Testing Insect Repellents Against Musca Sorbens, the Vector of Trachoma
Condition: Trachoma
MeSH terms: Trachoma
Study type: Interventional
Phase: Phase 2

Summary: 
      Musca sorbens, a fly that feeds from ocular and nasal discharge on humans, is thought to be
      the vector of trachoma. We are developing methods of fly control that specifically target
      this species, in the hope of interrupting Ct transmission. To our knowledge, the use of
      commercially available insect repellents has never been tested for prevention of Musca
      sorbens fly-eye contact (i.e. nuisance and landing in the peri-ocular area). Given the likely
      necessity for prolonged and/or high frequency fly-eye contact for Ct transmission, the
      reduction of these contacts through the use of fly repellents presents an exciting
      opportunity for disease control. Here we propose a within-subject, non-masked, trial of the
      use of commercially available insect repellents against Musca sorbens, with two consecutive
      participant groups in the laboratory and in the field, and a primary endpoint of measuring
      the protective efficacy of each repellent product. Repellent products will be chosen from:
      DEET (N,N-diethyl-3-methylbenzamide), IR3535 (3-[N-butyl-N-acetyl]-aminopropionic acid ethyl
      ester), Picaridin (2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1-methylpropyl ester); PMD
      (para-Menthane-3,8-diol) or permethrin
      (m-Phenoxybenzyl)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate).
      Products tested will be either (1) topical repellents, or (2) in long-lasting, plastic
      formulations of repellents that can be worn on the body (wearable repellent technologies).
      The insect repellent synergist Vanillin (4-Hydroxy-3-methoxybenzaldehyde) may be added to the
      long-lasting plastic formulations, to improve the duration of protection.
    

Detailed description: 
      Introduction

      Trachoma

      Trachoma, a Neglected Tropical Disease (NTD), is the commonest infectious cause of blindness
      globally, affecting some of the world's poorest communities. Trachoma is caused by repeated
      ocular infection with the bacterium Chlamydia trachomatis (Ct). Active trachoma begins in
      childhood with recurrent episodes of follicular conjunctivitis (TF). Chronic inflammation
      results in immunologically mediated conjunctival scarring and in-turned eyelashes scratching
      the eye: trichiasis. Eventually sight is lost from irreversible corneal opacification.

      Trachoma is currently endemic in 42 countries. The latest estimates from the Global Trachoma
      Mapping Programme (GTMP) suggest that 180 million people live in trachoma endemic areas and
      3.2 million people have trachomatous trichiasis. Around 2.2 million people are visually
      impaired, of whom 1.2 million are blind. More than 80% of the burden of active trachoma is
      concentrated in 14 countries, mainly in the Sahel of West Africa and savannahs of East and
      Central Africa, where water supplies are often scarce.

      Trachoma in Ethiopia

      Ethiopia is working towards eliminating trachoma by 2020 and began implementing the SAFE
      strategy as part of national policy in 2003. This has focused on the provision of improved
      trichiasis surgery, mass drug administration (MDA) and the distribution of public health
      messages by radio, video, and printed material. From 2001-2015 more than one million
      trichiasis surgeries were performed, over 170 million doses of azithromycin were given
      through MDA and more than 24 million latrines were built. Despite these encouraging efforts,
      trachoma remains a public health problem in many regions of the country, and the burden of
      disease is far above the elimination targets set by the World Health Organisation (WHO). In
      many of these communities, despite seven years of annual or biannual high-coverage MDA, the
      prevalence of TF remains well above threshold for continuing MDA. Data on Ct prevalence after
      repeated rounds of MDA in hyperendemic settings such as Ethiopia, indicate that reliable
      long-term control is not consistently achieved, with gradual re-emergence of infection being
      typical.

      Flies and Trachoma

      Flies are likely to contribute to Ct transmission in some locations. The three members of the
      species complex Musca sorbens live in close association with humans across the Old World
      tropics and sub-tropics, Asia, the Pacific Islands and Australasian regions. The African
      species, M. sorbens and Musca biseta, are collectively known as The Bazaar fly, but all are
      also known as 'face flies', because of their habit of aggressively visiting the face to
      obtain the protein and liquid found in ocular and nasal secretions. When M. sorbens flies
      visit the face to feed, they can pick up Ct and transfer it on their bodies to another
      person. This is called mechanical transmission. Sometimes the house fly, Musca domestica,
      will also display eye-seeking behaviour, but across most trachoma-endemic regions, the vast
      majority of fly-eye contacts are made by M. sorbens. As well as transmitting trachoma, M.
      sorbens has been found to harbour enteric pathogens. In communities without adequate
      sanitation such as pit latrines, filth flies including M. sorbens have direct access to
      faecal breeding sites in the form of open defection. Here, they contact diarrhoea-causing
      pathogens, and subsequent contact to children's faces, or contamination of eating surfaces,
      can lead to pathogen transmission.

      Ct can be cultured from guts and limbs of M. domestica fed on Ct-infected egg yolk. Using a
      tightly controlled guinea pig trachoma model, Chlamydia psittaci was transmitted by flies
      from infected to uninfected eyes. Infection was established consistently if the time between
      flies feeding on infected guinea pig ocular secretions and being exposed to uninfected guinea
      pigs was under one hour. Other, circumstantial, evidence suggests that flies contribute to
      the transmission of trachoma. In randomised controlled trials, significantly decreasing the
      M. sorbens population through long-term insecticide spraying led to decreases in the
      prevalence of clinical signs of active trachoma (infection not tested). However, azithromycin
      MDA combined with intensive insecticide spraying in other regions had no effect. Multiple
      transmission routes complicate trachoma epidemiology, and the extent to which flies
      contribute to transmission must also be dependent on local factors such as fly seasonality,
      abundance and local environmental factors that influence fly population dynamics. Two studies
      tested M. sorbens caught leaving faces of Ethiopian children for Ct by polymerase chain
      reaction (PCR); 15-23% of flies were positive. In The Gambia, Ct positive flies were also
      caught from children's faces. These data strongly suggest M. sorbens is a vector of trachoma,
      however, its relative importance probably varies by setting. Although it is probable that
      flies are involved in transmission, this pathway is poorly understood.

      Olfactory cues have been exploited for monitoring and control of vector populations for many
      years, through the deployment of odour-baited traps. However, in recent years the use of such
      traps for population suppression of disease vectors has received increased attention, and
      recently the potential of these methods for malaria control was empirically demonstrated for
      the first time. One of the most long-standing and established examples of the use of
      odour-baited traps is the control of tsetse flies and Human African Trypanosomiasis in East
      Africa.

      The investigators have recently conducted field studies in Oromia, Ethiopia, during Phase 1
      and Phase 2 of the Stronger SAFE programme, designing a trap from locally sourced and cheaply
      available materials. The performance of this trap was tested, baited with a commercial lure,
      relative to several other commercially available fly traps and found to be superior. A major
      advantage of odour-baited trapping for fly control is that it is not associated with
      environmental impact concerns. This is in contrast to widespread insecticide spraying, which
      although has been shown to suppress fly populations very successfully, can be damaging to the
      environment.

      Insect repellents are used world-wide to prevent nuisance biting by non-vector species, and
      to prevent disease transmission by vectors in disease-endemic regions. Although the use of
      plants with repellent qualities, either by burning leaves or presenting fresh foliage, is
      prevalent in many regions, commercially available topical repellents are rarely used by
      people in low-income and disease-endemic countries. This is because of cost, availability,
      and the impracticality of a product that requires repeat application. However, when use of
      insect repellents has been successfully adopted by communities, they have been found to be
      protective against malaria. Repellents have also been successfully used to control other
      arthropods of public health significance, including lice and the chigoe flea. A recent review
      of the evidence that topical insect repellents can be used to protect against clinical
      malaria or malaria infection found insufficient evidence, and called for better designed
      trials to generate higher-certainty evidence.

      There is growing interest in the use of repellents as personal protection from disease
      transmission, particularly around the use of insecticide-treated clothing, which can repel
      biting insects. In these instances, the insecticide used has spatially repellent properties
      or is a contact irritant, which protects the individual user and the insecticides are not
      sprayed into the environment. Insecticide-treated clothing has been shown to provide
      protection from both malaria and leishmaniasis. Another study looked at the use of
      permethrin-treated headscarves for Afghan women in a Pakistani refugee camp, and found a
      reduction in the incidence of malaria in people under 20 years old. There is better evidence
      for the use of insecticide-treated clothing against malaria transmission, particularly
      advocated in areas where more evidence-based vector control strategies such as long-lasting
      insecticide-treated bed nets are not appropriate. Again, however, further high-quality
      studies are required to improve the efficacy evidence base.

      Using the M. sorbens colony that the investigators have established at LSHTM, preliminary
      studies have been conducted that demonstrate M. sorbens are susceptible to most commercially
      available repellents. The investigators have found evidence that the insecticide permethrin
      has some spatial repellency to M. sorbens, if impregnated at safe doses into fabric scarves.
      In areas of high fly density, it is expected that the nuisance caused by these flies may
      allow such an intervention to be successful, as the immediate benefit of reduced face contact
      would encourage continued uptake of this intervention. Attractant (odour-baited trap) and
      repellent (commercially available repellents) technologies will be combined to create a
      "push-pull" strategy to reduce vector-host contact and attract flies to lethal odour-baited
      traps that will supress populations.

      Research hypothesis

      Commercially available insect repellent products can be used to decrease contact to the face,
      particularly the eyes, nose and mouth, by the eye-seeking fly Musca sorbens. The protection
      afforded by insect repellents will prevent transmission of Chlamydia trachomatis by infected
      flies, as well as reducing the nuisance caused by this species.
    

Intervention name(s): IR3535; Permethrin lower dose; Permethrin higher dose
Intervention type(s): Other; Other; Other
Intervention description(s): The topical repellent IR3535 (3-[N-butyl-N-acetyl]-aminopropionic acid ethyl ester) only; A fabric scarf, impregnated with the insecticide permethrin (m-Phenoxybenzyl)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate) that has contact irritancy/spatial repellency. Dose appropriate to children of 10-20 kg.; A fabric scarf, impregnated with the insecticide permethrin (m-Phenoxybenzyl)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate) that has contact irritancy/spatial repellency. Dose appropriate to children more than 20 kg.
Intervention MeSH terms: Permethrin
Allocation: Randomized
Intervention model: Single Group Assignment
Intervention model description: This is a within-subject, non-masked, trial of the use of commercially available insect repellents against Musca sorbens, with two consecutive participant groups in the laboratory and in the field, and a primary endpoint of measuring the protective efficacy of each repellent product.
The first (laboratory-based) study has one arm, in which all participants test all repellent products. Those that are found to generate at least 30 % protective efficacy will be tested in the second (field-based) study, which will have four arms. Up to three arms will test a repellent product and there will be a control arm.
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention