15 results on '"Yadava, Anjali"'
Search Results
2. Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.
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Bennett JW, Yadava A, Tosh D, Sattabongkot J, Komisar J, Ware LA, McCarthy WF, Cowden JJ, Regules J, Spring MD, Paolino K, Hartzell JD, Cummings JF, Richie TL, Lumsden J, Kamau E, Murphy J, Lee C, Parekh F, Birkett A, Cohen J, Ballou WR, Polhemus ME, Vanloubbeeck YF, Vekemans J, and Ockenhouse CF
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- Adolescent, Adult, Antibodies, Protozoan immunology, Female, Humans, Malaria Vaccines administration & dosage, Malaria Vaccines adverse effects, Malaria, Vivax immunology, Malaria, Vivax parasitology, Male, Middle Aged, Protozoan Proteins administration & dosage, Protozoan Proteins adverse effects, Vaccination, Young Adult, Malaria Vaccines immunology, Malaria, Vivax prevention & control, Plasmodium vivax immunology, Protozoan Proteins immunology
- Abstract
Background: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use., Methods: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls., Results: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period., Significance: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.
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- 2016
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3. Particle-based platforms for malaria vaccines.
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Wu Y, Narum DL, Fleury S, Jennings G, and Yadava A
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- Adjuvants, Immunologic, Antigens, Protozoan immunology, Humans, Malaria Vaccines administration & dosage, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, Vaccines, Virus-Like Particle administration & dosage, Malaria Vaccines immunology, Nanoparticles, Vaccines, Virus-Like Particle immunology
- Abstract
Recombinant subunit vaccines in general are poor immunogens likely due to the small size of peptides and proteins, combined with the lack or reduced presentation of repetitive motifs and missing complementary signal(s) for optimal triggering of the immune response. Therefore, recombinant subunit vaccines require enhancement by vaccine delivery vehicles in order to attain adequate protective immunity. Particle-based delivery platforms, including particulate antigens and particulate adjuvants, are promising delivery vehicles for modifying the way in which immunogens are presented to both the innate and adaptive immune systems. These particle delivery platforms can also co-deliver non-specific immunostimodulators as additional adjuvants. This paper reviews efforts and advances of the Particle-based delivery platforms in development of vaccines against malaria, a disease that claims over 600,000 lives per year, most of them are children under 5 years of age in sub-Sahara Africa., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
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- 2015
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4. Protective efficacy of a Plasmodium vivax circumsporozoite protein-based vaccine in Aotus nancymaae is associated with antibodies to the repeat region.
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Yadava A, Hall CE, Sullivan JS, Nace D, Williams T, Collins WE, Ockenhouse CF, and Barnwell JW
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- Adjuvants, Immunologic, Animals, Antibodies, Protozoan blood, Antibodies, Protozoan immunology, Aotidae parasitology, Female, Immunity, Humoral immunology, Malaria, Vivax parasitology, Malaria, Vivax prevention & control, Male, Mice, Monkey Diseases parasitology, Monkey Diseases prevention & control, Random Allocation, Toll-Like Receptor 9 immunology, Vaccination, Vaccines, Synthetic immunology, Aotidae immunology, Malaria Vaccines immunology, Malaria, Vivax immunology, Plasmodium vivax immunology, Protozoan Proteins immunology
- Abstract
We have previously reported that Vivax Malaria Protein 001 (VMP001), a vaccine candidate based on the circumsporozoite protein of Plasmodium vivax, is immunogenic in mice and rhesus monkeys in the presence of various adjuvants. In the present study, we evaluated the immunogenicity and efficacy of VMP001 formulated with a TLR9 agonist in a water-in-oil emulsion. Following immunization, the vaccine efficacy was assessed by challenging Aotus nancymaae monkeys with P. vivax sporozoites. Monkeys from both the low- and high-dose vaccine groups generated strong humoral immune responses to the vaccine (peak median titers of 291,622), and its subunits (peak median titers to the N-term, central repeat and C-term regions of 22,188; 66,120 and 179,947, respectively). 66.7% of vaccinated monkeys demonstrated sterile protection following challenge. Protection was associated with antibodies directed against the central repeat region. The protected monkeys had a median anti-repeat titer of 97,841 compared to 14,822 in the non-protected monkeys. This is the first report demonstrating P. vivax CSP vaccine-induced protection of Aotus monkeys challenged with P. vivax sporozoites.
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- 2014
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5. Comparison of the immune responses induced by soluble and particulate Plasmodium vivax circumsporozoite vaccine candidates formulated in AS01 in rhesus macaques.
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Vanloubbeeck Y, Pichyangkul S, Bayat B, Yongvanitchit K, Bennett JW, Sattabongkot J, Schaecher K, Ockenhouse CF, Cohen J, and Yadava A
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- Animals, Antibodies, Protozoan blood, CD4-Positive T-Lymphocytes immunology, Cytokines metabolism, Escherichia coli genetics, Gene Expression, Macaca mulatta, Malaria Vaccines administration & dosage, Malaria Vaccines genetics, Plasmodium vivax genetics, Protozoan Proteins genetics, Saccharomyces cerevisiae genetics, Vaccines, Subunit administration & dosage, Vaccines, Subunit genetics, Vaccines, Subunit immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Vaccines, Virus-Like Particle administration & dosage, Vaccines, Virus-Like Particle genetics, Vaccines, Virus-Like Particle immunology, Adjuvants, Immunologic administration & dosage, Malaria Vaccines immunology, Plasmodium vivax immunology, Protozoan Proteins immunology
- Abstract
We have designed a pre-erythrocytic vaccine candidate based on the Plasmodium vivax circumsporozoite (CSV) protein, which includes its N- and C-terminal parts and a truncated region containing repeat sequences from both the VK210 and the VK247 P. vivax subtypes. Two versions of this vaccine candidate were made: a soluble recombinant protein expressed in Escherichia coli, designated VMP001 and a particulate antigen expressed in Saccharomyces cerevisiae, designated CSV-S,S. The latter is composed of CSV-S, a fusion protein between VMP001 and hepatitis B surface antigen (HBsAg), and free HBsAg co-expressed in yeast and self-assembling into mixed particles. Both antigen versions, adjuvanted with AS01, were shown to be immunogenic in rhesus monkeys. CSV-S,S/AS01 induced higher levels of VMP001-specific antibodies than did VMP001/AS01. Antibody responses against the N- and C-terminal regions of CSV and the VK210 repeat motif were of a similar magnitude following immunization with either the soluble or the particulate antigen. However, antibodies against the AGDR region, a potentially protective B cell epitope, were only detected after immunization with CSV-S,S. Analysis of the induced CD4(+) T cells highlighted different cytokine profiles depending on the antigen form. These results warrant further clinical evaluation of these two vaccine candidates to assess the added value of a particulate versus soluble form of CSV, in terms of both immunogenicity and protective efficacy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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6. Development of a chimeric Plasmodium berghei strain expressing the repeat region of the P. vivax circumsporozoite protein for in vivo evaluation of vaccine efficacy.
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Espinosa DA, Yadava A, Angov E, Maurizio PL, Ockenhouse CF, and Zavala F
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- Animals, Antibodies, Protozoan immunology, Antigens, Protozoan immunology, Chimera immunology, Fluorescent Antibody Technique, Indirect, Mice, Plasmodium berghei immunology, Plasmodium vivax immunology, Protozoan Proteins immunology, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Chimera genetics, Malaria Vaccines immunology, Plasmodium berghei genetics, Plasmodium vivax genetics, Protozoan Proteins genetics
- Abstract
The development of vaccine candidates against Plasmodium vivax-the most geographically widespread human malaria species-is challenged by technical difficulties, such as the lack of in vitro culture systems and availability of animal models. Chimeric rodent Plasmodium parasites are safe and useful tools for the preclinical evaluation of new vaccine formulations. We report the successful development and characterization of chimeric Plasmodium berghei parasites bearing the type I repeat region of P. vivax circumsporozoite protein (CSP). The P. berghei-P. vivax chimeric strain develops normally in mosquitoes and produces highly infectious sporozoites that produce patent infection in mice that are exposed to the bites of as few as 3 P. berghei-P. vivax-infected mosquitoes. Using this transgenic parasite, we demonstrate that monoclonal and polyclonal antibodies against P. vivax CSP strongly inhibit parasite infection and thus support the notion that these antibodies play an important role in protective immunity. The chimeric parasites we developed represent a robust model for evaluating protective immune responses against P. vivax vaccines based on CSP.
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- 2013
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7. Evaluation of immune responses to a Plasmodium vivax CSP-based recombinant protein vaccine candidate in combination with second-generation adjuvants in mice.
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Lumsden JM, Nurmukhambetova S, Klein JH, Sattabongkot J, Bennett JW, Bertholet S, Fox CB, Reed SG, Ockenhouse CF, Howard RF, Polhemus ME, and Yadava A
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- Animals, Antibodies, Protozoan blood, CD4-Positive T-Lymphocytes immunology, Emulsions administration & dosage, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Indirect, Immunoglobulin G blood, Injections, Subcutaneous, Interferon-gamma metabolism, Interleukin-2 metabolism, Malaria Vaccines administration & dosage, Mice, Mice, Inbred C57BL, Protozoan Proteins genetics, Recombinant Proteins genetics, Recombinant Proteins immunology, Tumor Necrosis Factor-alpha metabolism, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic immunology, Adjuvants, Immunologic administration & dosage, Malaria Vaccines immunology, Plasmodium vivax immunology, Protozoan Proteins immunology
- Abstract
Plasmodium vivax is the major cause of malaria outside of sub-Saharan Africa and causes morbidity and results in significant economic impact in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study, groups of C57BL/6J mice were immunized subcutaneously three times with VMP001 emulsified with synthetic TLR4 (GLA) or TLR7/8 (R848) agonist in stable emulsion (SE), a combination of the TLR4 and TLR7/8 agonists, or SE alone. Sera and splenocytes were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of mice generated high titers of anti-P. vivax IgG antibodies as detected by ELISA and immunofluorescence assay. GLA-SE promoted a shift in the antibody response to a Th1 profile, as demonstrated by the change in IgG2c/IgG1 ratio. In addition, GLA-SE induced a strong cellular immune response characterized by multi-functional, antigen-specific CD4(+) T cells secreting IL-2, TNF and IFN-γ. In contrast, mice immunized with SE or R848-SE produced low numbers of antigen-specific CD4(+) T cells, and these T cells secreted IL-2 and TNF, but not IFN-γ. Finally, R848-SE did not enhance the immune response compared to GLA-SE alone. Based on these results, we conclude that the combination of VMP001 and GLA-SE is highly immunogenic in mice and may serve as a potential second-generation vaccine candidate against vivax malaria., (Published by Elsevier Ltd.)
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- 2012
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8. Cross-species immunity following immunization with a circumsporozoite protein-based vaccine for malaria.
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Yadava A, Nurmukhambetova S, Pichugin AV, and Lumsden JM
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- Africa, Amino Acid Sequence, Animals, Antibodies, Protozoan blood, Epitopes immunology, Female, Immunization, Malaria Vaccines genetics, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Plasmodium berghei immunology, Plasmodium falciparum immunology, Plasmodium vivax immunology, Protozoan Proteins genetics, Protozoan Proteins metabolism, Sequence Analysis, DNA, Species Specificity, Sporozoites immunology, Cross Protection, Malaria immunology, Malaria prevention & control, Malaria Vaccines immunology, Protozoan Proteins immunology
- Abstract
Malaria continues to be a major public health concern, and there are concerted efforts to eliminate it. The quest for a vaccine remains a top priority, and vaccines based on the circumsporozoite protein (CSP) are among the lead candidates, with the RTS,S vaccine currently undergoing phase 3 testing in Africa. Previous studies have reported anti-CSP antibody-mediated enhancement of in vitro invasion of homologous sporozoites. This effect has been shown to be concentration dependent; high-level antibodies are inhibitory, whereas low-level antibodies lead to enhancement of invasion. Nondominant shared epitopes may lead to the generation of low titers of cross-reactive antibodies that may prove to be detrimental. We report cross-species recognition of Plasmodium falciparum and Plasmodium berghei sporozoites by anti-Plasmodium vivax CSP serum samples. In addition, we report that vaccination of mice with VMP001, a P. vivax CSP vaccine candidate, reduces, not enhances, P. berghei infection in mice.
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- 2012
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9. Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction.
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Moon JJ, Suh H, Li AV, Ockenhouse CF, Yadava A, and Irvine DJ
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- Analysis of Variance, Antigens, Protozoan administration & dosage, Cross Reactions, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Germinal Center immunology, Immunohistochemistry, Lipid A analogs & derivatives, Lipid A immunology, Lipid Bilayers administration & dosage, Lipid Bilayers immunology, Microscopy, Confocal, Particle Size, Recombinant Proteins administration & dosage, Spectrometry, Fluorescence, Transport Vesicles metabolism, Antigens, Protozoan immunology, B-Lymphocytes immunology, Malaria Vaccines immunology, Nanoparticles administration & dosage, Plasmodium vivax immunology, Protozoan Proteins immunology, Recombinant Proteins immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
For subunit vaccines, adjuvants play a key role in shaping immunological memory. Nanoparticle (NP) delivery systems for antigens and/or molecular danger signals are promising adjuvants capable of promoting both cellular and humoral immune responses, but in most cases the mechanisms of action of these materials are poorly understood. Here, we studied the immune response elicited by NPs composed of multilamellar "stapled" lipid vesicles carrying a recombinant Plasmodium vivax circumsporozoite antigen, VMP001, both entrapped in the aqueous core and anchored to the lipid bilayer surfaces. Immunization with these particles and monophosphoryl lipid A (MPLA), a US Food and Drug Administration-approved immunostimulatory agonist for Toll-like receptor-4, promoted high-titer, high-avidity antibody responses against VMP001, lasting more than 1 y in mice at 10-fold lower doses than conventional adjuvants. Compared to soluble VMP001 mixed with MPLA, VMP001-NPs promoted broader humoral responses, targeting multiple epitopes of the protein and a more balanced Th1/Th2 cytokine profile from antigen-specific T cells. To begin to understand the underlying mechanisms, we examined components of the B-cell response and found that NPs promoted robust germinal center (GC) formation at low doses of antigen where no GC induction occurred with soluble protein immunization, and that GCs nucleated near depots of NPs accumulating in the draining lymph nodes over time. In parallel, NP vaccination enhanced the expansion of antigen-specific follicular helper T cells (T(fh)), compared to vaccinations with soluble VMP001 or alum. Thus, NP vaccines may be a promising strategy to enhance the durability, breadth, and potency of humoral immunity by enhancing key elements of the B-cell response.
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- 2012
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10. Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccine.
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Moon JJ, Suh H, Polhemus ME, Ockenhouse CF, Yadava A, and Irvine DJ
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- Animals, Malaria Vaccines chemistry, Mice, Polylactic Acid-Polyglycolic Acid Copolymer, Sporozoites immunology, Lactic Acid chemistry, Malaria Vaccines administration & dosage, Malaria, Vivax prevention & control, Nanoparticles chemistry, Plasmodium vivax immunology, Polyglycolic Acid chemistry
- Abstract
The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) "enveloped" by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.
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- 2012
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11. Evaluation of the safety and immunogenicity in rhesus monkeys of a recombinant malaria vaccine for Plasmodium vivax with a synthetic Toll-like receptor 4 agonist formulated in an emulsion.
- Author
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Lumsden JM, Pichyangkul S, Srichairatanakul U, Yongvanitchit K, Limsalakpetch A, Nurmukhambetova S, Klein J, Bertholet S, Vedvick TS, Reed SG, Sattabongkot J, Bennett JW, Polhemus ME, Ockenhouse CF, Howard RF, and Yadava A
- Subjects
- Adjuvants, Immunologic, Animals, Antigens, Protozoan immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes, Emulsions, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Immunoglobulin G blood, Interferon-gamma biosynthesis, Interleukin-2 biosynthesis, Interleukin-2 metabolism, Lipid A immunology, Macaca mulatta, Malaria, Vivax immunology, Protozoan Proteins immunology, Toll-Like Receptor 4 immunology, Tumor Necrosis Factor-alpha biosynthesis, Vaccines, Synthetic immunology, Malaria Vaccines immunology, Malaria, Vivax prevention & control, Plasmodium vivax immunology, Toll-Like Receptor 4 agonists
- Abstract
Plasmodium vivax is the major cause of malaria outside sub-Saharan Africa and inflicts debilitating morbidity and consequent economic impacts in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of a novel chimeric recombinant protein, VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Very few adjuvant formulations are currently available for human use. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study rhesus monkeys were immunized intramuscularly three times with VMP001 in combination with a stable emulsion (SE) or a synthetic Toll-like receptor 4 (TLR4) agonist (glucopyranosyl lipid A [GLA]) in SE (GLA-SE). Sera and peripheral blood mononuclear cells (PBMCs) were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of monkeys generated high titers of anti-P. vivax IgG antibodies, as detected by enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence assays. In addition, all groups generated a cellular immune response characterized by antigen-specific CD4(+) T cells secreting predominantly interleukin-2 (IL-2) and lesser amounts of tumor necrosis factor (TNF). We conclude that the combination of VMP001 and GLA-SE is safe and immunogenic in monkeys and may serve as a potential second-generation vaccine candidate against P. vivax malaria.
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- 2011
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12. Process development for the production of an E. coli produced clinical grade recombinant malaria vaccine for Plasmodium vivax.
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Bell BA, Wood JF, Bansal R, Ragab H, Cargo J 3rd, Washington MA, Wood CL, Ware LA, Ockenhouse CF, and Yadava A
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- Animals, Cloning, Molecular, Humans, Immunization methods, Malaria, Falciparum immunology, Plasmodium falciparum immunology, Rabbits immunology, Recombinant Fusion Proteins immunology, Escherichia coli immunology, Malaria Vaccines therapeutic use, Malaria, Vivax immunology, Plasmodium vivax immunology, Vaccines, Synthetic immunology
- Abstract
The global eradication of malaria will require the development of vaccines to prevent infection cause by Plasmodium vivax in addition to Plasmodium falciparum. In an attempt to contribute to this effort we have previously reported the cloning and expression of a vaccine based on the circumsporozoite protein of P. vivax. The synthetic vaccine encodes for a full-length molecule encompassing the N-terminal and C-terminal regions flanking a chimeric repeat region representing VK210 and VK247, the two major alleles of P. vivax CSP. The vaccine, designated vivax malaria protein 001 (VMP001), was purified to >95% homogeneity using a three-column purification scheme and had low endotoxin levels and passed the rabbit pyrogenicity assay. The protein is recognized by monoclonal antibodies directed against the two repeat motifs, as well as polyclonal antibodies. Immunization with VMP001 induced high titer antibodies in mice using Montanide ISA 720. We currently have more than 10,000 doses of purified bulk and 1800 vials of formulated bulk vaccine available for clinical testing and VMP001 is currently undergoing further development as a candidate vaccine to prevent malaria in humans.
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- 2009
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13. A novel chimeric Plasmodium vivax circumsporozoite protein induces biologically functional antibodies that recognize both VK210 and VK247 sporozoites.
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Yadava A, Sattabongkot J, Washington MA, Ware LA, Majam V, Zheng H, Kumar S, and Ockenhouse CF
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- Animals, Antibodies, Protozoan metabolism, Antibodies, Protozoan physiology, Female, Humans, Malaria Vaccines genetics, Malaria, Vivax immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Plasmodium vivax genetics, Protozoan Proteins genetics, Recombinant Fusion Proteins genetics, Sporozoites metabolism, Vaccines, Subunit genetics, Vaccines, Subunit immunology, Antibodies, Protozoan genetics, Malaria Vaccines immunology, Malaria, Vivax prevention & control, Plasmodium vivax immunology, Protozoan Proteins immunology, Recombinant Fusion Proteins immunology, Sporozoites immunology
- Abstract
A successful vaccine against Plasmodium vivax malaria would significantly improve the health and quality of the lives of more than 1 billion people around the world. A subunit vaccine is the only option in the absence of long-term culture of P. vivax parasites. The circumsporozoite protein that covers the surface of Plasmodium sporozoites is one of the best-studied malarial antigens and the most promising vaccine in clinical trials. We report here the development of a novel "immunologically optimal" recombinant vaccine expressed in Escherichia coli that encodes a chimeric CS protein encompassing repeats from the two major alleles, VK210 and VK247. This molecule is widely recognized by sera from patients naturally exposed to P. vivax infection and induces a highly potent immune response in genetically disparate strains of mice. Antibodies from immunized animals recognize both VK210 and VK247 sporozoites. Furthermore, these antibodies appear to be protective in nature since they cause the agglutination of live sporozoites, an in vitro surrogate of sporozoite infectivity. These results strongly suggest that recombinant CS is biologically active and highly immunogenic across major histocompatibility complex strains and raises the prospect that in humans this vaccine may induce protective immune responses.
- Published
- 2007
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14. Effect of codon optimization on expression levels of a functionally folded malaria vaccine candidate in prokaryotic and eukaryotic expression systems.
- Author
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Yadava A and Ockenhouse CF
- Subjects
- Animals, Antibodies, Protozoan biosynthesis, Carrier Proteins genetics, Carrier Proteins immunology, Codon genetics, Erythrocytes parasitology, Escherichia coli genetics, Fluorescent Antibody Technique, Genes, Protozoan, Humans, In Vitro Techniques, Malaria Vaccines chemistry, Malaria Vaccines immunology, Mice, Molecular Sequence Data, Pichia genetics, Protein Folding, Protozoan Proteins genetics, Protozoan Proteins immunology, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins immunology, Species Specificity, Vaccines, Synthetic chemistry, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Antigens, Protozoan, Malaria Vaccines genetics, Plasmodium falciparum genetics, Plasmodium falciparum immunology
- Abstract
We have produced two synthetic genes that code for the F2 domain located within region II of the 175-kDa Plasmodium falciparum erythrocyte binding antigen (EBA-175) to determine the effects of codon alteration on protein expression in homologous and heterologous host systems. EBA-175 plays a key role in the process of merozoite invasion into erythrocytes through a specific receptor-ligand interaction. The F2 domain of EBA-175 is the ligand that binds to the glycophorin A receptor on human erythrocytes and is therefore a target of vaccine development efforts. We designed synthetic genes based on P. falciparum, Escherichia coli, and Pichia codon usage and expressed recombinant F2 in E. coli and Pichia pastoris. Compared to the expression of the native F2 sequence, conversion to prokaryote (E. coli)- or eukaryote (Pichia)-based codon usage dramatically improved the levels of recombinant protein expression in both E. coli and P. pastoris. The majority of the protein expressed in E. coli, however, was produced as inclusion bodies. The protein expressed in P. pastoris, on the other hand, was expressed as a secreted, soluble protein. The P. pastoris-produced protein was superior to that produced in E. coli based on its ability to bind to red blood cells. Consistent with these observations, the antibodies generated against the Pichia-produced protein prevented the binding of recombinant EBA to red blood cells. These antibodies recognize EBA-175 present on merozoites as well as in sporozoites by immunofluorescence. Our results suggest that the Pichia-based EBA-F2 vaccine construct has further potential to be developed for clinical use.
- Published
- 2003
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15. Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.
- Author
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Bennett, Jason W., Yadava, Anjali, Tosh, Donna, Sattabongkot, Jetsumon, Komisar, Jack, Ware, Lisa A., McCarthy, William F., Cowden, Jessica J., Regules, Jason, Spring, Michele D., Paolino, Kristopher, Hartzell, Joshua D., Cummings, James F., Richie, Thomas L., Lumsden, Joanne, Kamau, Edwin, Murphy, Jittawadee, Lee, Cynthia, Parekh, Falgunee, and Birkett, Ashley
- Subjects
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MALARIA vaccines , *PLASMODIUM vivax , *MALARIA treatment , *CIRCUMSPOROZOITE protein , *IMMUNE response , *PARASITEMIA - Abstract
Background: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. Methods: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. Results: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. Significance: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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