Malaria vaccine clinical trials: what's on the horizon

Moreno, Alberto; Joyner, Chester J.

doi:10.1016/j.coi.2015.06.008

Cited by 23 publications

(24 citation statements)

References 64 publications

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“…To explore the versatility of the spy-VLP antigen display system we cloned and expressed 11 vaccine candidate antigens genetically fused to either a SpyTag or a SpyCatcher (Additional file 2 : Table S1). The panel of spy-antigens, representing very diverse proteins with respect to origin, structure and size (14.5–118 kDa) included; (a) malaria proteins: CSP, CIDR, VAR2CSA, and Pfs25, which are expressed at different developmental stages of the complex life cycle of Plasmodium falciparum and used in different vaccine strategies to reduce malaria transmission or disease [ 18 , 19 ]; (b) the Mycobacterium tuberculosis protein, Ag85A, in development for a tuberculosis vaccine; (c) mouse proteins involved in cancer (CTLA-4, PD-L1, Survivin and HER2), asthma/allergy (IL-5) or cardiovascular disease (PCSK9). The latter self-proteins are targets of therapies employing monoclonal antibody.…”

Section: Resultsmentioning

confidence: 99%

Bacterial superglue enables easy development of efficient virus-like particle based vaccines

et al. 2016

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BackgroundVirus-like particles (VLPs) represent a significant advance in the development of subunit vaccines, combining high safety and efficacy. Their particulate nature and dense repetitive subunit organization makes them ideal scaffolds for display of vaccine antigens. Traditional approaches for VLP-based antigen display require labor-intensive trial-and-error optimization, and often fail to generate dense antigen display. Here we utilize the split-intein (SpyTag/SpyCatcher) conjugation system to generate stable isopeptide bound antigen-VLP complexes by simply mixing of the antigen and VLP components.ResultsGenetic fusion of SpyTag or SpyCatcher to the N-terminus and/or C-terminus of the Acinetobacter phage AP205 capsid protein resulted in formation of stable, nonaggregated VLPs expressing one SpyCatcher, one SpyTag or two SpyTags per capsid protein. Mixing of spy-VLPs with eleven different vaccine antigens fused to SpyCatcher or SpyTag resulted in formation of antigen-VLP complexes with coupling efficiencies (% occupancy of total VLP binding sites) ranging from 22–88 %. In mice, spy-VLP vaccines presenting the malaria proteins Pfs25 or VAR2CSA markedly increased antibody titer, affinity, longevity and functional efficacy compared to corresponding vaccines employing monomeric proteins. The spy-VLP vaccines also effectively broke B cell self-tolerance and induced potent and durable antibody responses upon vaccination with cancer or allergy-associated self-antigens (PD-L1, CTLA-4 and IL-5).ConclusionsThe spy-VLP system constitutes a versatile and rapid method to develop highly immunogenic VLP-based vaccines. Our data provide proof-of-concept for the technology’s ability to present complex vaccine antigens to the immune system and elicit robust functional antibody responses as well as to efficiently break B cell self-tolerance. The spy-VLP-system may serve as a generic tool for the cost-effective development of effective VLP-vaccines against both infectious- and non-communicable diseases and could facilitate rapid and unbiased screening of vaccine candidate antigens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0181-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Bacterial superglue enables easy development of efficient virus-like particle based vaccines

et al. 2016

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“…Furthermore, a multi-stage and multi-strain vaccine inducing both antibody and cellular immune responses would likely be required to achieve robust protection against malaria in areas of different endemicity. Here, we present a comprehensive longitudinal study of naturally acquired antibody responses to nine Pv antigens, including the only two vaccine candidates in clinical development: circumsporozoite protein (PvCSP) and PvDBP ( 32 ). In addition, functional capacity of anti-PvDPB and T cell responses to PvDBP and one merozoite surface protein (PvMSP1 19 ) were assessed, as well as antibody responses to six Pf antigens.…”

Section: Introductionmentioning

confidence: 99%

Naturally Acquired Binding-Inhibitory Antibodies to Plasmodium vivax Duffy Binding Protein in Pregnant Women Are Associated with Higher Birth Weight in a Multicenter Study

et al. 2017

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A vaccine to eliminate malaria would need a multi-stage and multi-species composition to achieve robust protection, but the lack of knowledge about antigen targets and mechanisms of protection precludes the development of fully efficacious malaria vaccines, especially for Plasmodium vivax (Pv). Pregnant women constitute a risk population who would greatly benefit from a vaccine preventing the adverse events of Plasmodium infection during gestation. We hypothesized that functional immune responses against putative targets of naturally acquired immunity to malaria and vaccine candidates will be associated with protection against malaria infection and/or poor outcomes during pregnancy. We measured (i) IgG responses to a large panel of Pv and Plasmodium falciparum (Pf) antigens, (ii) the capacity of anti-Pv ligand Duffy binding protein (PvDBP) antibodies to inhibit binding to Duffy antigen, and (iii) cellular immune responses to two Pv antigens, in a subset of 1,056 pregnant women from Brazil, Colombia, Guatemala, India, and Papua New Guinea (PNG). There were significant intraspecies and interspecies correlations for most antibody responses (e.g., PfMSP119 versus PfAMA1, Spearman’s rho = 0.81). Women from PNG and Colombia had the highest levels of IgG overall. Submicroscopic infections seemed sufficient to boost antibody responses in Guatemala but not antigen-specific cellular responses in PNG. Brazil had the highest percentage of Duffy binding inhibition (p-values versus Colombia: 0.040; Guatemala: 0.047; India: 0.003, and PNG: 0.153) despite having low anti-PvDBP IgG levels. Almost all antibodies had a positive association with present infection, and coinfection with the other species increased this association. Anti-PvDBP, anti-PfMSP1, and anti-PfAMA1 IgG levels at recruitment were positively associated with infection at delivery (p-values: 0.010, 0.003, and 0.023, respectively), suggesting that they are markers of malaria exposure. Peripheral blood mononuclear cells from Pv-infected women presented fewer CD8+IFN-γ+ T cells and secreted more G-CSF and IL-4 independently of the stimulus used in vitro. Functional anti-PvDBP levels at recruitment had a positive association with birth weight (difference per doubling antibody levels: 45 g, p-value: 0.046). Thus, naturally acquired binding-inhibitory antibodies to PvDBP might confer protection against poor outcomes of Pv malaria in pregnancy.

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“…Several preclinical and clinical trials have been aimed to develop an ideal malaria vaccine formulation [ 8 ]. The main challenge in designing an effective malaria vaccine is the complexity of the Plasmodium life cycle, as each of the different stages in the host contains a unique set of antigens that hinders the development of protective immune responses [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

et al. 2016

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A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions (HVR) of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity and protective efficacy of adenoviral based malaria vaccines.

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Malaria vaccine clinical trials: what's on the horizon

Cited by 23 publications

References 64 publications

Bacterial superglue enables easy development of efficient virus-like particle based vaccines

Bacterial superglue enables easy development of efficient virus-like particle based vaccines

Naturally Acquired Binding-Inhibitory Antibodies to Plasmodium vivax Duffy Binding Protein in Pregnant Women Are Associated with Higher Birth Weight in a Multicenter Study

A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

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