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Targeted parasite elimination in the human and mosquito to reduce malaria transmission: A randomised controlled trial

A randomised controlled trial evaluating reactive focal drug administration (rfMDA) versus reactive case detection (RACD), with and without reactive vector control (RAVC) in a low endemic setting of Namibia.

Location of study: Zambezi, Namibia

LSHTM Investigators: Immo Kleinschmidt, Lindsey Wu, Chris Drakeley, Kevin Tetteh

External collaborators: UC San Francisco Malaria Elimination Initiative; University of Namibia; University of the Witwatersrand, South Africa; Ministry of Health and Social Services, Namibia; Zambezi Ministry of Health and Social Services Namibia; UC San Francisco, Division of Experimental Medicine, USA

Funding Body: Bill & Melinda Gates Foundation, Novartis Foundation 

A factorial design cluster-randomised controlled trial was conducted in Zambezi, Namibia to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC) as targeted parasite elimination strategies used alone and in combination. Reactive case detection (RACD) has been widely used as a malaria elimination strategy, but its effectiveness is not well validated due to the limited sensitivity of field diagnostics for asymptomatic infections. This study aimed to test the effectiveness of alternative elimination strategies targeting the parasite in both humans and mosquitoes, using a factorial design cluster randomised controlled trial.

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Fifty-six enumeration areas were randomised to the following study arms: reactive case detection only (RACD), reactive focal mass drug administration only (rfMDA), reactive case detection with reactive vector control (RACD + RAVC), or reactive focal mass drug administration with reactive vector control (rfMDA + RAVC).

Between January and November 2017, 56 enumeration areas in Zambezi, Namibia were randomised to four study arms: reactive case detection only (RACD), reactive case detection with reactive vector control (RACD + RAVC), reactive focal mass drug administration only (rfMDA), or reactive focal mass drug administration with reactive vector control (rfMDA + RAVC). Factorial trial design enabled comparisons of test vs. control interventions targeting the human reservoir (rfMDA vs. RACD), the mosquito reservoir (RAVC vs. no RAVC) and in combination (rfMDA + RAVC vs. RACD only). The largest effect was observed in the combined intervention arm. Locally-acquired cumulative incidence in the rfMDA + RAVC intervention arm was 18.5 per 1000 individuals compared to 30.8 cases per 1000 in the reactive case detection control arm.

The adjusted hazard ratio in the combined intervention compared to control was 0.56 (0.36 – 0.87, p=0.01). A cross-sectional survey was conducted at the end of the malaria season (May – August 2017) to measure P. falcparum infection prevalence using two rapid diagnostic tests (CareStart Malaria HRP2/pLDH(Pf/PAN) and ultra-sensitive HRP2-based Alere™ Malaria Ag P.f RDT)) quantitative PCR, and a panel of over 20 serological markers on the Luminex quantitative suspension array (qSAT) immuno-assay. The serological analysis led by LSHTM researchers observed that several markers of recent malaria exposure, such as Etramp5.Ag1, were correlated with primary trial endpoints (clinical incidence rate ratio) and may have potential as secondary endpoints in future cluster randomised trials.

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A. Area Under the Antibody Acquisition Curve (AUC) for Etramp5.Ag1 based on intention-to-treat (ITT) and per-protocol (PP) analysis B. Odds of sero-positivity to Etramp5.Ag1 and highly-sensitive rapid diagnostic test (hsRDT) positivity by study arm (intention-to-treat only) C. Clinical Incidence Rate Ratio (IRR) by intervention.

Diagnostic performance of ultra-sensitive rapid diagnostic tests for detecting asymptomatic P. falciparum on the Cambodian-Thai border

Location of study: Oddor Meachey Province, Cambodia

LSHTM Investigators: Shunmay Yeung, Nicola James, David McGregor

External collaborators: Soy Ty Kheang (Health and Social Development); Po Ly, Siv Sovannaroth (National Center for Parasitology, Entomology & Malaria Control, Cambodia); Saorin Kim, Nimol Khim, Benoit Witkowski (Institut Pasteur du Cambodge, Cambodia)

Funding Body: UK DFID through the Tracking Resistance to Artemisinins Collaboration

Proposed interventions for eliminating drug resistant P. falciparum malaria, include the targeting of asymptomatic carriers through screening and treatment. We compared the diagnostic performance of the recently developed ultra-sensitive rapid diagnostic test (uRDT) under field conditions in Cambodia, compared to screening with conventional RDTs (cRDT) and polymerase chain reaction (PCR). This study was nested within the PACES study, a cluster randomised control trial of active case detection for malaria which was carried out in Oddar Meanchey Province in Northwest of Cambodia.

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Conventional and ultra-sensitive Rapid Diagnostic Tests.

We carried out a comparison of uRDTs with conventional RDTs and PCR under two field conditions: active case detection and a cross-sectional survey. In total 2,729 tests were carried using all three diagnostic tests; 678 during active case detection and 2,051 during the cross-sectional survey. The positivity rate for P. falciparum infections by qPCR analysis was 3.8% (26/678) and 0.48% (10/2051) for active case detection and cross-sectional survey respectively. In both these contexts uRDT were shown to have similar sensitivity and specificity to cRDT. The results of this study therefore do not suggest an improved performance of uRDTs over conventional RDTs when used for either active screening or cross-sectional surveys in very low prevalence areas such as Northern Cambodia.

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Taking blood from forest goers on the back of timber truck.

 

Proactive case detection and community participation for the elimination of drugresistant malaria in Cambodia Study (PACES)

Location of study: Oddor Meachey Province, Cambodia

LSHTM Investigators: Shunmay Yeung, Nicola James

External collaborators: Soy Ty Kheang, Somphos Chhloeung, (Health and Social Development); Po Ly, Hu Rekol, Siv Sovannaroth, (National Center for Parasitology, Entomology & Malaria Control, Cambodia); Benoit Witkowski, Didier Ménard (Institut Pasteur du Cambodge, Cambodia); Koen Peeters (Institute of Tropical Medicine, Belgium); Iveth Gonzalez and Xavier Ding (Foundation for Innovative New Diagnostics, Switzerland)

Funding Body: UK DFID through the Tracking Resistance to Artemisinins Collaboration

The spread of artemisinin resistant P. falciparum malaria is one of the biggest threats to global malaria control and elimination. Cambodia, which is at the epicentre of multidrug resistant malaria, declared a goal of eliminating malaria by 2025. However it is unclear how to achieve this operationally, for example who to target for strategies such as active case detection, what screening tests to use and how acceptable these interventions are to the affected communities? The aim of our study was to address some of these questions and to contribute to the national and regional efforts to eliminate drug resistant malaria.

We carried out a mixed methods study at the core of which was a cluster randomised control trial of active case detection using village malaria workers in 130 villages in Oddor Meanchey province. We confirmed how focal and dynamic malaria is in this study area, and the importance of working very closely with the community. In most villages there was no local transmission, and little point in screening people who had not recently been to the forest. For at-risk contacts of patients who had presented to the village malaria worker with symptomatic malaria, around one-fifth tested positive for malaria.

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(top) Response team member getting instructions on where to find forest-going co-workers; (bottom) Discussions with health centre staff on where the forest goers are getting malaria.

The intervention was generally very well accepted however the majority of the asymptomatic malaria that we uncovered was not due to P. falciparum but P. vivax and that the relapsing nature of P. vivax poses as much, if not more of a burden in affected communities. However, this is not related to drug resistance. Future plans include operational research focusing on providing radical cure for P. vivax with prior G6PD testing. By understanding more about malaria and the at-risk population in these areas and sharing the lessons we have learnt in implementing active case detection, we hope to contribute to the national and regional efforts to eliminate drug resistant malaria.

Non-inferiority of targeted reactive IRS compared with generalised routine IRS and determination of transmission hotspots

Location of study: South Africa

LSHTM Investigators: Immo Kleinschmidt, Jackie Cook, David Bath, Catherine Pitt, Joseph Biggs

External collaborators: Maureen Coetzee (Wits Research Institute for Malaria, University of the Witwatersrand, South Africa); Natashia Morris, Rajendra Maharaj (South African Medical Research Council, South Africa); Aaron Mabuza (Mpumalanga Provincial Malaria Control Programme, South Africa)

Funding Body: MRC/DFID/Wellcome Trust Joint Global Health Trials

In areas of very low, pre-elimination malaria transmission the low number of incident cases may call into question the resources needed for spraying all houses annually with insecticide (generalised indoor residual spraying (GIRS)). An alternative that may be more cost-effective is to target IRS, reactively spraying only houses in the immediate neighbourhood of incident cases as they arise.

62 clusters consisting of settlements of approximately 5000 persons each in the provinces of Mpumalanga and Limpopo in South Africa, were randomly allocated to receive the currently practised GIRS whilst the other half received reactive targeted IRS (TIRS) in the immediate neighbourhood (about 8 houses) of every passively reported local case. Non-inferiority of TIRS was assessed as passive incidence of no more than 1 case/1000 per year above that of the GIRS arm. Dried blood spots were collected from neighbourhoods of index cases, and in randomly selected neighbourhoods where there were no cases occurred, to determine, using serology, whether new cases arise predominantly in areas of previous exposure to parasites.

Incidence in the targeted IRS was higher than in the generalised IRS arm by 0.29 cases per 1000 (95% CI -0.53-1.10). Antibody prevalence showed that cases arise in neighbourhoods with raised levels of previous exposure to malaria parasites. Although evidence of non-inferiority of TIRS compared to GIRS was weak, TIRS appears to be a safe, more sustainable method of deploying IRS in areas of very low transmission. Since the neighbourhoods of passively detected cases are characterised by raised levels of past exposure to parasites, it is important that these areas are targeted with additional interventions such as focal IRS.

Freedom from Infection: confirming the interruption of malaria transmission for elimination

Location of study: Cabo Verde, Indonesia, Haiti, Laos, Thailand, Vietnam

LSHTM Investigators: Lindsey Wu, Henry Surendra, Gillian Stresman, Chris Drakeley

External collaborators: Kim Linblade and Abdisalan Noor (WHO Global Malaria Programme), Arnaud Le Menach and Justin Cohen (Clinton Health Access Initiative), Pak Yono Supargiyono (Universitas Gadjah Mada, Indonesia), Adam Bennett and Andrew Lover (UC San Francisco Malaria Elimination Initiative), Adilson Jose de Pina (Cabo Verde Ministry of Health)

Funding Body: Bill & Melinda Gates Foundation

While a number of countries are targeting malaria elimination, epidemiologically confirming the absence of cases or infections is challenging. This project is adapting “Freedom from Infection” surveillance tools, used extensively in veterinary epidemiology, to guide national malaria control programmes in the design of optimal elimination surveillance strategies.

Freedom from Infection (FFI) surveillance tools have been used in veterinary epidemiology to demonstrate that infection in a population is below a defined threshold. These approaches characterise the absence of transmission within a degree of statistical certainty. This project is adapting FFI tools specifically for malaria in collaboration with national malaria control programmes (NMCPs) and research groups across a range of countries currently targeting elimination. Our analysis estimates the probability that regions are free from malaria transmission using routine health facility data or community surveys.

Analysis also includes determining feasible time frames required to confirm elimination at national or subnational levels and quantifying the value-added of additional diagnostics or surveillance endpoints to more accurately estimate freedom from infection. Preliminary analysis, such as from the Kulon Progo Regency in central Java, Indonesia, has shown that monthly surveillance data over the course of one year can be used to estimate the probability of freedom from malaria infection at the health facility level. Work is currently ongoing to demonstrate the use of these tools with surveillance data at national and subnational levels in Laos, Thailand, Vietnam, Haiti, and Cabo Verde. We are also partnering with NMCPs and the WHO to determine how these tools can be designed to contribute to programmatic decision-making for elimination certification.

Can dogs identify people with malaria parasites? A proof-of-principle study

Location of study: United Kingdom, The Gambia

LSHTM Investigators: James Logan, Sarah Dewhirst, Chelci Squires

External collaborators: Steven Lindsay (Durham University, UK); Umberto D’Alessandro & Margaret Pinder (MRC Unit The Gambia at the LSHTM); B. Kandeh (National Malaria Control Programme, Banjul, The Gambia); Jenny Corish, Clare Guest & Mark Doggett, (Medical Detection Dogs, UK); S. Morant, (Medicines Monitoring Unit, University of Dundee, UK)

Funding Body: Bill & Melinda Gates Foundation

The task of malaria elimination would be simpler if a noninvasive method was available for detecting infected individuals in populations where the number of malaria cases is low; infected individuals could then be treated with antimalarials. Dogs have a highly developed sense of smell and may be able to detect volatiles released from people carrying malaria parasites. We carried out a proof-of-principle study to determine whether trained dogs could detect malaria infections in Gambian children aged 5-13 years old.

Why was this study done?

  • The World Health Organization has a vision of a malaria-free world. Since 2000 *eight countries have been certified as free from malaria, with a further 12 reporting no indigenous cases. Once a country or region has been declared malaria-free detecting individuals with asymptomatic infections is critical so they can be treated with antimalarials and the transmission of the disease prevented.
  • Ideally a non-invasive diagnostic device that can detect malaria-infected subjects would be an advance, helping to keep the disease out of malaria-free countries.
  • In The Gambia, West Africa, the number of malaria infections has declined substantially since 2000 and provides an ideal site for detecting malaria at low frequencies.
  • We tested the hypothesis that dogs, with their powerful sense of smell, could be trained to distinguish between individuals with and without Plasmodium falciparum malaria

What did the researchers do and find?

  • Gambian schoolchildren were screened to detect malaria parasites in their blood to determine those carrying parasites and those without.
  • We provided socks for the schoolchildren to wear overnight in order to collect samples of their foot odours.
  • Two dogs were trained to distinguish between sock samples from malaria-infected and uninfected individuals tested in a double blind fashion.
  • Two dogs were able to identify strips of socks from malaria-infected and uninfected individuals with a sensitivity of 70% and 73% and a specificity of 90% and 91%.

What do these findings mean?

  • Dogs can identify malaria-infected individuals by their odour with a credible degree of accuracy. • In the future artificial odour sensors may be able to detect malaria parasites.
  • Until then, trained dogs may be useful at ports of entry to detect asymptomatic malaria carriers entering malaria-free countries.
  • Further studies are needed to detect falciparum malaria in people from different parts of the world before medical detection dogs can be used in the field.
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Medical Detection Dog, Lexi, sniffing skin odour loaded socks during testing at their Milton Keynes facility.

OPSIN: Optimising serological surveillance for malaria in Indonesia

Location of study: Indonesia

LSHTM Investigators: Henry Surendra, Chris Drakeley, Jackie Cook

External collaborators: Supargiyono & Riris Ahmad (Centre for Tropical Medicine, Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Indonesia)

Funding Body: Indonesia Endowment Fund for Education

This project explores the feasibility of optimising use of serological surveillance for estimating the magnitude and heterogeneity of malaria transmission in a pre-elimination setting in Indonesia. We integrate novel serological and geographical information system techniques with the existing public health surveillance system to better understand malaria transmission dynamics in this setting.

We found that rolling health facility-based cross-sectional surveys involving all facility attendees and their companions provide an alternative approach for quickly obtaining parasitological, serological, geolocation and epidemiological data. Simple addition of the use of mobile technology-based participatory mapping approaches into the surveys could provide attractive approach for remotely collecting accurate fine-scale geolocation data to study spatial pattern of disease in low resource areas without formal addresses and poor internet connection.

Although the parasiteprevalence was very low (5/10,000), analysis of serological samples against a panel of novel antigens could facilitate the measurement of recent and historical exposure to P. falciparum, P. vivax and P. knowlesi as well as the characterisation of the spatial patterns and risk factors of malaria exposure in a pre-elimination setting in Indonesia. In conclusion, use of serological surveillance could be optimised by utilising existing surveillance system to monitor disease transmission dynamics for control and elimination programmes planning. However, further implementation research is needed to enable integration of these methods with existing surveillance systems.

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(L-R) Luminex machine established at collaborator lab at Gadjah University, Indonesia; (top) Data collection and participatory mapping; (below) sample collection.

Bias in routinely collected Plasmodium falciparum malaria surveillance data due to asymptomatic infections according to transmission intensity: A pooled analysis of paired health system and community cross-sectional survey data

Location of study: Worldwide (Brazil, Cambodia, Ethiopia, The Gambia, Haiti, Kenya, Malaysia, Myanmar, Peru, Philippines, Tanzania, Zambia)

LSHTM Investigators: Gillian Stresman, Nuno Sepulveda, Chris Drakeley, Kimberly Fornace, Shunmay Yeung, Lynn Grignard (LSHTM, UK); Umberto D’Alessandro, Julia Mwesigwa, Jane Achan (MRC Unit The Gambia)

External collaborators: Katherine Battle, Ewan Cameron and Peter Gething, (Malaria Atlas Project, University of Oxford, UK); Andre Siqueira, (Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil); Emilie Poithin and Joanna Gallay, (Swiss Tropical and Public Health Institute, Basel, Switzerland); Siv Sovannaroth, (NMCP, Phnom Penh, Cambodia); Jennifer Stevenson and Antonio Quispe, (Johns Hopkins Bloomberg School of Public Health, Baltimore, US); Teun Bousema and Fitsum Tadesse, (Radboud University Medical Center, Nijmegen, The Netherlands); Effie Espino, Joy Lorenzo and Malou Macalinao, (Research Institute for Tropical Medicine, Manilla, Philippines); Jordi Landier, Gilles Delmas and Francois Nosten, (MAHIDOL Oxford Tropical Medicine Research Unit, Bangkok, Thailand); Jacklin Mosha, (NIMR, Mwanza, Tanzania); Thomas Eisele, (Center for Applied Malaria Research and Evaluation, Tulane University, US); John Miller and Daniel Bridges, (PATH, Lusaka, Zambia); Michelle Chang and Karen Hamre, (Centers for Disease Control and Prevention, Atlanta, US); Alyssa Young, (Clinton Health Access Initiative, Port-au-Prince, Haiti); Jean Frantz Lemoine, (Programme National de Controle de la Malaria, Port-auPrince, Haiti)

Funding Body: Wellcome Trust

Health systems data is the foundation information that malaria programs use to estimate malaria burden and inform control/elimination programming. However, the proportion of infected individuals that do not seek care, and thus not included in these statistics, can be significant. This work seeks to understand how well health systems data can mirror the total burden of infection, and how this changes according to transmission intensity. The aim was to determine the relationship between the proportion of all infections in the community that are identified within the health system and transmission intensity, as a proxy for levels of protective immunity in the community.

Paired community and health system data, concordant in both time and space, were collected from 435 clusters in 12 countries. The proportion of infections detected in the health system was estimated according to the number of infections detected at the facility using a binomial distribution and the total number of infections in the community according to a hypergeometric distribution. Uncertainty was determined by bootstrapping. The proportion detected was modelled according to transmission intensity, measured by overall population PCR prevalence.

Preliminary results indicate the proportion of infections detected by the health system starts to increase when overall malaria prevalence in the community is less than ~10%. Facilities detect up to 100% of infections in non-African settings when the probability of seeking care and bednet use are adjusted for. In African settings, the proportion of infections detected gradually increases linearly. These findings suggest that once transmission is sufficiently low, health systems can be relied upon to detect most malaria infections in a community.

Malaria Zero: The Alliance for A Malaria-Free Haiti. Convenience sampling vs. household survey gold standard: assessment of spatial bias in predicted malaria exposure

Location of study: Haiti

LSHTM Investigators: Chris Drakeley, Gillian Stresman, Lotus van den Hoogen, Kevin Tetteh, Nuno Sépulveda

External collaborators: Katherine Battle and Ewan Cameron, (Malaria Atlas Project, University of Oxford, UK); Thomas Eisele, Ruth Ashton and Thomas Druetz, (Center for Applied Malaria Research and Evaluation, Tulane University, US); Michelle Chang and Karen Hamre, (Centers for Disease Control and Prevention, Atlanta, US); Bernadette Fouche, (CDC Foundation, Port-au-Prince, Haiti); Jean Frantz Lemoine, (Programme National de Controle de la Malaria, Port-au-Prince, Haiti)

Funding Body: Bill & Melinda Gates Foundation

Maps showing the distribution of malaria are becoming an important tool for control and elimination activities. Here, we are determining if maps generated from data collected using convenient sampling methods can identify the same areas of high malaria exposure compared to the more accurate but labour intensive community-based data collection.

Convenience sampling in easy access groups (EAG) to measure malaria burden provides an attractive alternative to household (HH) surveys. Malaria seroprevalence estimates generated by sampling school-children as well as all health facility attendees have both been shown to provide reasonable estimates of malaria transmission in the community. Here, we assess the degree of spatial bias when generating maps of malaria seroprevalence according to the EAG sample compared to the gold standard HH survey conducted in the Artibonite Valley, Haiti. For the EAG study, 2126 children in 22 schools and 2108 individuals attending 9 health facilities were sampled with spatial coordinates of the household available for 1092 participants. EAG seroprevalence were compared to fitted estimates according to a geostatistical model according to data from a HH survey of 21620 individuals residing in 6847 households.

Preliminary results suggest that estimates from the EAG study overall underestimated seroprevalence, with a smaller degree of bias in the health facility sample. However, the maps generated from the EAG data were able to identify similar areas of high burden as the HH survey in areas where the EAG and HH survey data overlapped spatially.

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Map of intensity of responses to eTramp5, a marker associated with recent exposure to malaria. Each point is the location of participants sampled as part of the Easy Access Group surveys in primary school and health facilities in the Artibonite Valley, Haiti.

Antimalarial antibody detection assays: in search of a standardised tool to detect the absence of transmission

Location of study: Bataan, The Philippines; Praia, Cape Verde & LSHTM, UK

LSHTM Investigators: Lotus van den Hoogen, Nuno Sépulveda, Gillian Stresman, Kimberley Fornace, Kevin Tetteh & Chris Drakeley

External collaborators: Paolo Bareng, Ralph Reyes, Jennifer Luchavez, Malou Macalinao and Fe E. Espino (Research Institute for Tropical Medicine, Department of Health, the Philippines); Julio Rodrigues and Joana Alves (National Institute of Public Health, Cabo Verde); Alan Kitchen, (NHS Blood and Transplant, UK); Peter Chiodini, (Hospital for Tropical Diseases, UK)

Funding Body: Bill & Melinda Gates Foundation

The lack of antibody responses to malaria in young children signifies the absence of exposure to infections. As such, antibody detection may help in declaring an area malaria-free. At present there are no standardised assays to measure malaria antibodies for epidemiological use. There are several commercial assays but these have been developed to screen blood donations prior to transfusion. We aimed to evaluate the performance of commercially available assays for epidemiological use.

We compared five commercially available ELISA antibody detection assays for malaria. For Phase I, we assessed the ease-of-use, cost, sample volume needed and specificity (using malaria-naïve; n=223 as well as toxoplasma positive, malaria-naïve samples; n=191). Based on these results, one assay was taken forward for epidemiological evaluation. For Phase II, samples from Bataan, the Philippines were assayed (n=1824; an area without clinically reported cases at local health facilities since the early 90s) as well as Praia, Cape Verde (n=1396; unstable, low transmission over the past decades). Preliminary results from Bataan show a change-point in the force of infection (SCR: seroconversion rate), which overlapped with the recorded drop in malaria cases. When a more stringent threshold for seropositivity was used, only four children under the age of 16 were seropositive while the recent SCR was 0.0001 (95% confidence interval, 0.0000-0.0004), Figure 1.

Whether the four detected seropositive children indicate responses from asymptomatic infections, outliers of seronegative responses, or cross-reactive responses to antigens from other pathogens is unknown. These results are promising in the development of standardised serological assays as adjunct measures to confirm claims of cessation of malaria transmission at a sub-regional level.