ORCID Profile
0000-0001-7354-8817
Current Organisations
Seoul National University
,
Seoul-teracom, Inc.
,
University of Queensland
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biologically active molecules | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Immunology not elsewhere classified | Natural products and bioactive compounds | Environmental biotechnology | Medical Microbiology | Biochemistry and Cell Biology | Aquaculture | Medical Parasitology | Medical Virology | Gene expression (incl. microarray and other genome-wide approaches) | Biodiscovery | Public Health and Health Services not elsewhere classified | Genetics |
ANZSRC Socio-Economic Objective (SEO)
Public Health (excl. Specific Population Health) not elsewhere classified | Specific Population Health (excl. Indigenous Health) not elsewhere classified | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences
Related Links
Publications
Strategy for development of a pre-erythrocytic Plasmodium falciparum DNA vaccine for human use
Publisher: Elsevier BV
Date: 06-1997
DOI: 10.1016/S0264-410X(96)00273-3
Abstract: Data generated in the Plasmodium yoelii rodent model indicated that plasmid DNA vaccines encoding the P.yoelii circumsporozoite protein (PyCSP) or 17 kDa hepatocyte erythrocyte protein (PyHEP17) were potent inducers of protective CD8+ T cell responses directed against infected hepatocytes. Immunization with a mixture of these plasmids circumvented the genetic restriction of protective immunity and induced additive protection. A third DNA vaccine encoding the P. yoelii sporozoite surface protein 2 (PySSP2) also induced protection. The P. falciparum genes encoding the homologues of these three protective P. yoelii antigens as well as another P. falciparum gene encoding a protein that is expressed in infected hepatocytes have been chosen for the development of a human vaccine. The optimal plasmid constructs for human use will be selected on the basis of immunogenicity data generated in mice and nonhuman primates. We anticipate that optimization of multi-gene P. falciparum DNA vaccines designed to protect against malaria by inducing CD8+ T cells that target infected hepatocytes will require extensive clinical trials during the coming years.
Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation
Publisher: Springer Science and Business Media LLC
Date: 06-2017
DOI: 10.1038/S41598-017-02096-2
Abstract: Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum- parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro . Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-α). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to TLR stimulation, producing IFN-α and upregulating HLA-DR, CD86, CD123 at peak-infection. In clinical malaria, pDC retained HLA-DR but reduced CD123 expression compared to convalescence. These data demonstrate pDC retain function during a first blood-stage P. falciparum exposure despite sub-microscopic parasitaemia downregulating HLA-DR. The lack of evident pDC activation in both early infection and malaria suggests little response of circulating pDC to infection.
DNA-based vaccines against malaria: status and promise of the Multi-Stage Malaria DNA Vaccine Operation
Publisher: Elsevier BV
Date: 06-2001
DOI: 10.1016/S0020-7519(01)00184-9
Abstract: The introduction of DNA vaccine technology has facilitated an unprecedented multi-antigen approach to developing an effective vaccine against complex pathogens such as the Plasmodium spp. parasites that cause malaria. We have established the capacity of DNA vaccines encoding Plasmodium antigens to induce CD8(+) cytotoxic T lymphocyte and interferon-gamma responses in mice, monkeys and humans. However, like others, we have found that the first or second generation DNA vaccines on their own are not optimal, and have demonstrated the potential of heterologous prime/boost immunisation strategies involving priming with DNA and boosting with poxvirus or recombinant protein in adjuvant. In this review, we summarise the current status and promise of our programmatic efforts to develop a DNA-based vaccine against malaria, our Multi-Stage Malaria DNA Vaccine Operation, and illustrate the transition of promising developments in the laboratory to clinical assessment in humans.
Evaluation of Approaches to Identify the Targets of Cellular Immunity on a Proteome-Wide Scale
Publisher: Public Library of Science (PLoS)
Date: 11-11-2011
Novel antiinflammatory biologics shaped by parasite–host coevolution
Publisher: Proceedings of the National Academy of Sciences
Date: 29-08-2022
Abstract: Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host’s immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm’s excretory–secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.
The case for a rational genome-based vaccine against malaria
Publisher: Frontiers Media SA
Date: 22-01-2015
Identification and localization of minimal MHC-restricted CD8+ T cell epitopes within the Plasmodium falciparum AMA1 protein
Publisher: Springer Science and Business Media LLC
Date: 24-08-2010
Abstract: Plasmodium falciparum apical membrane antigen-1 (AMA1) is a leading malaria vaccine candidate antigen that is expressed by sporozoite, liver and blood stage parasites. Since CD8+ T cell responses have been implicated in protection against pre-erythrocytic stage malaria, this study was designed to identify MHC class I-restricted epitopes within AMA1. A recombinant adenovirus serotype 5 vector expressing P. falciparum AMA1 was highly immunogenic when administered to healthy, malaria-naive adult volunteers as determined by IFN-γ ELISpot responses to peptide pools containing overlapping 15-mer peptides spanning full-length AMA1. Computerized algorithms (NetMHC software) were used to predict minimal MHC-restricted 8-10-mer epitope sequences within AMA1 15-mer peptides active in ELISpot. A subset of epitopes was synthesized and tested for induction of CD8+ T cell IFN-γ responses by ELISpot depletion and ICS assays. A 3-dimensional model combining Domains I + II of P. falciparum AMA1 and Domain III of P. vivax AMA1 was used to map these epitopes. Fourteen 8-10-mer epitopes were predicted to bind to HLA supertypes A01 (3 epitopes), A02 (4 epitopes), B08 (2 epitopes) and B44 (5 epitopes). Nine of the 14 predicted epitopes were recognized in ELISpot or ELISpot and ICS assays by one or more volunteers. Depletion of T cell subsets confirmed that these epitopes were CD8+ T cell-dependent. A mixture of the 14 minimal epitopes was capable of recalling CD8+ T cell IFN-γ responses from PBMC of immunized volunteers. Thirteen of the 14 predicted epitopes were polymorphic and the majority localized to the more conserved front surface of the AMA1 model structure. This study predicted 14 and confirmed nine MHC class I-restricted CD8+ T cell epitopes on AMA1 recognized in the context of seven HLA alleles. These HLA alleles belong to four HLA supertypes that have a phenotypic frequency between 23% - 100% in different human populations.
CD161 expression defines new human γδ T cell subsets
Publisher: Springer Science and Business Media LLC
Date: 22-02-2022
DOI: 10.1186/S12979-022-00269-W
Abstract: γδ T cells are a highly versatile immune lineage involved in host defense and homeostasis, but questions remain around their heterogeneity, precise function and role during health and disease. We used multi − parametric flow cytometry, dimensionality reduction, unsupervised clustering, and self-organizing maps (SOM) to identify novel γδ T cell naïve/memory subsets chiefly defined by CD161 expression levels, a surface membrane receptor that can be activating or suppressive. We used middle-to-old age in iduals given immune blockade is commonly used in this population. Whilst most Vδ1 + subset cells exhibited a terminal differentiation phenotype, Vδ1 − subset cells showed an early memory phenotype. Dimensionality reduction revealed eight γδ T cell clusters chiefly erging through CD161 expression with CD4 and CD8 expression limited to specific subpopulations. Comparison of matched healthy elderly in iduals to bronchiectasis patients revealed elevated Vδ1 + terminally differentiated effector memory cells in patients potentially linking this population with chronic proinflammatory disease.
Sterile Protective Immunity to Malaria is Associated with a Panel of Novel P. falciparum Antigens
Publisher: Elsevier BV
Date: 09-2011
Alignment of Carbon Nanotubes inside the Fibers Through Interfacial Interaction of Nanoparticles for Using as Cathode for Field Emission
Publisher: IEEE
Date: 04-2019
Utilization of genomic sequence information to develop malaria vaccines
Publisher: The Company of Biologists
Date: 11-2003
DOI: 10.1242/JEB.00615
Abstract: Recent advances in the fields of genomics, proteomics and molecular immunology offer tremendous opportunities for the development of novel interventions against public health threats, including malaria. However, there is currently no algorithm that can effectively identify the targets of protective T cell or antibody responses from genomic data. Furthermore, the identification of antigens that will stimulate the most effective immunity against the target pathogen is problematic, particularly if the genome is large. Malaria is an attractive model for the development and validation of approaches to translate genomic information to vaccine development because of the critical need for effective anti-malarial interventions and because the Plasmodium parasite is a complex multistage pathogen targeted by multiple immune responses. Sterile protective immunity can be achieved by immunization with radiation-attenuated sporozoites, and anti-disease immunity can be induced in residents in malaria-endemic areas. However, the 23 Mb Plasmodium falciparum genome encodes more than 5300 proteins, each of which is a potential target of protective immune responses. The current generation of subunit vaccines is based on a single or few antigens and therefore might elicit too narrow a breadth of response. We are working towards the development of a new generation vaccine based on the presumption that duplicating the protection induced by the whole organism may require a vaccine nearly as complex as the organism itself. Here, we present our strategy to exploit the genomic sequence of P. falciparum for malaria vaccine development.
Pre–erythrocytic–stage immune effector mechanisms inPlasmodiumspp. infections
Publisher: The Royal Society
Date: 29-09-1997
Abstract: The potent protective immunity against malaria induced by immunization of mice and humans with radiation–attenuated Plasmodium spp. sporozoites is thought to be mediated primarily by T–cell responses directed against infected hepatocytes. This has led to considerable efforts to develop subunit vaccines that duplicate this protective immunity, but a universally effective vaccine is still not available and in vitro correlates of protective immunity have not been established. Contributing to this delay has been a lack of understanding of the mechanisms responsible for the protection. There are now data indicating that CD8+ T cells, CD4+ T cells, cytokines, and nitric oxide can all mediate the elimination of infected hepatocytes in vitro and in vivo . By dissecting the protection induced by immunization with irradiated sporozoite, DNA and synthetic peptide–adjuvant vaccines, we have demonstrated that different T–cell–dependent immune responses mediate protective immunity in the same inbred strain of mouse, depending on the method of immunization. Furthermore, the mechanism of protection induced by a single method of immunization may vary among different strains of mice. These data have important implications for the development of pre–erythrocytic–stage vaccines designed to protect a heterogeneous human population, and of assays that predict protective immunity.
DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity
Publisher: Public Library of Science (PLoS)
Date: 14-02-2013
Robust correlations across six SARS‐CoV‐2 serology assays detecting distinct antibody features
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1258
Characterizing and correcting immune dysfunction in non-tuberculous mycobacterial disease
Publisher: Frontiers Media SA
Date: 10-11-2022
DOI: 10.3389/FIMMU.2022.1047781
Abstract: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic, progressive, and growing worldwide health burden associated with mounting morbidity, mortality, and economic costs. Improvements in NTM-PD management are urgently needed, which requires a better understanding of fundamental immunopathology. Here, we examine temporal dynamics of the immune compartment during NTM-PD caused by Mycobacterium avium complex (MAC) and Mycobactereoides abscessus complex (MABS). We show that active MAC infection is characterized by elevated T cell immunoglobulin and mucin-domain containing-3 expression across multiple T cell subsets. In contrast, active MABS infection was characterized by increased expression of cytotoxic T-lymphocyte-associated protein 4. Patients who failed therapy closely mirrored the healthy in idual immune phenotype, with circulating immune network appearing to ‘ignore’ infection in the lung. Interestingly, immune biosignatures were identified that could inform disease stage and infecting species with high accuracy. Additionally, programmed cell death protein 1 blockade rescued antigen-specific IFN-γ secretion in all disease stages except persistent infection, suggesting the potential to redeploy checkpoint blockade inhibitors for NTM-PD. Collectively, our results provide new insight into species-specific ‘immune chatter’ occurring during NTM-PD and provide new targets, processes and pathways for diagnostics, prognostics, and treatments needed for this emerging and difficult to treat disease.
10Kin1day: A bottom-up neuroimaging initiative
Publisher: Cold Spring Harbor Laboratory
Date: 16-01-2019
DOI: 10.1101/509554
Abstract: We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.
Supplementary Table S1 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22724999.V1
Abstract: Supplementary Table S1 shows marker pathway allocation and corresponding citations
Identifying Epstein–Barr virus peptide sequences associated with differential IgG antibody response
Publisher: Elsevier BV
Date: 1212
DOI: 10.1016/J.IJID.2021.10.054
Abstract: Epstein-Barr virus (EBV) infection contributes to cancers in a fraction of seropositive in iduals, but much remains to be learned about variation in EBV-directed humoral immunity in cancer-free adults. A protein microarray was used to probe serum from 175 Taiwanese and 141 Northern European adults for immunoglobulin G (IgG) antibody responses to 115 different peptide sequences, representing protein segments or protein variants, from 45 EBV proteins. It was posited that this antibody-based approach could identify EBV peptide sequences representing immunodominant regions relevant for B-cell immunity. Analyses of 45 EBV proteins with multiple protein segments or variants printed on the array identified eight EBV peptide sequences that appear to play a role in immunogenicity. This included: (1) three proteins with segments/regions associated with IgG reactivity (BALF5, LMP1, LMP2A) and (2) five proteins with sequence variants/amino acid changes associated with IgG reactivity (BDLF4, EBNA3A, EBNA3B, EBNA-LP, LF1). This examination of IgG antibody responses against 115 EBV peptide sequences in 316 cancer-free adults represents an important step toward identifying specific EBV protein sequences that play a role in generating B-cell immunity in humans.
Plasmodium vivax but Not Plasmodium falciparum Blood-Stage Infection in Humans Is Associated with the Expansion of a CD8+ T Cell Population with Cytotoxic Potential
Publisher: Public Library of Science (PLoS)
Date: 08-12-2016
A dual antigen ELISA allows the assessment of SARS-CoV-2 antibody seroprevalence in a low transmission setting
Publisher: Cold Spring Harbor Laboratory
Date: 14-09-2020
DOI: 10.1101/2020.09.09.20191031
Abstract: Estimates of seroprevalence of SARS-CoV-2 antibodies have been h ered by inadequate assay sensitivity and specificity. Using an ELISA-based approach to that combines data about IgG responses to both the Nucleocapsid and Spike-receptor binding domain antigens, we show that near-optimal sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (0 to 0.72%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Identification of the Glycan Binding Profile of Human and Rodent Plasmodium Sporozoites
Publisher: American Chemical Society (ACS)
Date: 25-06-2021
Schistosomiasis vaccine discovery using immunomics
Publisher: Springer Science and Business Media LLC
Date: 2010
Induction of CD4+T cell-dependent CD8+type 1 responses in humans by a malaria DNA vaccine
Publisher: Proceedings of the National Academy of Sciences
Date: 28-08-2001
Abstract: We assessed immunogenicity of a malaria DNA vaccine administered by needle i.m. or needleless jet injection [i.m. or i.m./intradermally (i.d.)] in 14 volunteers. Antigen-specific IFN-γ responses were detected by enzyme-linked immunospot (ELISPOT) assays in all subjects to multiple 9- to 23-aa peptides containing class I and/or class II restricted epitopes, and were dependent on both CD8 + and CD4 + T cells. Overall, frequency of response was significantly greater after i.m. jet injection. CD8 + -dependent cytotoxic T lymphocytes (CTL) were detected in 8/14 volunteers. Demonstration in humans of elicitation of the class I restricted IFN-γ responses we believe necessary for protection against the liver stage of malaria parasites brings us closer to an effective malaria vaccine.
A novel population of memory‐activated natural killer cells associated with low parasitaemia in Plasmodium falciparum‐exposed sickle‐cell trait children
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1125
Proteins of Bovine Ephemeral Fever Virus
Publisher: Microbiology Society
Date: 1991
DOI: 10.1099/0022-1317-72-1-67
Abstract: The proteins of bovine ephemeral fever virus (BEFV) were examined in purified virions and in infected BHK-21 cells. Five structural proteins were named L (180K), G (81K), N (52K), M1 (43K) and M2 (29K). The 81K G protein incorporated [3H]glucosamine, was removed from virions by treatment with Triton X-100 and bound monoclonal antibodies which were both neutralizing and protective. Treatment of virions with Triton X-100 and 0.2 to 1.0 M-NaCl progressively released L, M1 and M2. The N protein remained associated with nucleocapsids in up to 2.5 M-NaCl. The glycoprotein (G), nucleoprotein (N) and matrix protein (M2) were phosphorylated. In BEFV-infected BHK-21 cells, five virus-induced proteins were detected from 12 h post-infection. The L, N, M1 and M2 proteins corresponded to those detected in virions whereas the G protein existed in two forms. In tunicamycin-treated cells these occurred as 67K and 71K non-glycosylated precursors. In the absence of tunicamycin, 77K and 79K glycosylated forms were further modified to produce the 81K virion G protein and a 90K cell-associated form. Five viral proteins were also detected in cells infected with the closely related Berrimah virus the Berrimah virus G protein was also present in two forms.
Non-toxic derivatives of LT as potent adjuvants
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.VACCINE.2010.11.091
Abstract: The heat-labile enterotoxin of Escherichia coli (LT) consists of an enzymatically active A subunit (LTA) and a pentameric B subunit (LTB). LT has been extensively studied as a potent modulator of immune responses but wild-type LT is toxic and therefore unsuitable for clinical use. Approaches pursued to avoid the toxicity associated with the use of the native toxin while retaining its adjuvant properties have included isolation of subunit B (LTB) and construction of non-toxic LT AB complex mutants, such as LTK63 mutant. Here we review the immunomodulatory characteristics of LTB and LTK63 and their potential as mucosal and parenteral vaccine adjuvants.
Reduced Plasmodium Parasite Burden Associates with CD38+ CD4+ T Cells Displaying Cytolytic Potential and Impaired IFN-gamma Production
Publisher: Public Library of Science (PLoS)
Date: 23-09-2016
A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2
Publisher: Elsevier BV
Date: 12-2021
Supplementary Table S3 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22724993
Abstract: Supplementary Table S3 shows positivity rates of the 46 in idual markers among cases and controls in each study
Supplementary Table S2 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22724996
Abstract: Supplementary Table S2 shows summary of participant characteristics
Supplementary Table S1 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22724999
Abstract: Supplementary Table S1 shows marker pathway allocation and corresponding citations
High production of pro-inflammatory cytokines by maternal blood mononuclear cells is associated with reduced maternal malaria but increased cord blood infection
Publisher: Springer Science and Business Media LLC
Date: 10-05-2018
Proceedings of the 7th Biannual International Symposium on Nasopharyngeal Carcinoma 2015
Publisher: Springer Science and Business Media LLC
Date: 04-2016
Plasmodium falciparum CS protein - prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation
Publisher: FapUNIFESP (SciELO)
Date: 1992
DOI: 10.1590/S0074-02761992000700040
Abstract: Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by cytotoxic T lymphocytes (CTL) specific for epitopes within the circumsporozoite (CS) protein. Humans, however, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans relies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.
Malaria Vaccine Design: Immunological Considerations
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.IMMUNI.2010.10.005
Abstract: The concept of a malaria vaccine has sparked great interest for decades however, the challenge is proving to be a difficult one. Immune dysregulation by Plasmodium and the ability of the parasite to mutate critical epitopes in surface antigens have proved to be strong defense weapons. This has led to reconsideration of polyvalent and whole parasite strategies and ways to enhance cellular immunity to malaria that may be more likely to target conserved antigens and an expanded repertoire of antigens. These and other concepts will be discussed in this review.
Systematic evaluation of self-adjuvanting lipopeptide nano-vaccine platforms for the induction of potent CD8+T-cell responses
Publisher: Future Medicine Ltd
Date: 2016
DOI: 10.2217/NNM.15.184
Abstract: Aim: Systematically evaluate lipid core peptide vaccine delivery platforms to identify core features promoting strong CD8 + T-cell responses. Materials & methods: Three different self-adjuvanting lipid core peptide nanovaccines each comprising four copies of the dominant ovalbumin CD8 + T-cell epitope and varying in the utilization of a polylysine or glucose core with 2-amino-hexadecanoic acid (C16) or 2-amino-dodecanoic acid (C12) lipids were synthesized. Vaccines were tested for ability to induce CD8 + T-cell responses and inhibit tumor growth in vivo. Results: The construct utilizing C12 lipids and polylysine core induced very robust effector T cells shown to have in vivo effector capability as demonstrated by in vivo cytotoxicity and ability to inhibit tumor growth as well as modulation of dendritic cell activation. Conclusion: The C12 polylysine platform was an effective configuration for induction of potent CD8 + T-cell responses.
Chemically Attenuated Blood-Stage Plasmodium yoelii Parasites Induce Long-Lived and Strain-Transcending Protection
Publisher: American Society for Microbiology
Date: 08-2016
DOI: 10.1128/IAI.00157-16
Abstract: The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4 + and CD8 + T cells was shown after vaccination however, in vivo studies demonstrated a pivotal role for both CD4 + T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8 + T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8 + T cells contribute to blood-stage protection rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4 + and CD8 + T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.
Protection of Humans against Malaria by Immunization with Radiation‐AttenuatedPlasmodium falciparumSporozoites
Publisher: Oxford University Press (OUP)
Date: 15-04-2002
DOI: 10.1086/339409
Abstract: During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.
Observing ice structure of micron-sized vapor-deposited ice with an x-ray free-electron laser
Publisher: AIP Publishing
Date: 07-2023
DOI: 10.1063/4.0000185
Abstract: The direct observation of the structure of micrometer-sized vapor-deposited ice is performed at Pohang Accelerator Laboratory x-ray free electron laser (PAL-XFEL). The formation of micrometer-sized ice crystals and their structure is important in various fields, including atmospheric science, cryobiology, and astrophysics, but understanding the structure of micrometer-sized ice crystals remains challenging due to the lack of direct observation. Using intense x-ray diffraction from PAL-XFEL, we could observe the structure of micrometer-sized vapor-deposited ice below 150 K with a thickness of 2–50 μm grown in an ultrahigh vacuum chamber. The structure of the ice grown comprises cubic and hexagonal sequences that are randomly arranged to produce a stacking-disordered ice. We observed that ice with a high cubicity of more than 80% was transformed to partially oriented hexagonal ice when the thickness of the ice deposition grew beyond 5 μm. This suggests that precise temperature control and clean deposition conditions allow μm-thick ice films with high cubicity to be grown on hydrophilic Si3N4 membranes. The low influence of impurities could enable in situ diffraction experiments of ice nucleation and growth from interfacial layers to bulk ice.
Identification of humoral immune responses in protein microarrays using DNA microarray data analysis techniques
Publisher: Oxford University Press (OUP)
Date: 27-04-2006
DOI: 10.1093/BIOINFORMATICS/BTL162
Abstract: Motivation: We present a study of antigen expression signals from a newly developed high-throughput protein microarray technique. These signals are a measure of antibody–antigen binding activity and provide a basis for understanding humoral immune responses to various infectious agents and supporting vaccine and diagnostic development. Results: We investigate the characteristics of these expression profiles and show that noise models, normalization, variance estimation and differential expression analysis techniques developed in the context of DNA microarray analysis can be adapted and applied to these protein arrays. Using a high-dimensional dataset containing measurements of expression profiles of antibody reactivity against each protein (295 antigens and 9 controls) in 42 malaria (Plasmodium falciparum) protein arrays derived from 22 donors with various clinical presentations of malaria, we present a methodology for the analysis and identification of significantly expressed antigens targeted by immune responses for in idual sera, groups of sera and across stages of infection. We also conduct a short study highlighting the top immunoreactive antigens where we identify three novel high priority antigens for future evaluation. Availability: All software programs (in R) used for the analysis described in this paper are freely available for academic purposes at Contact: pfbaldi@uci.edu
Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity
Publisher: Springer Science and Business Media LLC
Date: 22-07-2016
Nucleic Acid Vaccines against Malaria
Publisher: KARGER
Date: 2002
DOI: 10.1159/000058851
The Complexity of Protective Immunity Against Liver-Stage Malaria
Publisher: The American Association of Immunologists
Date: 08-2000
DOI: 10.4049/JIMMUNOL.165.3.1453
Abstract: Sterile protective immunity against challenge with Plasmodium spp. sporozoites can be induced in multiple model systems and humans by immunization with radiation-attenuated Plasmodium spp. sporozoites. The infected hepatocyte has been established as the primary target of this protection, but the underlying mechanisms have not been completely defined. Abs, CD8+ T cells, CD4+ T cells, cytokines (including IFN-γ and IL-12), and NO have all been implicated as critical effectors. Here, we have investigated the mechanisms of protective immunity induced by immunization with different vaccine delivery systems (irradiated sporozoites, plasmid DNA, synthetic peptide/adjuvant, and multiple Ag peptide) in genetically distinct inbred strains, genetically modified mice, and outbred mice. We establish that there is a marked ersity of T cell-dependent immune responses that mediate sterile protective immunity against liver-stage malaria. Furthermore, we demonstrate that distinct mechanisms of protection are induced in different strains of inbred mice by a single method of immunization, and in the same strain by different methods of immunization. These data underscore the complexity of the murine host response to a parasitic infection and suggest that an outbred human population may behave similarly. Data nevertheless suggest that a pre-erythrocytic-stage vaccine should be designed to induce CD8+ T cell- and IFN-γ-mediated immune responses and that IFN-γ responses may represent an in vitro correlate of pre-erythrocytic-stage protective immunity.
Protective immunity against severe malaria is associated with antibodies to a conserved repertoire of PfEMP1 variants
Publisher: Cold Spring Harbor Laboratory
Date: 19-11-2018
DOI: 10.1101/472159
Abstract: Extreme ersity of the major surface antigen and virulence determinant of the malaria parasite Plasmodium falciparum , Erythrocyte Membrane Protein-1 (PfEMP1), poses a major barrier to identifying targets of protective immunity. To overcome this problem, we developed a PfEMP1 protein microarray containing 456 DBLα domains, which was used to characterize the immunome of a cohort of semi-immune children and to identify variants associated with protective immune responses. Children with high mean antibody levels to DBLα group 2 had a 26-36% reduced risk of uncomplicated (clinical) malaria, however only 8 erse DBLα variants were weakly associated with protection from clinical malaria and had low predictive accuracy. On the other hand, children with high mean antibodies to DBLα groups 1 and 2 (which are markers for pathogenic “Type A” PfEMP1) and elevated antibodies to 85 (18.6%) of in idual DBLα variants had a 70 −100% reduced risk of severe malaria. Of the top 20 predictive variants for severe disease protection, 17 were strongly associated with protection (86 - 100% reduction in risk of severe malaria) and had high predictive accuracy for severe disease risk. Many variants were conserved and had highly correlated antibody responses, including the three highest-ranking variants, which were linked to EPCR-binding CIDR domains. The results suggest that while immunity to uncomplicated malaria is characterised by antibodies to a erse repertoire of PfEMP1, immunity to severe malaria requires antibodies to a limited subset of antigenically conserved variants. These findings provide new insights into antimalarial immunity and potential biomarkers for tracking disease risk.
Multi-gene vaccination against malaria: A multistage, multi-immune response approach
Publisher: Elsevier BV
Date: 05-1997
DOI: 10.1016/S0169-4758(97)01040-5
Abstract: An ideal malaria vaccine will induce immune responses against each stage of the Plasmodium spp life cycle. During its complicated life cycle, the parasite exists extracellularly in the host's bloodstream, within cells that express major histocompatibility complex (MHC) molecules (hepatocytes), within cells that do not express MHC molecules (erythrocytes) and within the mosquito vector. Different arms of the immune system are required to attack the parasite at the different stages. Therefore, a multistage vaccine must be a multi-immune response vaccine. In addition, given the unique antigenicities of the different stages of the life cycle, implicit in this definition is that the vaccine be multivalent. Here, Denise Doolan and Stephen Hoffman present the rationale for developing a multistage, multivalent, multi-immune response malaria vaccine and explain why, among currently available technologies, DNA vaccines may offer the best prospect for success.
Dissecting T cell or antibody immunodominance in a complex host-pathogen system
Publisher: Springer Science and Business Media LLC
Date: 10-2012
HLA-DR-Promiscuous T Cell Epitopes fromPlasmodium falciparumPre-Erythrocytic-Stage Antigens Restricted by Multiple HLA Class II Alleles
Publisher: The American Association of Immunologists
Date: 15-07-2000
DOI: 10.4049/JIMMUNOL.165.2.1123
Abstract: Previously, we identified and established the antigenicity of 17 CD8+ T cell epitopes from five P. falciparum Ags that are restricted by multiple common HLA class I alleles. Here, we report the identification of 11 peptides from the same Ags, cicumsporozoite protein, sporozoite surface protein 2, exported protein-1, and liver-stage Ag-1, that bind between at least five and up to 11 different HLA-DR molecules representative of the most common HLA-DR Ags worldwide. These peptides recall lymphoproliferative and cytokine responses in immune in iduals experimentally immunized with radiation-attenuated Plasmodium falciparum sporozoites (irradiated sporozoites) or semi-immune in iduals naturally exposed to malaria in Irian Jaya or Kenya. We establish that all peptides are recognized by in iduals of each of the three populations, and that the frequency and magnitude of helper T lymphocyte responses to each peptide is influenced by the intensity of exposure to P. falciparum sporozoites. Mean frequencies of lymphoproliferative responses are 53.2% (irradiated sporozoites) vs 22.4% (Kenyan) vs 5.8% (Javanese), and mean frequencies of IFN-γ responses are 66.3% (irradiated sporozoites) vs 27.3% (Kenyan) vs 8.7% (Javanese). The identification of HLA class II degenerate T cell epitopes from P. falciparum validates our predictive strategy in a biologically relevant system and supports the potential for developing a broadly efficacious epitope-based vaccine against malaria focused on a limited number of peptide specificities.
Proteomic identification of the contents of small extracellular vesicles from in vivo Plasmodium yoelii infection
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.IJPARA.2021.06.001
Abstract: Small extracellular vesicles, including exosomes, are formed by the endocytic pathway and contain genetic and protein material which reflect the contents of their cells of origin. These contents have a role in vesicle-mediated information transfer, as well as physiological and pathological functions. Thus, these vesicles are of great interest as therapeutic targets, or as vehicles for immunomodulatory control. In Plasmodium spp. infections, vesicles derived from the parasite or parasite-infected cells have been shown to induce the expression of pro-inflammatory elements, which have been correlated with manifestations of clinical disease. Herein, we characterised the protein cargo of naturally occurring sEVs in the plasma of P. yoelii-infected mice. After in vivo infections, extracellular vesicles in the size range of exosomes were collected by sequential centrifugation/ultracentrifugation followed by isopycnic gradient separation. Analysis of the vesicles was performed by transmission electron microscopy, dynamic light scattering, SDS-PAGE and flow cytometry. LC-MS analysis followed by bioinformatics analysis predicted parasite protein cargo associated with exosomes. Within these small extracellular vesicles, we identified proteins of interest as vaccine candidates, uncharacterized proteins which may be targets of T cell immunoreactivity, and proteins involved in metabolic processes, regulation, homeostasis and immunity. Importantly, the small extracellular vesicles studied in our work were obtained from in vivo infection rather than from the supernatant of in vitro cultures. These findings add to the growing interest in parasite small extracellular vesicles, further our understanding of the interactions between host and parasite, and identify novel proteins which may represent potential targets for vaccination against malaria.
Vaxfectin™ enhances immunogenicity and protective efficacy of P. yoelii circumsporozoite DNA vaccines
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.VACCINE.2005.10.041
Abstract: We evaluated the capacity of the cationic lipid based formulation, Vaxfectin, to enhance the immunogenicity and protective efficacy of DNA-based vaccine regimens in the Plasmodium yoelii murine malaria model. We immunized Balb/c mice with varying doses (0.4-50 microg) of plasmid DNA (pDNA) encoding the P. yoelii circumsporozoite protein (PyCSP), either in a homologous DNA/DNA regimen (D-D) or a heterologous prime-boost DNA-poxvirus regimen (D-V). At the lowest pDNA doses, Vaxfectin substantially enhanced IFA titers, ELISPOT frequencies, and protective efficacy. Clinical trials of pDNA vaccines have often used low pDNA doses based on a per kilogram weight basis. Formulation of pDNA vaccines in Vaxfectin may improve their potency in human clinical trials.
The Effect of Tropical Temperatures on the Quality of RNA Extracted from Stabilized Whole-Blood Samples
Publisher: MDPI AG
Date: 13-09-2022
Abstract: Whole-blood-derived transcriptional profiling is widely used in biomarker discovery, immunological research, and therapeutic development. Traditional molecular and high-throughput transcriptomic platforms, including molecular assays with quantitative PCR (qPCR) and RNA-sequencing (RNA-seq), are dependent upon high-quality and intact RNA. However, collecting high-quality RNA from field studies in remote tropical locations can be challenging due to resource restrictions and logistics of post-collection processing. The current study tested the relative performance of the two most widely used whole-blood RNA collection systems, PAXgene® and Tempus™, in optimal laboratory conditions as well as suboptimal conditions in tropical field sites, including the effects of extended storage times and high storage temperatures. We found that Tempus™ tubes maintained a slightly higher RNA quantity and integrity relative to PAXgene® tubes at suboptimal tropical conditions. Both PAXgene® and Tempus™ tubes gave similar RNA purity (A260/A280). Additionally, Tempus™ tubes preferentially maintained the stability of mRNA transcripts for two reference genes tested, Succinate dehydrogenase complex, subunit A (SDHA) and TATA-box-binding protein (TBP), even when RNA quality decreased with storage length and temperature. Both tube types preserved the rRNA transcript 18S ribosomal RNA (18S) equally. Our results suggest that Tempus™ blood RNA collection tubes are preferable to PAXgene® for whole-blood collection in suboptimal tropical conditions for RNA-based studies in resource-limited settings.
Adenovectors induce functional antibodies capable of potent inhibition of blood stage malaria parasite growth
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.VACCINE.2010.02.024
Abstract: An effective malaria vaccine remains a global health priority. Recombinant adenoviruses are a promising vaccine platform, and Plasmodium falciparum apical membrane antigen 1 (AMA1) and merozoite surface protein 1-42 (MSP1(42)) are leading blood stage vaccine candidates. We evaluated the importance of surface antigen localization and glycosylation on the immunogenicity of adenovector delivered AMA1 and MSP1(42) and assessed the ability of these vaccines to induce functional antibody responses capable of inhibiting parasite growth in vitro. Adenovector delivery induced unprecedented levels of biologically active antibodies in rabbits as indicated by the parasite growth inhibition assay. These responses were as potent as published results using any other vaccine system, including recombinant protein in adjuvant. The cell surface associated and glycosylated forms of AMA1 and MSP1(42) elicited 99% and 60% inhibition of parasite growth, respectively. Antigens that were expressed at the cell surface and glycosylated were much better than intracellular antigens at inducing antibody responses. Good T cell responses were observed for all forms of AMA1 and MSP1(42). Antigen-specific antibody responses, but typically not T cell responses, were boosted by a second administration of adenovector. These data highlight the importance of rational vaccine design and support the advancement of adenovector delivery technology for a malaria vaccine.
Mining, visualizing and comparing multidimensional biomolecular data using the Genomics Data Miner (GMine) Web-Server
Publisher: Springer Science and Business Media LLC
Date: 06-12-2016
DOI: 10.1038/SREP38178
Abstract: Genomics Data Miner (GMine) is a user-friendly online software that allows non-experts to mine, cluster and compare multidimensional biomolecular datasets. Various powerful visualization techniques are provided, generating high quality figures that can be directly incorporated into scientific publications. Robust and comprehensive analyses are provided via a broad range of data-mining techniques, including univariate and multivariate statistical analysis, supervised learning, correlation networks, clustering and multivariable regression. The software has a focus on multivariate techniques, which can attribute variance in the measurements to multiple explanatory variables and confounders. Various normalization methods are provided. Extensive help pages and a tutorial are available via a wiki server. Using GMine we reanalyzed proteome microarray data of host antibody response against Plasmodium falciparum . Our results support the hypothesis that immunity to malaria is a higher-order phenomenon related to a pattern of responses and not attributable to any single antigen. We also analyzed gene expression across resting and activated T cells, identifying many immune-related genes with differential expression. This highlights both the plasticity of T cells and the operation of a hardwired activation program. These application ex les demonstrate that GMine facilitates an accurate and in-depth analysis of complex molecular datasets, including genomics, transcriptomics and proteomics data.
Immunomics-guided discovery of serum and urine antibodies for diagnosing urogenital schistosomiasis: a biomarker identification study
Publisher: Elsevier BV
Date: 11-2021
Assessing Antigen-Specific CD8<sup>+</sup> CTL Responses in Humans
Publisher: Humana Press
Date: 2002
Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties
Publisher: American Chemical Society (ACS)
Date: 25-01-2016
DOI: 10.1021/ACS.BIOCONJCHEM.5B00547
Abstract: Present on the surface of antigen presenting cells (APCs), the mannose receptor (MR) has long been recognized as a front-line receptor in pathogen recognition. During the past decade many attempts have been made to target this receptor for applications including vaccine and drug development. In the present study, a library of vaccine constructs comprising fluorescently labeled mannosylated lipid-dendrimers that contained the ovalbumin CD4(+) epitope, OVA(323-339), as the model peptide antigen were synthesized using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in APCs. Uptake studies performed on F4/80(+) and CD11c(+) cells showed significant uptake and/or binding for lipopeptides containing mannose, and also the lipopeptide without mannose when compared to the control peptides (peptide with no lipid and peptide with no mannose and no lipid). Furthermore, mannan inhibition assays demonstrated that uptake of the mannosylated and lipidated peptides was receptor mediated. To address the specificity of receptor uptake, surface plasmon resonance studies were performed using biacore technology and confirmed high affinity of the mannosylated and lipidated vaccine constructs toward the MR. These studies confirm that both mannose and lipid moieties play significant roles in receptor-mediated uptake on APCs, potentially facilitating vaccine development.
A Novel Candidate Vaccine for Cytauxzoonosis Inferred from Comparative Apicomplexan Genomics
Publisher: Public Library of Science (PLoS)
Date: 20-08-2013
Schistosomiasis Vaccines – New Approaches to Antigen Discovery and Promising New Candidates
Publisher: Wiley
Date: 18-07-2012
Systems serology detects functionally distinct coronavirus antibody features in children and elderly
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1038/S41467-021-22236-7
Abstract: The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such ergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children ( n = 89), adults ( n = 98), elderly ( n = 57), and COVID-19 patients ( n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy in iduals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy in iduals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.
Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults
Publisher: Springer Science and Business Media LLC
Date: 20-06-2011
Abstract: To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays. In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinant Plasmodium falciparum CSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured by ex vivo IFN-γ ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of in idual s les using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing s les collected two weeks apart. In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of e x vivo ELISpot activities were similar in both communities. DR-restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants. All participants were positive for at least one malaria protein by ELISA, with results dependent on the criteria for positivity. Likewise, ELISpot responses varied among participants, but were relatively reproducible by the three methods tested, especially the least stringent, when assays were repeated. However, results often differed between s les taken two weeks apart, indicating significant biological variability over short intervals.
Vaxfectin® enhances both antibody and in vitro T cell responses to each component of a 5-gene Plasmodium falciparum plasmid DNA vaccine mixture administered at low doses
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.VACCINE.2009.10.044
Abstract: We previously reported the capacity of the cationic lipid-based formulation, Vaxfectin, to enhance the immunogenicity and protective efficacy of a low dose plasmid DNA vaccine against Plasmodium yoelii malaria in mice. Here, we have extended this finding to human Plasmodium falciparum genes, evaluating the immune enhancing effect of Vaxfectin formulation on a mixture, designated CSLAM, of five plasmid DNA vaccines encoding antigens from the sporozoite (PfCSP, PfSSP2/TRAP), intrahepatic (PfLSA1), and erythrocytic (PfAMA1, PfMSP1) life cycle stages of P. falciparum administered at 2, 10 or 50microg doses. Vaxfectin formulation enhanced both antibody and cellular immune responses to each component of the multi-antigen vaccine mixture, as assessed by ELISA, IFAT, and IFN-gamma ELIspot, respectively. There was no apparent antigenic competition, as indicated by comparison of responses induced in mice immunized with PfCSP vs. CSLAM. These data showing that Vaxfectin can enhance the immunogenicity of plasmid DNA vaccines administered at low doses per body weight, and in combinations, has important clinical implications for the development of a vaccine against malaria, as well as against other public health threats.
Vaccinomics for the major blood feeding helminths of humans
Publisher: Mary Ann Liebert Inc
Date: 09-2011
Abstract: Approximately one billion people are infected with hookworms and/or blood flukes (schistosomes) in developing countries. These two parasites are responsible for more disability adjusted life years lost than most other neglected tropical diseases (NTDs), and together, are second only to malaria. Although anthelmintic drugs are effective and widely available, they do not protect against reinfection, resistant parasites are likely to emerge, and mass drug administration programs are unsustainable. Therefore, there is a pressing need for the development of vaccines against these parasites. In recent years, there have been major advances in our understanding of hookworms and schistosomes at the molecular level through the use of "omics" technologies. The secretomes of these parasites have been characterized using transcriptomics, genomics, proteomics, and newly developed gene manipulation and silencing techniques, and the proteins of interest are now the target of novel antigen discovery approaches, notably immunomics. This research has resulted in the discovery, development, and early stage clinical trials of subunit vaccines against hookworms and schistosomes.
Data from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.C.6624590.V1
Abstract: AbstractBackground: Epstein–Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Methods: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case–control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 in idual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle cHL with antibodies in the early lytic, late lytic and glycoprotein stages and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer. /
Memory CD8+ T cell compartment associated with delayed onset of Plasmodium falciparum infection and better parasite control in sickle‐cell trait children
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1265
CD4+T-Cell- and Gamma Interferon-Dependent Protection against Murine Malaria by Immunization with Linear Synthetic Peptides from aPlasmodium yoelii17-Kilodalton Hepatocyte Erythrocyt
Publisher: American Society for Microbiology
Date: 11-1999
DOI: 10.1128/IAI.67.11.5604-5614.1999
Abstract: Most work on protective immunity against the pre-erythrocytic stages of malaria has focused on induction of antibodies that prevent sporozoite invasion of hepatocytes, and CD8 + T-cell responses that eliminate infected hepatocytes. We recently reported that immunization of A/J mice with an 18-amino-acid synthetic linear peptide from Plasmodium yoelii sporozoite surface protein 2 (SSP2) in TiterMax adjuvant induces sterile protection that is dependent on CD4 + T cells and gamma interferon (IFN-γ). We now report that immunization of inbred A/J mice and outbred CD1 mice with each of two linear synthetic peptides from the 17-kDa P. yoelii hepatocyte erythrocyte protein (HEP17) in the same adjuvant also induces protection against sporozoite challenge that is dependent on CD4 + T cells and IFN-γ. The SSP2 peptide and the two HEP17 peptides are recognized by B cells as well as T cells, and the protection induced by these peptides appears to be directed against the infected hepatocytes. In contrast to the peptide-induced protection, immunization of eight different strains of mice with radiation-attenuated sporozoites induces protection that is absolutely dependent on CD8 + T cells. Data represented here demonstrate that CD4 + T-cell-dependent protection can be induced by immunization with linear synthetic peptides. These studies therefore provide the foundation for an approach to pre-erythrocytic-stage malaria vaccine development, based on the induction of protective CD4 + T-cell responses, which will complement efforts to induce protective antibody and CD8 + T-cell responses.
ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries
Publisher: Springer Science and Business Media LLC
Date: 20-03-2020
DOI: 10.1038/S41398-020-0705-1
Abstract: This review summarizes the last decade of work by the ENIGMA ( E nhancing N euro I maging G enetics through M eta A nalysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has ersified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across erse s les and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
Hydrothermally prepared reduced graphene oxide free standing film as high current field emitter
Publisher: IEEE
Date: 04-2019
The development of a multivalent DNA vaccine for malaria
Publisher: Springer Science and Business Media LLC
Date: 06-1997
DOI: 10.1007/BF00870265
Validation of an Epstein-Barr Virus Antibody Risk Stratification Signature for Nasopharyngeal Carcinoma by Use of Multiplex Serology
Publisher: American Society for Microbiology
Date: 23-04-2020
DOI: 10.1128/JCM.00077-20
Abstract: Serological testing for nasopharyngeal carcinoma (NPC) has recently been reinvigorated by the implementation of novel Epstein-Barr virus (EBV)-specific IgA and IgG antibodies from a proteome array. Although proteome arrays are well suited for comprehensive antigen selection, they are not applicable for large-scale studies. We adapted a 13-marker EBV antigen signature for NPC risk identified by proteome arrays to multiplex serology to establish an assay for large-scale studies. Taiwanese NPC cases ( n = 175) and matched controls ( n = 175) were used for assay validation.
Subcutaneous cholera toxin exposure induces potent CD103⁺ dermal dendritic cell activation and migration.
Publisher: Wiley
Date: 09-2013
Abstract: CD103⁺ dermal dendritic cells (dDCs) are a recently described DC subset of the skin shown to be the principal migratory DCs capable of efficiently cross-presenting antigens and activating CD8⁺ T cells. Harnessing their activity would promote vaccine efficacy, but it has been unclear how this can be achieved. We tested a panel of adjuvants for their ability to affect dDCs. In comparison to the other adjuvants tested, the capacity of cholera toxin (CT) to induce the migration of dDCs was unique. Within 24 h of CT injection, large numbers of highly activated dDCs (including CD103⁺ dDCs) migrated to the draining lymph nodes and cross-presented coinjected antigens, potently activating naïve CD8⁺ T cells. Peptide vaccines adjuvanted with CT induced T-cell responses uniquely characterized by dynamic cytokine responses including the production of IL-2, and such vaccines were protective in situations reliant on CD8⁺ T-cell responses, including liver-stage Plasmodium challenge, or tumor challenge. This study is the first to examine the effects of adjuvants on CD103⁺ dDCs and identifies CT as a prototypical adjuvant for the activation of CD103⁺ dDCs, opening the way to development of vaccines and adjuvants that specifically target dDCs and generate effective CD8⁺ T-cell responses.
Malaria research in Australia: looking through the lens of the past towards the future
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.IJPARA.2021.11.005
Abstract: Malaria remains a global health priority, with substantial resources devoted to control and intervention since the causative parasite was first identified in 1880. Major advances have been made in discovery and translational research activities aimed at prevention, treatment and control. Laboratory-based, clinical, and field-based studies have complemented public health approaches. Australian scientists have played important roles, developing and applying innovative approaches, novel research tools and cutting-edge technologies in animal and human models of disease, as well as in disease-endemic settings. This article will provide an insight into 50 years of Australian efforts to discover mechanisms and targets of immunity and pathogenesis develop new diagnostics, drugs, vaccines, and therapeutics and assess new public health interventions and control measures in malaria-endemic settings.
Induction of Antigen-Specific Cytotoxic T Lymphocytes in Humans by a Malaria DNA Vaccine
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-10-1998
DOI: 10.1126/SCIENCE.282.5388.476
Abstract: CD8 + cytotoxic T lymphocytes (CTLs) are critical for protection against intracellular pathogens but often have been difficult to induce by subunit vaccines in animals. DNA vaccines elicit protective CD8 + T cell responses. Malaria-naı̈ve volunteers who were vaccinated with plasmid DNA encoding a malaria protein developed antigen-specific, genetically restricted, CD8 + T cell–dependent CTLs. Responses were directed against all 10 peptides tested and were restricted by six human lymphocyte antigen (HLA) class I alleles. This first demonstration in healthy naı̈ve humans of the induction of CD8 + CTLs by DNA vaccines, including CTLs that were restricted by multiple HLA alleles in the same in idual, provides a foundation for further human testing of this potentially revolutionary vaccine technology.
Malaria's journey through the lymph node
Publisher: Springer Science and Business Media LLC
Date: 09-2007
DOI: 10.1038/NM0907-1023
Of Monkeys and Men: Immunomic Profiling of Sera from Humans and Non-Human Primates Resistant to Schistosomiasis Reveals Novel Potential Vaccine Candidates
Publisher: Frontiers Media SA
Date: 05-05-2015
Profoundly Reduced CD1c + Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria
Publisher: American Society for Microbiology
Date: 05-2016
DOI: 10.1128/IAI.01522-15
Abstract: Dendritic cells (DCs) are sentinels of the immune system that uniquely prime naive cells and initiate adaptive immune responses. CD1c (BDCA-1) myeloid DCs (CD1c + mDCs) highly express HLA-DR, have a broad Toll-like receptor (TLR) repertoire, and secrete immune modulatory cytokines. To better understand immune responses to malaria, CD1c + mDC maturation and cytokine production were examined in healthy volunteers before and after experimental intravenous Plasmodium falciparum infection with 150- or 1,800-parasite-infected red blood cells (pRBCs). After either dose, CD1c + mDCs significantly reduced HLA-DR expression in prepatent infections. Circulating CD1c + mDCs did not upregulate HLA-DR after pRBC or TLR ligand stimulation and exhibited reduced CD86 expression. At peak parasitemia, CD1c + mDCs produced significantly more tumor necrosis factor (TNF), whereas interleukin-12 (IL-12) production was unchanged. Interestingly, only the 1,800-pRBC dose caused a reduction in the circulating CD1c + mDC count with evidence of apoptosis. The 1,800-pRBC dose produced no change in T cell IFN-γ or IL-2 production at peak parasitemia or at 3 weeks posttreatment. Overall, CD1c + mDCs are compromised by P. falciparum exposure, with impaired HLA-DR and CD86 expression, and have an increased capacity for TNF but not IL-12 production. A first prepatent P. falciparum infection is sufficient to modulate CD1c + mDC responsiveness, likely contributing to h ered effector T cell cytokine responses and assisting parasite immune evasion.
Anomalies in T Cell Function Are Associated With Individuals at Risk of Mycobacterium abscessus Complex Infection
Publisher: Frontiers Media SA
Date: 11-06-2018
Dichotomous miR expression and immune responses following primary blood- stage malaria
Publisher: American Society for Clinical Investigation
Date: 03-08-2017
The Stability and Complexity of Antibody Responses to the Major Surface Antigen of Plasmodium falciparum Are Associated with Age in a Malaria Endemic Area
Publisher: Elsevier BV
Date: 11-2011
Antibody signatures reflect different disease pathologies in patients with schistosomiasis due to schistosoma japonicum
Publisher: Oxford University Press (OUP)
Date: 06-07-2016
Abstract: Infection with Schistosoma japonicum causes high levels of pathology that is predominantly determined by the cellular and humoral response of the host. However, the specific antibody response that arises during the development of disease is largely undescribed in Asian schistosomiasis-endemic populations. A schistosome protein microarray was used to compare the antibody profiles of subjects with acute infection, with early or advanced disease associated with severe pathology, with chronic infection, and subjects exposed but stool negative for S. japonicum eggs to the antibody profiles of nonexposed controls. Twenty-five immunodominant antigens were identified, including vaccine candidates, tetraspanin-related proteins, transporter molecules, and unannotated proteins. Additionally, in iduals with severe pathology had a limited specific antibody response, suggesting that in iduals with mild disease may use a broad and strong antibody response, particularly against surface-exposed proteins, to control pathology and/or infection. Our study has identified specific antigens that can discriminate between S. japonicum-exposed groups with different pathologies and may also allow the host to control disease pathology and provide resistance to parasite infection.
Geographically restricted heterogeneity of the Plasmodium falciparum circumsporozoite protein: relevance for vaccine development
Publisher: American Society for Microbiology
Date: 02-1992
DOI: 10.1128/IAI.60.2.675-682.1992
Abstract: The design of a subunit vaccine against the malaria parasite relies on the epitopes recognized by T cells being identified and polymorphisms therein being defined. Here we present the analysis of a 354-bp fragment of the circumsporozoite (CS) protein encompassing defined proliferative and cytotoxic T-cell recognition regions. We reveal that the polymorphism of CS protein T-cell sites appears to be very limited among Plasmodium falciparum isolates prevalent in certain geographical regions, in particular Papua New Guinea. Furthermore, the more extensive polymorphism noted in other areas appears to be restricted. Although the extent of variation observed for the T-cell recognition domains suggests that any vaccine designed to stimulate this form of immunity will need to be polyvalent, this variation appears to be finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways to increase immune responsiveness can be found, then a vaccine designed to stimulate CS protein-specific T-cell activity may prevent malaria.
A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray
Publisher: Proceedings of the National Academy of Sciences
Date: 29-03-2010
Abstract: Abs are central to malaria immunity, which is only acquired after years of exposure to Plasmodium falciparum ( Pf ). Despite the enormous worldwide burden of malaria, the targets of protective Abs and the basis of their inefficient acquisition are unknown. Addressing these knowledge gaps could accelerate malaria vaccine development. To this end, we developed a protein microarray containing ∼23% of the Pf 5,400-protein proteome and used this array to probe plasma from 220 in iduals between the ages of 2–10 years and 18–25 years in Mali before and after the 6-month malaria season. Episodes of malaria were detected by passive surveillance over the 8-month study period. Ab reactivity to Pf proteins rose dramatically in children during the malaria season however, most of this response appeared to be short-lived based on cross-sectional analysis before the malaria season, which revealed only modest incremental increases in Ab reactivity with age. Ab reactivities to 49 Pf proteins measured before the malaria season were significantly higher in 8–10-year-old children who were infected with Pf during the malaria season but did not experience malaria ( n = 12) vs. those who experienced malaria ( n = 29). This analysis also provided insight into patterns of Ab reactivity against Pf proteins based on the life cycle stage at which proteins are expressed, subcellular location, and other proteomic features. This approach, if validated in larger studies and in other epidemiological settings, could prove to be a useful strategy for better understanding fundamental properties of the human immune response to Pf and for identifying previously undescribed vaccine targets.
Polyfunctional and IFN-gamma monofunctional human CD4(+) T cell populations are molecularly distinct
Publisher: American Society for Clinical Investigation
Date: 09-02-2017
The Role of Age and Exposure to Plasmodium falciparum in the Rate of Acquisition of Naturally Acquired Immunity: A Randomized Controlled Trial
Publisher: Public Library of Science (PLoS)
Date: 07-03-2012
High Precursor Frequency and Promiscuity in Αβ T Cell Receptor Pairing Underpin CD8+ T-Cell Responses to an Immunodominant SARS-CoV-2 Nucleocapsid Epitope
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3751796
DNA Vaccines against Malaria: Immunogenicity and Protection in a Rodent Model
Publisher: American Geophysical Union (AGU)
Date: 12-1996
DOI: 10.1021/JS960147H
A Balanced Proinflammatory and Regulatory Cytokine Signature in Young African Children Is Associated With Lower Risk of Clinical Malaria
Publisher: Oxford University Press (OUP)
Date: 31-10-2018
DOI: 10.1093/CID/CIY934
Abstract: The effect of timing of exposure to first Plasmodium falciparum infections during early childhood on the induction of innate and adaptive cytokine responses and their contribution to the development of clinical malaria immunity is not well established. As part of a double-blind, randomized, placebo-controlled trial in Mozambique using monthly chemoprophylaxis with sulfadoxine-pyrimethamine plus artesunate to selectively control timing of malaria exposure during infancy, peripheral blood mononuclear cells collected from participants at age 2.5, 5.5, 10.5, 15, and 24 months were stimulated ex vivo with parasite schizont and erythrocyte lysates. Cytokine messenger RNA expressed in cell pellets and proteins secreted in supernatants were quantified by reverse-transcription quantitative polymerase chain reaction and multiplex flow cytometry, respectively. Children were followed up for clinical malaria from birth until 4 years of age. Higher proinflammatory (interleukin [IL] 1, IL-6, tumor necrosis factor) and regulatory (IL-10) cytokine concentrations during the second year of life were associated with reduced incidence of clinical malaria up to 4 years of age, adjusting by chemoprophylaxis and prior malaria exposure. Significantly lower concentrations of antigen-specific T-helper 1 (IL-2, IL-12, interferon-γ) and T-helper 2 (IL-4, IL-5) cytokines by 2 years of age were measured in children undergoing chemoprophylaxis compared to children receiving placebo (P & .03). Selective chemoprophylaxis altering early natural exposure to malaria blood stage antigens during infancy had a significant effect on T-helper lymphocyte cytokine production & year later. Importantly, a balanced proinflammatory and anti-inflammatory cytokine signature, probably by innate cells, around age 2 years was associated with protective clinical immunity during childhood. NCT00231452.
Interleukin-12- and Gamma Interferon-Dependent Protection against Malaria Conferred by CpG Oligodeoxynucleotide in Mice
Publisher: American Society for Microbiology
Date: 09-2002
Genome-based vaccine design: the promise for malaria and other infectious diseases
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.IJPARA.2014.07.010
Abstract: Vaccines are one of the most effective interventions to improve public health, however, the generation of highly effective vaccines for many diseases has remained difficult. Three chronic diseases that characterise these difficulties include malaria, tuberculosis and HIV, and they alone account for half of the global infectious disease burden. The whole organism vaccine approach pioneered by Jenner in 1796 and refined by Pasteur in 1857 with the "isolate, inactivate and inject" paradigm has proved highly successful for many viral and bacterial pathogens causing acute disease but has failed with respect to malaria, tuberculosis and HIV as well as many other diseases. A significant advance of the past decade has been the elucidation of the genomes, proteomes and transcriptomes of many pathogens. This information provides the foundation for new 21st Century approaches to identify target antigens for the development of vaccines, drugs and diagnostic tests. Innovative genome-based vaccine strategies have shown potential for a number of challenging pathogens, including malaria. We advocate that genome-based rational vaccine design will overcome the problem of poorly immunogenic, poorly protective vaccines that has plagued vaccine developers for many years.
Supplementary Methods S1 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22725002
Abstract: Supplementary Methods S1 expands upon data and statistical methods.
Modification of Ad5 Hexon Hypervariable Regions Circumvents Pre-Existing Ad5 Neutralizing Antibodies and Induces Protective Immune Responses
Publisher: Public Library of Science (PLoS)
Date: 05-04-2012
A Small Peptide (CEL-1000) Derived from the β-Chain of the Human Major Histocompatibility Complex Class II Molecule Induces Complete Protection against Malaria in an Antigen-Independent Manner
Publisher: American Society for Microbiology
Date: 07-1970
DOI: 10.1128/AAC.48.7.2455-2463.2004
Abstract: CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J ( H - 2 a ) and C3H/HeJ ( H - 2 k ) mice but not in BALB/c ( H - 2 d ) or CAF1 (A/J × BALB/c F 1 hybrid) mice. In CEL-1000-treated and protected mice, high levels of gamma interferon (IFN-γ) in serum and elevated frequencies of hepatic and splenic CD4 + IFN-γ-positive T cells were detected 24 h after administration of an additional dose of CEL-1000. Treatment of A/J mice that received CEL-1000 with antibodies against IFN-γ just prior to challenge abolished the protection, and a similar treatment with antibodies against CD4 + T cells partially reduced the level of protection, while treatment with control antibodies or antibodies specific for interleukin-12 (IL-12), CD8 + T cells, or NK cells had no effect. Our data establish that the protection induced by CEL-1000 is dependent on IFN-γ and is partially dependent on CD4 + T cells but is independent of CD8 + T cells, NK cells, and IL-12 at the effector phase and does not induce a detectable antibody response.
Expression of the chemokine MIG is a sensitive and predictive marker for antigen-specific, genetically restricted IFN-γ production and IFN-γ-secreting cells
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1016/S0022-1759(01)00446-X
Abstract: The evaluation of antigen-specific immune responses is critical for understanding the mechanisms of immune protection and for establishing the efficacy of candidate vaccines. Here, we describe a novel assay for IFN-gamma activity which is based on the flow cytometric detection of the chemokine, monokine induced by gamma interferon (MIG) as a sensitive and predictive measure of IFN-gamma-mediated effector function, and a surrogate marker for IFN-gamma-producing cells. Upregulation of MIG expression was demonstrated following in vitro activation of peripheral blood mononuclear cells (PBMCs) with defined CD8+ T-cell epitopes derived from influenza virus, cytomegalovirus (CMV), or Epstein-Barr virus (EBV) and was antigen-specific, genetically restricted and dependent on both CD8+ T cells and IFN-gamma. Furthermore, antigen-specific MIG expression was also demonstrated with Plasmodium falciparum circumsporozoite protein (CSP) peptides, using PBMCs from volunteers immunized with irradiated P. falciparum sporozoites. In multiple parallel experiments, the MIG assay was compared to conventional IFN-gamma ELISPOT, IFN-gamma ELISA, MIG ELISA and intracellular cytokine staining assays. The level of MIG expression was shown to be directly associated with the number of IFN-gamma spot-forming cells (SFCs) detected by ELISPOT (r2=0.94). Moreover, in all instances where cultures were considered positive by ELISPOT, a higher stimulation index was noted with the MIG assay as compared with the ELISPOT assay (on average at least threefold higher) and, in some cases, responses as detected by the MIG assay were significant, but the corresponding response as measured by ELISPOT was not significant. Finally, the flow-based MIG assay offers a number of practical and technical advantages over the ELISPOT assay. Our data validate this novel method for the detection of low as well as high levels of antigen-specific and genetically restricted IFN-gamma activity.
Identification of Cytauxzoon felis antigens via protein microarray and assessment of expression library immunization against cytauxzoonosis
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Location of human cytotoxic T cell epitopes within a polymorphic domain of the Plasmodium falciparum circumsporozoite protein
Publisher: Oxford University Press (OUP)
Date: 1991
Abstract: Studies in mice have shown that cytotoxic T lymphocytes (CTL) specific for epitopes within the circumsporozoite (CS) protein of malaria sporozoites can prevent malaria probably by destroying infected hepatocytes. This has provided a model for the development of a sporozoite vaccine. It has not been shown whether humans can mount a CTL response to this protein nor what determinants on the protein could be considered as target epitopes for such cells and thus merit inclusion in a sporozoite vaccine. We have used a novel technique to study a caucasian population which would benefit from a sporozoite vaccine and have been able to demonstrate that some in iduals with a history of sporozoite exposure do contain peripheral blood CTL specific for the Plasmodium falciparum CS protein. The prevalence of CTL among different in iduals is low and there is evidence that recent malaria exposure may be a prerequisite for finding such CTL. In three in iduals, CTL could be repeatedly found and in all cases the epitopes mapped to one of the two polymorphic C-terminal domains. Using a CTL line, we mapped a recognition site to residues 351-395 of the CS protein, overlapping the region of the protein recognized by murine CTL.
Supplementary Table S3 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22724993.V1
Abstract: Supplementary Table S3 shows positivity rates of the 46 in idual markers among cases and controls in each study
A Plasmodium vivax Plasmid DNA- and Adenovirus-Vectored Malaria Vaccine Encoding Blood-Stage Antigens AMA1 and MSP1 42 in a Prime/Boost Heterologous Immunization Reg
Publisher: American Society for Microbiology
Date: 04-2017
DOI: 10.1128/CVI.00539-16
Abstract: Malaria is caused by parasites of the genus Plasmodium , which are transmitted to humans by the bites of Anopheles mosquitoes. After the elimination of Plasmodium falciparum , it is predicted that Plasmodium vivax will remain an important cause of morbidity and mortality outside Africa, stressing the importance of developing a vaccine against P. vivax malaria. In this study, we assessed the immunogenicity and protective efficacy of two P. vivax antigens, apical membrane antigen 1 (AMA1) and the 42-kDa C-terminal fragment of merozoite surface protein 1 (MSP1 42 ) in a plasmid recombinant DNA prime/adenoviral (Ad) vector boost regimen in Aotus monkeys. Groups of 4 to 5 monkeys were immunized with plasmid DNA alone, Ad alone, prime/boost regimens with each antigen, prime/boost regimens with both antigens, and empty vector controls and then subjected to blood-stage challenge. The heterologous immunization regimen with the antigen pair was more protective than either antigen alone or both antigens delivered with a single vaccine platform, on the basis of their ability to induce the longest prepatent period and the longest time to the peak level of parasitemia, the lowest peak and mean levels of parasitemia, the smallest area under the parasitemia curve, and the highest self-cure rate. Overall, prechallenge MSP1 42 antibody titers strongly correlated with a decreased parasite burden. Nevertheless, a significant proportion of immunized animals developed anemia. In conclusion, the P. vivax plasmid DNA/Ad serotype 5 vaccine encoding blood-stage parasite antigens AMA1 and MSP1 42 in a heterologous prime/boost immunization regimen provided significant protection against blood-stage challenge in Aotus monkeys, indicating the suitability of these antigens and this regimen for further development.
Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component
Publisher: Public Library of Science (PLoS)
Date: 07-10-2011
Enhancement of antibody and cellular immune responses to malaria DNA vaccines by in vivo electroporation
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.VACCINE.2007.06.036
Abstract: We evaluated the effectiveness of in vivo electroporation (EP) for the enhancement of immune responses induced by DNA plasmids encoding the pre-erythrocytic Plasmodium yoelii antigens PyCSP and PyHEP17 administered intramuscularly and intradermally to mice. EP resulted in a 16- and 2-fold enhancement of antibody responses to PyCSP and PyHEP17, respectively. Immunization with 5 microg of DNA via EP was equivalent to 50 microg of DNA via conventional needle, thus reducing by 10-fold the required dose to produce a given effect. Moreover, IFN-gamma responses were increased by approximately 2-fold. Data demonstrate the potential of EP to enhance immune responses to DNA vaccines against infectious agents.
Distinct systems serology features in children, elderly and COVID patients
Publisher: Cold Spring Harbor Laboratory
Date: 18-05-2020
DOI: 10.1101/2020.05.11.20098459
Abstract: SARS-CoV-2, the pandemic coronavirus that causes COVID-19, has infected millions worldwide, causing unparalleled social and economic disruptions. COVID-19 results in higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive coronavirus immunological responses, induced by circulating human coronaviruses, is critical to understand such ergent clinical outcomes. The cross-reactivity of coronavirus antibody responses of healthy children (n=89), adults (n=98), elderly (n=57), and COVID-19 patients (n=19) were analysed by systems serology. While moderate levels of cross-reactive SARS-CoV-2 IgG, IgM, and IgA were detected in healthy in iduals, we identified serological signatures associated with SARS-CoV-2 antigen-specific Fcγ receptor binding, which accurately distinguished COVID-19 patients from healthy in iduals and suggested that SARS-CoV-2 induces qualitative changes to antibody Fc upon infection, enhancing Fcγ receptor engagement. Vastly different serological signatures were observed between healthy children and elderly, with markedly higher cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas children displayed elevated SARS-CoV-2 IgM, including receptor binding domain-specific IgM with higher avidity. These results suggest that less-experienced humoral immunity associated with higher IgM, as observed in children, may have the potential to induce more potent antibodies upon SARS-CoV-2 infection. These key insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.
Class I HLA-restricted cytotoxic T lymphocyte responses against malaria-elucidation on the basis of HLA peptide binding motifs
Publisher: Springer Science and Business Media LLC
Date: 12-1996
DOI: 10.1007/BF02935313
Abstract: In developing countries, the long delays in consultation lead to a delay in diagnosis and management of the skin tumors. The lesions are often large and bring the problem of skin coverage after their resections. Several reconstruction techniques allow skin coverage. The objective of this study is to describe the place of O-to-Z technique in the surgical treatment of skin cancers in Ouagadougou. We hypothesized that O-to-Z technique reduces healing times and the number of dressings compared with directed wound healing. It was a two-center, retrospective, descriptive study on O-to-Z technique in skin cancers. It included patients who underwent surgery between January 1st, 2013 and March 30th, 2021 in Ouagadougou. Scar quality and healing time in Z-plasty were compared with those of secondary healing. We used the Student's t test. In 8 years and 3 months, 171 skin cancers were identified. The mean time to consultation was 13.6 months. The average size of the tumors was 9 cm. An O-to-Z technique was performed in 42 cases, being 58.3% of the patients operated on. The average healing time was 15 days. It was four and a half times shorter in O-to-Z technique than in secondary healing. Ischemic necrosis of the Z-corner was noted in 7 cases. The recurrence rate in O-to-Z technique and secondary healing was 7.1% and 9.1% respectively. Hypertrophic or keloidal scars were noticed in 7 cases and hypochromia in 2 cases. O-to-Z technique is a technique of choice for skin coverage after large resections in surgical oncology. It reduces the healing time and the cost of postoperative care without increasing the risk of tumor recurrence.
IgM in human immunity to Plasmodium falciparum malaria
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2019
Abstract: IgM is an important and long-lived component of anti-malarial immunity in humans and blocks infection of red blood cells.
Meet the fellows: Everything about ISV
Publisher: Informa UK Limited
Date: 19-07-2022
The US Capitol Bioterrorism Anthrax Exposures: Clinical Epidemiological and Immunological Characteristics
Publisher: Oxford University Press (OUP)
Date: 15-01-2007
DOI: 10.1086/510312
Abstract: Bioterrorism-related anthrax exposures occurred at the US Capitol in 2001. Exposed in iduals received antibiotics and anthrax vaccine adsorbed immunization. A prospective longitudinal study of 124 subjects--stratified on the basis of spore exposure, nasopharyngeal culture results, and immunization status from inside and outside an epidemiologically defined exposure zone--was performed to describe clinical outcome and immune responses after Bacillus anthracis exposure. Antibody and cell-mediated immune (CMI) responses to protective antigen (PA) and lethal factor were assayed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting. Antibody and CMI dose-exposure responses, albeit generally of low magnitude, were seen for unimmunized subjects from inside, within the perimeter, and outside the exposure zone and in nonexposed control subjects. Anti-PA antibody and CMI responses were detected in 94% and 86% of immunized subjects. No associations were seen between symptoms and exposure levels or immune responses. Anthrax spores primed cellular and possibly antibody immune responses in a dose-dependent manner and may have enhanced vaccine boost and recall responses. Immune responses were detected inside the perimeter and outside the exposure zone, which implies more-extensive spore exposure than was predicted. Despite postexposure prophylaxis with antibiotics, inhalation of B. anthracis spores resulted in stimulation of the immune system and possibly subclinical infection, and the greater the exposure, the more complete the immune response. The significance of low-level exposure should not be underestimated.
Correction: Modification of Ad5 Hexon Hypervariable Regions Circumvents Pre-Existing Ad5 Neutralizing Antibodies and Induces Protective Immune Responses
Publisher: Public Library of Science (PLoS)
Date: 04-05-2012
DOI: 10.1371/ANNOTATION/C110BEED-3CAC-48DB-9039-BA4498D5DB50
Induction of multi-antigen multi-stage immune responses against Plasmodium falciparum in rhesus monkeys, in the absence of antigen interference, with heterologous DNA prime/poxvirus boost immunization
Publisher: Springer Science and Business Media LLC
Date: 09-10-2007
Abstract: The present study has evaluated the immunogenicity of single or multiple Plasmodium falciparum (Pf) antigens administered in a DNA prime oxvirus boost regimen with or without the poloxamer CRL1005 in rhesus monkeys. Animals were primed with Pf CSP plasmid DNA or a mixture of Pf CSP, Pf SSP2/TRAP, Pf LSA1, Pf AMA1 and Pf MSP1-42 (CSLAM) DNA vaccines in PBS or formulated with CRL1005, and subsequently boosted with ALVAC- Pf 7, a canarypox virus expressing the CSLAM antigens. Cell-mediated immune responses were evaluated by IFN-γ ELIspot and intracellular cytokine staining, using recombinant proteins and overlapping synthetic peptides. Antigen-specific and parasite-specific antibody responses were evaluated by ELISA and IFAT, respectively. Immune responses to all components of the multi-antigen mixture were demonstrated following immunization with either DNA/PBS or DNA/CRL1005, and no antigen interference was observed in animals receiving CSLAM as compared to Pf CSP alone. These data support the down-selection of the CSLAM antigen combination. CRL1005 formulation had no apparent effect on vaccine-induced T cell or antibody responses, either before or after viral boost. In high responder monkeys, CD4+IL-2+ responses were more predominant than CD8+ T cell responses. Furthermore, CD8+ IFN-γ responses were detected only in the presence of detectable CD4+ T cell responses. Overall, this study demonstrates the potential for multivalent Pf vaccines based on rational antigen selection and combination, and suggests that further formulation development to increase the immunogenicity of DNA encoded antigens is warranted.
Immune Response to Pre-Erythrocytic Stages of Malaria Parasites
Publisher: Bentham Science Publishers Ltd.
Date: 03-2006
DOI: 10.2174/156652406776055249
Abstract: Immunization with radiation-attenuated Plasmodium spp. sporozoites induces sterile protective immunity against parasite challenge. This immunity is targeted primarily against the intrahepatic parasite and appears to be sustained long term even in the absence of sporozoite exposure. It is mediated by multifactorial mechanisms, including T cells directed against parasite antigens expressed in the liver stage of the parasite life cycle and antibodies directed against sporozoite surface proteins. In rodent models, CD8+ T cells have been implicated as the principal effector cells, and IFN-gamma as a critical effector molecule. IL-4 secreting CD4+ T cells are required for induction of the CD8+ T cell responses, and Th1 CD4+ T cells provide help for optimal CD8+ T cell effector activity. Components of the innate immune system, including gamma-delta T cells, natural killer cells and natural killer T cells, also play a role. The precise nature of pre-erythrocytic stage immunity in humans, including the contribution of these immune responses to the age-dependent immunity naturally acquired by residents of malaria endemic areas, is still poorly defined. The importance of immune effector targets at the pre-erythrocytic stage of the parasite life cycle is highlighted by the fact that infection-blocking immunity in humans rarely, if ever, occurs under natural conditions. Herein, we review our current understanding of the molecular and cellular aspects of pre-erythrocytic stage immunity.
Highly Sensitive Quantitative Real-Time PCR for the Detection of Plasmodium Liver-Stage Parasite Burden following Low-Dose Sporozoite Challenge
Publisher: Public Library of Science (PLoS)
Date: 02-10-2013
Sterile Protection against Plasmodium knowlesi in Rhesus Monkeys from a Malaria Vaccine: Comparison of Heterologous Prime Boost Strategies
Publisher: Public Library of Science (PLoS)
Date: 10-08-2009
Immunomics: a 21st century approach to vaccine development for complex pathogens
Publisher: Cambridge University Press (CUP)
Date: 07-01-2016
DOI: 10.1017/S0031182015001079
Abstract: Immunomics is a relatively new field of research which integrates the disciplines of immunology, genomics, proteomics, transcriptomics and bioinformatics to characterize the host-pathogen interface. Herein, we discuss how rapid advances in molecular immunology, sophisticated tools and molecular databases are facilitating in-depth exploration of the immunome. In our opinion, an immunomics-based approach presides over traditional antigen and vaccine discovery methods that have proved ineffective for highly complex pathogens such as the causative agents of malaria, tuberculosis and schistosomiasis that have evolved genetic and immunological host-parasite adaptations over time. By using an integrative multidisciplinary approach, immunomics offers enormous potential to advance 21 st century antigen discovery and rational vaccine design against complex pathogens such as the Plasmodium parasite.
Correction: A Novel Candidate Vaccine for Cytauxzoonosis Inferred from Comparative Apicomplexan Genomics
Publisher: Public Library of Science (PLoS)
Date: 23-10-2013
DOI: 10.1371/ANNOTATION/943B121E-343B-4DF1-A06B-7F8A205A057D
Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma
Publisher: Springer Science and Business Media LLC
Date: 08-12-2021
DOI: 10.1038/S41598-021-02788-W
Abstract: Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma s les from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case–control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORs highest vs. lowest tertile 6.0 (Bonferroni-corrected P -values 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.
Induction in Humans of CD8+ and CD4+ T Cell and Antibody Responses by Sequential Immunization with Malaria DNA and Recombinant Protein
Publisher: The American Association of Immunologists
Date: 05-2004
DOI: 10.4049/JIMMUNOL.172.9.5561
Abstract: Vaccine-induced protection against diseases like malaria, AIDS, and cancer may require induction of Ag-specific CD8+ and CD4+ T cell and Ab responses in the same in idual. In humans, a recombinant Plasmodium falciparum circumsporozoite protein (PfCSP) candidate vaccine, RTS,S/adjuvant system number 2A (AS02A), induces T cells and Abs, but no measurable CD8+ T cells by CTL or short-term (ex vivo) IFN-γ ELISPOT assays, and partial short-term protection. P. falciparum DNA vaccines elicit CD8+ T cells by these assays, but no protection. We report that sequential immunization with a PfCSP DNA vaccine and RTS,S/AS02A induced PfCSP-specific Abs and Th1 CD4+ T cells, and CD8+ cytotoxic and Tc1 T cells. Depending upon the immunization regime, CD4+ T cells were involved in both the induction and production phases of PfCSP-specific IFN-γ responses, whereas, CD8+ T cells were involved only in the production phase. IFN-γ mRNA up-regulation was detected in both CD45RA− (CD45RO+) and CD45RA+CD4+ and CD8+ T cell populations after stimulation with PfCSP peptides. This finding suggests CD45RA+ cells function as effector T cells. The induction in humans of the three primary Ag-specific adaptive immune responses establishes a strategy for developing immunization regimens against diseases in desperate need of vaccines.
Efficacy of Smoking Cessation Intervention Among Special Populations
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2006
DOI: 10.1097/00006199-200607001-00005
Abstract: The United States Public Health Service acknowledges in the 2000 Clinical Practice Guideline for Treating Tobacco Use and Dependence that certain special populations have unique needs and considerations in regard to smoking cessation interventions. In a review of the current smoking cessation literature, the following special populations were identified: women older adults gay, lesbian, bisexual, and transgender smokers smokers with psychiatric diagnoses smokers addicted to illicit drugs, alcohol, or both American Indians and Alaska Natives African Americans Hispanics and Asian Americans. Existing smoking cessation research pertaining to these special populations was assessed, and an agenda for future research is proposed in this presentation. The available smoking cessation randomized clinical trials for efficacy and other research relevant to these groups is insufficient. Recent progress has been made in research in the areas of smoking cessation and women smokers with psychiatric diagnoses smokers addicted to illicit drugs, alcohol, or both and African Americans. There is, however, a paucity of research evaluating smoking cessation interventions and older adults gay, lesbian, bisexual, and transgender smokers American Indians and Alaska Natives Hispanics and Asian Americans. Further research relevant to the smoking cessation needs of these special populations can enable nurses and other healthcare providers to administer culturally adequate and efficacious smoking cessation interventions to these groups.
High-throughput multi-parameter flow-cytometric analysis from micro-quantities of Plasmodium-infected blood
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.IJPARA.2011.07.010
Abstract: Despite significant technological and conceptual advances over the last century, evaluation of the efficacy of anti-malarial vaccines or drugs continues to rely principally on direct microscopic visualisation of parasites on thick and/or thin Giemsa-stained blood smears. This requires technical expertise of the microscopist, is highly subjective and error-prone, and does not account for aberrations such as anaemia. Many published methods have shown that flow cytometric analysis of blood is a highly versatile method that can readily detect nucleic acid-stained parasitised red blood cells within cultured cell populations and in ex-vivo s les. However several impediments, including the difficulty in distinguishing reticulocytes from infected red blood cells and the fickle nature of red blood cells, have precluded the development and universal adoption of flow-cytometric based assays for ex-vivo s le analysis. We have developed a novel high-throughput assay for the flow cytometric assessment of blood that overcomes these impediments by utilising the unique properties of the nucleic acid stain DAPI to differentially stain RNA and DNA, combined with novel fixation and analysis protocols. The assay allows the rapid and reliable analysis of multiple parameters from micro-volumes of blood, including: parasitaemia, platelet count, reticulocyte count, normocyte count, white blood cell count and delineation of subsets and phenotypic markers including, but not limited to, CD4(+) and CD8(+) T cells, and the expression of phenotypic markers such as PD-L1 or intracellular cytokines. The assay requires less than one drop of blood and is therefore suitable for short interval time-course experiments and allows the progression of infection and immune responses to be closely monitored in the laboratory or cytometer-equipped field locations. Herein, we describe the technique and demonstrate its application in vaccinology and with a range of rodent and human parasite species including Plasmodium yoelii, Plasmodium chabaudi, Plasmodium berghei and Plasmodium falciparum.
Development and validation of serological markers for detecting recent Plasmodium vivax infection
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Malaria's journey through the lymph node.
Publisher: Springer Science and Business Media LLC
Date: 09-2007
DOI: 10.1038/NM0907-1015
ISV Congress back to Europe
Publisher: Informa UK Limited
Date: 02-09-2018
Chimeric Virus-Like Particles and Capsomeres Induce Similar CD8+ T Cell Responses but Differ in Capacity to Induce CD4+ T Cell Responses and Antibody Responses.
Publisher: Frontiers Media SA
Date: 29-09-2020
Harnessing immune responses against Plasmodium for rational vaccine design
Publisher: Elsevier BV
Date: 06-2011
Abstract: In recent years, groundbreaking advances have been made in understanding the biology of and immune mechanisms against the Plasmodium spp. parasite, the causative agent of malaria. Novel features of the Plasmodium life cycle have been unravelled and immune mechanisms, which take place during both infection and immunization, have been dissected. We have undoubtedly enhanced our knowledge, but the question now is how to use this information to manipulate immune responses against Plasmodium and to develop an efficacious malaria vaccine. In this review, we discuss the latest developments in the field and speculate on how immune responses against Plasmodium could be harnessed for rational vaccine design and application.
Integrated immune dynamics define correlates of COVID-19 severity and antibody responses
Publisher: Elsevier BV
Date: 03-2021
Estimating the global burden of Epstein–Barr virus-related cancers
Publisher: Springer Science and Business Media LLC
Date: 27-10-2022
DOI: 10.1007/S00432-021-03824-Y
Abstract: More than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers. We have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein. We estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.
An Analytically and Diagnostically Sensitive RNA Extraction and RT-qPCR Protocol for Peripheral Blood Mononuclear Cells
Publisher: Frontiers Media SA
Date: 20-03-2020
Suboptimal SARS-CoV-2-specific CD8+ T-cell response associated with the prominent HLA-A*02:01 phenotype
Publisher: Cold Spring Harbor Laboratory
Date: 19-08-2020
DOI: 10.1101/2020.08.17.20176370
Abstract: An improved understanding of human T-cell-mediated immunity in COVID-19 is important if we are to optimize therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8 + T-cell memory to shared peptides presented by common HLA types like HLA-A2. Following re-infection, cross-reactive CD8 + T-cells enhance recovery and diminish clinical severity. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from SARS-CoV-2 Spike, Nucleocapsid and Membrane proteins led to the clonal expansion of SARS-CoV-2-specific CD8 + and CD4 + T-cells in vitro , with CD4 + sets being typically robust. For CD8 + T-cells taken directly ex vivo , we identified two HLA-A*02:01-restricted SARS-CoV-2 epitopes, A2/S 269–277 and A2/Orf1ab 3183–3191 . Using peptide-HLA tetramer enrichment, direct ex vivo assessment of the A2/S 269 + CD8 + and A2/Orf1ab 3183 + CD8 + populations indicated that the more prominent A2/S 269 + CD8 + set was detected at comparable frequency (∼1.3×10 −5 ) in acute and convalescent HLA-A*02:01 + patients. But, while the numbers were higher than those found in uninfected HLA-A*02:01 + donors (∼ 2.5×10 −6 ), they were low when compared with frequencies for influenza-specific (A2/M1 58 ) and EBV-specific (A2/BMLF 1280 ) (∼ 1.38×10 −4 ) populations. Phenotypic analysis ex vivo of A2/S 269 + CD8 + T-cells from COVID-19 convalescents showed that A2/S 269 + CD8 + T-cells were predominantly negative for the CD38, HLA-DR, PD-1 and CD71 activation markers, although the majority of total CD8 + T-cells were granzyme and/or perforin-positive. Furthermore, the bias towards naïve, stem cell memory and central memory A2/S 269 + CD8 + T-cells rather than effector memory populations suggests that SARS-CoV2 infection may be compromising CD8 + T-cell activation. Priming with an appropriate vaccine may thus have great value for optimizing protective CD8 + T-cell immunity in COVID-19.
Type I Interferons Regulate Immune Responses in Humans with Blood-Stage Plasmodium falciparum Infection
Publisher: Elsevier BV
Date: 10-2016
Systems Approaches towards Molecular Profiling of Human Immunity
Publisher: Elsevier BV
Date: 2016
Abstract: Systems immunology integrates cutting-edge technologies with bioinformatics to comprehensively interrogate the immune response to infection at an organismal level. Here, we review studies that have leveraged transcriptomic, genomic, proteomic, and metabolomic approaches towards the identification of cells, molecules, and pathways implicated in host-pathogen interactions. We discuss the potential of single cell technologies for the study of human immune responses and, in this context, we advocate that systems immunology provides a conceptual and methodological framework to harness these approaches to address longstanding questions of fundamental and applied immunology. Recognizing that the field is still in its infancy, we also discuss current limitations of systems immunology, as well as the need for validation of key findings for the discipline to fulfill its promise.
Evaluation of the antibody response to the EBV proteome in EBV‐associated classical Hodgkin lymphoma
Publisher: Wiley
Date: 14-11-2019
DOI: 10.1002/IJC.32741
Abstract: The humoral immune response to Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratios
Nucleic Acid Malaria Vaccines
Publisher: Wiley
Date: 11-1995
Editorial
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2012
Mutating the anchor residues associated with MHC binding inhibits and deviates CD8+ T cell mediated protective immunity against malaria
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.MOLIMM.2006.11.003
Abstract: We investigated whether immune responses induced by immunization with plasmid DNA are restricted predominantly to immunodominant CD8+ T cell epitopes, or are raised against a breadth of epitopes including subdominant CD8+ and CD4+ T cell epitopes. Site-directed mutagenesis was used to change one or more primary anchor residues of the immunodominant CD8+ T cell epitope on the Plasmodium yoelii circumsporozoite protein, and in vivo protective efficacy and immune responses against defined PyCSP CD8+ and/or CD4+ epitopes were determined. Mutation of the P2 but not P9 or P10 anchor residues decreased protection and completely abrogated the antigen-specific CD8+ CTL activity and CD8+ dependent IFN-gamma responses to the immunodominant CD8+ epitope and overlapping CD8+/CD4+ epitope. Moreover, mutation deviated the immune response towards a CD4+ T cell IFN-gamma dependent profile, with enhanced lymphoproliferative responses to the immunodominant and subdominant CD4+ epitopes and enhanced antibody responses. Responses to the subdominant CD8+ epitope were not induced. Our data demonstrate that protective immunity induced by PyCSP DNA vaccination is directed predominantly against the single immunodominant CD8+ epitope, and that although responses can be induced against other epitopes, these are mediated by CD4+ T cells and are not capable of conferring optimal protection against challenge.
Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenin
Publisher: American Society for Microbiology
Date: 06-2017
DOI: 10.1128/IAI.00986-16
Abstract: Plasmodium vivax malaria remains a major public health problem. The requirements for acquisition of protective immunity to the species are not clear. Dendritic cells (DC) are essential for immune cell priming but also perform immune regulatory functions, along with regulatory T cells (Treg). An important function of DC involves activation of the kynurenine pathway via indoleamine 2,3-dioxygenase (IDO). Using a controlled human experimental infection study with blood-stage P. vivax , we characterized plasmacytoid DC (pDC) and myeloid DC (mDC) subset maturation, CD4 + CD25 + CD127 lo Treg activation, and IDO activity. Blood s les were collected from six healthy adults preinoculation, at peak parasitemia (day 14 ∼31,400 parasites/ml), and 24 and 48 h after antimalarial treatment. CD1c + and CD141 + mDC and pDC numbers markedly declined at peak parasitemia, while CD16 + mDC numbers appeared less affected. HLA-DR expression was selectively reduced on CD1c + mDC, increased on CD16 + mDC, and was unaltered on pDC. Plasma IFN-γ increased significantly and was correlated with an increased kynurenine/tryptophan (KT) ratio, a measure of IDO activity. At peak parasitemia, Treg presented an activated CD4 + CD25 + CD127 lo CD45RA − phenotype and upregulated TNFR2 expression. In a mixed-effects model, the KT ratio was positively associated with an increase in activated Treg. Our data demonstrate that a primary P. vivax infection exerts immune modulatory effects by impairing HLA-DR expression on CD1c + mDC while activating CD16 + mDC. Induction of the kynurenine pathway and increased Treg activation, together with skewed mDC maturation, suggest P. vivax promotes an immunosuppressive environment, likely impairing the development of a protective host immune response.
Plasmodium: Mammalian codon optimization of malaria plasmid DNA vaccines enhances antibody responses but not T cell responses nor protective immunity
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.EXPPARA.2009.02.010
Abstract: We have evaluated the effect of mammalian codon optimization on the immunogenicity and protective efficacy of plasmid DNA vaccines encoding pre-erythrocytic stage Plasmodium falciparum and Plasmodium yoelii antigens in mice. Codon optimization significantly enhanced in vitro expression and in vivo antibody responses for P. falciparum circumsporozoite protein (PfCSP) and P. yoelii hepatocyte erythrocyte protein 17 kDa (PyHEP17) but not for P. yoelii circumsporozoite protein (PyCSP). Unexpectedly, more robust CD4+ and CD8+ T cell responses as measured by IFN-gamma ELIspot, lymphoproliferation, and cytotoxic T lymphocyte assays were noted with native as compared with codon optimization constructs. Codon optimization also failed to enhance CD8+ T cell dependent protection against P. yoelii sporozoite challenge as measured by liver-stage parasite burden. These data demonstrate that the effect of mammalian codon optimization is antigen-dependent and may not be beneficial for vaccines designed to induce T cell dependent protective immunity in this malaria model.
Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus.
Publisher: Rockefeller University Press
Date: 12-1994
Abstract: To examine T cell receptor (TCR) ersity involved in the memory response to a persistent human pathogen, we determined nucleotide sequences encoding TCR-alpha and -beta chains from HLA-B8-restricted, CD8+ cytotoxic T cell clones specific for an immunodominant epitope (FLRGRAYGL) in Epstein-Barr virus (EBV) nuclear antigen 3. Herein, we show that identical TCR protein sequences are used by clones from each of four healthy unrelated virus carriers a clone from a fifth varied conservatively at only two residues. This dominant selection of alpha and beta chain rearrangements suggest that a persistent viral infection can select for a highly focused memory response and indicates a strong bias in gene segment usage and recombination. A novel double-step semiquantitative polymerase chain reaction (PCR) procedure and direct sequencing of lified TCR cDNA from fresh lymphocytes derived from three HLA-B8 in iduals detected transcripts specific for the conserved beta chain in an EBV-seropositive donor but not in two seronegative donors. This report describes an unprecedented degree of conservation in TCR selected in response to a natural persistent infection.
Re: Integrated Immune Dynamics Define Correlates of COVID-19 Severity and Antibody Responses
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3701261
Large screen approaches to identify novel malaria vaccine candidates
Publisher: Elsevier BV
Date: 12-2015
Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2018
DOI: 10.1101/481168
Abstract: In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of in iduals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, in iduals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these in iduals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of in iduals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria. The manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.
Meta‐analysis of immune epitope data for all Plasmodia: overview and applications for malarial immunobiology and vaccine‐related issues
Publisher: Wiley
Date: 12-01-2009
A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2021
DOI: 10.1101/2021.04.12.21255368
Abstract: As vaccines against SARS-CoV-2 are now being rolled out, a better understanding of immunity to the virus whether through infection, or passive or active immunisation, and the durability of this protection is required. This will benefit from the ability to measure SARS-CoV-2 immunity, ideally with rapid turnaround and without the need for laboratory-based testing. Current rapid point-of-care (POC) tests measure antibodies (Ab) against the SARS-CoV-2 virus, however, these tests provide no information on whether the antibodies can neutralise virus infectivity and are potentially protective, especially against newly emerging variants of the virus. Neutralising Antibodies (NAb) are emerging as a strong correlate of protection, but most current NAb assays require many hours or days, s les of venous blood, and access to laboratory facilities, which is especially problematic in resource-limited settings. We have developed a lateral flow POC test that can measure levels of RBD-ACE2 neutralising antibodies from whole blood, with a result that can be determined by eye (semi-quantitative) or on a small instrument (quantitative), and results show high correlation with microneutralisation assays. This assay also provides a measure of total anti-RBD antibody, thereby providing evidence of exposure to SARS-CoV-2 or immunisation, regardless of whether NAb are present in the s le. By testing s les from immunised macaques, we demonstrate that this test is equally applicable for use with animal s les, and we show that this assay is readily adaptable to test for immunity to newly emerging SARS-CoV-2 variants. Lastly, using a cohort of vaccinated humans, we demonstrate that our whole-blood test correlates closely with microneutralisation assay data (R 2 =0.75, p .0001), and that fingerprick whole blood s les are sufficient for this test. Accordingly, the COVID-19 NAb-test™ device described here can provide a rapid readout of immunity to SARS-CoV-2 at the point of care.
Association Between Serum MicroRNAs and Abdominal Aortic Aneurysm Diagnosis and Growth
Publisher: Elsevier BV
Date: 04-2023
The Association between the Comprehensive Epstein–Barr Virus Serologic Profile and Endemic Burkitt Lymphoma
Publisher: American Association for Cancer Research (AACR)
Date: 2020
DOI: 10.1158/1055-9965.EPI-19-0551
Abstract: The discovery of Epstein–Barr virus (EBV) in Burkitt lymphoma tumors represented the first link between a virus and cancer in humans, but the underlying role of this virus in endemic Burkitt lymphoma remains unclear. Nearly all children in Burkitt lymphoma–endemic areas are seropositive for EBV, but only a small percentage develop disease. Variation in EBV-directed immunity could be an explanatory cofactor. We examined serum from 150 Burkitt lymphoma cases and 150 controls using a protein microarray that measured IgG and IgA antibodies against 202 sequences across the entire EBV proteome. Variation in the EBV-directed antibody repertoire between Burkitt lymphoma cases and controls was assessed using unpaired t tests. ORs quantifying the association between anti-EBV IgG response tertiles and Burkitt lymphoma status were adjusted for age, sex, and study year. Thirty-three anti-EBV IgG responses were elevated in Burkitt lymphoma cases compared with controls (P ≤ 0.0003). Burkitt lymphoma–associated IgG elevations were strongest for EBV proteins involved in viral replication and antiapoptotic signaling. Specifically, we observed ORs ≥4 for BMRF1 (early antigen), BBLF1 (tegument protein), BHRF1 (Bcl-2 homolog), BZLF1 (Zebra), BILF2 (glycoprotein), BLRF2 [viral capsid antigen (VCA)p23], BDLF4, and BFRF3 (VCAp18). Adjustment for malaria exposure and inheritance of the sickle cell variant did not alter associations. Our data suggest that the anti-EBV serologic profile in patients with Burkitt lymphoma is altered, with strong elevations in 33 of the measured anti-EBV IgG antibodies relative to disease-free children. The Burkitt lymphoma–specific signature included EBV-based markers relevant for viral replication and antiapoptotic activity, providing clues for future Burkitt lymphoma pathogenesis research.
Vaccination with Lipid Core Peptides Fails to Induce Epitope-Specific T Cell Responses but Confers Non-Specific Protective Immunity in a Malaria Model
Publisher: Public Library of Science (PLoS)
Date: 24-08-2012
Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model
Publisher: American Society for Microbiology
Date: 10-2013
DOI: 10.1128/IAI.00544-13
Abstract: Apical membrane antigen 1 (AMA-1) is a leading blood-stage malaria vaccine candidate. Consistent with a key role in erythrocytic invasion, AMA-1-specific antibodies have been implicated in AMA-1-induced protective immunity. AMA-1 is also expressed in sporozoites and in mature liver schizonts where it may be a target of protective cell-mediated immunity. Here, we demonstrate for the first time that immunization with AMA-1 can induce sterile infection-blocking immunity against Plasmodium sporozoite challenge in 80% of immunized mice. Significantly higher levels of gamma interferon (IFN-γ)/interleukin-2 (IL-2)/tumor necrosis factor (TNF) multifunctional T cells were noted in immunized mice than in control mice. We also report the first identification of minimal CD8 + and CD4 + T cell epitopes on Plasmodium yoelii AMA-1. These data establish AMA-1 as a target of both preerythrocytic- and erythrocytic-stage protective immune responses and validate vaccine approaches designed to induce both cellular and humoral immunity.
Toward a Surrogate Marker of Malaria Exposure: Modeling Longitudinal Antibody Measurements under Outbreak Conditions
Publisher: Public Library of Science (PLoS)
Date: 27-07-2011
Degenerate Cytotoxic T Cell Epitopes from P. falciparum Restricted by Multiple HLA-A and HLA-B Supertype Alleles
Publisher: Elsevier BV
Date: 07-1997
DOI: 10.1016/S1074-7613(00)80513-0
Abstract: We recently described human leukocyte antigen (HLA) A2, A3 and B7 supertypes, characterized by largely overlapping peptide-binding specificities and represented in a high percentage of different populations. Here, we identified 17 Plasmodium falciparum peptides capable of binding these supertypes and assessed antigenicity in both vaccinated and naturally exposed populations. Positive cytotoxic T lymphocyte recall and cytokine (interferon-gamma and tumor necrosis factor alpha) responses were detected for all peptides all were recognized in the context of more than one HLA class I molecule and at least 12 of the 17 were recognized in the context of all HLA alleles studied. These data validate the concept of HLA supertypes at the biological level, show that highly degenerate peptides are almost always recognized as epitopes, and demonstrate the feasibility of developing a universally effective vaccine by focusing on a limited number of peptide specificities.
Interleukin-12- and Gamma Interferon-Dependent Protection against Malaria Conferred by CpG Oligodeoxynucleotide in Mice
Publisher: American Society for Microbiology
Date: 03-2001
DOI: 10.1128/IAI.69.3.1643-1649.2001
Abstract: Unmethylated CpG dinucleotides in bacterial DNA or synthetic oligodeoxynucleotides (ODNs) cause B-cell proliferation and immunoglobulin secretion, monocyte cytokine secretion, and activation of natural killer (NK) cell lytic activity and gamma interferon (IFN-γ) secretion in vivo and in vitro. The potent Th1-like immune activation by CpG ODNs suggests a possible utility for enhancing innate immunity against infectious pathogens. We therefore investigated whether the innate immune response could protect against malaria. Treatment of mice with CpG ODN 1826 (TCCATGA CG TTCCTGA CG TT, with the CpG dinucleotides underlined) or 1585 (ggGGTCAA CG TTGAgggggG, with g representing diester linkages and phosphorothioate linkages being to the right of lowercase letters) in the absence of antigen 1 to 2 days prior to challenge with Plasmodium yoelii sporozoites conferred sterile protection against infection. A higher level of protection was consistently induced by CpG ODN 1826 compared with CpG ODN 1585. The protective effects of both CpG ODNs were dependent on interleukin-12, as well as IFN-γ. Moreover, CD8 + T cells (but not CD4 + T cells), NK cells, and nitric oxide were implicated in the CpG ODN 1585-induced protection. These data establish that the protective mechanism induced by administration of CpG ODN 1585 in the absence of parasite antigen is similar in nature to the mechanism induced by immunization with radiation-attenuated P. yoelii sporozoites or with plasmid DNA encoding preerythrocytic-stage P. yoelii antigens. We were unable to confirm whether CD8 + T cells, NK cells, or nitric oxide were required for the CpG ODN 1826-induced protection, but this may reflect differences in the potency of the ODNs rather than a real difference in the mechanism of action of the two ODNs. This is the first report that stimulation of the innate immune system by CpG immunostimulatory motifs can confer sterile protection against malaria.
Plasmodium immunomics
Publisher: Elsevier BV
Date: 2011
In vitro expression and in vivo immunogenicity of Plasmodium falciparum pre-erythrocytic stage DNA vaccines.
Publisher: Spandidos Publications
Date: 07-1998
DOI: 10.3892/IJMM.2.1.29
Abstract: DNA vaccine plasmids were constructed that encoded four pre-erythrocytic antigens from the human malaria parasite Plasmodium falciparum: circumsporozoite protein (PfCSP) sporozoite surface protein 2 (PfSSP2) carboxyl terminus of liver stage antigen 1 (PfLSA-1 c-term) and, exported protein 1 (PfExp-1). Antigen expression was evaluated in vitro by immunoblot analysis of tissue culture cells following transient transfection with each plasmid. Clearly detectable levels of expression depended upon, or were markedly enhanced by, fusion of the antigen encoding sequences in-frame with the initiation complex and peptide leader sequence of human tissue plasminogen activator protein. Mice injected with these plasmids produced antigen specific antibody and cytotoxic T lymphocyte responses. However, the magnitudes of the responses were not always predicted by the in vitro expression assay. The results of this study provided the basis for further testing of these plasmids in primates and the formulation of multi-component pre-erythrocytic DNA vaccines for efficacy testing in human volunteers.
Identification of minimal CD8+ and CD4+ T cell epitopes in the Plasmodium yoelii hepatocyte erythrocyte protein 17kDa
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.MOLIMM.2007.01.001
Abstract: Immunization of mice with subunit vaccines based on the Plasmodium yoelii 17kDa hepatocyte erythrocyte protein (PyHEP17), orthologue of Plasmodium falciparum exported protein 1 (PfExp1), induces antigen-specific immune responses and protects against sporozoite challenge. To aid in the characterization of candidate subunit vaccines based on this antigen, we have mapped the immunodominant and subdominant CD8+ and CD4+ T cell epitopes on PyHEP17. Using a panel of 29 15-mer synthetic peptides representing the complete sequence of PyHEP17 (amino acids 1-153), and overlapping each other by 10 residues, we identified an immunogenic region between amino acids 61-85. To define the minimal CD4+ and CD8+ T cell epitopes within this region, we synthesized 25 9-mer peptides overlapping each other by one residue. We screened the capacity of the 15-mer and 9-mer peptides to be recognized by splenocytes and lymph node cells from mice immunized with PyHEP17 plasmid DNA or peptides in Freund's adjuvant, as assessed by cytokine secretion, lymphoproliferation, and cytotoxicity. The profile of response to the T cell epitopes varied depending upon the immunization regimen. Antigen-specific T cell responses were detected to three 15-mer peptides (residues 61-75, 66-80 and 71-85) representing two 10-mer epitopes mapping to residues 66-75 (LTKNKKSLRK) and 71-80 (KSLRKINVAL). IFN-gamma responses after DNA immunization predominantly mapped to two overlapping 9-mer peptides (residues 73-81 and 74-82) sharing an eight amino acid overlap (residues 74-81, RKINVALA), whereas CTL responses predominantly mapped to four 9-mer peptides (residues 61-69, 70-78, 76-84, and 84-92). In addition, a subdominant 10-mer CD8+ T cell epitope recognized by peptide immunization but not DNA immunization mapped to residues 31-40 (GKYGSQNVIK). The identification of these epitopes will allow the evaluation of delivery systems for malaria vaccine candidates as well as the delineation of protective immune mechanisms.
Supplementary Table S2 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22724996.V1
Abstract: Supplementary Table S2 shows summary of participant characteristics
Extended immunization intervals enhance the immunogenicity and protective efficacy of plasmid DNA vaccines
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.MICINF.2007.07.009
Abstract: Effective vaccines against infectious diseases and biological warfare agents remain an urgent public health priority. Studies have characterized the differentiation of effector and memory T cells and identified a subset of T cells capable of conferring enhanced protective immunity against pathogen challenge. We hypothesized that the kinetics of T cell differentiation influences the immunogenicity and protective efficacy of plasmid DNA vaccines, and tested this hypothesis in the Plasmodium yoelii murine model of malaria. We found that increasing the interval between immunizations significantly enhanced the frequency and magnitude of CD8+ and CD4+ T cell responses as well as protective immunity against sporozoite challenge. Moreover, the interval between immunizations was more important than the total number of immunizations. Immunization interval had a significantly greater impact on T cell responses and protective immunity than on antibody responses. With prolonged immunization intervals, T cell responses induced by homologous DNA only regimens achieved levels similar to those induced by heterologous DNA prime/ virus boost immunization at standard intervals. Our studies establish that the dosing interval significantly impacts the immunogenicity and protective efficacy of plasmid DNA vaccines.
Determining liver stage parasite burden by real time quantitative PCR as a method for evaluating pre-erythrocytic malaria vaccine efficacy
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0166-6851(01)00372-3
Abstract: The detection and quantitation of blood stage parasitaemia is typically used as a surrogate endpoint for estimating the efficacy of vaccines targeted against the hepatic stage, as well as the erythrocytic stage, of the parasite. However, this does not provide an adequate means of evaluating the efficacy of vaccines, which may be only partially effective at the liver-stage. This is a particular concern for effective evaluation of immune enhancement strategies for candidate pre-erythrocytic stage vaccines. Here, we have developed and validated a method for detecting and quantitating liver stage parasites, using the TaqMan fluorescent real-time quantitative PCR system (PE Applied Biosystems). This method uses TaqMan primers designed to the Plasmodium yoelii 18S rRNA gene and rodent GAPDH to lify products from infected mouse liver cDNA. The technique is highly reproducible as demonstrated with plasmid controls and capable of efficiently quantitating liver-stage parasite burden following a range of sporozoite challenge doses in strains of mice, which differ in their susceptibility to sporozoite infection. We have further demonstrated the capacity of this technique to evaluate the efficacy of a range of pre-erythrocytic stage vaccines. Our data establish this quantitative real-time PCR assay to be a fast and reproducible way of accurately assessing liver stage parasite burden and vaccine efficacy in rodent malaria models.
Synthesis and Characterisation of Self‐Assembled and Self‐Adjuvanting Asymmetric Multi‐Epitope Lipopeptides of Ovalbumin
Publisher: Wiley
Date: 14-11-2014
Abstract: Designing a lipopeptide (LP) vaccine with a specific asymmetric arrangement of epitopes may result in an improved display of antigens, increasing host-cell recognition and immunogenicity. This study aimed to synthesise and characterise the physicochemical properties of a library of asymmetric LP-based vaccine candidates that contained multiple CD4(+) and CD8(+) T-cell epitopes from the model protein antigen, ovalbumin. These fully synthetic vaccine candidates were prepared by microwave-assisted solid phase peptide synthesis. The C12 or C16 lipoamino acids were coupled to the N or C terminus of the OVA CD4 peptide epitope. The OVA CD4 LPs and OVA CD8 peptide constructs were then conjugated using azide-alkyne Huisgen cycloaddition to give multivalent synthetic vaccines. Physiochemical characterisation of these vaccines showed a tendency to self-assemble in aqueous media. Changes in lipid length and position induced self-assembly with significant changes to their morphology and secondary structure as shown by transmission electron microscopy and circular dichroism.
Suboptimal SARS-CoV-2−specific CD8 + T cell response associated with the prominent HLA-A*02:01 phenotype
Publisher: Proceedings of the National Academy of Sciences
Date: 10-09-2020
Abstract: As the recall of CD8 + T cell memory promotes rapid recovery in, for ex le, influenza, we investigated circulating SARS-CoV-2−specific CD8 + T cells from COVID-19 patients. For two HLA-A*02:01 SARS-CoV-2−specific CD8 + T cell epitopes, we found that, while ex vivo frequencies of responding T cells were approximately fivefold higher than for pre−COVID-19 s les, they were ∼10-fold lower than for influenza or EBV-specific memory CD8 + T cells. Additionally, SARS-CoV-2−specific CD8 + T cells recovered from convalescent COVID-19 patients had an atypically high prevalence of stem cell memory, central memory, and naïve phenotypes. Might this unexpectedly low prevalence of classical effector memory T cells be a negative consequence of the infectious process that could be avoided by prior priming with an appropriately constituted vaccine?
Malaria DNA vaccines in Aotus monkeys
Publisher: Elsevier BV
Date: 06-1997
DOI: 10.1016/S0264-410X(96)00270-8
Abstract: In preparation for the development of DNA vaccines designed to produce protective antibodies against Plasmodium falciparum antigens (Ag), we conducted studies to optimize antibody responses in Aotus monkeys after immunization with the P. yoelli circumsporozoite (CSP) DNA vaccine. We demonstrate in Aotus monkeys that an intradermal route of immunization with a PyCSP plasmid DNA vaccine generates antibody responses equivalent to a multiple antigen peptide/adjuvant based vaccine, and that these data support the use of the intradermal route for initial studies of the efficacy of DNA vaccines in inducing protective antibodies against P. falciparum antigens in Aotus monkeys.
Persistence of Protective Immunity to Malaria Induced by DNA Priming and Poxvirus Boosting: Characterization of Effector and Memory CD8+-T-Cell Populations
Publisher: American Society for Microbiology
Date: 07-2002
DOI: 10.1128/IAI.70.7.3493-3499.2002
Abstract: The persistence of immunity to malaria induced in mice by a heterologous DNA priming and poxvirus boosting regimen was characterized. Mice were immunized by priming with DNA vaccine plasmids encoding the Plasmodium yoelii circumsporozoite protein (PyCSP) and murine granulocyte-macrophage colony-stimulating factor and boosting with recombinant vaccinia encoding PyCSP. BALB/c mice immunized with either high-dose (100 μg of p Py CSP plus 30 μg of pGM-CSF) or low-dose (1 μg of p Py CSP plus 1 μg of pGM-CSF DNA) priming were protected against challenge with 50 P. yoelii sporozoites. Protection 2 weeks after immunization was 70 to 100%, persisted at this level for at least 20 weeks, and declined to 30 to 40% by 28 weeks. Eight of eight mice protected at 20 weeks were still protected when rechallenged at 40 weeks. The antigen (Ag)-specific effector CD8 + -T-cell population present 2 weeks after boosting had ex vivo Ag-specific cytolytic activity, expressed both gamma interferon (IFN-γ) and tumor necrosis factor alpha, and constituted 12 to 20% of splenic CD8 + T cells. In contrast, the memory CD8 + -Ag-specific-cell population at 28 weeks lacked cytolytic activity and constituted only 6% of splenic CD8 + T cells, but at the single-cell level it produced significantly higher levels of IFN-γ than the effectors. High levels of Ag- or parasite-specific antibodies present 2 weeks after boosting had declined three- to sevenfold by 28 weeks. Low-dose priming was similarly immunogenic and as protective as high-dose priming against a 50-, but not a 250-, sporozoite challenge. These results demonstrate that a heterologous priming and boosting vaccination can provide lasting protection against malaria in this model system.
Uptake of Schistosoma mansoni extracellular vesicles by human endothelial and monocytic cell lines and impact on vascular endothelial cell gene expression
Publisher: Elsevier BV
Date: 08-2020
CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity
Publisher: Elsevier BV
Date: 05-2021
Circumventing genetic restriction of protection against malaria with multigene DNA immunization: CD8+ cell-, interferon gamma-, and nitric oxide-dependent immunity.
Publisher: Rockefeller University Press
Date: 04-1996
Abstract: Despite efforts to develop vaccines that protect against malaria by inducing CD8+ T cells that kill infected hepatocytes, no subunit vaccine has been shown to circumvent the genetic restriction inherent in this approach, and little is known about the interaction of subunit vaccine-induced immune effectors and infected hepatocytes. We now report that immunization with plasmid DNA encoding the plasmodium yoelii circumsporozoite protein protected one of five strains of mice against malaria (H-2d, 75%) a PyHEP17 DNA vaccine protected three of the five strains (H-2a, 71% H-2k, 54% H-2d, 26%) and the combination protected 82% of H-2a, 90% of H-2k, and 88% of H-2d mice. Protection was absolutely dependent on CD8+ T cells, INF-gamma, or nitric oxide. These data introduce a new target of protective preerythrocytic immune responses, PyHEP 17 and its P. falciparum homologue, and provide a realistic perspective on the opportunities and challenges inherent in developing malaria vaccines that target the infected hepatocyte.
Recent advances in proteomic applications for schistosomiasis research: potential clinical impact
Publisher: Informa UK Limited
Date: 22-12-2016
DOI: 10.1080/14789450.2017.1271327
Abstract: Schistosomiasis is a neglected tropical disease affecting hundreds of millions of people worldwide. Recent advances in the field of proteomics and the development of new and highly sensitive mass spectrometers and quantitative techniques have provided new tools for advancing the molecular biology, cell biology, diagnosis and vaccine development for public health threats such as schistosomiasis. Areas covered: In this review we describe the latest advances in research that utilizes proteomics-based tools to address some of the key challenges to developing effective interventions against schistosomiasis. We also provide information about the potential of extracellular vesicles to advance the fight against this devastating disease. Expert commentary: Different proteins are already being tested as vaccines against schistosomiasis with promising results. The re-analysis of the Schistosoma spp. proteomes using new and more sensitive mass spectrometers as well as better separation approaches will help identify more vaccine targets in a rational and informed manner. In addition, the recent development of new proteome microarrays will facilitate characterisation of novel markers of infection as well as new vaccine and diagnostic candidate antigens.
Immune effector mechanisms in malaria
Publisher: Elsevier BV
Date: 08-1999
Protective Immunity Against Severe Malaria is Associated with a Repertoire of Antibodies to Conserved PfEMP1 Variants
Publisher: Elsevier BV
Date: 2019
DOI: 10.2139/SSRN.3353221
Immune Signature Against Plasmodium falciparum Antigens Predicts Clinical Immunity in Distinct Malaria Endemic Communities
Publisher: Elsevier BV
Date: 2020
Protein Microarrays for Parasite Antigen Discovery
Publisher: Springer New York
Date: 07-10-2014
DOI: 10.1007/978-1-4939-1438-8_13
Abstract: The host serological profile to a parasitic infection, such as schistosomiasis, can be used to define potential vaccine and diagnostic targets. Determining the host antibody response using traditional approaches is hindered by the large number of putative antigens in any parasite proteome. Parasite protein microarrays offer the potential for a high-throughput host antibody screen to simplify this task. In order to construct the array, parasite proteins are selected from available genomic sequence and protein databases using bioinformatic tools. Selected open reading frames are PCR lified, incorporated into a vector for cell-free protein expression, and printed robotically onto glass slides. The protein microarrays can be probed with antisera from infected/immune animals or humans and the antibody reactivity measured with fluorophore labeled antibodies on a confocal laser microarray scanner to identify potential targets for diagnosis or therapeutic or prophylactic intervention.
Transcriptionally active PCR for antigen identification and vaccine development: In vitro genome-wide screening and in vivo immunogenicity
Publisher: Elsevier BV
Date: 03-2008
Editorial: Coronavirus Disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management and Public Health Response
Publisher: Frontiers Media SA
Date: 30-11-2021
High-Q THz Fano Metamaterial Interacting With Vacuum Electron
Publisher: IEEE
Date: 09-2019
Evidence for limited activation of distinct CD4+ T cell subsets in response to the Plasmodium falciparum circumsporozoite protein in Papua New Guinea
Publisher: Wiley
Date: 03-1994
DOI: 10.1111/J.1365-3024.1994.TB00332.X
Abstract: Both CD4+ and CD8+ T cells, as well as antibody, are known to be important in sporozoite immunity. Data from animal studies suggest that cytokines, in particular gamma-interferon and interleukin-6, are involved. The interplay of these various factors and their importance in vaccine development has, however, not yet been elucidated. In this study, we have studied cellular and humoral responses of in iduals naturally exposed to malaria in a highly endemic region of Papua New Guinea to the circumsporozoite protein of Plasmodium falciparum, a prime vaccine candidate antigen. A paucity of any CD4+ lymphoproliferative response to this protein by Papua New Guineans was notable which parallels our recent observation of a paucity of CD8+ T cell response and contrasts markedly with the responses of other endemic populations. There was nevertheless a significant antibody response to the central conserved B cell epitope, (NANP)n, as well as to other critical epitopes. An inverse relationship between gamma-interferon production and interleukin-6 production and a positive correlation between gamma-interferon production and CS peptide-specific lymphoproliferation was observed. High levels of peptide-specific IL-6 production were associated with high levels of peptide-specific serum antibodies. Our data provide evidence for the limited activation of distinct CD4+ T cell subsets and for the existence of functionally distinct subpopulations of human CD4+ T cells with respect to cytokines known to be important in sporozoite immunity.
Simultaneous Induction of Multiple Antigen-Specific Cytotoxic T Lymphocytes in Nonhuman Primates by Immunization with a Mixture of Four Plasmodium falciparum DNA Plasmids
Publisher: American Society for Microbiology
Date: 1998
Development of a cytokine-secreting-based assay for the identification, sorting and transcriptomic analysis of polyfunctional human T cells
Publisher: John Libbey Eurotext
Date: 10-2015
Abstract: Polyfunctional T cells that simultaneously produce the cytokines IFN-γ, IL-2 and TNF have been correlated with better clinical outcomes in various diseases. To date, cytokine polyfunctionality within T cells has been exclusively studied by intracellular cytokine staining coupled with flow cytometric analysis. Thus, further downstream interrogation of polyfunctional T cell characteristics such as transcriptomic analysis has not been possible. Here, we report the use of a flow cytometric method based on cytokine secretion assay technology to detect and isolate, for the first time, viable human polyfunctional T cells directly from in vitro stimulated whole blood s les. We demonstrate the successful application of this method to sort polyfunctional T cells obtained from human volunteers, which can be then used for downstream applications such as transcriptomic analysis using RT-qPCR. This assay will facilitate in-depth investigations of T cells with distinct cytokine polyfunctionality, including defining their molecular profile and understanding the mechanisms regulating their generation and function.
An Immunomics Approach to Schistosome Antigen Discovery: Antibody Signatures of Naturally Resistant and Chronically Infected Individuals from Endemic Areas
Publisher: Public Library of Science (PLoS)
Date: 27-03-2014
Addressing the bottleneck at clinical testing of candidate malaria vaccines
Publisher: Informa UK Limited
Date: 10-2012
Correction: Identification of a Novel, EBV-based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan
Publisher: American Association for Cancer Research (AACR)
Date: 07-2020
Antibodies Targeting the Comprehensive Epstein-Barr Virus Proteome and Hodgkin Lymphoma
Publisher: Elsevier BV
Date: 2018
DOI: 10.2139/SSRN.3266983
Identification ofPlasmodium falciparumantigens by antigenic analysis of genomic and proteomic data
Publisher: Proceedings of the National Academy of Sciences
Date: 28-07-2003
Abstract: The recent explosion in genomic sequencing has made available a wealth of data that can now be analyzed to identify protein antigens, potential targets for vaccine development. Here we present, in the context of Plasmodium falciparum , a strategy that rapidly identifies target antigens from large and complex genomes. Sixteen antigenic proteins recognized by volunteers immunized with radiation-attenuated P. falciparum sporozoites, but not by mock immunized controls, were identified. Several of these were more antigenic than previously identified and well characterized P. falciparum -derived protein antigens. The data suggest that immune responses to Plasmodium are dispersed on a relatively large number of parasite antigens. These studies have implications for our understanding of immunodominance and breadth of responses to complex pathogens.
Influence of Physicochemical Properties of Lipopeptide Adjuvants on the Immune Response: A Rationale for Engineering a Potent Vaccine
Publisher: Wiley
Date: 19-06-2018
Abstract: Adjuvant development and understanding the physicochemical properties of particles and interpreting the subsequent immunological responses is a challenge faced by many researchers in the vaccine field. We synthesized and investigated the physicochemical properties and immunogenicity of a library of multiple epitope self-adjuvant lipopeptides in a novel asymmetric arrangement. Vaccine candidates were synthesized using a combination of solid-phase peptide synthesis and copper-mediated click chemistry. In vivo studies showed that vaccine constructs containing a single OVA CD8
Supplementary Methods S1 from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.22725002.V1
Abstract: Supplementary Methods S1 expands upon data and statistical methods.
DNA vaccination against malaria
Publisher: Elsevier BV
Date: 08-1996
Human T cell recognition of the blood stage antigen Plasmodium hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) in acute malaria
Publisher: Springer Science and Business Media LLC
Date: 07-06-2009
Special issue on malaria vaccine development
Publisher: Informa UK Limited
Date: 2010
DOI: 10.4161/HV.6.1.10703
Novel Plasmodium antigens identified via genome-based antibody screen induce protection associated with polyfunctional T cell responses
Publisher: Springer Science and Business Media LLC
Date: 08-11-2017
DOI: 10.1038/S41598-017-15354-0
Abstract: The development of vaccines against complex intracellular pathogens, such as Plasmodium spp ., where protection is likely mediated by cellular immune responses, has proven elusive. The availability of whole genome, proteome and transcriptome data has the potential to advance rational vaccine development but yet there are no licensed vaccines against malaria based on antigens identified from genomic data. Here, we show that the Plasmodium yoelii orthologs of four Plasmodium falciparum proteins identified by an antibody-based genome-wide screening strategy induce a high degree of sterile infection-blocking protection against sporozoite challenge in a stringent rodent malaria model. Protection increased in multi-antigen formulations. Importantly, protection was highly correlated with the induction of multifunctional triple-positive T cells expressing high amounts of IFN-γ, IL-2 and TNF. These data demonstrate that antigens identified by serological screening are targets of multifunctional cellular immune responses that correlate with protection. Our results provide experimental validation for the concept of rational vaccine design from genomic sequence data.
Acquired Immunity to Malaria
Publisher: American Society for Microbiology
Date: 2009
DOI: 10.1128/CMR.00025-08
Abstract: Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum . The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.
Chimeric murine polyomavirus virus-like particles induce Plasmodium antigen-specific CD8+ T cell and antibody responses
Publisher: Frontiers Media SA
Date: 19-06-2019
Profiling the Targets of Protective CD8+ T Cell Responses to Infection
Publisher: Elsevier BV
Date: 12-2017
Defining the targets of antiparasitic compounds.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.DRUDIS.2016.01.002
Abstract: The treatment of major human parasitic infections is dependent on drugs that are plagued by issues of drug resistance. New chemotherapeutics with novel mechanisms of action (MOA) are desperately needed to combat multi-drug-resistant parasites. Although widespread screening strategies are identifying potential new hits for development against most major human parasitic diseases, in many cases such efforts are hindered by limited MOA data. Although MOA data are not essential for drug development, they can facilitate compound triage and provide a mechanism to combat drug resistance. Here we describe and discuss methods currently used to identify the targets of antiparasitic compounds, which could circumvent this bottleneck and facilitate the development of new antiparasitic drugs.
Deciphering host immunity to malaria using systems immunology
Publisher: Wiley
Date: 14-10-2019
DOI: 10.1111/IMR.12814
Abstract: A century of conceptual and technological advances in infectious disease research has changed the face of medicine. However, there remains a lack of effective interventions and a poor understanding of host immunity to the most significant and complex pathogens, including malaria. The development of successful interventions against such intractable diseases requires a comprehensive understanding of host-pathogen immune responses. A major advance of the past decade has been a paradigm switch in thinking from the contemporary reductionist (gene-by-gene or protein-by-protein) view to a more holistic (whole organism) view. Also, a recognition that host-pathogen immunity is composed of complex, dynamic interactions of cellular and molecular components and networks that cannot be represented by any in idual component in isolation. Systems immunology integrates the field of immunology with omics technologies and computational sciences to comprehensively interrogate the immune response at a systems level. Herein, we describe the system immunology toolkit and report recent studies deploying systems-level approaches in the context of natural exposure to malaria or controlled human malaria infection. We contribute our perspective on the potential of systems immunity for the rational design and development of effective interventions to improve global public health.
Cytotoxic T lymphocyte (CTL) low-responsiveness to the Plasmodium falciparum circumsporozoite protein in naturally-exposed endemic populations: analysis of human CTL response to most known vari
Publisher: Oxford University Press (OUP)
Date: 1993
Abstract: Cytotoxic T lymphocytes (CTL) specific for epitope(s) within the circumsporozoite (CS) protein of malaria sporozoites have been shown to play an important role in protective immunity against malaria, at least in murine models. Their role in sporozoite immunity in the human host has, however, not yet been elucidated. Immunological non-responsiveness and antigenic ersity within T cell epitopes of the CS protein have been identified as potential problems in producing a sporozoite vaccine. These factors may contribute to the widespread lack of sporozoite immunity in endemic populations. In this study, 137 in iduals with a history of natural endemic exposure to falciparum sporozoites (119 resident in north west Thailand and 18 resident in coastal Papua New Guinea) were tested for a CTL response to the Plasmodium falciparum CS protein. Fifty-four overlapping peptides, spanning the entire sequence of the CS protein of P. falciparum including most known variants, were studied. While most in iduals had antibodies to the immunodominant B cell repeat, (NANP)n, and while CTL specific for an influenza virus matrix synthetic peptide could be generated from five of 23 Karen Thai in iduals tested, no CS protein-specific CTL could be detected in these populations. Our data have important implications for vaccine programs.
Casting a Wide Net around Immunity to Malaria Catches p53
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.IMMUNI.2019.09.011
Abstract: The mechanisms underlying acquisition of naturally acquired immunity to malaria are poorly understood. In this issue of Immunity, Tran and colleagues (2019) demonstrate that systems immunology is a powerful tool to decipher molecular and cellular components contributing to this immunity.
Profiling humoral immune responses to P. falciparum infection with protein microarrays
Publisher: Wiley
Date: 11-2008
HLA degenerate T‐cell epitopes from Plasmodium falciparum liver stage‐specific antigen 1 (LSA‐1) are highly conserved in isolates from geographically distinct areas
Publisher: Wiley
Date: 09-2000
DOI: 10.1046/J.1365-3024.2000.00324.X
Abstract: Considerable effort is directed at the development of a malaria vaccine that elicits antigen-specific T-cell responses against pre-erythrocytic antigens of Plasmodium falciparum. Genetic restriction of host T-cell responses and polymorphism of target epitopes on parasite antigens pose obstacles to the development of such a vaccine. Liver stage-specific antigen-1 (LSA-1) is a prime candidate vaccine antigen and five T-cell epitopes that are degenerately restricted by HLA molecules common in most populations have been identified on LSA-1. To define the extent of polymorphism within these T-cell epitopes, the N-terminal non-repetitive region of the LSA-1 gene from Malaysian P. falciparum field isolates was sequenced and compared with data of isolates from Brazil, Kenya and Papua New Guinea. Three of the T-cell epitopes were completely conserved while the remaining two were highly conserved in the isolates examined. Our findings underscore the potential of including these HLA-degenerate T-cell epitopes of LSA-1 in a subunit vaccine.
Adenovirus 5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part A: Safety and Immunogenicity in Seronegative Adults
Publisher: Public Library of Science (PLoS)
Date: 07-10-2011
Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stagePlasmodium falciparumDNA vaccin
Publisher: Informa UK Limited
Date: 24-11-2012
DOI: 10.4161/HV.22129
Human challenge models: tools to accelerate the development of malaria vaccines.
Publisher: Informa UK Limited
Date: 27-02-2019
DOI: 10.1080/14760584.2019.1580577
Abstract: Malaria challenge models, where healthy human volunteers are intentionally infected with Plasmodium species parasites under controlled conditions, can be undertaken in several well-defined ways. These challenge models enable evaluation of the kinetics of parasite growth and clearance, host-pathogen interactions and the host immune response. They can facilitate discovery of candidate diagnostic biomarkers and novel vaccine targets. As translational tools they can facilitate testing of candidate vaccines and drugs and evaluation of diagnostic tests. Until recently, malaria human challenge models have been limited to only a few Plasmodium falciparum strains and used exclusively in malaria-naïve volunteers in non-endemic regions. Several recent advances include the use of alternate P. falciparum strains and other species of Plasmodia, as well as strains attenuated by chemical, radiation or genetic modification, and the conduct of studies in pre-exposed in iduals. Herein, we discuss how this ersification is enabling more thorough vaccine efficacy testing and informing rational vaccine development. The ability to comprehensively evaluate vaccine efficacy in controlled settings will continue to accelerate the translation of candidate malaria vaccines to the clinic, and inform the development and optimisation of potential vaccines that would be effective against multiple strains in geographically and demographically erse settings.
The Australasian contribution to malaria vaccine development
Publisher: Wiley
Date: 12-07-2010
DOI: 10.1111/J.1365-3024.2010.01229.X
Abstract: Malaria remains a major threat to public health worldwide, despite intense research efforts spanning decades. Much of this work has been directed towards developing an effective malaria vaccine, and scientists from Australasia have made significant contributions to progress in this area. Herein, we review the research undertaken in Australasia and summarize some of the important roles that Australasian researchers have played in malaria vaccine development that has occurred outside the region.
Foreword—MBP thematic issue on genomics
Publisher: Elsevier BV
Date: 12-2001
A population of CD4hiCD38hi T cells correlates with disease severity in patients with acute malaria
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1209
A Dual-Antigen Enzyme-Linked Immunosorbent Assay Allows the Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in a Low-Transmission Setting
Publisher: Oxford University Press (OUP)
Date: 03-10-2021
Abstract: Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been h ered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay–based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0–1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Status of malaria vaccine R&D in 2007
Publisher: Informa UK Limited
Date: 12-2007
The Rise of Non-Tuberculosis Mycobacterial Lung Disease
Publisher: Frontiers Media SA
Date: 03-03-2020
Identification and Characterization of the Protective Gene of homolog of Exported Protein 1
Publisher: Elsevier BV
Date: 07-1996
Probing of a human proteome microarray with a recombinant pathogen protein reveals a novel mechanism by which hookworms suppress B-cell receptor signaling
Publisher: Oxford University Press (OUP)
Date: 19-08-2015
Abstract: Na-ASP-2 is an efficacious hookworm vaccine antigen. However, despite elucidation of its crystal structure and studies addressing its immunobiology, the function of Na-ASP-2 has remained elusive. We probed a 9000-protein human proteome microarray with Na-ASP-2 and showed binding to CD79A, a component of the B-cell antigen receptor complex. Na-ASP-2 bound to human B lymphocytes ex vivo and downregulated the transcription of approximately 1000 B-cell messenger RNAs (mRNAs), while only approximately 100 mRNAs were upregulated, compared with control-treated cells. The expression of a range of molecules was affected by Na-ASP-2, including factors involved in leukocyte transendothelial migration pathways and the B-cell signaling receptor pathway. Of note was the downregulated transcription of lyn and pi3k, molecules that are known to interact with CD79A and control B-cell receptor signaling processes. Together, these results highlight a previously unknown interaction between a hookworm-secreted protein and B cells, which has implications for helminth-driven immunomodulation and vaccine development. Further, the novel use of human protein microarrays to identify host-pathogen interactions, coupled with ex vivo binding studies and subsequent analyses of global gene expression in human host cells, demonstrates a new pipeline by which to explore the molecular basis of infectious diseases.
Defined Small Molecules Produced by Himalayan Medicinal Plants Display Immunomodulatory Properties
Publisher: MDPI AG
Date: 06-11-2018
DOI: 10.3390/IJMS19113490
Abstract: Plant-derived compounds that modulate the immune responses are emerging as frontline treatment agents for cancer, infectious diseases and autoimmunity. Herein we have isolated 40 phytochemicals from five Bhutanese Sowa Rigpa medicinal plants—Aconitum laciniatum, Ajania nubegina, Corydalis crispa, Corydalis dubia and Pleurospermum amabile—and tested 14 purified compounds for their immunomodulatory properties using a murine dendritic cell (DC) line, and cytotoxicity against a human cholangiocyte cell line using xCELLigence real time cell monitoring. These compounds were: pseudaconitine, 14-veratryolpseudaconitine, 14-O-acetylneoline, linalool oxide acetate, (E)-spiroether, luteolin, luteolin-7-O-β-d-glucopyranoside, protopine, ochrobirine, scoulerine, capnoidine, isomyristicin, bergapten, and isoimperatorin. Of the 14 compounds tested here, scoulerine had adjuvant-like properties and strongly upregulated MHC-I gene and protein expression whereas bergapten displayed immunosuppressive properties and strongly down-regulated gene and protein expression of MHC-I and other co-stimulatory molecules. Both scoulerine and bergapten showed low cytotoxicity against normal healthy cells that were consistent with their immunoregulatory properties. These findings highlight the breadth of immunomodulatory properties of defined compounds from Bhutanese medicinal plants and show that some of these compounds exert their mechanisms of action by modulating DC activity.
Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP)
Publisher: Springer Science and Business Media LLC
Date: 05-06-2013
Malaria vaccines–targeting infected hepatocytes
Publisher: Springer Science and Business Media LLC
Date: 11-2000
DOI: 10.1038/81315
Intermittent preventive treatment with sulfadoxine-pyrimethamine does not modify plasma cytokines and chemokines or intracellular cytokine responses to Plasmodium falciparum in Mozambican Children
Publisher: Springer Science and Business Media LLC
Date: 26-01-2012
Abstract: Cytokines and chemokines are key mediators of anti-malarial immunity. We evaluated whether Intermittent Preventive Treatment in infants with Sulfadoxine-Pyrimethamine (IPTi-SP) had an effect on the acquisition of these cellular immune responses in Mozambican children. Multiple cytokines and chemokines were quantified in plasma by luminex, and antigen-specific cytokine production in whole blood was determined by intracellular cytokine staining and flow cytometry, at ages 5, 9, 12 and 24 months. IPTi-SP did not significantly affect the proportion of CD3+ cells producing IFN-γ, IL-4 or IL-10. Overall, plasma cytokine or chemokine concentrations did not differ between treatment groups. Th1 and pro-inflammatory responses were higher than Th2 and anti-inflammatory responses, respectively, and IFN-γ:IL-4 ratios were higher for placebo than for SP recipients. Levels of cytokines and chemokines varied according to age, declining from 5 to 9 months. Plasma concentrations of IL-10, IL-12 and IL-13 were associated with current infection or prior malaria episodes. Higher frequencies of IFN-γ and IL-10 producing CD3+ cells and elevated IL-10, IFN-γ, MCP-1 and IL-13 in plasma were in idually associated with increased malaria incidence, at different time points. When all markers were analyzed together, only higher IL-17 at 12 months was associated with lower incidence of malaria up to 24 months. Our work has confirmed that IPTi-SP does not negatively affect the development of cellular immune response during early childhood. This study has also provided new insights as to how these cytokine responses are acquired upon age and exposure to P. falciparum , as well as their associations with malaria susceptibility. ClinicalTrials.gov: NCT00209795
The path of discovery
Publisher: Informa UK Limited
Date: 09-2008
DOI: 10.4161/HV.4.5.6707
Specific humoral response of hosts with variable schistosomiasis susceptibility
Publisher: Wiley
Date: 07-07-2016
DOI: 10.1038/ICB.2015.61
Abstract: The schistosome blood flukes are some of the largest global causes of parasitic morbidity. Further study of the specific antibody response during schistosomiasis may yield the vaccines and diagnostics needed to combat this disease. Therefore, for the purposes of antigen discovery, sera and antibody-secreting cell (ASC) probes from semi-permissive rats and sera from susceptible mice were used to screen a schistosome protein microarray. Following Schistosoma japonicum infection, rats had reduced pathology, increased antibody responses and broader antigen recognition profiles compared with mice. With successive infections, rat global serological reactivity and the number of recognized antigens increased. The local antibody response in rat skin and lung, measured with ASC probes, increased after parasite migration and contributed antigen-specific antibodies to the multivalent serological response. In addition, the temporal variation of anti-parasite serum antibodies after infection and reinfection followed patterns that appear related to the antigen driving the response. Among the 29 antigens differentially recognized by the infected hosts were numerous known vaccine candidates, drug targets and several S. japonicum homologs of human schistosomiasis resistance markers-the tegument allergen-like proteins. From this set, we prioritized eight proteins that may prove to be novel schistosome vaccine and diagnostic antigens.
Genome- and proteome-wide screening strategies for antigen discovery and immunogen design
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.BIOTECHADV.2013.12.006
Abstract: Infectious diseases remain a leading global cause of morbidity and mortality and there is an urgent need for effective approaches to develop vaccines, especially against complex pathogens. The availability of comprehensive genomic, proteomic and transcriptomic datasets has shifted the paradigm of vaccine development from microbiological to sequence-based approaches. However, how to effectively translate raw data into candidate vaccines is not yet obvious. Herein, we review cutting-edge technologies and screening strategies to mine genomic sequence information for state-of-the-art rational vaccine design, and highlight recent trends. Interdisciplinary approaches which cross the traditional boundaries of genomics, molecular biology, cell biology, immunology and computer science, and which prioritise antigens according to clinically relevant criteria, offer potential solutions to the widespread threat that complex pathogens pose to public health.
Patterns of Interindividual Variability in the Antibody Repertoire Targeting Proteins Across the Epstein-Barr Virus Proteome
Publisher: Oxford University Press (OUP)
Date: 02-03-2018
Targeting antigen to MHC Class I and Class II antigen presentation pathways for malaria DNA vaccines
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.IMLET.2007.05.007
Abstract: An effective malaria vaccine which protects against all stages of Plasmodium infection may need to elicit robust CD8(+) and CD4(+) T cell and antibody responses. To achieve this, we have investigated strategies designed to improve the immunogenicity of DNA vaccines encoding the Plasmodium yoelii pre-erythrocytic stage antigens PyCSP and PyHEP17, by targeting the encoded proteins to the MHC Classes I and II processing and presentation pathways. For enhancement of CD8(+) T cell responses, we targeted the antigens for degradation by the ubiquitin (Ub) roteosome pathway following the N-terminal rule. We constructed plasmids containing PyCSP or PyHEP17 genes fused to the Ub gene: plasmids where the N-terminal antigen residues were mutated from the stabilizing amino acid methionine to destabilizing arginine, plasmids where the C-terminal residues of Ub were mutated from glycine to alanine, and plasmids in which the potential hydrophobic leader sequences of the antigens were deleted. For enhancement of CD4(+) T cell and antibody responses, we targeted the antigens for degradation by the endosomal/lysosomal pathway by linking the antigen to the lysosome-associated membrane protein (LAMP). We found that immunization with DNA vaccine encoding PyHEP17 fused to Ub and bearing arginine induced higher IFN-gamma, cytotoxic and proliferative T cell responses than unmodified vaccines. However, no effect was seen for PyCSP using the same targeting strategies. Regarding Class II antigen targeting, fusion to LAMP did not enhance antibody responses to either PyHEP17 or PyCSP, and resulted in a marginal increase in lymphoproliferative CD4(+) T cell responses. Our data highlight the antigen dependence of immune enhancement strategies that target antigen to the MHC Class I and II pathways for vaccine development.
Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 14-02-2023
DOI: 10.1158/1055-9965.EPI-22-0452
Abstract: Epstein–Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case–control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 in idual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle cHL with antibodies in the early lytic, late lytic and glycoprotein stages and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.
A high-throughput screening RT-qPCR assay for quantifying surrogate markers of immunity from PBMCs
Publisher: Frontiers Media SA
Date: 30-08-2022
DOI: 10.3389/FIMMU.2022.962220
Abstract: Immunoassays that quantitate cytokines and other surrogate markers of immunity from peripheral blood mononuclear cells (PBMCs), such as flow cytometry or Enzyme-Linked Immunosorbent Spot (ELIspot), allow highly sensitive measurements of immune effector function. However, those assays consume relatively high numbers of cells and expensive reagents, precluding comprehensive analyses and high-throughput screening (HTS). To address this issue, we developed a sensitive and specific reverse transcription-quantitative PCR (RT-qPCR)-based HTS assay, specifically designed to quantify surrogate markers of immunity from very low numbers of PBMCs. We systematically evaluated the volumes and concentrations of critical reagents within the RT-qPCR protocol, miniaturizing the assay and ultimately reducing the cost by almost 90% compared to current standard practice. We assessed the suitability of this cost-optimized RT-qPCR protocol as an HTS tool and determined the assay exceeds HTS uniformity and signal variance testing standards. Furthermore, we demonstrate this technique can effectively delineate a hierarchy of responses from as little as 50,000 PBMCs stimulated with CD4 + or CD8 + T cell peptide epitopes. Finally, we establish that this HTS-optimized protocol has single-cell analytical sensitivity and a diagnostic sensitivity equivalent to detecting 1:10,000 responding cells ( i.e. , 100 Spot Forming Cells/10 6 PBMCs by ELIspot) with over 90% accuracy. We anticipate this assay will have widespread applicability in preclinical and clinical studies, especially when s les are limited, and cost is an important consideration.
Multilaboratory Assessment of Epstein-Barr Virus Serologic Assays: the Case for Standardization
Publisher: American Society for Microbiology
Date: 11-2019
DOI: 10.1128/JCM.01107-19
Abstract: IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum s les and 66 pooled plasma s les generated from in iduals with a broad range of IgA antibody levels.
Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2018
DOI: 10.1158/1078-0432.CCR-17-1929
Abstract: Background. Epstein–Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of in iduals test EBV-positive, but only a fraction develop cancer. Factors that identify which in iduals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese in iduals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts. Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls (P & 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status—BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%–98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82% 95% CI, 75%–90%, P ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89% 95% CI, 82%–96%) compared with current biomarkers (78% 95% CI, 66%–90%, P ≤ 0.03). Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. Clin Cancer Res 24(6) 1305–14. ©2017 AACR.
2018 ISV Congress: advances in the 100 years since the world’s deadliest pandemic
Publisher: Informa UK Limited
Date: 02-09-2019
Toward clinical trials of DNA vaccines against malaria
Publisher: Wiley
Date: 08-1997
DOI: 10.1038/ICB.1997.59
Abstract: In mid 1997 the first malaria DNA vaccine will enter clinical trials. This single gene DNA vaccine encoding the Plasmodium falciparum circumsporozoite protein (PfCSP) will be studied for safety and immunogenicity. If these criteria are met, a multi-gene DNA vaccine designed to induce protective CD8+ T cell responses against P. falciparum infected hepatocytes will be subsequently assessed for safety, immunogenicity and capacity to protect immunized volunteers against experimental challenge with P. falciparum sporozoites. Our perspectives on malaria vaccine development in general, and on a multi-gene DNA vaccine in particular, have been recently reviewed. Herein, we review the rationale and experimental foundation for the anticipated P. falciparum DNA vaccine trials.
The establishment of a WHO Reference Reagent for anti-malaria (Plasmodium falciparum) human serum.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2017
Safety, tolerability and humoral immune responses after intramuscular administration of a malaria DNA vaccine to healthy adult volunteers
Publisher: Elsevier BV
Date: 03-2000
DOI: 10.1016/S0264-410X(99)00407-7
Abstract: DNA-based vaccines are considered to be potentially revolutionary due to their ease of production, low cost, long shelf life, lack of requirement for a cold chain and ability to induce good T-cell responses. Twenty healthy adult volunteers were enrolled in a Phase I safety and tolerability clinical study of a DNA vaccine encoding a malaria antigen. Volunteers received 3 intramuscular injections of one of four different dosages (20, 100, 500 and 2500 microg) of the Plasmodium falciparum circumsporozoite protein (PfCSP) plasmid DNA at monthly intervals and were followed for up to twelve months. Local reactogenicity and systemic symptoms were few and mild. There were no severe or serious adverse events, clinically significant biochemical or hematologic changes, or detectable anti-dsDNA antibodies. Despite induction of excellent CTL responses, intramuscular DNA vaccination via needle injection failed to induce detectable antigen-specific antibodies in any of the volunteers.
Data from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/1055-9965.C.6624590
Abstract: AbstractBackground: Epstein–Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Methods: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case–control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 in idual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle cHL with antibodies in the early lytic, late lytic and glycoprotein stages and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer. /
Third meeting on Novel Adjuvants Currently in or Close to Clinical Testing
Publisher: Elsevier BV
Date: 09-2003
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