Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection against Pf in non-human primate malaria models, clinical trials using recombinant AMA1 alone (apoAMA1) yielded no protection due to insufficient functional antibodies. Immunization with AMA1 bound to RON2L, a 49-amino acid peptide from its ligand RON2, has shown superior protection by increasing the proportion of neutralizing antibodies. However, this approach relies on the formation of a complex in solution between the two vaccine components. To advance vaccine development, here we engineered chimeric antigens by replacing the AMA1 DII loop, displaced upon ligand binding, with RON2L. Structural analysis confirmed that the fusion chimera (Fusion-FD12) closely mimics the binary AMA1-RON2L complex. Immunization studies in female rats demonstrated that Fusion-FD12 immune sera, but not purified IgG, neutralized vaccine-type parasites more efficiently compared to apoAMA1, despite lower overall anti-AMA1 titers. Interestingly, Fusion-FD12 immunization enhanced antibodies targeting conserved epitopes on AMA1, leading to increased neutralization of non-vaccine type parasites. Identifying these cross-neutralizing antibody epitopes holds promise for developing an effective, strain-transcending malaria vaccine.

Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

Invasion of human red blood cells (RBCs) by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) 1,2 . Antibodies to AMA1 confer limited protection against P. falciparum in non-human primate malaria models 3,4 . However, clinical trials with recombinant AMA1 alone (apoAMA1) saw no protection, likely due to inadequate levels of functional antibodies 5-8 . Notably, immunization with AMA1 in its ligand bound conformation using RON2L, a 49 amino acid peptide from RON2, confers superior protection against P. falciparum malaria by enhancing the proportion of neutralizing antibodies 9,10 . A limitation of this approach, however, is that it requires the two vaccine components to form a complex in solution. To facilitate vaccine development, we engineered chimeric antigens by strategically replacing the AMA1 DII loop that is displaced upon ligand binding with RON2L. Structural characterization of the fusion chimera, Fusion-F D12 to 1.55 Å resolution showed that it closely mimics the binary receptor-ligand complex. Immunization studies showed that Fusion-F D12 immune sera neutralized parasites more efficiently than apoAMA1 immune sera despite having an overall lower anti-AMA1 titer, suggesting improvement in antibody quality. Furthermore, immunization with Fusion-F D12 enhanced antibodies targeting conserved epitopes on AMA1 resulting in greater neutralization of non-vaccine type parasites. Identifying epitopes of such cross-neutralizing antibodies will help in the development of an effective, strain-transcending malaria vaccine. Our fusion protein design is a robust vaccine platform that can be enhanced by incorporating polymorphisms in AMA1 to effectively neutralize all P. falciparum parasites.

Water filtration using plant xylem.

Effective point-of-use devices for providing safe drinking water are urgently needed to reduce the global burden of waterborne disease. Here we show that plant xylem from the sapwood of coniferous trees--a readily available, inexpensive, biodegradable, and disposable material--can remove bacteria from water by simple pressure-driven filtration. Approximately 3 cm(3) of sapwood can filter water at the rate of several liters per day, sufficient to meet the clean drinking water needs of one person. The results demonstrate the potential of plant xylem to address the need for pathogen-free drinking water in developing countries and resource-limited settings.