Sarah E. Silk
A5063777614- Malaria Research and Control
- Mosquito-borne diseases and control
- Complement system in diseases
- HIV Research and Treatment
- vaccines and immunoinformatics approaches
- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- Immunotherapy and Immune Responses
- Hepatitis B Virus Studies
- Invertebrate Immune Response Mechanisms
- Parasites and Host Interactions
- Trypanosoma species research and implications
- Monoclonal and Polyclonal Antibodies Research
- Drug Transport and Resistance Mechanisms
- Immune Cell Function and Interaction
- COVID-19 Clinical Research Studies
- T-cell and B-cell Immunology
- Diphtheria, Corynebacterium, and Tetanus
- COVID-19 epidemiological studies
- Mycobacterium research and diagnosis
- Infections and bacterial resistance
- Virology and Viral Diseases
- Hepatitis C virus research
- Herpesvirus Infections and Treatments
- Vaccine Coverage and Hesitancy
University of Oxford
2016-2025
Jenner Institute
2016-2025
Oxford BioMedica (United Kingdom)
2020-2024
Oxfam
2023
Kavli Energy NanoScience Institute
2023
Amref Health Africa
2022
Newcastle University
2016
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...
A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is soluble protein candidate for P falciparum, formulated with Matrix-M adjuvant assess safety and immunogenicity in malaria-endemic adult paediatric population first time.
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...
The development of a highly effective vaccine remains key strategic goal to aid the control and eventual eradication Plasmodium falciparum malaria. In recent years, reticulocyte-binding protein homolog 5 (RH5) has emerged as most promising blood-stage P. candidate antigen date, capable conferring protection against stringent challenge in Aotus monkeys. We report on first clinical trial our knowledge assess RH5 — dose-escalation phase Ia study 24 healthy, malaria-naive adult volunteers....
Background. Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing blood-stage parasite vaccines, however, has generally relied on larger-scale 2b field trials malaria-endemic populations. We report the use a P. falciparum CHMI model candidates, using their impact multiplication rate (PMR) as primary end point. Methods....
Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by P. merozoite depends on an interaction between Duffy antigen receptor for chemokines (DARC) and region II of parasite's Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this associate with clinical immunity, but it unknown whether these responses can be induced vaccination.Safety immunogenicity replication-deficient...
Significance Malaria is one of the world’s most devastating infectious diseases, affecting hundreds millions people and resulting in nearly half a million deaths each year. The parasites that cause malaria must invade red blood cells an infected patient, while blocking this process prevents disease. PfRH5 protein exciting vaccine candidate required for cell invasion by Plasmodium falciparum , deadly parasite. Here, we describe our use streamlined computational methodology to design variants...
RH5 is a leading blood-stage candidate antigen for Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown.
There are no licensed vaccines against Plasmodium vivax. We conducted two phase 1/2a clinical trials to assess targeting P. vivax Duffy-binding protein region II (PvDBPII). Recombinant viral using chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) vectors as well a adjuvant formulation (PvDBPII/Matrix-M) were tested in both standard delayed dosing regimen. Volunteers underwent controlled human malaria infection (CHMI) after their last vaccination, alongside...
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...
Abstract Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate protection. We previously demonstrated strong association between protection merozoite-neutralizing antibody responses following vaccination non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test mechanism Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, produce...
Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is a leading asexual blood-stage vaccine candidate for malaria. In preparation clinical trials, full-length PfRH5 called "RH5.1" was produced as soluble product under cGMP using the ExpreS2 platform (based on Drosophila melanogaster S2 stable cell line system). Following development of high-producing monoclonal line, master bank prior to campaign. Culture supernatants were processed C-tag affinity chromatography followed by...
Development of bespoke biomanufacturing processes remains a critical bottleneck for translational studies, in particular when modest quantities novel product are required proof-of-concept Phase I/II clinical trials. In these instances the ability to develop process quickly and relatively cheaply, without risk quality or safety, provides great advantage by allowing new antigens concepts immunogen design more rapidly enter human testing. These challenges with production purification...
Abstract The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has recently emerged as a leading candidate antigen against the blood-stage human malaria parasite. However it proved challenging to identify heterologous expression platform that can produce soluble protein-based vaccine in manner compliant with current Good Manufacturing Practice (cGMP). Here we report production of full-length PfRH5 using cGMP-compliant called ExpreS 2 , based on Drosophila melanogaster...
Interactions between B cells and CD4+ T follicular helper (Tfh) are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen Plasmodium falciparum merozoite protein (PfRH5), we compare frequency, phenotype, gene expression profiles PfRH5-specific circulating Tfh (cTfh) elicited by two leading human delivery platforms: heterologous viral vector prime boost AS01B adjuvant. We demonstrate that protein/AS01B platform induces a...
Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown a delayed fractional (DFx) dosing schedule (0-1-6 month) - using AS01B-adjuvanted RH5.1 malaria antigen substantially improves IgG durability as compared with monthly (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there wider immunological changes DFx were unclear. Here, PfRH5-specific Ig B cell responses analyzed in depth...
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...
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...
Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and being evaluated for efficacy in endemic regions, emphasizing need to study underlying antibody response RH5 during natural infection, which could augment or counteract responses vaccination. Here, we found that RH5-reactive B cells were rare, circulating immunoglobulin G (IgG) short-lived malaria-exposed Malian individuals, despite repeated infections over...
Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for Plasmodium falciparum malaria. However, neither induces blood-stage immunity against parasites that break through from the liver. RH5.1/Matrix-M, a P malaria vaccine candidate, was highly immunogenic in Tanzanian adults children. We therefore assessed safety efficacy of RH5.1/Matrix-M Burkinabe
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...