Progress towards malaria elimination in the Greater Mekong Subregion: perspectives from the World Health Organization.

Malaria remains a global health challenge, disproportionately affecting vulnerable communities. Despite substantial progress, the emergence of anti-malarial drug resistance poses a constant threat. The Greater Mekong Subregion (GMS), which includes Cambodia, China's Yunnan province, Lao People's Democratic Republic, Myanmar, Thailand, and Viet Nam has been the epicentre for the emergence of resistance to successive generations of anti-malarial therapies. From the perspective of the World Health Organization (WHO), this article considers the collaborative efforts in the GMS, to contain Plasmodium falciparum artemisinin partial resistance and multi-drug resistance and to advance malaria elimination. The emergence of artemisinin partial resistance in the GMS necessitated urgent action and regional collaboration resulting in the Strategy for Malaria Elimination in the Greater Mekong Subregion (2015-2030), advocating for accelerated malaria elimination interventions tailored to country needs, co-ordinated and supported by the WHO Mekong malaria elimination programme. The strategy has delivered substantial reductions in malaria across all GMS countries, with a 77% reduction in malaria cases and a 97% reduction in malaria deaths across the GMS between 2012 and 2022. Notably, China was certified malaria-free by WHO in 2021. Countries' ownership and accountability have been pivotal, with each GMS country outlining its priorities in strategic and annual work plans. The development of strong networks for anti-malarial drug resistance surveillance and epidemiological surveillance was essential. Harmonization of policies and guidelines enhanced collaboration, ensuring that activities were driven by evidence. Challenges persist, particularly in Myanmar, where security concerns have limited recent progress, though an intensification and acceleration plan aims to regain momentum. Barriers to implementation can slow progress and continuing innovation is needed. Accessing mobile and migrant populations is key to addressing remaining transmission foci, requiring effective cross-border collaboration. In conclusion, the GMS has made significant progress towards malaria elimination, particularly in the east where several countries are close to P. falciparum elimination. New and persisting challenges require sustained efforts and continued close collaboration. The GMS countries have repeatedly risen to every obstacle presented, and now is the time to re-double efforts and achieve the 2030 goal of malaria elimination for the region.

Expanding the roles of community health workers to sustain programmes during malaria elimination: a meeting report on operational research in Southeast Asia.

In Southeast Asia malaria elimination is targeted by 2030. Cambodia aims to achieve this by 2025, driven in large part by the urgent need to control the spread of artemisinin-resistant falciparum malaria infections. Rapid elimination depends on sustaining early access to diagnosis and effective treatment. In much of Cambodia, rapid elimination will rely on a village malaria worker (VMW) network. Yet as malaria declines and is no longer a common cause of febrile illness, VMWs may become less popular with febrile patients, as VMWs do not diagnose or treat other conditions at present. There is a risk that VMWs become inactive and malaria rebounds before the complete interruption of transmission is achieved.During 2021-23 a large-scale operational research study was conducted in western Cambodia to explore how a VMW network could be sustained by including health activities that cover non-malarial illnesses to encourage febrile patients to continue to attend. 105 VMWs received new rapid diagnostic tests (including dengue antigen-antibody and combined malaria/C-reactive protein tests), were trained in electronic data collection, and attended health education packages on hygiene and sanitation, disease surveillance and first aid, management of mild illness, and vaccination and antenatal care.In August 2023 the National Malaria Control Programme of Cambodia convened a stakeholder meeting in Battambang, Cambodia. Findings from the study were reviewed in the context of current malaria elimination strategies. The discussions informed policy options to sustain the relevance of the VMW network in Cambodia, and the potential for its integration with other health worker networks. This expansion could ensure VMWs remain active and relevant until malaria elimination is accomplished.

Knowledge, attitudes and practices with regard to schistosomiasis prevention and control: Two cross-sectional household surveys before and after a Community Dialogue intervention in Nampula province, Mozambique.

BACKGROUND: The Community Dialogue Approach is a promising social and behaviour change intervention, which has shown potential for improving health seeking behaviour. To test if this approach can strengthen prevention and control of schistosomiasis at community level, Malaria Consortium implemented a Community Dialogue intervention in four districts of Nampula province, Mozambique, between August 2014 and September 2015. METHODOLOGY/PRINCIPAL FINDINGS: Cross-sectional household surveys were conducted before (N = 791) and after (N = 792) implementation of the intervention to assess its impact on knowledge, attitudes and practices at population level. At both baseline and endline, awareness of schistosomiasis was high at over 90%. After the intervention, respondents were almost twice as likely to correctly name a risk behaviour associated with schistosomiasis (baseline: 18.02%; endline: 30.11%; adjusted odds ratio: 1.91; 95% confidence interval: 1.14-2.58). Increases were also seen in the proportion of people who knew that schistosomiasis can be spread by infected persons and who could name at least one correct transmission route (baseline: 25.74%; endline: 32.20%; adjusted odds ratio: 1.36; 95% confidence interval: 1.01-1.84), those who knew that there is a drug that treats the disease (baseline: 29.20%, endline: 47.55%; adjusted odds ratio: 2.19; 95% confidence interval: 1.67-2.87) and those who stated that they actively protect themselves from the disease and cited an effective behaviour (baseline: 40.09%, endline: 59.30%; adjusted odds ratio: 2.14; 95% confidence interval: 1.40-3.28). The intervention did not appear to lead to a reduction in misconceptions. In particular, the belief that the disease is sexually transmitted continued to be widespread. CONCLUSIONS/SIGNIFICANCE: Given its overall positive impact on knowledge and behaviour at population level, Community Dialogue can play an important role in schistosomiasis prevention and control. The intervention could be further strengthened by better enabling communities to take suitable action and linking more closely with community governance structures and health system programmes.

Improving health worker performance through text messaging: A mixed-methods evaluation of a pilot intervention designed to increase coverage of intermittent preventive treatment of malaria in pregnancy in West Nile, Uganda.

Poor health worker performance is a well-documented obstacle to quality service provision. Due to the increasingly widespread availability of mobile devices, mobile health (mHealth) has received growing attention as a service improvement tool. This pilot study explored feasibility, acceptability and outcomes of an mHealth intervention designed to increase coverage of intermittent preventive treatment of malaria in pregnancy (IPTp) in two districts of West Nile, Uganda. In both districts, selected health workers (N = 48) received classroom training on malaria in pregnancy. All health workers in one district (N = 49) subsequently received 24 text messages reinforcing the training content. The intervention was evaluated using a mixed-methods approach, including four focus group discussions with health workers and three in-depth interviews with district health officials, health worker knowledge assessments one month (N = 90) and six months (N = 89) after the classroom training, and calculation of IPTp coverage from participating health facilities' (N = 16) antenatal care registers covering six months pre- and post-intervention. Complementing classroom training with text messaging was found to be a feasible, acceptable and inexpensive approach to improving health worker performance. The messages served as reminders to those who had attended the classroom training and helped spread information to those who had not. Health workers in the district where text messages were sent had significantly better knowledge of IPTp, achieving an increased composite knowledge score of 6.00 points (maximum score: 40) compared with those in the district where only classroom training was provided. Average facility coverage of three doses of IPTp was also significantly higher where text messages were sent (85.8%) compared with the district where only classroom training was provided (54.1%). This intervention shows promise for the improvement of health worker performance for delivery of IPTp, and could have significant broader application.

Larval and adult environmental temperatures influence the adult reproductive traits of Anopheles gambiae s.s.

BACKGROUND: Anopheles mosquito life-history parameters and population dynamics strongly influence malaria transmission, and environmental factors, particularly temperature, strongly affect these parameters. There are currently some studies on how temperature affects Anopheles gambiae s.s. survival but very few exist examining other life-history traits. We investigate here the effect of temperature on population dynamics parameters. METHODS: Anopheles gambiae s.s. immatures were reared individually at 23 ± 1 °C, 27 ± 1 °C, 31 ± 1 °C, and 35 ± 1 °C, and adults were held at their larval temperature or at one of the other temperatures. Larvae were checked every 24 h for development to the next stage and measured for size; wing length was measured as a proxy for adult size. Females were blood fed three times, and the number of females feeding and laying eggs was counted. The numbers of eggs and percentage of eggs hatched were recorded. RESULTS: Increasing temperatures during the larval stages resulted in significantly smaller larvae (p = 0.005) and smaller adults (p < 0.001). Adult temperature had no effect on the time to egg laying, and the larval temperature of adults only affected the incubation period of the first egg batch. Temperature influenced the time to hatching of eggs, as well as the time to development at every stage. The number of eggs laid was highest when adults were kept at 27 °C, and lowest at 31 °C, and higher adult temperatures decreased the proportion of eggs hatching after the second and third blood meal. Higher adult temperatures significantly decreased the probability of blood feeding, but the larval temperature of adults had no influence on the probability of taking a blood meal. Differences were observed between the first, second, and third blood meal in the times to egg laying and hatching, number of eggs laid, and probabilities of feeding and laying eggs. CONCLUSIONS: Our study shows that environmental temperature during the larval stages as well as during the adult stages affects Anopheles life-history parameters. Data on how temperature and other climatic factors affect vector life-history parameters are necessary to parameterise more reliably models predicting how global warming may influence malaria transmission.

Modelling Anopheles gambiae s.s. Population Dynamics with Temperature- and Age-Dependent Survival.

Climate change and global warming are emerging as important threats to human health, particularly through the potential increase in vector- and water-borne diseases. Environmental variables are known to affect substantially the population dynamics and abundance of the poikilothermic vectors of disease, but the exact extent of this sensitivity is not well established. Focusing on malaria and its main vector in Africa, Anopheles gambiae sensu stricto, we present a set of novel mathematical models of climate-driven mosquito population dynamics motivated by experimental data suggesting that in An. gambiae, mortality is temperature and age dependent. We compared the performance of these models to that of a "standard" model ignoring age dependence. We used a longitudinal dataset of vector abundance over 36 months in sub-Saharan Africa for comparison between models that incorporate age dependence and one that does not, and observe that age-dependent models consistently fitted the data better than the reference model. This highlights that including age dependence in the vector component of mosquito-borne disease models may be important to predict more reliably disease transmission dynamics. Further data and studies are needed to enable improved fitting, leading to more accurate and informative model predictions for the An. gambiae malaria vector as well as for other disease vectors.

Temperature during larval development and adult maintenance influences the survival of Anopheles gambiae s.s.

BACKGROUND: Malaria transmission depends on vector life-history parameters and population dynamics, and particularly on the survival of adult Anopheles mosquitoes. These dynamics are sensitive to climatic and environmental factors, and temperature is a particularly important driver. Data currently exist on the influence of constant and fluctuating adult environmental temperature on adult Anopheles gambiae s.s. survival and on the effect of larval environmental temperature on larval survival, but none on how larval temperature affects adult life-history parameters. METHODS: Mosquito larvae and pupae were reared individually at different temperatures (23 ± 1°C, 27 ± 1°C, 31 ± 1°C, and 35 ± 1°C), 75 ± 5% relative humidity. Upon emergence into imagoes, individual adult females were either left at their larval temperature or placed at a different temperature within the range above. Survival was monitored every 24 hours and data were analysed using non-parametric and parametric methods. The Gompertz distribution fitted the survivorship data better than the gamma, Weibull, and exponential distributions overall and was adopted to describe mosquito mortality rates. RESULTS: Increasing environmental temperature during the larval stages decreased larval survival (p < 0.001). Increases of 4°C (from 23°C to 27°C, 27°C to 31°C, and 31°C to 35°C), 8°C (27°C to 35°C) and 12°C (23°C to 35°C) statistically significantly increased larval mortality (p < 0.001). Higher environmental temperature during the adult stages significantly lowered adult survival overall (p < 0.001), with increases of 4°C and 8°C significantly influencing survival (p < 0.001). Increasing the larval environment temperature also significantly increased adult mortality overall (p < 0.001): a 4°C increase (23°C to 27°C) did not significantly affect adult survival (p > 0.05), but an 8°C increase did (p < 0.05). The effect of a 4°C increase in larval temperature from 27°C to 31°C depended on the adult environmental temperature. The data also suggest that differences between the temperatures of the larval and adult environments affects adult mosquito survival. CONCLUSIONS: Environmental temperature affects Anopheles survival directly during the juvenile and adult stages, and indirectly, since temperature during larval development significantly influences adult survival. These results will help to parameterise more reliable mathematical models investigating the potential impact of temperature and global warming on malaria transmission.

Modeling the role of environmental variables on the population dynamics of the malaria vector Anopheles gambiae sensu stricto.

BACKGROUND: The impact of weather and climate on malaria transmission has attracted considerable attention in recent years, yet uncertainties around future disease trends under climate change remain. Mathematical models provide powerful tools for addressing such questions and understanding the implications for interventions and eradication strategies, but these require realistic modeling of the vector population dynamics and its response to environmental variables. METHODS: Published and unpublished field and experimental data are used to develop new formulations for modeling the relationships between key aspects of vector ecology and environmental variables. These relationships are integrated within a validated deterministic model of Anopheles gambiae s.s. population dynamics to provide a valuable tool for understanding vector response to biotic and abiotic variables. RESULTS: A novel, parsimonious framework for assessing the effects of rainfall, cloudiness, wind speed, desiccation, temperature, relative humidity and density-dependence on vector abundance is developed, allowing ease of construction, analysis, and integration into malaria transmission models. Model validation shows good agreement with longitudinal vector abundance data from Tanzania, suggesting that recent malaria reductions in certain areas of Africa could be due to changing environmental conditions affecting vector populations. CONCLUSIONS: Mathematical models provide a powerful, explanatory means of understanding the role of environmental variables on mosquito populations and hence for predicting future malaria transmission under global change. The framework developed provides a valuable advance in this respect, but also highlights key research gaps that need to be resolved if we are to better understand future malaria risk in vulnerable communities.

Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization.

Inhibitory receptors mediate CD8 T-cell hyporesponsiveness against cancer and infectious diseases. PD-1 and CTLA-4 have been extensively studied, and blocking antibodies have already shown clinical benefit for cancer patients. Only little is known on extended co-expression of inhibitory receptors and their ligands. Here we analyzed the expression of eight inhibitory receptors by tumor-antigen specific CD8 T-cells. We found that the majority of effector T-cells simultaneously expressed four or more of the inhibitory receptors BTLA, TIM-3, LAG-3, KRLG-1, 2B4, CD160, PD-1 and CTLA-4. There were major differences depending on antigen-specificity, differentiation and anatomical localization of T-cells. On the other hand, naive T-cells were only single or double positive for BTLA and TIM-3. Extended co-expression is likely relevant for effector T-cells, as we found expression of multiple ligands in metastatic lesions of melanoma patients. Together, our data suggest that naive T-cells are primarily regulated by BTLA and TIM-3, whereas effector cells interact via larger numbers of inhibitory receptors. Blocking multiple inhibitory receptors simultaneously or sequentially may improve T-cell based therapies, but further studies are necessary to clarify the role of each receptor-ligand pair.