An Invariant Protein That Colocalizes With VAR2CSA on Plasmodium falciparum-Infected Red Cells Binds to Chondroitin Sulfate A.

BACKGROUND: Plasmodium falciparum-infected red blood cells (iRBCs) bind and sequester in deep vascular beds, causing malaria-related disease and death. In pregnant women, VAR2CSA binds to chondroitin sulfate A (CSA) and mediates placental sequestration, making it the major placental malaria (PM) vaccine target. METHODS: In this study, we characterize an invariant protein associated with PM called P falciparum chondroitin sulfate A ligand (PfCSA-L). RESULTS: Recombinant PfCSA-L binds both placental CSA and VAR2CSA with nanomolar affinity, and it is coexpressed on the iRBC surface with VAR2CSA. Unlike VAR2CSA, which is anchored by a transmembrane domain, PfCSA-L is peripherally associated with the outer surface of knobs through high-affinity protein-protein interactions with VAR2CSA. This suggests that iRBC sequestration involves complexes of invariant and variant surface proteins, allowing parasites to maintain both diversity and function at the iRBC surface. CONCLUSIONS: The PfCSA-L is a promising target for intervention because it is well conserved, exposed on infected cells, and expressed and localized with VAR2CSA.

Plasmodium Preerythrocytic Vaccine Antigens Enhance Sterile Protection in Mice Induced by Circumsporozoite Protein.

Preerythrocytic vaccines prevent malaria by targeting parasites in the clinically silent sporozoite and liver stages and preventing progression to the virulent blood stages. The leading preerythrocytic vaccine, RTS,S/AS01E (Mosquirix), entered implementation programs in 2019 and targets the major sporozoite surface antigen, circumsporozoite protein (CSP). However, in phase III clinical trials, RTS,S conferred partial protection with limited durability, indicating a need to improve CSP-based vaccination. Previously, we identified highly expressed liver-stage proteins that could potentially be used in combination with CSP; they are referred to as preerythrocytic vaccine antigens (PEVAs). Here, we developed heterologous prime-boost CSP vaccination models to confer partial sterilizing immunity against Plasmodium yoelii (protein prime-adenovirus 5 [Ad5] boost) and Plasmodium berghei (DNA prime-Ad5 boost) in mice. When combined as individual antigens with P. yoelii CSP (PyCSP), three of eight P. yoelii PEVAs significantly enhanced sterile protection against sporozoite challenge, compared to PyCSP alone. Similar results were obtained when three P. berghei PEVAs and P. berghei CSP were combined in a single vaccine regimen. In general, PyCSP antibody responses were similar after CSP alone versus CSP plus PEVA vaccinations. Both P. yoelii and P. berghei CSP plus PEVA combination vaccines induced robust CD8+ T cell responses, including signature gamma interferon (IFN-γ) increases. In the P. berghei model system, IFN-γ responses were significantly higher in hepatic versus splenic CD8+ T cells. The addition of novel antigens may enhance the degree and duration of sterile protective immunity conferred by a human vaccine such as RTS,S.

Shorter break-in period is a viable option with tighter PD catheter securing during the insertion.

BACKGROUND: Recent single-arm studies reported good catheter outcome despite shorter break-in periods after peritoneal dialysis (PD) catheter insertions. These results were attributed to tight catheter securing during the insertions. OBJECTIVE: To compare catheter-related outcomes after different break-in periods in the tightly secured PD catheters. PATIENTS AND METHODS: The study cohort comprised 48 patients, who underwent catheter insertions with the modified insertion technique. Based on the duration of break-in period, the patients were grouped into a shorter break-in period arm, with break-in period of 7 days or less and a standard break-in period arm, with break-in period of about 2 weeks. Mean patient follow up was 9.68 +/- 4.35 months, with a similar follow-up duration between the two break-in period arms (P = 0.94). RESULTS: In the study cohort, the incidence of pericatheter leaks, pericatheter haemorrhage, catheter malfunction and peritonitis was 2/48 (4%), 1/48 (2%), 1/48 (2%) and 3/48 (6%), respectively. There was no other-site leak, bowel perforation, hernia formation or wound dehiscence. Of these complications, two pericatheter leaks, one catheter malfunction and three peritonitis episodes followed standard break-in periods, whereas, one pericatheter haemorrhage occurred in the shorter break-in period arm. CONCLUSION: After a tight catheter securing during the insertions, overall pericatheter leak incidence remained low in the whole study cohort, and it did not worsen despite a shorter break-in period. Future studies with larger patient numbers are needed to validate the role of shorter break-in period in PD practice.