Immunization with Transgenic Rodent Malaria Parasites Expressing Pfs25 Induces Potent Transmission-Blocking Activity.

An anti-malarial transmission blocking vaccine (TBV) would be an important tool for disease control or elimination, though current candidates have failed to induce high efficacy in clinical studies. The ookinete surface protein P25 is a primary target for TBV development, but heterologous expression of P25 with appropriate conformation is problematic and a pre-requisite for achieving functional titers. A potential alternative to recombinant/sub-unit vaccine is immunization with a non-pathogenic, whole-parasite vaccine. This study examines the ability of a purified transgenic rodent-malaria parasite (PbPfs25DR3), expressing Plasmodium falciparum P25 in native conformation on the P. berghei ookinete surface, to act as a TBV. Vaccination with purified PbPfs25DR3 ookinetes produces a potent anti-Pfs25 response and high transmission-blocking efficacy in the laboratory, findings that are then translated to experimentation on natural field isolates of P. falciparum from infected individuals in Burkina Faso. Efficacy is demonstrated in the lab and the field (up to 93.3%/97.1% reductions in transmission intensity respectively), with both a homologous strategy with one and two boosts, and as part of a prime-boost regime, providing support for the future development of a whole-parasite TBV.

Comparative assessment of transmission-blocking vaccine candidates against Plasmodium falciparum.

Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasites within the mosquito, with the aim of preventing malaria transmission from one infected individual to another. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leading candidate antigens, have been developed independently and have reported varied transmission-blocking activities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modified vaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated. Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/c mice were boosted by the administration of MVA expressing the same antigen. These antibodies exhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum in Anopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with anti-Pfs230-C and anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibition was replicated against P. falciparum African field isolates in A. gambiae in direct membrane feeding assays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first head-to-head comparative analysis of leading antigens using two different parasite sources in two different vector species, and can be used to guide selection of TBVs for future clinical development using the viral-vectored delivery platform.

Stress dependent infection cost of the human malaria agent Plasmodium falciparum on its natural vector Anopheles coluzzii.

Unraveling selective forces that shape vector-parasite interactions has critical implications for malaria control. However, it remains unclear whether Plasmodium infection induces a fitness cost to their natural mosquito vectors. Moreover, environmental conditions are known to affect infection outcome and may impact the effect of infection on mosquito fitness. We investigated in the laboratory the effects of exposition to and infection by field isolates of Plasmodium falciparum on fecundity and survival of a major vector in the field, Anopheles coluzzii under different conditions of access to sugar resources after blood feeding. The results evidenced fitness costs induced by exposition and infection. When sugar was available after blood meal, infected and exposed mosquitoes had either reduced or equal to survival to unexposed mosquitoes while fecundity was either increased or decreased depending on the blood donor. Under strong nutritional stress, survival was reduced for exposed and infected mosquitoes in all assays. We therefore provide here evidence of an environmental-dependant reduced survival in mosquitoes exposed to infection in a natural and one of the most important parasite-mosquito species associations for human malaria transmission.