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Malaria Transmission Blocking by Vaccines, Drugs and Immune Mosquitoes: Efficacy Assessment and Targets

Final Report Summary - TRANSMALARIABLOC (Malaria Transmission Blocking by Vaccines, Drugs and Immune Mosquitoes: Efficacy Assessment and Targets)

Executive Summary:
TransMalariaBloc has made a significant contribution in the field of malaria elimination by establishing the foundations for the future exploitation of data derived by the project toward development of malaria transmission blocking interventions. Specifically, we have developed an analytical framework that can be used to determine the effective reservoir of infection in different endemic settings and the required efficacy of transmission blocking interventions. Using this framework and experimental data we have revealed that parasite density can strongly influence the reported success and efficacy of transmission-blocking interventions. A number of transmission blocking vaccine candidates have been tested, including the anti-Pfs25 that is currently at Phase 1 clinical trial and anti-P230 which can be an equally effective vaccine. We showed that Neem tree, among other, extracts have a great efficacy in blocking P. falciparum transmission and can complement the therapeutic properties of ACTs. We also revealed that specific HIV Protease Inhibitors cause strong Plasmodium developmental arrest, opening new avenues in the design of integrated HIV/AIDS and malaria chemotherapies. We demonstrated that antibiotics present in the human blood increase the mosquito capacity to transmit P. falciparum. Since antibiotic use in Africa is high and recommended in WHO-led disease elimination programmes, these findings are of particular importance to public health. Toward developing transgenic refractory mosquitoes, we generated lines overexpressing the anti-plasmodial mosquito complement pathway, which are now tested for their capacity to block or reduce parasite infection and hence affect malaria transmission. We also completed analysis of the genome-wide transcriptional responses of the A. gambiae and A. arabiensis to infections with P. falciparum populations sampled from infected children and identified an important role of GPCR signalling during infection. At the same time we identified several parasite genes showing strong phenotypes associated with mosquito midgut infection; some of them are currently explored as potential candidates for transmission blocking drugs and vaccines. Our work to characterise genotype*genotype interactions involved in P. falciparum infections of the A. gambiae midgut in natural settings has catalysed the development of novel technological platforms and yielded several candidates that are now being studied for their effect on parasite infections, including a group of proteins involved in maintaining the mosquito gut homeostasis. Finally we showed that A. gambiae and P. falciparum are highly resilient to seasonally variable, and occasionally extreme, weather conditions. In conclusion, TransMalariaBloc has precipitated existing and initiated new strong collaborations between academic and research institutions in Europe and Africa, has educated and trained a number of graduates and research professionals in malaria research and has opened new research and exploitation avenues that could assist in the effort to eliminate malaria.
Project Context and Objectives:
There are approximately 250 million malaria cases annually, causing ~1 million deaths of mainly children in Africa. In order to effectively control and eventually eradicate malaria, it is now recognized that blocking malaria transmission, which occurs through an obligatory passage of the malaria parasite through its mosquito vector, is of paramount importance. Indeed current effective control measures are largely based on reducing the vector populations or their contact with humans. However, these measures are thought to be inadequate as resistance to insecticides used for bed-net impregnation and indoor residual spraying is spreading fast, while mosquito vectors are thought to be evolving to change their biting habits, thus incapacitating indoor interventions. The TransMalariaBloc project was established to investigate novel means to stop malaria transmission by rendering mosquitoes unable to transmit the parasite. They include transmission-blocking vaccines and transmission-blocking drugs or remedies, which although administered to humans function to stop the parasite in the mosquito or to incapacitate the mosquito itself, and engineering mosquitoes to become resistant to parasite infections, by boosting their natural immune system or by supplying them with alternative resistance properties. The project aims at both a detailed biological understanding of the impact of such interventions on malaria transmission and epidemiology, and the development and testing of interventions.
Project Results:
• We have developed malaria transmission and transmission-blocking models and showed that in high transmission areas current measures are inadequate and that transmission-blocking interventions can have a significant impact.
• We have established state-of-art infrastructure including experimental transmission facilities and transmission blocking assays in both the laboratory and the field. Especially the latter infrastructure is internationally unique.
• We have confirmed experimentally the efficacy of transmission blocking vaccines and showed that it is parasite density dependent. We have highlighted that anti P25 and P230 are the best transmission blocking vaccines to date.
• We have identified hundreds of transmission blocking compounds, including remedies and plant extracts. We have shown that extracts of the Neem tree are very potent transmission blockers and can complement current ACT therapies.
• We have identified the presence of antibiotics in the blood of malaria-infected children as a new risk of increasing disease transmission.
• We have identified several new transmission blocking targets in both parasites and mosquitoes, and characterized some of them in great detail. These targets should now enter a translational research path.
• We have generated genetically modified mosquitoes expressing immune factors that can eliminate parasites, the effect of which on infections remains to be confirmed.
• We have characterized the impact of infection, insecticides and environmental factors on malaria transmission, which will assist the design of transmission-blocking interventions.
• We have generated tools and contributed to e-infrastructures that can help the study of mosquito population biology and understanding the mosquito population structure.
• We have revealed a strong genetic component of the mosquito vectorial capacity that can help to identify the specific ecological and geographical characteristics of malaria transmission, and fine-tune the transmission blocking interventions.

(for details see the Annex to the Final Report)
Potential Impact:
Malaria affects almost half of the world population and kills about 1 million people every year, while its socioeconomic impacts especially on endemic countries are devastating. Whilst the development of new therapeutics for symptomatic treatment of patients is imperative, this alone cannot lead to elimination of malaria, which is now a top priority in the global malaria agenda. Elimination of the disease can be achieved by either of three ways or indeed a combination of them: vector management and control, a vaccine-mediated prevention of new infections, and blockade of transmission from infected to otherwise healthy people. TransMalariaBloc has aimed to make a significant impact on achieving the latter through informed development and detailed assessment of transmission-blocking vaccines, drugs, and remedies or through generating mosquitoes that do not transmit the disease. At the end of this first phase of the project, we can report. At the end of this initial phase of the project, we can confidently report that transmission blocking can work and that there is substantial groundwork and a critical mass to take these studies further toward exploitation. Our conclusion and vision from analysing the data we, and others prior to this project, have produced over the years and by reviewing past breakthroughs in the elimination of infectious diseases is that transmission blocking may be a path to success. Specifically:
• TransMalariaBloc has been one of the cornerstones of the transmission blocking concept that has been now established as an important framework in the fight against malaria. Therefore, TransMalariaBloc has had substantial impact on its field.
• TransMalariaBloc has contributed or directly given rise to many new consortia and projects supported by the Medicines for Malaria Ventures (MMV) on transmission blocking drugs, the Malaria Vaccine Initiative (MVI) on the impact of transmission blocking interventions in field settings, the Bill and Melinda Gates Foundation on the impact of transmission blocking interventions on the population level and others. Therefore, our project has had substantial impact in initiating new thrusts aiming at exploitation of the results and development of interventions.
• TransMalariaBloc has generated results that could be directly or indirectly exploited towards transmission blocking. This includes transmission blocking vaccines, transmission blocking drugs and transmission blocking remedies. Two well-understood transmission blocking vaccine candidates have been shown to be the most promising: P25 and P230. The former is already in Phase I trial. Robust assays have been developed to report for transmission blocking drug efficacy, and indeed hundreds of such drugs have been discovered through spin-off projects in collaboration with non-academic partnerships described above. One of these drugs is targeting a pathway that is essential for mosquitoes to survive after a bloodmeal. This drug is currently being tested in field settings. Plant extracts with transmission blocking capacities have been characterized, which now need to be further studies towards the development of novel interventions. Indeed, these data have precipitated the formation of a new enterprise (http://www.proherbalcare.com/) that would assist in further exploitation of these data.
• TransMalariaBloc has generated experimental protocols and facilities that can be used in future malaria transmission blocking research. The protocol we established for mosquito infections with malaria parasites directly sampled from infected children and the coupling of this protocol to the various transmission blocking interventions we have developed is a significant breakthrough in linking laboratory discoveries to field tests. Coupled with a state-of-the-art facility we generated to carry out such work in Bobo Dioulasso, Burkina Faso, this protocol can be used for future exploitation of our results and discoveries made by others. The malaria house facility we contributed to establish in Iganga, Uganda, to test anti-malarial vaccines could be used for Phase I trials of transmission blocking vaccines.
• TransMalariaBloc has educated, trained and contributed to career development of several new investigators that will continue the research in field of malaria transmission. Many of these investigators have now established their own research programs continuing the translational work of data derived from the project in collaboration with academic and non-academic sponsors.
• TransMalariaBloc has identified several new transmission blocking targets and has developed new screening assays that can fuel future translational and applied research for many years. A new consortium aiming to explore the value of new parasite targets for the development of transmission blocking vaccines has been already formed with the inclusion of additional partners specializing on anti-malarial vaccines. With regards to mosquito molecules that can be used as transmission blocking targets, a new concept has emerged from discoveries made in the context of the project, whereby antibodies ingested by with the blood would render mosquitoes incapable of controlling opportunistic infections and therefore die before transmitting the disease. We are now validating this concept in field settings and are seeking funds to further extent the project.
• TransMalariaBloc has revealed that antibiotics present in human blood increase the capacity of mosquitoes to transmit malaria. Since antibiotic use in Africa is high and recommended in WHO-led disease elimination programmes, these data are of particular importance to public health. Towards exploitation of these data we now aim to directly test antibiotic treatment of malaria-infected patients and examine a number of antibiotics that are currently in use in malaria-endemic countries. Following these work, specific recommendations can be made to national and international health services for tightly regulated antibiotic prescription in areas with high malaria transmission, prescription of specific antibiotics to malaria-infected patients, and couple mass antibiotic administration programs to increased bednet coverage.
List of Websites:
http://www.transmalariabloc.net