A5044057964- Malaria Research and Control
- Complement system in diseases
- Mosquito-borne diseases and control
- vaccines and immunoinformatics approaches
- HIV Research and Treatment
- Hepatitis B Virus Studies
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Hemoglobinopathies and Related Disorders
- Hepatitis C virus research
- Iron Metabolism and Disorders
- Trypanosoma species research and implications
- Signaling Pathways in Disease
- Drug Transport and Resistance Mechanisms
- Trace Elements in Health
- Diphtheria, Corynebacterium, and Tetanus
- Parasites and Host Interactions
- Viral Infectious Diseases and Gene Expression in Insects
- interferon and immune responses
- Virus-based gene therapy research
- Antifungal resistance and susceptibility
- Mycobacterium research and diagnosis
- Clostridium difficile and Clostridium perfringens research
- Aquaculture disease management and microbiota
- Drug-Induced Hepatotoxicity and Protection
University of Oxford
2018-2024
Jenner Institute
2018-2024
Heidelberg University
2007-2010
BackgroundDevelopment of an effective vaccine against the pathogenic blood-stage infection human malaria has proved challenging, and no candidate affected parasitemia following controlled (CHMI) with Plasmodium falciparum.MethodsWe undertook a phase I/IIa clinical trial in healthy adults United Kingdom RH5.1 recombinant protein vaccine, targeting P. falciparum reticulocyte-binding homolog 5 (RH5), formulated AS01B adjuvant. We assessed safety, immunogenicity, efficacy CHMI. Trial registered...
ABSTRACT The hepatitis C virus (HCV) encodes a large polyprotein; therefore, all viral proteins are produced in equimolar amounts regardless of their function. aim our study was to determine the ratio nonstructural RNA that is required for HCV replication. We analyzed Huh-7 cells harboring full-length genomes or subgenomic replicons and found cases >1,000-fold excess over positive- negative-strand RNA. To examine whether protein copies involved synthesis, we isolated active replication...
Highlights•Human PfRH5 vaccination induces cross-reactive neutralizing antimalarial antibodies•Neutralizing human antibodies bind epitopes close to the basigin binding site•Some non-neutralizing potentiate those several malaria proteins•Potentiating slow erythrocyte invasion by a new epitope on PfRH5SummaryThe Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is leading target for next-generation vaccines against disease-causing blood-stage of malaria. However, little...
Hepatitis C virus (HCV) is an important human pathogen affecting 170 million chronically infected individuals. In search for cellular proteins involved in HCV replication, we have developed a purification strategy viral replication complexes and identified annexin A2 (ANXA2) as associated host factor. ANXA2 colocalized with nonstructural cells harboring genotype 1 or 2 replicons well cells. contrast, found no obvious colocalization of sites other positive-strand RNA viruses. The silencing...
Abstract Understanding mechanisms of antibody synergy is important for vaccine design and cocktail development. Examples between antibodies are well-documented, but the underlying these relationships often remain poorly understood. The leading blood-stage malaria candidate, CyRPA, essential invasion Plasmodium falciparum into human erythrocytes. Here we present a panel anti-CyRPA monoclonal that strongly inhibit parasite growth in vitro assays. Structural studies show growth-inhibitory bind...
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against disease-causing blood stage of malaria. However, features human vaccine-induced antibody response that confer potent inhibition malaria parasite invasion into red cells are not well defined. Here, we characterize 236 IgG monoclonal antibodies, derived from 15 donors, induced by most advanced PfRH5 vaccine. We define antigenic landscape...
Abstract Clinical immunity to malaria can reduce fever and lead asymptomatic infection but the underlying mechanisms remain unclear. To examine development of clinical immunity, we conducted a multi-cohort, repeat controlled human (CHMI) study with Plasmodium vivax , heterologous rechallenge P. falciparum . Malaria-naïve adults underwent CHMI up three times, at an interval 5 20 months, by administration red blood cells infected PvW1 clone. In final cohort study, subset participants 3D7...
Highlights•Inhibitory antibodies from RH5.1/AS01B vaccinees target the RH5 α-helical core•A truncated and thermostabilized RH5.2 immunogen induces more potent antibodies•Bioconjugation of to VLPs enhances antibody immunogenicity in rodents•RH5.2-VLP/Matrix-M highest functional antimalarial ratsSummaryPlasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently phase 2b clinical trial as full-length soluble...
Abstract Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting (RIPR) to form an essential heterotrimeric “RCR-complex”. We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each are surface-exposed the mAb pairs targeting different antigens...
ABSTRACT The 5′ nontranslated region (NTR) and the X tail in 3′ NTR are least variable parts of hepatitis C virus (HCV) genome play an important role initiation RNA synthesis. By using subgenomic replicons HCV isolates Con1 (genotype 1) JFH1 2), we characterized genotype specificities replication signals contained NTRs. replacement with corresponding sequence resulted a significant decrease efficiency. Exchange specifically reduced negative-strand synthesis, whereas substitution impaired...
Abstract The development of a highly effective vaccine against the pathogenic blood-stage infection human malaria will require delivery platform that can induce an antibody response both maximal quantity and functional quality. One strategy to achieve this includes presenting antigens immune system on virus-like particles (VLPs). Here we sought improve design Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) antigen, which is currently in Phase 2 clinical trial as...
The malaria genome encodes over 5000 proteins and many of these have also been proposed to be potential vaccine candidates, although few tested clinically. RH5 is one the leading blood-stage Plasmodium falciparum antigens Phase I/II clinical trials vaccines containing this antigen are currently underway. Its likely mechanism action elicit antibodies that can neutralize merozoites by blocking their invasion red blood cells (RBC). However, other could neutralizing against merozoite, most never...
Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe suitable for use modern CHMI models limited. Here, 2 healthy malaria-naive United Kingdom adults with universal donor blood group were safely infected clone from Thailand by mosquito-bite CHMI. Parasitemia...
SUMMARY The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines that seek to protect against disease-causing blood-stage of malaria. However, features human vaccine-induced antibody response confer potent inhibition malaria parasite invasion into red blood cells are not well defined. Here we characterize over 200 IgG monoclonal antibodies induced by most advanced PfRH5 vaccine. We define antigenic...
In endemic settings it is known that natural malaria immunity gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage would occur parasite exposure by controlled human infection (CHMI). We report the findings repeat homologous Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 NCT02927145). total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary followed...
The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the current leading blood-stage malaria vaccine candidate. PfRH5 functions as part of pentameric PCRCR complex containing PTRAMP, CSS, PfCyRPA and PfRIPR, all which are essential for infection human red blood cells (RBCs). To trigger RBC invasion, engages with basigin in a step termed RH5-basigin binding stage. Although we know increasingly more about how antibodies specific can block much less known recognizing...
Malaria, an infection caused by apicomplexan parasites of the genus Plasmodium , continues to exact a significant toll on public health with over 200 million cases world-wide, and annual deaths in excess 600,000. Considerable progress has been made reduce malaria burden endemic countries last two decades. However, parasite mosquito resistance frontline chemotherapies insecticides, respectively, highlights continuing need for development safe effective vaccines. Here we describe recombinant...
Plasmodium falciparum RH5 is a secreted parasite ligand that essential for erythrocyte invasion through direct interaction with the host receptor basigin. forms tripartite complex two other proteins, CyRPA and RIPR, tethered to surface of membrane-anchored P113. Antibodies against RH5, CyRPA, RIPR can inhibit invasion, suggesting vaccines containing these three components have potential prevent blood-stage malaria. To further explore role P113-RH5 interaction, we selected monoclonal...
Abstract Despite recent success in licencing of two malaria vaccines, there continues to be an urgent need for improved vaccine immunogens as the world aims eradication. The invasion erythrocytes by Plasmodium falciparum is essential step life cycle parasite, preceding symptoms disease and parasite transmission. Antibodies which target PfRH5 protein are highly effective at preventing erythrocyte most growth-inhibitory antibodies bind a single epitope. Here we used Rosetta-based design...
Recent data indicate increasing disease burden and importance of Plasmodium vivax (Pv) malaria. A robust assay will be essential for blood-stage Pv vaccine development. Results the in vitro growth inhibition (GIA) with transgenic P. knowlesi (Pk) parasites expressing Duffy-binding protein region II (PvDBPII) correlate vivo protection first PvDBPII controlled human malaria infection (CHMI) trials, making PkGIA an ideal selection tool once precision is defined. To determine percentage GIA (%GIA)
Abstract Background Sporozoite invasion of hepatocytes is an essential step in the Plasmodium life-cycle and has similarities, at cellular level, to merozoite erythrocytes. In case blood-stage, efforts identify host–pathogen protein–protein interactions have yielded important insights including vaccine candidates. sporozoite-hepatocyte invasion, involved are poorly understood. Methods To gain a better understanding interaction between sporozoite ligands host receptors, systematic screen was...