be created beyond the natural limit of 18, but clearly each would have a smaller population size. The choice of buffer zone size might also have an impact on the power of the study. Large buffer zones will reduce the possibility of population mixing, but might demand that some sites are excluded from the study altogether.
Cluster selection and the use of buffer zones. Hypothetical buffer zones of 2.5 km radius (shown as blue discs) around villages (shown as blue dots) potentially allow for the establishment of multiple clusters on a single island (a). Buffer zones of 5 km radius, requiring villages to be at least 10 km apart, would prevent nearby villages from being in different intervention clusters (b). As a result, some villages (shown in orange) could be excluded from the study (c). Jones et al. (2020).

A cluster-randomised control trial investigating the use of adjunctive ivermectin mass drug administration  to control Malaria will be conducted in the Bijagós islands. Through interruption of transmission of Malaria by reducing the Human reservoir of Plasmodium falciparum and vector survival, dihydroartemisinin–piperaquine and adjunctive ivermectin mass drug administration is expected to reduce the prevalence of the disease. Ivermectin has transformed the treatment of parasitic diseases, having been used effectively in mass drug administration campaigns against Onchocerciasis and Lymphatic Filariasis. The drug has also been administered for Head Lice and has had effects on Scabies and intestinal Helminths. Ivermectin mass drug administration for Malaria control would provide an opportunity for collaboration between various disease control programmes, such as the Global Programme to Eliminate Lymphatic Filariasis and the Onchocerciasis Elimination Program of the Americas

Ivermectin is an attractive option for the control of Malaria, as it kills Mosquitoes that feed on individuals who have been administered an appropriate dose, and so targets Mosquitoes regardless of whether they feed indoors or outdoors, during the day or at night. Therefore, it can be used as a tool to complement insecticide-treated nets and indoor residual spraying. Sub-lethal effects of ivermectin on mosquitoes include reductions in fecundity and egg hatch rate, and it has also been shown to have a sporontocidal effect against Plasmodium vivax in host Anopheles. This means that there can be communitywide effects of mass drug administration campaigns, and modelling predictions suggest that ivermectin could be a valuable addition to Malaria control in areas with seasonally persistent high Malaria transmission, where existing interventions have failed to provide sufficient protection, or in areas that are approaching elimination. 

The Bijagós Archipelago has been targeted for an ivermectin campaign owing to its highly seasonal and stable Malaria transmission. It also is co-endemic for Malaria and neglected tropical diseases such as Lymphatic Filariasis, soil-transmitted Helminths and Scabies. The control and elimination of these diseases has been prioritised by the Guinea Bissau Ministry of Public Health. Previous Trachoma research on the islands has shown that mass drug administration can be an effective and feasible strategy to eliminate infectious diseases in these communities. Mass drug administration studies implemented to assess the efficacy of ivermectin for Malaria control should employ both clinical and entomological primary outcomes. Assessors should be blinded to the intervention received by participants to reduce detection biases, and entomological data should be collected through standardised methods, such as indoor traps for Mosquito counts and an ovarian tracheation technique for determining Mosquito age through parity. Given that reductions in Malaria prevalence may not necessarily correspond to reductions in clinical incidence, clinical outcomes should ideally include both measures of prevalence in the study population and measures of clinical incidence, determined through active case detection in cohorts.

The proposed ivermectin trial potentially places restrictions on the further use of the Bijagós Archipelago for intervention studies. The number of islands, and size of their populations, only allow for a single trial of this type to be conducted at any one time. It may be expected that the ‘treated’ clusters would have considerably different epidemics to take into consideration for follow-on trials, and it would be necessary to treat the ‘control’ clusters before subsequent trials can begin. It would also be necessary to allow a suitable period of time to pass before these clusters reach equivalence.

The evaluation of vector control tools requires well-designed studies that generate evidence of efficacy while minimising potential biases. Although islands can have limitations, including restrictions on eligible populations and geography, they have unique features that align them well with cluster-randomised trials with novel vector control tools. The Bijagós islands are endemic for a range of vector-borne and neglected tropical diseases and have already been the subject of entomological and demographic studies that will facilitate future intervention and surveillance studies on the islands.

Caution should be taken in regarding islands as small-scale models of the wider world, but it is also important to avoid the danger of exceptionalism, regarding islands as being unique. Many of the interventions that are currently in use or are in development could benefit from studies of efficacy and suitability, and conducting such trials on the Bijagós Archipelago or other island groups will demonstrate their field suitability and potential value to public health.

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