Biology subjects

Thomas, A. A.

Publications and source records attributed to Thomas, A. A..

4 recordsLinked to original sources

bioRxiv2026

Dose-sparing self-amplifying RNA vaccine induces high functional antibodies to blood-stage Plasmodium falciparum malaria

IntroductionNext-generation malaria vaccines are urgently needed to provide greater efficacy and longevity. Antibodies targeting blood-stage merozoites can confer protection against clinical malaria through multiple Fc-mediated functions. In particular, merozoite surface protein 2 (PfMSP2), is a known target of protective antibodies that can clear merozoites via multiple antibody Fc-mediated functions, making is a highly promising vaccine candidate. MethodsWe developed PfMSP2 as a self-amplifying RNA (saRNA) vaccine, which was successfully validated for in vitro expression in mammalian cells. Subsequently, the PfMSP2-saRNA was formulated as lipid nanoparticles (LNP) and evaluated for immunogenicity in mice in a 3-dose regimen comparing 1 g and 10 g doses. We evaluated the induction of antibodies with functional activities relevant to protective immunity. ResultsOur PfMSP2-saRNA vaccine induced antigen-specific IgG responses that recognised the surface of whole merozoites. Both 1 g and 10 g dosing induced comparable antibodies to PfMSP2, and responses were predominantly murine cytophilic IgG subclasses. These vaccine-induced antibodies demonstrated potent Fc-mediated functions, including complement fixation and binding of human Fc{gamma}-receptor I (Fc{gamma}RI), after only two doses, which remained consistent after the third dose. ConclusionsPfMSP2 is highly immunogenic using the saRNA vaccine platform in a dose-sparing regimen, and induces antibodies with multiple Fc-mediated functions associated with protective immunity in humans. This saRNA platform is a promising strategy to develop highly efficacious vaccines requiring lower and fewer doses.

immunology↗

bioRxiv2026

Targeting a malaria merozoite surface protein with mRNA vaccine generates multifunctional antibodies

IntroductionMalaria is a leading health problem with high disease burden and mortality rates worldwide. Currently approved vaccines target the sporozoite form of Plasmodium falciparum that initially infects the liver, but only provide modest protection against malaria in young children. There is an urgent need to develop next-generation malaria vaccines that target multiple parasite developmental stages for greater efficacy. Antibodies to merozoites, which are involved in blood-stage replication, and are associated with clinical illness, have multiple functional activities and can protect against malaria. A promising merozoite vaccine candidate is Merozoite Surface Protein 2 (PfMSP2). Antibodies to PfMSP2 can promote multiple antibody Fc-mediated functional activities to clear merozoites. MethodsWe developed and evaluated monovalent and bivalent (3D7 and FC27 variants) PfMSP2-based mRNA vaccines. We designed and codon-optimised mRNA, which was validated for in vitro expression in mammalian cells, and subsequently formulated as lipid nanoparticles for vaccination of mice in a 3-dose regimen. Vaccination with recombinant PfMSP2 protein with adjuvant was performed for comparison. We evaluated the induction of antibodies and functional activities relevant to protective immunity. ResultsmRNA vaccines induced prominent IgG responses using monovalent (3D7 allele) and bivalent (3D7 and FC27 alleles) vaccines encoding near full-length PfMSP2, and antibodies recognised the surface of whole merozoites. Vaccine responses were equivalent to, or superior than, a recombinant protein-based PfMSP2 vaccine. The bivalent vaccine induced equivalent antibodies to the two PfMSP2 alleles. Vaccination induced cytophilic IgG subclasses with multiple functional activities, including complement fixation, binding of human Fc{gamma}-receptors I and IIa, and opsonic phagocytosis. ConclusionsPfMSP2 is highly immunogenic using the mRNA vaccine platform and induces antibodies with multiple functional activities associated with protective immunity in humans. Combining PfMSP2 with other merozoite and sporozoite antigens is a promising strategy to develop highly efficacious vaccines to achieve malaria control and elimination goals.

immunology↗

bioRxiv2024

An Emirati pangenome incorporating a diploid telomere-to-telomere reference

Reference data on genomic variation form the basis of genetic research. Limitations in identifying genetic variation from single reference sequences have been recently overcome, as improvements in sequencing technologies have allowed the generation of pangenomic references from multiple accurate, chromosome-level de novo assemblies. Here, we present a comprehensive Emirati telomere-to-telomere (T2T) pangenome generated from 58 individuals, comprising 28 trio-based and 30 single-sample assemblies. The resulting 116 haplotype-resolved assemblies demonstrate high contiguity, with a median continuity of 150 Mb and a median quality value (QV) of 59, achieving T2T-level scaffold status for 71.9% of chromosomes. These assemblies form the foundation of the Emirati T2T pangenome graph. The graph reveals levels of genomic diversity comparable to those reported by the Human Pangenome Reference Consortium, while also capturing regionally enriched and difficult-to-assemble variation, uniquely accessible through the Emirati T2T assemblies. This reference makes a valuable global contribution to human pangenomics and serves as a critical resource for advancing precision medicine in the United Arab Emirates.

genomics↗

bioRxiv2022

Describing Inhibitor Specificity for the Amino Acid Transporter LAT1 from Metainference Simulations

The human L-type amino acid transporter 1 (LAT1; SLC7A5) is a membrane transporter of amino acids, thyroid hormones, and drugs such as the Parkinsons disease drug L-Dopa. LAT1 is found in the blood-brain-barrier (BBB), testis, bone marrow, and placenta, and its dysregulation has been associated with various neurological diseases such as autism and epilepsy as well as cancer. In this study, we combine metainference molecular dynamics (MD) simulations, molecular docking, and experimental testing, to characterize LAT1-inhibitor interactions. We first conducted a series of molecular docking experiments to identify the most relevant interactions between LAT1s substrate binding site and ligan ds, including both inhibitors and substrates. We then performed metainference MD simulations using cryo-EM structures in different conformations of LAT1 with the electron density map as a spatial restraint, to explore the inherent heterogeneity in the structures. We analyzed the LAT1 substrate binding site to map important LAT1-ligand interactions as well as newly described druggable pockets. Finally, this analysis guided the discovery of previously unknown LAT1 ligands using virtual screening and cellular uptake experiments. Our results improve our understanding of LAT1-inhibitor recognition, providing a framework for rational design of future lead compounds targeting this key drug target. Statement of SignificanceLAT1 is a membrane transporter of amino acids, thyroid hormones, and therapeutic drugs, that is primarily found in the BBB and placenta, as well as in tumor cells of several cancer types. We combine metainference MD simulations, molecular docking, and experimental testing, to characterize LAT1-inhibitor interactions. Our computational analysis predicts S66, G67, F252, G255, Y259, W405 are critical residues for inhibitor binding and druggable sub-pockets in the outward-occluded conformation that are ideal for LAT1 inhibitor discovery. Using virtual screening and functional testing, we discovered multiple LAT1 inhibitors with diverse scaffolds and binding modes. Our results improve our understanding of LAT1s structure and function, providing a framework for development of future therapeutics targeting LAT1 and other SLC transporters.

biophysics↗