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Results: 1 to 9 of 9

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Evaluation of candidate vaccine approaches for MERS-CoV.
Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y, Leung K, Lees CR, Zhou T, Yassine HM, Kanekiyo M, Yang ZY, Chen X, Becker MM, Freeman M, Vogel L, Johnson JC, Olinger G, Todd JP, Bagci U, Solomon J, Mollura DJ, Hensley L, Jahrling P, Denison MR, Rao SS, Subbarao K, Kwong PD, Mascola JR, Kong WP, Graham BS
(2015) Nat Commun 6: 7712
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Coronavirus Infections, DNA, Viral, Female, HEK293 Cells, Humans, Immunoglobulin G, Macaca mulatta, Male, Mice, Mice, Inbred BALB C, Middle East Respiratory Syndrome Coronavirus, Spike Glycoprotein, Coronavirus, Vaccines, DNA, Viral Vaccines
Show Abstract · Added February 22, 2016
The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.
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18 MeSH Terms
Peripheral immunization induces functional intrahepatic hepatitis C specific immunity following selective retention of vaccine-specific CD8 T cells by the liver.
Lang Kuhs KA, Toporovski R, Ginsberg AA, Olsen AL, Shedlock DJ, Morrow MP, Yan J, Wells RG, Weiner DB
(2011) Hum Vaccin 7: 1326-35
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Carrier Proteins, Female, Hepacivirus, Hepatitis C, Humans, Interferon-gamma, Intracellular Signaling Peptides and Proteins, Liver, Mice, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic, Transfection, Vaccination, Vaccines, DNA, Viral Nonstructural Proteins
Show Abstract · Added August 15, 2017
It is believed that an effective HCV vaccine must induce strong HCV-specific cytotoxic IFN-γ⁺ CD8⁺ T cells able to migrate into and become fully activated within the liver, an organ known to suppress T cell responses and induce tolerance. Given the importance of intrahepatic HCV-specific T cells in the clearance of acute infection, the goal of this present study was to determine if peripheral immunization was able to induce functional intrahepatic HCV-specific T cell based immunity both in the presence and absence of HCV antigen expression within the liver. Using a novel HCV NS3/NS4A DNA vaccine, we show that peripheral immunization of C57BL/6 mice results in the formation of a large pool of fully functional HCV-specific cytotoxic IFN-γ⁺ CD8⁺ T cells within the liver and that these cells were highly enriched within the liver as compared to the spleen. Following hepatic expression of cognate HCV antigen using a previously described liver transfection method, we show that this pool of vaccine-induced HCV-specific CD8⁺ T cells retained its ability to become highly activated as shown by the upregulation of IFN-γ and CCR5 expression, as well as by the clearance of HCV NS3 expressing hepatocytes. Taken together, these findings suggest that T cell effector function is preserved within the liver and that selective recruitment of antigen-specific T cells to the liver may play a previously unappreciated role in the process of immune surveillance, which may be exploited for future T cell based HCV vaccines.
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17 MeSH Terms
Hepatitis C virus NS3/NS4A DNA vaccine induces multiepitope T cell responses in rhesus macaques mimicking human immune responses [corrected].
Lang Kuhs KA, Ginsberg AA, Yan J, Wiseman RW, Khan AS, Sardesai NY, O'Connor DH, Weiner DB
(2012) Mol Ther 20: 669-78
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Epitope Mapping, Epitopes, T-Lymphocyte, Genes, MHC Class I, Genotype, Hepacivirus, Humans, Lymphocyte Activation, Macaca mulatta, T-Lymphocytes, Vaccines, DNA, Viral Hepatitis Vaccines, Viral Nonstructural Proteins
Show Abstract · Added August 15, 2017
Numerous studies have suggested that an effective hepatitis C virus (HCV) vaccine must induce a strong T helper 1 (Th1) T cell response. While several therapeutic vaccine candidates have shown promise in clinical trials, response rates have been low suggesting that further optimization is important. However, such optimization has been hindered by a lack of a benchmark animal model in which to test vaccine-induced immune responses before clinical evaluation. The goal of this study was to analyze the utility of the rhesus macaque vaccination model in assessing HCV vaccine-induced T cell responses. To test this, we employed the use of a novel HCV genotype 1a/1b consensus DNA vaccine encoding both HCV nonstructural protein 3 (NS3) and nonstructural protein 4A (NS4A) proteins. Following immunization, rhesus macaques mounted HCV-specific responses strikingly similar to those reported in resolving patients, including strong NS3-specific interferon-γ (IFN-γ) responses, robust CD4(+) and CD8(+) T cell proliferation, and induction of polyfunctional T cells. Additionally, fine epitope mapping revealed one animal that mounted a T cell response against a known HCV NS3 human leukocyte antigen A2 (HLA-A2) epitope previously identified in humans. Taken together our findings suggest that the rhesus macaque vaccination model is a useful tool in the evaluation of immune responses induced by HCV immunogens.
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16 MeSH Terms
Strong HCV NS3- and NS4A-specific cellular immune responses induced in mice and Rhesus macaques by a novel HCV genotype 1a/1b consensus DNA vaccine.
Lang KA, Yan J, Draghia-Akli R, Khan A, Weiner DB
(2008) Vaccine 26: 6225-31
MeSH Terms: Amino Acid Sequence, Animals, Carrier Proteins, Cell Separation, Electroporation, Enzyme-Linked Immunosorbent Assay, Epitope Mapping, Fluorescent Antibody Technique, Genotype, Hepacivirus, Immunity, Cellular, Immunization, Interferon-gamma, Intracellular Signaling Peptides and Proteins, Macaca mulatta, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Spleen, Vaccines, DNA, Viral Nonstructural Proteins, Viral Proteins
Show Abstract · Added August 15, 2017
Hepatitis C virus (HCV) represents a major health burden with more than 170 million individuals currently infected worldwide, equaling roughly 3% of the world's population. HCV preferentially infects hepatocytes and is able to persist in up to 70% of infected individuals. It is estimated that up to 30% of chronically infected individuals will go on to develop progressive liver disease as a result of HCV infection, making the virus the leading cause of liver transplantation in the world. Currently there is no vaccine for HCV. In this study, we have taken a multi-step approach to develop a novel genotype 1a/1b consensus HCV NS3/NS4A DNA vaccine able to induce strong cellular immunity. We show that this construct is able to induce strong anti-NS3/NS4A T cell responses in C57BL/6 mice, as well as, in Rhesus macaques. Our data suggest that DNA vaccines encoding HCV proteins NS3/NS4A merit further study in the context of future prophylactic and therapeutic HCV T cell based vaccines.
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22 MeSH Terms
Enhancement of the CD8+ T cell response to a subdominant epitope of respiratory syncytial virus by deletion of an immunodominant epitope.
Mok H, Lee S, Wright DW, Crowe JE
(2008) Vaccine 26: 4775-82
MeSH Terms: Amino Acid Substitution, Animals, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Female, Immunodominant Epitopes, Mice, Mice, Inbred BALB C, Plasmids, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Viruses, Vaccines, DNA, Viral Proteins
Show Abstract · Added August 6, 2012
Cytotoxic T lymphocytes (CTLs) are critical for the control of respiratory syncytial virus infection (RSV) in humans and mice. Recently, we identified a new H-2K(d)-restricted subdominant epitope in the respiratory syncytial virus M2 protein. In this study, we investigated if modification of anchor residues at positions 2 and 9 in the dominant M2(82-90) epitope in the M2 protein would alter the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 proteins. We showed that immunogenicity of the subdominant epitope M2(127-135) was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to the subdominant epitope.
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13 MeSH Terms
Enhanced immunity to Plasmodium falciparum circumsporozoite protein (PfCSP) by using Salmonella enterica serovar Typhi expressing PfCSP and a PfCSP-encoding DNA vaccine in a heterologous prime-boost strategy.
Chinchilla M, Pasetti MF, Medina-Moreno S, Wang JY, Gomez-Duarte OG, Stout R, Levine MM, Galen JE
(2007) Infect Immun 75: 3769-79
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Protozoan, Bacterial Proteins, Cells, Cultured, Epitopes, Female, Genetic Vectors, Hemolysin Proteins, Immunity, Mucosal, Immunization, Secondary, Interferon-gamma, Leukocytes, Mononuclear, Malaria Vaccines, Mice, Mice, Inbred BALB C, Models, Animal, Molecular Sequence Data, Plasmodium falciparum, Protozoan Proteins, Recombinant Fusion Proteins, Salmonella typhi, Vaccines, DNA
Show Abstract · Added May 27, 2014
Two Salmonella enterica serovar Typhi strains that express and export a truncated version of Plasmodium falciparum circumsporozoite surface protein (tCSP) fused to Salmonella serovar Typhi cytolysin A (ClyA) were constructed as a first step in the development of a preerythrocytic malaria vaccine. Synthetic codon-optimized genes (t-csp1 and t-csp2), containing immunodominant B- and T-cell epitopes present in native P. falciparum circumsporozoite surface protein (PfCSP), were fused in frame to the carboxyl terminus of the ClyA gene (clyA::t-csp) in genetically stabilized expression plasmids. Expression and export of ClyA-tCSP1 and ClyA-tCSP2 by Salmonella serovar Typhi vaccine strain CVD 908-htrA were demonstrated by immunoblotting of whole-cell lysates and culture supernatants. The immunogenicity of these constructs was evaluated using a "heterologous prime-boost" approach consisting of mucosal priming with Salmonella serovar Typhi expressing ClyA-tCSP1 and ClyA-tCSP2, followed by parenteral boosting with PfCSP DNA vaccines pVR2510 and pVR2571. Mice primed intranasally on days 0 and 28 with CVD 908-htrA(pSEC10tcsp2) and boosted intradermally on day 56 with PfCSP DNA vaccine pVR2571 induced high titers of serum NANP immunoglobulin G (IgG) (predominantly IgG2a); no serological responses to DNA vaccination were observed in the absence of Salmonella serovar Typhi-PfCSP priming. Mice primed with Salmonella serovar Typhi expressing tCSP2 and boosted with PfCSP DNA also developed high frequencies of gamma interferon-secreting cells, which surpassed those produced by PfCSP DNA in the absence of priming. A prime-boost regimen consisting of mucosal delivery of PfCSP exported from a Salmonella-based live-vector vaccine followed by a parenteral PfCSP DNA boosting is a promising strategy for the development of a live-vector-based malaria vaccine.
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23 MeSH Terms
Evaluation of the murine immune response to Leishmania meta 1 antigen delivered as recombinant protein or DNA vaccine.
Serezani CH, Franco AR, Wajc M, Umada Yokoyama-Yasunaka JK, Wunderlich G, Borges MM, Uliana SR
(2002) Vaccine 20: 3755-63
MeSH Terms: Animals, Antibodies, Protozoan, COS Cells, Cell Line, Chemokine CCL7, Chlorocebus aethiops, Cytokines, Female, Leishmania major, Leishmania mexicana, Leishmaniasis, Cutaneous, Leishmaniasis, Diffuse Cutaneous, Mice, Mice, Inbred BALB C, Monocyte Chemoattractant Proteins, Protozoan Proteins, Protozoan Vaccines, Recombinant Proteins, Solubility, T-Lymphocyte Subsets, Th1 Cells, Th2 Cells, Vaccines, DNA, Vaccines, Synthetic
Show Abstract · Added May 4, 2017
The meta 1 gene of Leishmania is conserved across the genus and encodes a protein upregulated in metacyclic promastigotes. Meta 1 constitutive overexpressing mutants show increased virulence to mice. In this paper, both meta 1 recombinant protein and plasmids bearing the meta 1 gene were tested for their antigenicity and potential for inducing protective immunity in mice. Vaccination with the recombinant protein induced a predominant Th2-type of response and did not result in protection upon challenge with live parasites. Surprisingly, the expected reversal to a CD4(+) Th1-type of response upon genetic immunisation by the intramuscular route was not observed. Instead, vaccination with either the meta 1 gene alone or in fusion with the monocyte chemotactic protein (MCP)-3 cDNA induced a Th2-type of response that correlated with lack of protection against infection.
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24 MeSH Terms
Respiratory syncytial virus vaccine development.
Crowe JE
(2001) Vaccine 20 Suppl 1: S32-7
MeSH Terms: Animals, Genetic Engineering, Humans, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus Vaccines, Vaccines, DNA, Vaccines, Inactivated, Vaccines, Subunit
Show Abstract · Added August 6, 2012
Development of an RSV vaccine for infants has been hindered by the lack of an ideal animal model that exhibits disease, and the challenge of effectively immunizing very young infants who are immunologically immature. Nevertheless, significant progress has been made recently in developing live attenuated viruses and protein subunit vaccine candidates. Numerous vaccine candidates are currently in early clinical trials. This paper reviews the significant obstacles to development of RSV vaccines, and the progress made to date.
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8 MeSH Terms
Expression, extracellular secretion, and immunogenicity of the Plasmodium falciparum sporozoite surface protein 2 in Salmonella vaccine strains.
Gómez-Duarte OG, Pasetti MF, Santiago A, Sztein MB, Hoffman SL, Levine MM
(2001) Infect Immun 69: 1192-8
MeSH Terms: Animals, Antigens, Protozoan, Female, Immunization, Lymphocyte Activation, Malaria Vaccines, Mice, Mice, Inbred C57BL, Molecular Weight, Plasmodium falciparum, Protozoan Proteins, Salmonella, T-Lymphocytes, Cytotoxic, Vaccines, DNA
Show Abstract · Added May 27, 2014
Deleting transmembrane alpha-helix motifs from Plasmodium falciparum sporozoite surface protein (SSP-2) allowed its secretion from Salmonella enterica serovar Typhimurium SL3261 and S. enterica serovar Typhi CVD 908-htrA by the Hly type I secretion system. In mice immunized intranasally, serovar Typhimurium constructs secreting SSP-2 stimulated greater gamma interferon splenocyte responses than did nonsecreting constructs (P = 0.04).
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14 MeSH Terms