The Need for Novel Asexual Blood-Stage Malaria Vaccine Candidates for Plasmodium falciparum.

Extensive control efforts have significantly reduced malaria cases and deaths over the past two decades, but in recent years, coupled with the COVID-19 pandemic, success has stalled. The WHO has urged the implementation of a number of interventions, including vaccines. The modestly effective RTS,S/AS01 pre-erythrocytic vaccine has been recommended by the WHO for use in sub-Saharan Africa against Plasmodium falciparum in children residing in moderate to high malaria transmission regions. A second pre-erythrocytic vaccine, R21/Matrix-M, was also recommended by the WHO on 3 October 2023. However, the paucity and limitations of pre-erythrocytic vaccines highlight the need for asexual blood-stage malaria vaccines that prevent disease caused by blood-stage parasites. Few asexual blood-stage vaccine candidates have reached phase 2 clinical development, and the challenges in terms of their efficacy include antigen polymorphisms and low immunogenicity in humans. This review summarizes the history and progress of asexual blood-stage malaria vaccine development, highlighting the need for novel candidate vaccine antigens/molecules.

Severe Macular Ischemia Is Associated with a Poor Visual Prognosis and Serious Complications in Eyes with Central Retinal Vein Occlusion.

PURPOSE: This study aims to investigate the factors influencing post-treatment visual acuity (VA) in patients with central retinal vein occlusion (CRVO) with macular edema (ME). METHODS: The subjects of this study were patients who visited our clinic from May 2013 to July 2019 and who could be followed up with for at least 12 months. Cases with hemi CRVO were excluded from this study. Factors considered in the evaluation of visual prognosis at the 12 months included initial best-corrected VA, central subfoveal thickness, CRVO subtype (nonischemic, ischemic, or converted from nonischemic to ischemic), time taken for the first treatment, number of anti-vascular endothelial growth factor agent injections, structural changes in the inner and outer retinal layers, and the presence of macular ischemia in a multiple regression analysis. RESULTS: There were 41 patients with 41 eyes, 27 males and 14 females. The mean age of the patients was 70.5 ± 12.2 (mean ± standard deviation) years. The mean VA was 0.544 ± 0.576, 0.456 ± 0.568, and 0.586 ± 0.665 at the initial visit, 12 months later, and time of last observation, respectively. There were no significant differences in VAs observed between the baseline, month 12, and final visit. Multiple regression analysis revealed that the external limiting membrane score at month 12 (p = 0.030), the VA at initial visit (p < 0.001), and the presence of severe macular ischemia (p < 0.001) were the key factors associated with VA at month 12. Moreover, severe macular ischemia was identified as the only factor affecting decimal VA less than 20/200 at the last observation (p = 0.0092). CONCLUSIONS: Severe macular ischemia is strongly linked to a poor visual prognosis in patients with ME associated with CRVO.

AUTOLOGOUS POSTERIOR CAPSULE FLAP TRANSPLANTATION IN THE MANAGEMENT OF REFRACTORY MACULAR HOLE IN A PSEUDOPHAKIC EYE.

PURPOSE: To report a case of refractory macular hole (MH) in pseudophakic eye treated with autologous posterior capsule flaps transplantation. METHODS: Case report. RESULTS: A 48-year-old man visited our hospital with visual loss in the right eye because of unclosed MH. The patient had undergone two previous surgeries in another hospital, that is, the first included a cataract surgery, vitrectomy, and internal limiting membrane peeling with sulfur hexafluoride (SF 6 ) gas tamponade, and the second included an ineffective autologous internal limiting membrane flap technique and massaging the edges of the MH with a soft-tipped flute needle followed by the same gas, but the MH remained open. In our hospital, posterior capsule flaps were acquired from the same eye, inserted into the MH, and the same gas tamponade was performed, which was about four months after the disease onset (3 months after the prior second surgery). The patient kept face-down position for a week after the surgery and the MH was closed, which remained for over 12 months. The visual acuity improved from 20/250 to 20/60, and the retinal sensitivities around the MH gradually improved. CONCLUSION: An autologous posterior capsule flaps transplantation was effective in the management of refractory MH to not only close the MH but also improve the visual outcomes.

Plasmodium yoelii Erythrocyte Binding Like Protein Interacts With Basigin, an Erythrocyte Surface Protein.

Erythrocyte recognition and invasion is critical for the intra-erythrocytic development of Plasmodium spp. parasites. The multistep invasion process involves specific interactions between parasite ligands and erythrocyte receptors. Erythrocyte-binding-like (EBL) proteins, type I integral transmembrane proteins released from the merozoite micronemes, are known to play an important role in the initiation and formation of tight junctions between the apical end of the merozoite and the erythrocyte surface. In Plasmodium yoelii EBL (PyEBL), a single amino acid substitution in the putative Duffy binding domain dramatically changes parasite growth rate and virulence. This suggests that PyEBL is important for modulating the virulence of P. yoelii parasites. Based on these observations, we sought to elucidate the receptor of PyEBL that mediates its role as an invasion ligand. Using the eukaryotic wheat germ cell-free system, we systematically developed and screened a library of mouse erythrocyte proteins against native PyEBL using AlphaScreen technology. We report that PyEBL specifically interacts with basigin, an erythrocyte surface protein. We further confirmed that the N-terminal cysteine-rich Duffy binding-like region (EBL region 2), is responsible for the interaction, and that the binding is not affected by the C351Y mutation, which was previously shown to modulate virulence of P. yoelii. The identification of basigin as the putative PyEBL receptor offers new insights into the role of this molecule and provides an important base for in-depth studies towards developing novel interventions against malaria.

PfMSA180 is a novel Plasmodium falciparum vaccine antigen that interacts with human erythrocyte integrin associated protein (CD47).

Malaria symptoms and pathology are initiated by invasion of host erythrocytes by Plasmodium merozoites in a complex process that involves interactions between parasite and host erythrocyte proteins. Erythrocyte invasion presents attractive targets for malaria vaccine and drug development. Recently it was observed that antibodies against PfMSA180 (PF3D7_1014100) are associated with protection from symptomatic malaria, suggesting that this protein is a target of naturally acquired protective antibodies. Here we characterize PfMSA180, a ~170 kDa merozoite surface antigen that is potentially involved in erythrocyte invasion. PfMSA180 synthesized by the wheat germ cell-free system was used to raise antibodies in rabbits. Growth inhibition assays revealed that parasite invasion is inhibited by antibodies to the PfMSA180 C-terminal region, which contains an erythrocyte-binding domain. Surface plasmon resonance analysis showed that PfMSA180 specifically interacts with human erythrocyte integrin associated protein (CD47), suggesting that PfMSA180 plays a role during merozoite invasion of erythrocytes. Polymorphism analysis revealed that pfmsa180 is highly conserved among field isolates. We show that naturally acquired PfMSA180-specific antibodies responses are associated with protective immunity in a malaria-exposed Thai population. In sum, the data presented here supports further evaluation of the conserved erythrocyte-binding C-terminal region of PfMSA180 as an asexual blood-stage malaria vaccine candidate.