Utilizing gametocyte immunity to reduce malaria transmission

The continuing success of the current malaria elimination campaign requires novel tools to efficiently block human infection and subsequent transmission of the parasite to mosquitoes. Current transmission blocking strategies target the development of the parasite in the mosquito stage, requiring complicated mosquito feeding readouts to measure efficacy. We recently identified the bone marrow as the major site of transmission stage development during infection. Based on this finding we hypothesized that the underlying host parasite interactions could be exploited to block parasite transmission. Indeed our preliminary studies demonstrate natural immune responses against parasite surface antigens and their functionality in terms of immune clearance. Here we utilize this new understanding to systematically define the immunity targeting malaria transmission with the ultimate goal of prioritizing a set of novel transmission blocking vaccine candidates.

Malaria transmission from man to mosquito requires the uptake of male and female gametocytes from an infected host during a mosquito blood meal. Gametocytes are therefore essential for successful onward infection to new hosts and a major target for interventions. Our recent work demonstrates that gametocytes, together with a subset of asexual parasites, develop in the hematopoietic environment of the bone marrow before being released into circulation as transmission competent mature forms. Our preliminary studies have revealed natural immune responses targeting immature gametocytes that are correlated with reduced gametocyte burden in malaria patients. Using a combination of surface proteomics and immune profiling of immunised mice we have identified a series of putative surface antigens on gametocyte-infected red blood cells. The majority of them is shared with asexual stage parasites suggesting shared function in host cell interactions during development in the bone marrow. Here we propose to systematically investigate the targets and functionality of natural gametocyte immunity as a basis for novel vaccine development. For this purpose, we will combine a series of field studies in malaria endemic areas and experimental human infections, in vitro functional assays to define antigen-specific antibody activity and B-cell epitopes, as well proof-of-principle experiments in the rodent malaria model.

The recent gains in malaria control have contributed to a renewed interest in malaria elimination and worldwide eradication. Thirty-five countries have fewer than 1000 malaria cases per year and are actively pursuing malaria elimination. In most African settings, malaria elimination is considered unrealistic with the currently available tools such as firstline treatment with artemisinin combination therapy (ACT), deployment of insecticide treated nets and indoor residual spraying. Tools or approaches that specifically aim to reduce malaria transmission are considered highly valuable for elimination efforts in these settings. In addition, the genuine threat of ACT resistant malaria parasites in the Greater Mekong Subregion has highlighted the need for interventions that can reduce and prevent the spread of (resistant) malaria parasites.

Malaria transmission blocking vaccines are high on the priority list of international academic groups that set the research agenda for malaria eradication (e.g. malERA), policy makers including the World Health Organization and funders with an interest in malaria vaccination or elimination strategies (e.g. PATH Malaria Vaccine Initiative and the Bill & Melinda Gates Foundation). The current project answers fundamental questions about malaria biology and immunology, which in itself forms an excellent justification for academic research. In addition, it forms a solid basis for future vaccine development projects. If successful, the current project will open new avenues for malaria vaccine development and vaccination strategies. All current and historic efforts to develop malaria transmission blocking vaccines focus on gamete antigens or mosquito antigens. The current project is the first to directly target gametocytes prior to ingestion by mosquitoes. A vaccination approach that aims to prevent gametocyte formation or maturation has utility as stand-alone intervention in settings of resistant malaria, epidemic or seasonal malaria and may be of particular use when combined with other vaccines that target other malaria life stages. When combined with pre-erythrocytic or bloodstage malaria vaccines, a vaccine targeting (the formation of) gametocytes may protect the partner vaccine and augment its community impact in reducing the force of infection.

The investigators and collaborators have solid networks that involve the above mentioned stakeholders, maximizing the chance that the findings from the current project will result in follow-up funding, are disseminated to policy makers at the highest possible level (as well as at a lower level to national malaria control programmes and country managers) and are shared with academic think tanks on malaria elimination and eradication.