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Peter F. Billingsley

Bio: Peter F. Billingsley is an academic researcher from University of Aberdeen. The author has contributed to research in topics: Malaria & PfSPZ vaccine. The author has an hindex of 46, co-authored 118 publications receiving 7810 citations. Previous affiliations of Peter F. Billingsley include International Centre of Insect Physiology and Ecology & Imperial College London.


Papers
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Journal ArticleDOI
20 Sep 2013-Science
TL;DR: There is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.
Abstract: Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.

698 citations

Journal ArticleDOI
28 Oct 2011-Science
TL;DR: The results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Plasmodium falciparum malaria and suboptimally immunogenic and protective.
Abstract: Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans Such protection is thought to be mediated by CD8+ T cells in the liver that secrete interferon-γ (IFN-γ) We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8+, IFN-γ–producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice) Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria

488 citations

Book
30 Sep 2011
TL;DR: This work focuses on the structure and ultrastructure of the insect midgut, which is concerned with its role in digestion and transport, and its role as a target for control strategies in insects and other organisms.
Abstract: List of contributors. Preface. Part One: Structural biology of the midgut. 1. Structure and ultrastructure of the insect midgut P.F. Billingsley, M.J. Lehane. 2. Midgut development K.M. Baldwin, et al. 3. Midgut endocrine cells F. Sehnal, D. Zitnan. 4. The peritrophic matrix R.L. Tellam. 5. Structural macromolecules of the cell membranes and the extracellular matrices of the insect midgut N.J. Lane, et al. Part Two: Digestion and transport. 6. Digestive enzymes W.R. Terra, et al. 7. Mechanisms controlling the synthesis and secretion of digestive enzymes in insects M.J. Lehane, et al. 8. Compartmentalization of digestion W.R. Terra, et al. 9. Ion transport in Lepidoptera U. Klein, et al. 10. Amino acid absorption V.F. Sacchi, M.G. Wolfersberger. 11. Lipid and sugar absorption S. Turunen, K. Crailsheim. Part Three: The midgut as a target for control strategies. 12. Immune intervention against blood-feeding insects P. Willadsen, P.F. Billingsley. 13. Bacillus thuringiensis endotoxins: action on the insect midgut P.V. Pietrantonio, S.S. Gill. 14. Antinutritive plant defence mechanisms G.W. Felton, J.A. Gatehouse. Part Four: The midgut as an environment for other organisms. 15. Microbialsymbioses in the midgut of insects A.E. Douglas, C.B. Beard. 16. Insect-transmitted pathogens in the insect midgut D.C. Kaslow, S. Welburn. Index.

437 citations

Journal ArticleDOI
23 Feb 2017-Nature
TL;DR: PfSPZ-CVac is a highly efficacious vaccine candidate that could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas when able to optimize the immunization regimen.
Abstract: Immunization with Plasmodium falciparum sporozoites under chemoprophylaxis can protect against controlled human malaria infection with the same strain for at least 10 weeks, and protection correlates with polyfunctional T-cell memory. The best candidates for a malaria vaccine so far have been radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) inoculated by mosquitos, intravenous injection of radiation-attenuated, cryopreserved PfSPZ, and infectious PfSPZ inoculated by mosquitos in people taking chloroquine or mefloquine. Here Stephen Hoffman, Peter Kremsner and colleagues report that inoculation of volunteers taking chloroquine with direct intravenous injection of aseptic, cryopreserved, non-irradiated PfSPZ can induce protection against infection with the same strain for at least ten weeks. The authors show that protection correlates with polyfunctional T-cell memory. A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites1. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes2,3,4; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’)5,6; or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine7,8,9,10 or mefloquine11 (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’12,13) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac)14. Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge12,13 at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

311 citations

Journal ArticleDOI
TL;DR: Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the vaccine to the primary target population of African children in the shortest possible period of time.
Abstract: Immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated Plasmodium falciparum sporozoites protects greater than 90% of such volunteers against malaria, if adequate numbers of immunizing biting sessions and sporozoite-infected mosquitoes are used. Nonetheless, until recently it was considered impossible to develop, license and commercialize a live, whole parasite P. falciparum sporozoite (PfSPZ) vaccine. In 2003 Sanaria scientists reappraised the potential impact of a metabolically active, non-replicating PfSPZ vaccine, and outlined the challenges to producing such a vaccine. Six years later, significant progress has been made in overcoming these challenges. This progress has enabled the manufacture and release of multiple clinical lots of a 1(st) generation metabolically active, non-replicating PfSPZ vaccine, the Sanaria PfSPZ Vaccine, submission of a successful Investigational New Drug application to the US Food and Drug Administration, and initiation of safety, immunogenicity and protective efficacy studies in volunteers in MD, US. Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the vaccine to the primary target population of African children in the shortest possible period of time. This will require implementation of a systematic, efficient clinical development plan. Short term challenges include optimizing the (1) efficiency and scale up of the manufacturing process and quality control assays, (2) dosage regimen and method of administration, (3) potency of the vaccine, and (4) logistics of delivering the vaccine to those who need it most, and finalizing the methods for vaccine stabilization and attenuation. A medium term goal is to design and build a facility for manufacturing highly potent and stable vaccine for pivotal Phase 3 studies and commercial launch.

307 citations


Cited by
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Journal ArticleDOI
TL;DR: The transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.
Abstract: Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

1,444 citations

Journal ArticleDOI
TL;DR: The superfamily of proteins containing C‐type lectin‐like domains (CTLDs) is a large group of extracellular Metazoan proteins with diverse functions that have evolved to specifically recognize protein, lipid and inorganic ligands, including the vertebrate clade‐specific snake venoms, and fish antifreeze and bird egg‐shell proteins.
Abstract: The superfamily of proteins containing C-type lectin-like domains (CTLDs) is a large group of extracellular Metazoan proteins with diverse functions. The CTLD structure has a characteristic double-loop ('loop-in-a-loop') stabilized by two highly conserved disulfide bridges located at the bases of the loops, as well as a set of conserved hydrophobic and polar interactions. The second loop, called the long loop region, is structurally and evolutionarily flexible, and is involved in Ca2+-dependent carbohydrate binding and interaction with other ligands. This loop is completely absent in a subset of CTLDs, which we refer to as compact CTLDs; these include the Link/PTR domain and bacterial CTLDs. CTLD-containing proteins (CTLDcps) were originally classified into seven groups based on their overall domain structure. Analyses of the superfamily representation in several completely sequenced genomes have added 10 new groups to the classification, and shown that it is applicable only to vertebrate CTLDcps; despite the abundance of CTLDcps in the invertebrate genomes studied, the domain architectures of these proteins do not match those of the vertebrate groups. Ca2+-dependent carbohydrate binding is the most common CTLD function in vertebrates, and apparently the ancestral one, as suggested by the many humoral defense CTLDcps characterized in insects and other invertebrates. However, many CTLDs have evolved to specifically recognize protein, lipid and inorganic ligands, including the vertebrate clade-specific snake venoms, and fish antifreeze and bird egg-shell proteins. Recent studies highlight the functional versatility of this protein superfamily and the CTLD scaffold, and suggest further interesting discoveries have yet to be made.

1,206 citations

Journal ArticleDOI
14 Jul 1995-Cell
TL;DR: A large and extremely diverse family of P. falciparum genes (var) that encode 200-350 kDa proteins having the expected properties of antigenically variant adhesion molecules are described.

1,189 citations

Journal ArticleDOI

1,148 citations

Journal ArticleDOI
TL;DR: This review of recent advances in understanding chitin synthesis and its degradation in insects will summarize recent advances.
Abstract: Chitin is one of the most important biopolymers in nature. It is mainly produced by fungi, arthropods and nematodes. In insects, it functions as scaffold material, supporting the cuticles of the epidermis and trachea as well as the peritrophic matrices lining the gut epithelium. Insect growth and morphogenesis are strictly dependent on the capability to remodel chitin-containing structures. For this purpose, insects repeatedly produce chitin synthases and chitinolytic enzymes in different tissues. Coordination of chitin synthesis and its degradation requires strict control of the participating enzymes during development. In this review, we will summarize recent advances in understanding chitin synthesis and its degradation in insects.

1,037 citations