A5076943757- HIV Research and Treatment
- Mosquito-borne diseases and control
- Malaria Research and Control
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Immune Cell Function and Interaction
- interferon and immune responses
- Tuberculosis Research and Epidemiology
- vaccines and immunoinformatics approaches
- Viral gastroenteritis research and epidemiology
- Invertebrate Immune Response Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Biochemical and Structural Characterization
- RNA Research and Splicing
- Immune responses and vaccinations
- Aquaculture disease management and microbiota
- CRISPR and Genetic Engineering
- Hepatitis B Virus Studies
- Vector-Borne Animal Diseases
- Viral Infections and Vectors
- Virology and Viral Diseases
- Pneumocystis jirovecii pneumonia detection and treatment
- Immunodeficiency and Autoimmune Disorders
- Hepatitis C virus research
- Immunotherapy and Immune Responses
King's College London
2015-2021
Jenner Institute
2010-2016
University of Oxford
2009-2016
National Institute of Allergy and Infectious Diseases
2011
Heidelberg University
2011
Translational Therapeutics (United States)
2011
University of Pennsylvania
2011
National Institutes of Health
2011
Biomedical Primate Research Centre
2011
University Hospital Heidelberg
2011
Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, development of new vectors has focused on serotypes to which human population is less exposed in order circumvent pre-existing anti vector immunity. This study describes derivation a based chimpanzee adenovirus, Y25, together with comparative assessment its potential elicit transgene product specific immune responses mice. The was constructed bacterial artificial chromosome facilitate genetic...
Adenoviruses are potent vectors for inducing and boosting cellular immunity to encoded recombinant antigens. However, the widespread seroprevalence of neutralizing antibodies common human adenovirus serotypes limits their use. Simian adenoviruses do not suffer from same drawbacks. We have constructed a replication-deficient chimpanzee adenovirus-vectored vaccine expressing conserved influenza antigens, nucleoprotein (NP), matrix protein 1 (M1). Here, we report safety T-cell immunogenicity...
Efficacy trials of antibody-inducing protein-in-adjuvant vaccines targeting the blood-stage Plasmodium falciparum malaria parasite have so far shown disappointing results. The induction cell-mediated responses in conjunction with antibody is thought to be one alternative strategy that could achieve protective efficacy humans. Here, we prepared chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient vectors encoding well-studied P. antigen merozoite...
Background Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, date no such encoding a antigen(s) alone induced significant protective efficacy erythrocytic-stage pre-specified primary endpoint Phase IIa/b clinical trial designed assess efficacy. Cell-mediated responses, acting conjunction with functional antibodies,...
A replication-deficient chimpanzee adenovirus expressing Ag85A (ChAdOx1.85A) was assessed, both alone and in combination with modified vaccinia Ankara also (MVA85A), for its immunogenicity protective efficacy against a Mycobacterium tuberculosis (M.tb) challenge mice. Naïve BCG-primed mice were vaccinated or boosted ChAdOx1.85A MVA85A different combinations. Although intranasally administered induced strong immune responses the lungs, it failed to consistently protect aerosol M.tb challenge....
Transmission-blocking vaccines (TBV) target the sexual-stages of malaria parasite in mosquito midgut and are widely considered to be an essential tool for elimination. High-titer functional antibodies required against antigens achieve effective transmission-blocking activity. We have fused Pfs25, leading TBV candidate antigen IMX313, a molecular adjuvant expressed it both ChAd63 MVA viral vectors as secreted protein-nanoparticle. Pfs25-IMX313 from or protein-nanoparticle is significantly...
Protein-in-adjuvant formulations and viral-vectored vaccines encoding blood-stage malaria Ags have shown efficacy in rodent models vitro assays against Plasmodium falciparum. Abs CD4(+) T cell responses are associated with protective malaria, whereas CD8(+) cells some classical can also a effect liver-stage parasites. No subunit vaccine strategy alone has generated demonstrable high-level infection clinical trials. The induction of Ab responses, as well potent B effector memory populations,...
Human myxovirus resistance 2 (MX2/MXB) is an interferon-induced post-entry inhibitor of human immunodeficiency virus type-1 (HIV-1) infection. While the precise mechanism viral inhibition remains unclear, MX2 localized to nuclear envelope, and blocks import cDNAs. The amino-terminus (N-MX2) essential for anti-viral function, mutation a triple arginine motif at residues 11 13 abrogates anti-HIV-1 activity. In this study, we sought investigate role N-MX2 in activity by identifying functionally...
Subunit vaccination modalities tend to induce particular immune effector responses. Viral vectors are well known for their ability strong T cell responses, while protein-adjuvant vaccines have been used primarily induction of antibody Here, we demonstrate in mice using a Plasmodium falciparum merozoite surface protein 1 (PfMSP1) antigen that novel regimes combining adenovirus and poxvirus vectored with Montanide ISA720 adjuvant can achieve simultaneous responses which equal, or some cases...
Rift Valley Fever (RVF) is a viral zoonosis that historically affects livestock production and human health in sub-Saharan Africa, though epizootics have also occurred the Arabian Peninsula. Whilst an effective live-attenuated vaccine available for livestock, there currently no licensed RVF vaccine. Replication-deficient chimpanzee adenovirus (ChAd) vectors are ideal platform development of vaccine, given low prevalence neutralizing antibodies against them population, their excellent safety...
Background Apical membrane antigen 1 (AMA1) is a leading candidate vaccine against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human simian adenoviral (AdHu5 ChAd63) orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1). Methodology/Principal Findings AdHu5-MVA prime-boost vaccination in...
ABSTRACT Human myxovirus resistance 2 (MX2/MXB) is an interferon-stimulated gene (ISG) and was recently identified as a late postentry suppressor of human immunodeficiency virus type 1 (HIV-1) infection, inhibiting the nuclear accumulation viral cDNAs. Although HIV-1 capsid (CA) protein believed to be determinant MX2-mediated inhibition, precise mechanism antiviral action remains unclear. The MX family dynamin-like GTPases also includes MX1/MXA, well-studied inhibitor range RNA DNA viruses,...
Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited part by antigenic polymorphism and potentially the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we report design novel vectored Plasmodium falciparum capable overcoming such limitations. We optimized an insert comprising four conserved blocks MSP-1 fused tandemly arranged sequences that represent...
Abstract Replication defective adenoviruses are promising vectors for the delivery of vaccine antigens. However, potential a vector to elicit transgene-specific adaptive immune responses is largely dependent on viral serotype used. HAdV-5 ( Human adenovirus C ) more immunogenic than chimpanzee from species E (ChAdOx1 and AdC68) in mice, though mechanisms responsible these differences immunogenicity remain poorly understood. In this study, superior was associated with markedly higher levels...
Myxovirus resistance 2 (MX2/MXB) is an interferon (IFN)-induced HIV-1 restriction factor that inhibits viral nuclear DNA accumulation. The amino-terminal domain of MX2 binds the capsid and essential for inhibition. Using in vitro assembled Capsid-Nucleocapsid (CANC) complexes as a surrogate lattice, we reveal GTPase (G) contains second, independent capsid-binding site. importance this interaction was addressed competition assays using naturally occurring non-antiviral short isoform lacks 25...
Substantial protection can be provided against the pre-erythrocytic stages of malaria by vaccination first with an adenoviral and then modified vaccinia virus Ankara (MVA) poxviral vector encoding same ME.TRAP transgene. We investigated whether two vaccine components adenovirus (Ad) MVA could coinjected as a mixture to enhance malaria. A single-shot at specific ratios Ad (Ad+MVA) enhanced CD8+ T cell-dependant mice challenge Plasmodium berghei. Moreover, degree after homologous boosting...
Rodent malaria species Plasmodium yoelii and P. chabaudi have been widely used to validate vaccine approaches targeting blood-stage merozoite antigens. However, increasing data suggest the berghei rodent may be able circumvent vaccine-induced anti-merozoite responses. Here we confirm a failure protect against berghei, despite successful antibody induction leading antigens using protein-in-adjuvant or viral vectored delivery. No subunit approach showed efficacy in mice following immunization...
Adenovirus vector vaccines have been widely and successfully deployed in response to coronavirus disease 2019 (COVID-19). However, despite inducing potent T cell immunity, improvement of vaccine-specific antibody responses upon homologous boosting is modest compared with other technologies. Here, we describe a system enabling modular decoration adenovirus capsid surfaces antigens demonstrate induction humoral immunity against these displayed antigens. Ligand attachment via covalent bond was...
Adenovirus vaccine vectors generated from new viral serotypes are routinely screened in pre-clinical laboratory animal models to identify the most immunogenic and efficacious candidates for further evaluation clinical human veterinary settings. Here, we show that studies a species do not necessarily predict hierarchy of vector performance other mammals. In mice, after intramuscular immunization, HAdV-5 (Human adenovirus C) based elicited cellular humoral adaptive responses higher magnitudes...
Abstract Adenovirus vector vaccines have been widely and successfully deployed in response to COVID-19. However, despite inducing potent T cell immunity, improvement of vaccine-specific antibody responses upon homologous boosting is modest compared other technologies. Here, we describe a system enable modular decoration adenovirus capsid surfaces with protein antigens demonstrate induction humoral immunity against these displayed antigens. Ligand attachment via covalent isopeptide bond was...
Abstract Interferon (IFN) mobilizes a cellular anti-viral state by inducing the expression of IFN-stimulated genes (ISGs). Myxovirus resistance 2 (MX2/MxB) is an ISG that inhibits HIV-1 infection suppressing viral import into nucleus. The amino-terminal domain (NTD) MX2 plays essential role in inhibition and, here, we exploit proteomic screening to identify myosin light chain phosphatase (MLCP) components MYPT1 and PPP1CB as key NTD binding partners. Experimental depletion either protein, or...