Abstract
Stimulated by recent advances in malaria control and increased funding, the elimination of malaria is now considered to be an attainable goal for an increasing number of malaria-endemic regions. This has boosted the interest in transmission-reducing interventions including vaccines that target sexual, sporogenic, and/or mosquito-stage antigens to interrupt malaria transmission (SSM-VIMT). SSM-VIMT aim to prevent human malaria infection in vaccinated communities by inhibiting parasite development within the mosquito after a blood meal taken from a gametocyte carrier. Only a handful of target antigens are in clinical development and progress has been slow over the years. Major stumbling blocks include (i) the expression of appropriately folded target proteins and their downstream purification, (ii) insufficient induction of sustained functional blocking antibody titers by candidate vaccines in humans, and (iii) validation of a number of (bio)-assays as correlate for blocking activity in the field. Here we discuss clinical manufacturing and testing of current SSM-VIMT candidates and the latest bio-assay development for clinical evaluation. New testing strategies are discussed that may accelerate the evaluation and application of SSM-VIMT.
Highlights
The World Malaria Report 2014 documented major progress with a considerable reduction of the malaria burden in several countries
Vaccines interrupting malaria transmission (VIMT), introduced in the malaria vaccine roadmap, that effectively interrupt transmission from humans to mosquitoes have the potential to fill a critical gap in the malaria vaccine portfolio
The biological endpoints of Phase 2 clinical trials in endemic settings will allow determination of: (i) antibody concentration and dynamics; (ii) dynamics of functional transmission blocking activity in the standard membrane feeding assay (SMFA) with cultured gametocytes; (iii) dynamics of functional transmission blocking activity in the direct membrane feeding assays (DMFA) with naturally infected gametocyte donors; (iv) in a subset of vaccinees who become gametocytaemic, functional transmission blocking activity can be assessed by DMFA and Direct Feedings Assay (DFA) with naturally acquired gametocytes from the vaccinee
Summary
The World Malaria Report 2014 documented major progress with a considerable reduction of the malaria burden in several countries. The genes encoding Pfs48/45, Pfs230 and Pfs in Plasmodium falciparum as well as its ortholog Pvs in Plasmodium vivax, were isolated and these target proteins remained the major candidates for clinical development of transmission blocking vaccines for already for the past three decades [12,13,14,15] During this period, several workshops have been organized by, amongst others, the World Health Organization, the United States National Institutes of Health (NIH), Malaria Vaccine Initiative and the Bill & Melinda Gates Foundation to discuss clinical trial design and endpoints, efficacy evaluation assays, regulatory aspects and application strategies [2,3,16,17,18]. We will discuss the latest progress in clinical development of SSM-VIMTs and evaluation of biological endpoint measures with suggestions for future steps
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