Publications
381 results found
Smith NC, Sinden RE, Ramakrishnan C, 2021, Editorial: get over the gut: apicomplexan parasite interaction, survival and sage progression in vertebrate and invertebrate digestive tracts, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-3, ISSN: 2235-2988
Haltalli MLR, Watcham S, Wilson NK, et al., 2020, Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection, Nature Cell Biology, Vol: 22, Pages: 1399-1410, ISSN: 1465-7392
Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and—coupled with reactive oxygen species quenching—enables partial rescuing of HSC function.
Depoix D, Marques SR, Ferguson DJP, et al., 2020, Vital role for Plasmodium berghei Kinesin8B in axoneme assembly during male gamete formation and mosquito transmission, Cellular Microbiology, Vol: 22, Pages: 1-16, ISSN: 1462-5814
Sexual development is an essential phase in the Plasmodium life cycle, where male gametogenesis is an unusual and extraordinarily rapid process. It produces 8 haploid motile microgametes, from a microgametocyte within 15 minutes. Its unique achievement lies in linking the assembly of 8 axonemes in the cytoplasm to the three rounds of intranuclear genome replication, forming motile microgametes, which are expelled in a process called exflagellation. Surprisingly little is known about the actors involved in these processes. We are interested in kinesins, molecular motors that could play potential roles in male gametogenesis. We have undertaken a functional characterization in Plasmodium berghei of kinesin‐8B (PbKIN8B) expressed specifically in male gametocytes and gametes. By generating Pbkin8B‐gfp parasites, we show that PbKIN8B is specifically expressed during male gametogenesis and is associated with the axoneme. We created a ΔPbkin8B knockout cell line and analysed the consequences of the absence of PbKIN8B on male gametogenesis. We show that the ability to produce sexually differentiated gametocytes is not affected in ΔPbkin8B parasites and that the 3 rounds of genome replication occur normally. Nevertheless, the development to free motile microgametes is halted and the life cycle is interrupted in vivo. Ultrastructural analysis revealed that intranuclear mitoses are unaffected whereas cytoplasmic microtubules, although assembled in doublets and elongated, fail to assemble in the normal axonemal ‘9+2' structure and become motile. Absence of a functional axoneme prevented microgamete assembly and release from the microgametocyte, severely reducing infection of the mosquito vector. This is the first functional study of a kinesin involved in male gametogenesis. These results reveal a previously unknown role for PbKIN8B in male gametogenesis, providing new insights into Plasmodium flagellar formation.
Delves M, Lafuente-Monasterio MJ, Upton L, et al., 2019, Fueling Open Innovation for Malaria Transmission-Blocking Drugs: Hundreds of Molecules Targeting Early Parasite Mosquito Stages, FRONTIERS IN MICROBIOLOGY, Vol: 10, ISSN: 1664-302X
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- Citations: 15
Norcross NR, Wilson C, Baragana B, et al., 2019, Substituted Aminoacetamides as Novel Leads for Malaria Treatment, CHEMMEDCHEM, Vol: 14, Pages: 1329-1335, ISSN: 1860-7179
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- Citations: 2
Baragaña B, Forte B, Choi R, et al., 2019, Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis., Proc Natl Acad Sci U S A
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.
Marti Coma-Cros E, Biosca A, Marques J, et al., 2018, Polyamidoamine Nanoparticles for the Oral Administration of Antimalarial Drugs, PHARMACEUTICS, Vol: 10, ISSN: 1999-4923
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- Citations: 15
Rampling T, Ewer KJ, Bowyer G, et al., 2018, Safety and efficacy of novel malaria vaccine regimens of RTS, S/AS01B alone, or with concomitant ChAd63-MVA-vectored vaccines expressing ME-TRAP, npj Vaccines, Vol: 3, ISSN: 2059-0105
We assessed a combination multi-stage malaria vaccine schedule in which RTS,S/AS01B was given concomitantly with viral vectors expressing multiple-epitope thrombospondin-related adhesion protein (ME-TRAP) in a 0-month, 1-month, and 2-month schedule. RTS,S/AS01B was given as either three full doses or with a fractional (1/5th) third dose. Efficacy was assessed by controlled human malaria infection (CHMI). Safety and immunogenicity of the vaccine regimen was also assessed. Forty-one malaria-naive adults received RTS,S/AS01B at 0, 4 and 8 weeks, either alone (Groups 1 and 2) or with ChAd63 ME-TRAP at week 0, and modified vaccinia Ankara (MVA) ME-TRAP at weeks 4 and 8 (Groups 3 and 4). Groups 2 and 4 received a fractional (1/5th) dose of RTS,S/AS01B at week 8. CHMI was delivered by mosquito bite 11 weeks after first vaccination. Vaccine efficacy was 6/8 (75%), 8/9 (88.9%), 6/10 (60%), and 5/9 (55.6%) of subjects in Groups 1, 2, 3, and 4, respectively. Immunological analysis indicated significant reductions in anti-circumsporozoite protein antibodies and TRAP-specific T cells at CHMI in the combination vaccine groups. This reduced immunogenicity was only observed after concomitant administration of the third dose of RTS,S/AS01B with the second dose of MVA ME-TRAP. The second dose of the MVA vector with a four-week interval caused significantly higher anti-vector immunity than the first and may have been the cause of immunological interference. Co-administration of ChAd63/MVA ME-TRAP with RTS,S/AS01B led to reduced immunogenicity and efficacy, indicating the need for evaluation of alternative schedules or immunization sites in attempts to generate optimal efficacy.
Delves M, Miguel-Blanco C, Matthews H, et al., 2018, A high throughput screen for next-generation leads targeting malaria parasite transmission, Nature Communications, Vol: 9, ISSN: 2041-1723
Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.
Miguel-Blanco C, Molina I, Bardera AI, et al., 2017, ACCELERATING THE DISCOVERY OF TRANSMISSION-BLOCKING DRUGS: HT SCREENING WITH A NOVEL PLASMODIUM FALCIPARUM FUNCTIONAL GAMETOCYTE ASSAY, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 82-82, ISSN: 0002-9637
Vanaerschot M, Lucantoni L, Li T, et al., 2017, Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity, NATURE MICROBIOLOGY, Vol: 2, Pages: 1403-1414, ISSN: 2058-5276
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- Citations: 31
Sinden RE, 2017, Developing transmission-blocking strategies for malaria control, PLOS PATHOGENS, Vol: 13, ISSN: 1553-7366
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- Citations: 49
O'Neill PM, Amewu RK, Charman SA, et al., 2017, A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
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- Citations: 48
Miguel-Blanco C, Molina I, Bardera AI, et al., 2017, Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen, Nature Communications, Vol: 8, ISSN: 2041-1723
Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.
Churcher TS, Sinden RE, Edwards NJ, et al., 2017, Probability of transmission of malaria from mosquito to human Is regulated by mosquito parasite density in naïve and vaccinated hosts, PLOS Pathogens, Vol: 13, ISSN: 1553-7366
Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.
Vanaerschot M, Lucantoni L, Li T, et al., 2017, IDENTIFYING HEXAHYDROQUINOLINES AS NEW ANTIMALARIALS WITH POTENT BLOOD STAGE AND TRANSMISSION-BLOCKING ACTIVITY, 66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 496-497, ISSN: 0002-9637
Sinden RE, 2017, Targeting the Parasite to Suppress Malaria Transmission, ADVANCES IN PARASITOLOGY, VOL 97, Vol: 97, Pages: 147-185, ISSN: 0065-308X
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- Citations: 13
Churcher TS, Sinden RE, Edwards NJ, et al., 2017, PROBABILITY OF TRANSMISSION OF MALARIA FROM MOSQUITO TO HUMAN IS REGULATED BY PARASITE DENSITY IN NAIVE AND VACCINATED HOSTS, 66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 230-230, ISSN: 0002-9637
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- Citations: 1
Marques J, Valle-Delgado JJ, Urbán P, et al., 2016, Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery., Nanomedicine: Nanotechnology, Biology and Medicine, ISSN: 1549-9634
The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial drugs to Plasmodium-infected red blood cells (pRBCs). These new models include: (i) immunoliposome-mediated release of new lipid-based antimalarials; (ii) liposomes targeted to pRBCs with covalently linked heparin to reduce anticoagulation risks; (iii) adaptation of heparin to pRBC targeting of chitosan nanoparticles; (iv) use of heparin for the targeting of Plasmodium stages in the mosquito vector; and (v) use of the non-anticoagulant glycosaminoglycan chondroitin 4-sulfate as an heparin surrogate for pRBC targeting. The results presented indicate that the tuning of existing nanovessels to new malaria-related targets is a valid low-cost alternative to the de novo development of targeted nanosystems.
Le Bihan A, de Kanter R, Angulo-Barturen I, et al., 2016, Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling., PLOS Medicine, Vol: 13, ISSN: 1549-1277
BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity
Baragaña B, Norcross NR, Wilson C, et al., 2016, Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy, Journal of Medicinal Chemistry, Vol: 59, Pages: 9672-9685, ISSN: 0022-2623
The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
Lamas Oliveira Marques S, 2016, Routine in vitro culture of P. falciparum gametocytes to evaluate novel transmission-blocking interventions., Nature Protocols, Vol: 11, Pages: 1668-1680, ISSN: 1754-2189
The prevention of parasite transmission from the human host to the mosquito has been recognized as a vital tool for malaria eradication campaigns. However, transmission-blocking antimalarial drug and/or vaccine discovery and development is currently hampered by the expense and difficulty of producing mature Plasmodium falciparum gametocytes in vitro-the parasite stage responsible for mosquito infection. Current protocols for P. falciparum gametocyte culture usually require complex parasite synchronization and addition of stimulating and/or inhibitory factors, and they may not have demonstrated the essential property of mosquito infectivity. This protocol details all the steps required for reliable P. falciparum gametocyte production and highlights common factors that influence culture success. The protocol can be completed in 15 d, and particular emphasis is placed upon operating a gametocyte culture facility on a continuous cycle. In addition, we show how functionally viable gametocytes can be used to evaluate transmission-blocking drugs both in a field setting and at high throughput (HTP) for drug discovery.
Van Voorhis WC, Adams JH, Adelfio R, et al., 2016, Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond., PLOS Pathogens, Vol: 12, Pages: e1005763-e1005763, ISSN: 1553-7366
A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis
Vainieri ML, Blagborough AM, MacLean AL, et al., 2016, Systematic tracking of altered haematopoiesis during sporozoite-mediated malaria development reveals multiple response points, Open Biology, Vol: 6, ISSN: 2046-2441
Haematopoiesis is the complex developmental process that maintainsthe turn-over of all blood cell lineages. It critically depends on the correct functioning of rare, quiescent haematopoietic stem cells (HSCs) and more numerous, HSC-derived, highly proliferative and differentiating haematopoietic progenitor cells (HPCs). Infection is known to affect HSCs, with severe and chronic inflammatory stimuli leading to stem cell pool depletion, while acute, non-lethal infections exert transient and even potentiating effects. Both whetherthis paradigm applies to all infections and whether the HSC response is the dominant driver of the changes observed during stressed haematopoiesis remain open questions. We use a mouse model of malaria, based on natural, sporozoite-driven Plasmodium bergheiinfection as an experimental platform to gain a global view of haematopoietic perturbations during infection progression. We observe coordinated responses by the most primitive HSCs and multiple HPCs, some starting before blood parasitaemia is detected. Weshow that, despite highly variable inter-host responses, primitive HSCsbecome highly proliferative, but mathematical modelling suggests that this alone is not sufficient to significantly impact the whole haematopoietic cascade. We observe that the dramatic expansion of Sca-1þ progenitors results from combined proliferation of direct HSC progeny and phenotypic changes in downstream populations. We observe that the simultaneous perturbation of HSC/HPC population dynamics is coupled with early signs of anaemia onset. Our data uncover a complex relationship between Plasmodium and itshost’s haematopoiesis and raise the question whether the variable responses observed may affect the outcome of the infection itself and its long-term consequences on the host.
Rampling T, Ewer KJ, Bowyer G, et al., 2016, Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B with ChAd-MVA Vectored Vaccines Expressing ME-TRAP., Journal of Infectious Diseases, Vol: 214, Pages: 772-781, ISSN: 1537-6613
BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining two distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to CSP (RTS,S/AS01B) and the other inducing potent T-cell responses to TRAP using viral vectors. METHOD: 37 healthy malaria-naïve adults were vaccinated with either ChAd63-MVA expressing ME-TRAP and 3 doses of RTS,S/AS01B (Group 1, n=20) or 3 doses of RTS,S/AS01B alone (Group 2, n=17). CHMI was delivered by mosquito bites in 33 vaccinated subjects at week 12 after first vaccination, and 6 unvaccinated controls. RESULTS: No SUSAR or SAEs related to vaccination were reported. Protective vaccine efficacy was observed in 14/17 (82.4%) subjects in Group 1 and 12/16 (75%) subjects in Group 2. All control subjects were diagnosed with blood stage malaria. Both vaccination regimens were immunogenic. 14 protected subjects underwent repeat CHMI 6 months after initial CHMI; 7/8 (87.5%) Group 1 subjects and 5/6 (83.3%) Group 2 subjects remained protected. CONCLUSION: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.Clinicaltrials.gov Registration. NCT01883609.
Baragaña B, Hallyburton I, Lee MC, et al., 2016, Corrigendum: A novel multiple-stage antimalarial agent that inhibits protein synthesis., Nature, Vol: 537, Pages: 122-122, ISSN: 0028-0836
Blagborough AM, Musiychuk K, Bi H, et al., 2016, Transmission blocking potency and immunogenicity of a plant-produced Pvs25-based subunit vaccine against Plasmodium vivax, Vaccine, Vol: 34, Pages: 3252-3259, ISSN: 1873-2518
Malaria transmission blocking (TB) vaccines (TBVs) directed against proteins expressed on the sexual stages of Plasmodium parasites are a potentially effective means to reduce transmission. Antibodies induced by TBVs block parasite development in the mosquito, and thus inhibit transmission to further human hosts. The ookinete surface protein P25 is a primary target for TBV development. Recently, transient expression in plants using hybrid viral vectors has demonstrated potential as a strategy for cost-effective and scalable production of recombinant vaccines. Using a plant virus-based expression system, we produced recombinant P25 protein of Plasmodium vivax (Pvs25) in Nicotiana benthamiana fused to a modified lichenase carrier protein. This candidate vaccine, Pvs25-FhCMB, was purified, characterized and evaluated for immunogenicity and efficacy using multiple adjuvants in a transgenic rodent model. An in vivo TB effect of up to a 65% reduction in intensity and 54% reduction in prevalence was observed using Abisco-100 adjuvant. The ability of this immunogen to induce a TB response was additionally combined with heterologous prime-boost vaccination with viral vectors expressing Pvs25. Significant blockade was observed when combining both platforms, achieving a 74% and 68% reduction in intensity and prevalence, respectively. This observation was confirmed by direct membrane feeding on field P. vivax samples, resulting in reductions in intensity/prevalence of 85.3% and 25.5%. These data demonstrate the potential of this vaccine candidate and support the feasibility of expressing Plasmodium antigens in a plant-based system for the production of TBVs, while demonstrating the potential advantages of combining multiple vaccine delivery systems to maximize efficacy.
Rampling T, Bowyer G, Wright D, et al., 2015, SAFETY, IMMUNOGENICITY AND EFFICACY OF THE COMBINATION MALARIA VACCINE REGIMEN OF RTS, S/AS01B CONCOMITANTLY ADMINISTERED WITH CHAD-MVA VIRAL VECTORS EXPRESSING ME-TRAP, Publisher: AMER SOC TROP MED & HYGIENE, Pages: 391-391, ISSN: 0002-9637
Phillips MA, Lotharius J, Marsh K, et al., 2015, A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria, SCIENCE TRANSLATIONAL MEDICINE, Vol: 7, ISSN: 1946-6234
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Depoix D, Marques S, Ferguson D, et al., 2015, An essential role of Plasmodium berghei kinesin 8 in axoneme assembly and male gametogenesis, Cilia, Vol: 4, ISSN: 2046-2530
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