117 results on '"Hannaman D"'
Search Results
2. Electroporation (EP)-related technical errors experienced during an HIV vaccine clinical trial conducted in Rwanda and Uganda: lessons learned
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Bayingana R, Nanvubya A, Karita E, Nyombayire J, Ingabire R, Chinyenze K, Lehrman J, Schimidt C, Hannaman D, Allen S, and Fast P
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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3. OA05-01. In vivo electroporation enhances the immunogenicity of ADVAX, a DNA-based HIV-1 vaccine candidate, in healthy volunteers
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Park H, Schmidt C, Smith C, Dally L, Clark L, Cheeseman H, Gill DK, Tarragona T, Cox J, Huang Y, Andersen J, Caskey M, Vittorino RM, Boente-Carrera MM, Dugin DP, Gardiner DF, Hannaman D, Schlesinger SJ, Hurley A, Vasan S, Sayeed E, Gilmour J, Fast P, Bernard R, and Ho DD
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
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4. A Phase 1 clinical trial of Hantaan virus and Puumala virus M-segment DNA vaccines for haemorrhagic fever with renal syndrome delivered by intramuscular electroporation
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Hooper, J.W., Moon, J.E., Paolino, K.M., Newcomer, R., McLain, D.E., Josleyn, M., Hannaman, D., and Schmaljohn, C.
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- 2014
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5. A DNA vaccination regime including protein boost and electroporation protects cattle against foot-and-mouth disease
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Fowler, V., Robinson, L., Bankowski, B., Cox, S., Parida, S., Lawlor, C., Gibson, D., O’Brien, F., Ellefsen, B., Hannaman, D., Takamatsu, H.-H., and Barnett, P.V.
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- 2012
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6. Electroporation-based DNA transfer enhances gene expression and immune responses to DNA vaccines in cattle
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van Drunen Littel-van den Hurk, S., Luxembourg, A., Ellefsen, B., Wilson, D., Ubach, A., Hannaman, D., and van den Hurk, J.V.
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- 2008
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7. Potentiation of an anthrax DNA vaccine with electroporation
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Luxembourg, A., Hannaman, D., Nolan, E., Ellefsen, B., Nakamura, G., Chau, L., Tellez, O., Little, S., and Bernard, R.
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- 2008
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8. Enhancement of immune responses to an HBV DNA vaccine by electroporation
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Luxembourg, A., Hannaman, D., Ellefsen, B., Nakamura, G., and Bernard, R.
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- 2006
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9. A Phase 2a Randomized, Double-Blind, Dose-Optimizing Study to Evaluate the Immunogenicity and Safety of a Bivalent DNA Vaccine for Hemorrhagic Fever with Renal Syndrome Delivered by Intramuscular Electroporation
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Hooper, Jay, primary, Paolino, K. M., additional, Mills, K., additional, Kwilas, S., additional, Josleyn, M., additional, Cohen, M., additional, Somerville, B., additional, Wisniewski, M., additional, Norris, S., additional, Hill, B., additional, Sanchez-Lockhart, M., additional, Hannaman, D., additional, and Schmaljohn, C. S., additional
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- 2020
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10. Electroporation for DNA immunization: clinical application
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van Drunen Littel-van den Hurk, Sylvia and Hannaman, D
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- 2010
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11. End-of-fabrication CMOS process monitor
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Buehler, M. G, Allen, R. A, Blaes, B. R, Hannaman, D. J, Lieneweg, U, Lin, Y.-S, and Sayah, H. R
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Electronics And Electrical Engineering - Abstract
A set of test 'modules' for verifying the quality of a complementary metal oxide semiconductor (CMOS) process at the end of the wafer fabrication is documented. By electrical testing of specific structures, over thirty parameters are collected characterizing interconnects, dielectrics, contacts, transistors, and inverters. Each test module contains a specification of its purpose, the layout of the test structure, the test procedures, the data reduction algorithms, and exemplary results obtained from 3-, 2-, or 1.6-micrometer CMOS/bulk processes. The document is intended to establish standard process qualification procedures for Application Specific Integrated Circuits (ASIC's).
- Published
- 1990
12. Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial
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Haidari, G., primary, Cope, A., additional, Miller, A., additional, Venables, S., additional, Yan, C., additional, Ridgers, H., additional, Reijonen, K., additional, Hannaman, D., additional, Spentzou, A., additional, Hayes, P., additional, Bouliotis, G., additional, Vogt, A., additional, Joseph, S., additional, Combadiere, B., additional, McCormack, S., additional, and Shattock, R. J., additional
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- 2017
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13. A clinical trial of a DNA vaccine (SCIB1) that targets dendritic cells in vivo in fully resected melanoma patients; a vaccine to prevent disease recurrence?
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Durrant, L G, Ottensmeier, C H, Mulatero, C, Lorigan, P, Plummer, R, Cunnell, M, Metheringham, R, Brentville, V, Machado, Lee, Daniels, I, Hannaman, D, and Patel, P M
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Background: SCIB1 is a DNA vaccine encoding a human IgG1 antibody with CDRs that contain four epitopes from two melanoma antigens (three from gp100 and one from TRP2). The vaccine elicits potent anti-tumour responses by stimulating high frequency, high avidity T-cells via both direct and cross-presentation of antibody. A clinical study in stage III/IV melanoma patients, all with tumour present at study entry, showed that 2-8mg doses could induce T-cell responses in 7/9 patients with no associated toxicity. Encouragingly overall survival was 31 months. This study addresses the question as to whether SCIB1 can be used as an adjuvant therapy in fully resected melanoma patients to prevent further disease. Methods: Sixteen patients with fully resected stage III (n=9) or stage IV (n=7) melanoma were immunised with 4mg of SCIB1 by intramuscular electroporation at 3 weekly intervals and subsequently at 3 and 6 months. Patients could continue treatment for 5 years. Results: All 16 patients showed vaccine-epitope-specific T-cell responses (i.e. proliferation ex vivo and/or γIFN Elispot responses in-vitro). Twelve patients responded to all four epitopes, two patients to three epitopes, one to two epitopes and one to a single epitope. Five patients remain in the continuation phase - all show strong T-cell memory responses following boosting. At present, median survival time is 37 months from trial entry and 41.5 months from diagnosis of metastases. Overall survival is 100% for both groups. Five patients relapsed at 1, 4, 14, 17 and 18 months but have shown no further recurrences at follow-up. Conclusion: These results show that a DNA vaccine encoding epitopes from melanoma antigens can induce measurable T-cell responses and, furthermore, it may confer protection from recurrence of melanoma with little associated toxicity. SCIB1 deserves further evaluation as an adjuvant therapy.
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- 2015
14. 446 IN VIVO ELECTROPORATION SIGNIFICANTLY IMPROVES THERAPEUTIC POTENCY OF A DNA VACCINE TARGETING HEPADNAVIRAL PROTEINS
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Khawaja, G., primary, Buronfosse, T., additional, Guerret, S., additional, Zoulim, F., additional, Luxembourg, A., additional, Hannaman, D., additional, Evans, C.F., additional, Hartmann, D., additional, and Cova, L., additional
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- 2012
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15. Electroporation Enhances Immunogenicity of a DNA Vaccine Expressing Woodchuck Hepatitis Virus Surface Antigen in Woodchucks
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Liu, K. H., primary, Ascenzi, M. A., additional, Bellezza, C. A., additional, Bezuidenhout, A. J., additional, Cote, P. J., additional, Gonzalez-Aseguinolaza, G., additional, Hannaman, D., additional, Luxembourg, A., additional, Evans, C. F., additional, Tennant, B. C., additional, and Menne, S., additional
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- 2011
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16. Codon-optimization of the hemagglutinin gene from the novel swine origin H1N1 influenza virus has differential effects on CD4+ T-cell responses and immune effector mechanisms following DNA electroporation in mice
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Tenbusch, M., primary, Grunwald, T., additional, Niezold, T., additional, Bonsmann, M. Storcksdieck genannt, additional, Hannaman, D., additional, Norley, S., additional, and Überla, K., additional
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- 2010
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17. OA05-01. In vivo electroporation enhances the immunogenicity of ADVAX, a DNA-based HIV-1 vaccine candidate, in healthy volunteers
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Vasan, S, primary, Hurley, A, additional, Schlesinger, SJ, additional, Hannaman, D, additional, Gardiner, DF, additional, Dugin, DP, additional, Boente-Carrera, MM, additional, Vittorino, RM, additional, Caskey, M, additional, Andersen, J, additional, Huang, Y, additional, Cox, J, additional, Tarragona, T, additional, Gill, DK, additional, Cheeseman, H, additional, Clark, L, additional, Dally, L, additional, Smith, C, additional, Schmidt, C, additional, Park, H, additional, Sayeed, E, additional, Gilmour, J, additional, Fast, P, additional, Bernard, R, additional, and Ho, DD, additional
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- 2009
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18. BiCom3HV - A 36V Complementary SiGe Bipolar- and JFET-Technology
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Schwartz, W., primary, Yasuda, H., additional, Steinmann, Ph., additional, Boyd, W., additional, Meinel, W., additional, Hannaman, D., additional, and Parsons, S., additional
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- 2007
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19. Thin-Gate CMOS and Super-Thick Gate DECMOS Integration in 0? On-axis ≪100≫ Starting Wafer: Process Challenges and Solutions.
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Xiaoju Wu, Mahalingam, P., Knerr, R., Patton, Y., Pinghai Hao, Khan, I., and Hannaman, D.
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- 2006
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20. The optimization of LBC6 power/mixed-signal IC BiCMOS process.
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Nehrer, W., Brito, J.C., DeBolske, T., Efland, T., Fleischmann, P., Hannaman, D., Higgins, R., Hutter, L., McNutt, M., Mindricelu, E., Pendharkar, S., Smith, J., and Taylor, R.V.
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- 2001
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21. New degradation mechanism associated with hydrogen in bipolar transistors under hot carrier stress
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Gopi, P. K., primary, Li, G. P., additional, Sonek, G. J., additional, Dunkley, J., additional, Hannaman, D., additional, Patterson, J., additional, and Willard, S., additional
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- 1993
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22. Error Analysis for Optimal Design of Accelerated Tests
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Hannaman, D. J., primary, Zamani, N., additional, Dhiman, J., additional, and Buehler, M. G., additional
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- 1990
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23. The optimization of LBC6 power/mixed-signal IC BiCMOS process
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Nehrer, W., primary, Brito, J.C., additional, DeBolske, T., additional, Efland, T., additional, Fleischmann, P., additional, Hannaman, D., additional, Higgins, R., additional, Hutter, L., additional, McNutt, M., additional, Mindricelu, E., additional, Pendharkar, S., additional, Smith, J., additional, and Taylor, R.V., additional
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24. Surface structure of the (111) face of the non-ordered Fe-32%Ni alloy
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Hannaman, D. J. and Passler, M. A.
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- 1994
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25. Codon-optimization of the hemagglutinin gene from the novel swine origin H1N1 influenza virus has differential effects on CD4+ T-cell responses and immune effector mechanisms following DNA electroporation in mice
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Tenbusch, M., Grunwald, T., Niezold, T., Bonsmann, M. Storcksdieck genannt, Hannaman, D., Norley, S., and Überla, K.
- Subjects
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INFLUENZA A virus, H1N1 subtype , *HEMAGGLUTININ , *SWINE influenza , *T cells , *DNA vaccines , *ELECTROPORATION , *IMMUNE response , *ANIMAL vaccination , *GENETIC vectors - Abstract
Abstract: DNA electroporation is a powerful vaccine strategy that could be rapidly adapted to address emerging viruses. We therefore compared cellular and humoral immune responses in mice vaccinated with DNA expression plasmids encoding either the wildtype or a codon-optimized sequence of hemagglutinin from the novel swine origin H1N1 influenza virus. While expression of HA from the wildtype sequence was hardly detectable, the H1N1 hemagglutinin was well expressed from the codon-optimized sequence. Despite poor expression of the wildtype sequence, both plasmids induced similar levels of CD4+ T-cell responses. However, CD8+ T-cell and antibody responses were substantially higher after immunization with the codon-optimized DNA vaccine. Thus, efficient induction of immune effector mechanisms against HA of the novel H1N1 influenza virus requires codon-optimization of the DNA vaccines. Since DNA vaccines and several viral vector vaccines employ the same cellular RNA-Polymerase II dependent expression pathway, the poor expression levels from wildtype HA sequences might also limit the induction of immune effector mechanisms by such viral vector vaccines. [Copyright &y& Elsevier]
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- 2010
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26. Focusing HIV-1 Gag T-cell Responses to Highly Conserved Regions by DNA Vaccination in HVTN 119.
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Kalams SA, Felber BK, Mullins JI, Scott HM, Allen MA, De Rosa SC, Heptinstall J, Tomaras GD, Hu J, deCamp AC, Rosati M, Bear J, Pensiero MN, Eldridge J, Egan MA, Hannaman D, McElrath MJ, and Pavlakis GN
- Abstract
Background: An HIV-1 DNA vaccine composed of seven highly conserved, structurally important elements (Conserved Elements, CE) of HIV p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. A CE prime- CE+full-length p55Gag boost DNA vaccine was compared to p55Gag DNA vaccination only., Methods: Two groups (n=25 each) received 4 DNA vaccinations [2xCE prime- 2xCE+p55Gag boost or 4x p55Gag] by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n=6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses., Results: Both regimens were safe and generally well-tolerated. The p24CE vaccine was immunogenic (29% CD4+ and 4% CD8+ responders) and was significantly boosted by CE+p55Gag (64% CD4+, p=0.037; 42% CD8+, p=0.004). CE+p55Gag induced CD4+ responses to 5 of 7 CE, compared to only 2 CE by p55Gag DNA alone, with a higher reponse to CE5 in 30% of individuals (p=0.006). CE+p55Gag induced significantly higher mean CD4+ CE Tcell breadth (0.68 vs 0.22 CE; p=0.029) and a strong trend for increased CD4+ and CD8+ T-cell breadth (1.14 vs. 0.52 CE; p=0.051) compared to p55Gag alone. Both groups developed high p55Gag T-cell (91% each) and p24Gag antibody (91% vs. 80%) responses. p24CE vaccine-induced CD4+ CE T-cell responses correlated (p=0.007) with p24Gag antibody responses., Conclusion: The combination CE/CE+p55Gag DNA vaccine induced T-cell immune responses to conserved regions in p24Gag resulting in significant increases in breadth and epitope recognition throughout p55Gag. Vaccines able to focus immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy., Clinical Trials: gov NCT03181789 Study URL: https://www., Clinicaltrials: gov/search?term=NCT03181789 FUNDING. HIV vaccine trial network (HVTN), NIAID/NIH.
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- 2024
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27. The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.
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Jacobson JM, Felber BK, Chen H, Pavlakis GN, Mullins JI, De Rosa SC, Kuritzkes DR, Tomaras GD, Kinslow J, Bao Y, Olefsky M, Rosati M, Bear J, Heptinstall JR, Zhang L, Sawant S, Hannaman D, Laird GM, Cyktor JC, Heath SL, Collier AC, Koletar SL, Taiwo BO, Tebas P, Wohl DA, Belaunzaran-Zamudio PF, McElrath MJ, and Landay AL
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- Humans, Double-Blind Method, Male, Female, Adult, Middle Aged, Anti-Retroviral Agents therapeutic use, Placebos administration & dosage, CD4 Lymphocyte Count, Viral Load, Injections, Intramuscular, Treatment Outcome, Electroporation, Vaccines, DNA immunology, Vaccines, DNA administration & dosage, HIV Infections drug therapy, HIV Infections immunology, AIDS Vaccines immunology, AIDS Vaccines administration & dosage, HIV-1 immunology, HIV-1 genetics, gag Gene Products, Human Immunodeficiency Virus immunology, gag Gene Products, Human Immunodeficiency Virus genetics
- Abstract
Objective: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART)., Design: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4 + T-cell counts greater than 500 cells/μl, and nadir CD4 + T-cell counts greater than 350 cells/μl., Methods: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55 Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55 Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm C). The active and placebo vaccines were administered by intramuscular electroporation., Results: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4 + and/or CD8 + T cells in arm A compared with arm C ( P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) ( P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements., Conclusion: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55 Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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28. Cellular and humoral responses to an HIV DNA prime by electroporation boosted with recombinant vesicular stomatitis virus expressing HIV subtype C Env in a randomized controlled clinical trial.
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Wilson GJ, Rodriguez B, Li SS, Allen M, Frank I, Rudnicki E, Trahey M, Kalams S, Hannaman D, Clarke DK, Xu R, Egan M, Eldridge J, Pensiero M, Latham T, Ferrari G, Montefiori DC, Tomaras GD, De Rosa SC, Jacobson JM, Miner MD, and Elizaga M
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- Adult, Animals, Humans, Immunization, Secondary, Electroporation, Antibodies, Neutralizing, DNA, HIV Antibodies, HIV Infections prevention & control, Vesicular Stomatitis, AIDS Vaccines, Vaccines, DNA
- Abstract
Background: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost., Methods: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses., Results: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected., Conclusions: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications., Clinicaltrials: gov: NCT02654080., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The following authors declare no conflicts of interest: MT, MDM, JE, DCM, JMJ, ME, DKC, GJW, GDT, GF, SK, ER, ME, TL, RX, SL. MA and MP are employed by NIAID but had no role in the funding decisions or grant oversight. DH is a full-time employee of Ichor Medical Systems, Inc. and receives a salary and equity for this work. SCDR reports funding from NIH, Bill & Melinda Gates Foundation for the work. IF gets research support from Moderna, Janssen, Pfizer and Sanofi, and is a consultant for Gilead, GlaxoSmithKline and Merck., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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29. Acceptability and tolerability of repeated intramuscular electroporation of Multi-antigenic HIV (HIVMAG) DNA vaccine among healthy African participants in a phase 1 randomized controlled trial.
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Mpendo J, Mutua G, Nanvubya A, Anzala O, Nyombayire J, Karita E, Dally L, Hannaman D, Price M, Fast PE, Priddy F, Gelderblom HC, and Hills NK
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- Adolescent, Adult, Double-Blind Method, Female, Humans, Male, Middle Aged, AIDS Vaccines administration & dosage, Electroporation, Muscle Contraction, Muscle, Skeletal, Vaccination, Vaccines, DNA administration & dosage
- Abstract
Introduction: Intramuscular electroporation (IM/EP) is a vaccine delivery technique that improves the immunogenicity of DNA vaccines. We evaluated the acceptability and tolerability of electroporation among healthy African study participants., Methods: Forty-five participants were administered a DNA vaccine (HIV-MAG) or placebo by electroporation at three visits occurring at four week-intervals. At the end of each visit, participants were asked to rate pain at four times: (1) when the device was placed on the skin and vaccine injected, before the electrical stimulation, (2) at the time of electrical stimulation and muscle contraction, and (3) at 10 minutes and (4) 30 minutes after the procedure was completed. For analyses, pain level was dichotomized as either "acceptable" (none/slight/uncomfortable) or "too much" (Intense, severe, and very severe) and examined over time using repeated measures models. Optional brief comments made by participants were summarized anecdotally., Results: All 45 participants completed all three vaccination visits; none withdrew from the study due to the electroporation procedure. Most (76%) reported pain levels as acceptable at every time point across all vaccination visits. The majority of "unacceptable" pain was reported at the time of electrical stimulation. The majority of the participants (97%) commented that they preferred electroporation to standard injection., Conclusion: Repeated intramuscular electroporation for vaccine delivery was found to be acceptable and feasible among healthy African HIV vaccine trial participants. The majority of participants reported an acceptable pain level at all vaccination time points. Further investigation may be warranted into the value of EP to improve immunization outcomes. ClinicalTrials.gov NCT01496989., Competing Interests: PEF, MP and FP were employees of IAVI at the time of the study. DH is an employee of Ichor Medical Sciences Inc which owns the rights to the TriGrid Delivery System. The rest of the authors have no competing interests.
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- 2020
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30. The Safety and Immunogenicity of GTU ® MultiHIV DNA Vaccine Delivered by Transcutaneous and Intramuscular Injection With or Without Electroporation in HIV-1 Positive Subjects on Suppressive ART.
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Haidari G, Day S, Wood M, Ridgers H, Cope AV, Fleck S, Yan C, Reijonen K, Hannaman D, Spentzou A, Hayes P, Vogt A, Combadiere B, Cook A, McCormack S, and Shattock RJ
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines adverse effects, Administration, Cutaneous, Antiretroviral Therapy, Highly Active, Cytokines metabolism, Electroporation, HIV Infections drug therapy, Humans, Injections, Intramuscular, Patient Outcome Assessment, Vaccination, Vaccines, DNA administration & dosage, Vaccines, DNA adverse effects, AIDS Vaccines immunology, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology, Immunogenicity, Vaccine, Vaccines, DNA immunology
- Abstract
Previous studies have shown targeting different tissues via the transcutaneous (TC) and intramuscular injection (IM) with or without electroporation (EP) has the potential to trigger immune responses to DNA vaccination. The CUTHIVTHER 001 Phase I/II randomized controlled clinical trial was designed to determine whether the mode of DNA vaccination delivery (TC+IM or EP+IM) could influence the quality and function of induced cellular immune responses compared to placebo, in an HIV positive clade B cohort on antiretroviral therapy (ART). The GTU
® MultiHIV B DNA vaccine DNA vaccine encoded a MultiHIV B clade fusion protein to target the cellular response. Overall the vaccine and regimens were safe and well-tolerated. There were robust pre-vaccination IFN-γ responses with no measurable change following vaccination compared to placebo. However, modest intracellular cytokine staining (ICS) responses were seen in the TC+IM group. A high proportion of individuals demonstrated potent viral inhibition at baseline that was not improved by vaccination. These results show that HIV positive subjects with nadir CD4+ counts ≥250 on suppressive ART display potent levels of cellular immunity and viral inhibition, and that DNA vaccination alone is insufficient to improve such responses. These data suggest that more potent prime-boost vaccination strategies are likely needed to improve pre-existing responses in similar HIV-1 cohorts (This study has been registered at http://ClinicalTrials.gov under registration no. NCT02457689)., (Copyright © 2019 Haidari, Day, Wood, Ridgers, Cope, Fleck, Yan, Reijonen, Hannaman, Spentzou, Hayes, Vogt, Combadiere, Cook, McCormack and Shattock.)- Published
- 2019
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31. Glycosylation of HIV Env Impacts IgG Subtype Responses to Vaccination.
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Heß R, Storcksdieck Genannt Bonsmann M, Lapuente D, Maaske A, Kirschning C, Ruland J, Lepenies B, Hannaman D, Tenbusch M, and Überla K
- Subjects
- Animals, Glycosylation, Hemagglutinin Glycoproteins, Influenza Virus genetics, Hemagglutinin Glycoproteins, Influenza Virus immunology, Immunity, Humoral, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Th2 Cells immunology, Viral Fusion Proteins genetics, Viral Fusion Proteins immunology, AIDS Vaccines immunology, HIV Antibodies immunology, Immunoglobulin G immunology, Vaccines, DNA immunology, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
The envelope protein (Env) is the only surface protein of the human immunodeficiency virus (HIV) and as such the exclusive target for protective antibody responses. Experimental evidences from mouse models suggest a modulating property of Env to steer antibody class switching towards the less effective antibody subclass IgG1 accompanied with strong TH2 helper responses. By simple physical linkage we were able to imprint this bias, exemplified by a low IgG2a/IgG1 ratio of antigen-specific antibodies, onto an unrelated antigen, namely the HIV capsid protein p24. Here, our results indicate the glycan moiety of Env as the responsible immune modulating activity. Firstly, in Card9
-/- mice lacking specific C-Type lectin responsiveness, DNA immunization significantly increased the IgG2a/IgG1 ratio for the Env-specific antibodies while the antibody response against the F-protein of the respiratory syncytial virus (RSV) serving as control antigen remained unchanged. Secondly, sequential shortening of the Env encoding sequence revealed the C2V3 domain as responsible for the strong IgG1 responses and TH2 cytokine production. Removing all potential N-glycosylation sites from the C2V3 domain by site-specific mutagenesis reversed the vaccine-induced immune response towards a Th1-dominated T-cell response and a balanced IgG2a/IgG1 ratio. Accordingly, the stretch of oligomannose glycans in the C2V3 domain of Env might mediate a specific uptake and/or signaling modus in antigen presenting cells by involving interaction with an as yet unknown C-type lectin receptor. Our results contribute to a deeper understanding of the impact of Env glycosylation on HIV antigen-specific immune responses, which will further support HIV vaccine development.- Published
- 2019
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32. Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial.
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Elizaga ML, Li SS, Kochar NK, Wilson GJ, Allen MA, Tieu HVN, Frank I, Sobieszczyk ME, Cohen KW, Sanchez B, Latham TE, Clarke DK, Egan MA, Eldridge JH, Hannaman D, Xu R, Ota-Setlik A, McElrath MJ, and Hay CM
- Subjects
- AIDS Vaccines adverse effects, Adult, Combined Modality Therapy, Double-Blind Method, Electroporation, Female, Genetic Vectors adverse effects, HIV-1, Healthy Volunteers, Humans, Immunization, Secondary, Injections, Intramuscular, Male, Middle Aged, Plasmids genetics, Vaccines, Attenuated adverse effects, Vaccines, DNA adverse effects, Young Adult, gag Gene Products, Human Immunodeficiency Virus, AIDS Vaccines administration & dosage, Genetic Vectors administration & dosage, Interleukin-12 genetics, Vaccines, Attenuated administration & dosage, Vaccines, DNA administration & dosage, Vesicular stomatitis Indiana virus genetics
- Abstract
Background: The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant., Methods: In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 μg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 μg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 ⊆ 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months., Results: The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination., Conclusions: HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated., Trial Registration: Clinical Trials.gov NCT01578889., Competing Interests: The authors have read the journal policy and the authors of this manuscript have the following competing interests: MAA is employed by the National Institute of Allergy and Infectious Diseases (NIAID), the study sponsor. MLE, SSL, NKK, GJW, HVNT, IF, MES, KWC, BSP, JHE, MJM and CMH are recipients of NIAID funding, and this publication is a result of activities funded by NIAID. MAA is not involved with the process of funding these awards, nor in their administration of scientific aspects and, in accordance with NIAID policies, is deferred from decisions regarding funding of coauthors for a requisite period. TEL, DKC, JHE, RX, and AOS are employees and stakeholders of Profectus BioSciences, Inc. DKC is the principal author/inventor on a patent for the rVSVN4CT1 vector. At the time the study was conducted, MAE was an employee and stakeholder of Profectus BioSciences, Inc. and is now an employee of Takeda Pharmaceuticals, which has no affiliation with the study. DH is an employee and stakeholder of Ichor Medical Systems, Inc. IF serves on advisory boards for Gilead Sciences and ViiV Healthcare. HVNT has received research grant funding from Merck & Co. These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.
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- 2018
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33. Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine.
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Cheeseman HM, Day S, McFarlane LR, Fleck S, Miller A, Cole T, Sousa-Santos N, Cope A, Cizmeci D, Tolazzi M, Hwekwete E, Hannaman D, Kratochvil S, McKay PF, Chung AW, Kent SJ, Cook A, Scarlatti G, Abraham S, Combadiere B, McCormack S, Lewis DJ, and Shattock RJ
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines immunology, Adolescent, Adult, Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, DNA Primers immunology, Electroporation, Female, HIV-1 immunology, HIV-1 pathogenicity, Healthy Volunteers, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II immunology, Humans, Immunity, Cellular drug effects, Immunity, Cellular immunology, Immunity, Humoral drug effects, Immunity, Humoral immunology, Injections, Intradermal, Injections, Intramuscular, Male, Middle Aged, Vaccination methods, Vaccines, DNA immunology, Young Adult, env Gene Products, Human Immunodeficiency Virus genetics, env Gene Products, Human Immunodeficiency Virus immunology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, Vaccines, DNA administration & dosage, env Gene Products, Human Immunodeficiency Virus administration & dosage
- Abstract
Intradermal (i.d.) and intramuscular (i.m.) injections when administered with or without electroporation (EP) have the potential to tailor the immune response to DNA vaccination. This Phase I randomized controlled clinical trial in human immunodeficiency virus type 1-negative volunteers investigated whether the site and mode of DNA vaccination influences the quality of induced cellular and humoral immune responses following the DNA priming phase and subsequent protein boost with recombinant clade C CN54 gp140. A strategy of concurrent i.d. and i.m. DNA immunizations administered with or without EP was adopted. Subtle differences were observed in the shaping of vaccine-induced virus-specific CD4+ and CD8+ T cell-mediated immune responses between groups receiving: i.d.
EP + i.m., i.d. + i.m.EP , and i.d.EP + i.m.EP regimens. The DNA priming phase induced 100% seroconversion in all of the groups. A single, non-adjuvanted protein boost induced a rapid and profound increase in binding antibodies in all groups, with a trend for higher responses in i.d.EP + i.m.EP . The magnitude of antigen-specific binding immunoglobulin G correlated with neutralization of closely matched clade C 93MW965 virus and Fc-dimer receptor binding (FcγRIIa and FcγRIIIa). These results offer new perspectives on the use of combined skin and muscle DNA immunization in priming humoral and cellular responses to recombinant protein.- Published
- 2018
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34. A Multiagent Alphavirus DNA Vaccine Delivered by Intramuscular Electroporation Elicits Robust and Durable Virus-Specific Immune Responses in Mice and Rabbits and Completely Protects Mice against Lethal Venezuelan, Western, and Eastern Equine Encephalitis Virus Aerosol Challenges.
- Author
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Dupuy LC, Richards MJ, Livingston BD, Hannaman D, and Schmaljohn CS
- Subjects
- Aerosols, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Antibody Specificity immunology, Disease Models, Animal, Electroporation, Female, Immunity, Cellular immunology, Immunization, Mice, Rabbits, Vaccines, DNA administration & dosage, Viral Vaccines administration & dosage, Alphavirus genetics, Alphavirus immunology, Encephalitis Virus, Eastern Equine immunology, Encephalomyelitis, Equine immunology, Encephalomyelitis, Equine prevention & control, Genetic Vectors administration & dosage, Genetic Vectors genetics, Genetic Vectors immunology, Vaccines, DNA immunology, Viral Vaccines immunology
- Abstract
There remains a need for vaccines that can safely and effectively protect against the biological threat agents Venezuelan (VEEV), western (WEEV), and eastern (EEEV) equine encephalitis virus. Previously, we demonstrated that a VEEV DNA vaccine that was optimized for increased antigen expression and delivered by intramuscular (IM) electroporation (EP) elicited robust and durable virus-specific antibody responses in multiple animal species and provided complete protection against VEEV aerosol challenge in mice and nonhuman primates. Here, we performed a comparative evaluation of the immunogenicity and protective efficacy of individual optimized VEEV, WEEV, and EEEV DNA vaccines with that of a 1 : 1 : 1 mixture of these vaccines, which we have termed the 3-EEV DNA vaccine, when delivered by IM EP. The individual DNA vaccines and the 3-EEV DNA vaccine elicited robust and durable virus-specific antibody responses in mice and rabbits and completely protected mice from homologous VEEV, WEEV, and EEEV aerosol challenges. Taken together, the results from these studies demonstrate that the individual VEEV, WEEV, and EEEV DNA vaccines and the 3-EEV DNA vaccine delivered by IM EP provide an effective means of eliciting protection against lethal encephalitic alphavirus infections in a murine model and represent viable next-generation vaccine candidates that warrant further development.
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- 2018
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35. Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial.
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Patel PM, Ottensmeier CH, Mulatero C, Lorigan P, Plummer R, Pandha H, Elsheikh S, Hadjimichael E, Villasanti N, Adams SE, Cunnell M, Metheringham RL, Brentville VA, Machado L, Daniels I, Gijon M, Hannaman D, and Durrant LG
- Abstract
A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2-8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor ( p < 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose ( p < 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy ( p = 0.027). We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease.
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- 2018
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36. Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques.
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Datta D, Bansal GP, Grasperge B, Martin DS, Philipp M, Gerloff D, Ellefsen B, Hannaman D, and Kumar N
- Subjects
- Animals, DNA, Protozoan administration & dosage, Electroporation, Female, Immunization Schedule, Macaca mulatta, Male, Membrane Glycoproteins genetics, Plasmids administration & dosage, Plasmodium falciparum genetics, Protozoan Proteins genetics, Treatment Outcome, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Antibodies, Protozoan blood, Membrane Glycoproteins immunology, Plasmodium falciparum immunology, Protozoan Proteins immunology, Vaccines, DNA immunology
- Abstract
Antibodies recognizing conformational epitopes in Pfs48/45, an antigen expressed on the surface of Plasmodium falciparum gametes and zygotes, have firmly established Pfs48/45 as a promising transmission blocking vaccine (TBV) candidate. However, it has been difficult to reproducibly express Pfs48/45 in a variety of recombinant expression systems. The goal of our studies was to evaluate functional immunogenicity of Pfs48/45 using DNA vaccine format in rhesus macaques. An additional goal was to ensure that when used in combination with another malarial antigen, specific immunity to both antigens was not compromised. For testing combination vaccines, we employed Pfs25 DNA plasmids that have previously undergone evaluations in rodents and nonhuman primates. Pfs25 is expressed on the surface of parasites after fertilization and is also a lead TBV candidate. DNA plasmids based on codon-optimized sequences of Pfs48/45 and Pfs25 were administered by in vivo electroporation, followed by a final recombinant protein boost. Our studies demonstrate that Pfs48/45 encoded by DNA plasmids is capable of inducing potent transmission blocking antibody responses, and such transmission blocking immune potency of Pfs48/45 was not compromised when tested in combination with Pfs25, These findings provide the evidence in favor of further studies on Pfs48/45 and Pfs25, either alone or in combination with other known malaria vaccine candidates for developing effective vaccines capable of interrupting malaria transmission., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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37. An immunoinformatics-derived DNA vaccine encoding human class II T cell epitopes of Ebola virus, Sudan virus, and Venezuelan equine encephalitis virus is immunogenic in HLA transgenic mice.
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Bounds CE, Terry FE, Moise L, Hannaman D, Martin WD, De Groot AS, Suschak JJ, Dupuy LC, and Schmaljohn CS
- Subjects
- Animals, Ebolavirus genetics, Encephalitis Virus, Venezuelan Equine genetics, Enzyme-Linked Immunospot Assay, Epitopes, T-Lymphocyte genetics, Female, Histocompatibility Antigens Class II genetics, Humans, Interferon-gamma metabolism, Mice, Inbred BALB C, Mice, Transgenic, Protein Binding, T-Lymphocytes immunology, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Viral Vaccines administration & dosage, Viral Vaccines genetics, Ebolavirus immunology, Encephalitis Virus, Venezuelan Equine immunology, Epitopes, T-Lymphocyte immunology, Histocompatibility Antigens Class II metabolism, Vaccines, DNA immunology, Viral Vaccines immunology
- Abstract
Immunoinformatics tools were used to predict human leukocyte antigen (HLA) class II-restricted T cell epitopes within the envelope glycoproteins and nucleocapsid proteins of Ebola virus (EBOV) and Sudan virus (SUDV) and the structural proteins of Venezuelan equine encephalitis virus (VEEV). Selected epitopes were tested for binding to soluble HLA molecules representing 5 class II alleles (DRB1*0101, DRB1*0301, DRB1*0401, DRB1*0701, and DRB1*1501). All but one of the 25 tested peptides bound to at least one of the DRB1 alleles, and 4 of the peptides bound at least moderately or weakly to all 5 DRB1 alleles. Additional algorithms were used to design a single "string-of-beads" expression construct with 44 selected epitopes arranged to avoid creation of spurious junctional epitopes. Seventeen of these 44 predicted epitopes were conserved between the major histocompatibility complex (MHC) of humans and mice, allowing initial testing in mice. BALB/c mice vaccinated with the multi-epitope construct developed statistically significant cellular immune responses to EBOV, SUDV, and VEEV peptides as measured by interferon (IFN)-γ ELISpot assays. Significant levels of antibodies to VEEV, but not EBOV, were also detected in vaccinated BALB/c mice. To assess immunogenicity in the context of a human MHC, HLA-DR3 transgenic mice were vaccinated with the multi-epitope construct and boosted with a mixture of the 25 peptides used in the binding assays. The vaccinated HLA-DR3 mice developed significant cellular immune responses to 4 of the 25 (16%) tested individual class II peptides as measured by IFN-γ ELISpot assays. In addition, these mice developed antibodies against EBOV and VEEV as measured by ELISA. While a low but significant level of protection was observed in vaccinated transgenic mice after aerosol exposure to VEEV, no protection was observed after intraperitoneal challenge with mouse-adapted EBOV. These studies provide proof of concept for the use of an informatics approach to design a multi-agent, multi-epitope immunogen and provide a basis for further testing aimed at focusing immune responses toward desired protective T cell epitopes.
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- 2017
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38. DNA Priming Increases Frequency of T-Cell Responses to a Vesicular Stomatitis Virus HIV Vaccine with Specific Enhancement of CD8 + T-Cell Responses by Interleukin-12 Plasmid DNA.
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Li SS, Kochar NK, Elizaga M, Hay CM, Wilson GJ, Cohen KW, De Rosa SC, Xu R, Ota-Setlik A, Morris D, Finak G, Allen M, Tieu HV, Frank I, Sobieszczyk ME, Hannaman D, Gottardo R, Gilbert PB, Tomaras GD, Corey L, Clarke DK, Egan MA, Eldridge JH, McElrath MJ, and Frahm N
- Subjects
- AIDS Vaccines administration & dosage, Adjuvants, Immunologic, Adult, Epitope Mapping, Female, Genetic Vectors, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology, Humans, Immunization, Secondary, Interleukin-12 genetics, Male, Middle Aged, Plasmids, Vaccination, Vaccines, DNA administration & dosage, Vesicular stomatitis Indiana virus immunology, Young Adult, gag Gene Products, Human Immunodeficiency Virus genetics, gag Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines immunology, CD8-Positive T-Lymphocytes immunology, Immunogenicity, Vaccine, Interleukin-12 immunology, Vaccines, DNA immunology, Vesicular stomatitis Indiana virus genetics
- Abstract
The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 gag / pol or ProfectusVax nef / tat / vif , env ) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 μg intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 × 10
7 PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. High-dose pIL-12 increased the magnitude of CD8+ T-cell responses postboost compared to no pIL-12 ( P = 0.02), while CD4+ T-cell responses after the prime were higher in the absence of pIL-12 than with low- and medium-dose pIL-12 ( P ≤ 0.05). The VSV boost increased Gag-specific CD4+ and CD8+ T-cell responses in all groups ( P < 0.001 for CD4+ T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8+ T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8+ T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8+ T-cell responses but decreased the CD4+ responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.)., (Copyright © 2017 American Society for Microbiology.)- Published
- 2017
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39. A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models.
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Garrison AR, Shoemaker CJ, Golden JW, Fitzpatrick CJ, Suschak JJ, Richards MJ, Badger CV, Six CM, Martin JD, Hannaman D, Zivcec M, Bergeron E, Koehler JW, and Schmaljohn CS
- Subjects
- Animals, Disease Models, Animal, Glycoproteins genetics, Glycoproteins immunology, Hemorrhagic Fever Virus, Crimean-Congo genetics, Hemorrhagic Fever Virus, Crimean-Congo isolation & purification, Hemorrhagic Fever, Crimean immunology, Hemorrhagic Fever, Crimean virology, Humans, Immunity, Humoral, Immunocompromised Host, Mice, Mice, Knockout, Receptor, Interferon alpha-beta deficiency, Receptor, Interferon alpha-beta genetics, Th1 Cells immunology, Th2 Cells immunology, Vaccination, Vaccines, DNA administration & dosage, Viral Proteins genetics, Viral Proteins immunology, Viral Vaccines administration & dosage, Antibodies, Neutralizing blood, Antibodies, Viral blood, Hemorrhagic Fever Virus, Crimean-Congo immunology, Hemorrhagic Fever, Crimean prevention & control, Immunogenicity, Vaccine, Vaccines, DNA immunology, Viral Vaccines immunology
- Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a severe hemorrhagic fever disease in humans. There are currently no licensed vaccines to prevent CCHFV-associated disease. We developed a DNA vaccine expressing the M-segment glycoprotein precursor gene of CCHFV and assessed its immunogenicity and protective efficacy in two lethal mouse models of disease: type I interferon receptor knockout (IFNAR-/-) mice; and a novel transiently immune suppressed (IS) mouse model. Vaccination of mice by muscle electroporation of the M-segment DNA vaccine elicited strong antigen-specific humoral immune responses with neutralizing titers after three vaccinations in both IFNAR-/- and IS mouse models. To compare the protective efficacy of the vaccine in the two models, groups of vaccinated mice (7-10 per group) were intraperitoneally (IP) challenged with a lethal dose of CCHFV strain IbAr 10200. Weight loss was markedly reduced in CCHFV DNA-vaccinated mice as compared to controls. Furthermore, whereas all vector-control vaccinated mice succumbed to disease by day 5, the DNA vaccine protected >60% of the animals from lethal disease. Mice from both models developed comparable levels of antibodies, but the IS mice had a more balanced Th1/Th2 response to vaccination. There were no statistical differences in the protective efficacies of the vaccine in the two models. Our results provide the first comparison of these two mouse models for assessing a vaccine against CCHFV and offer supportive data indicating that a DNA vaccine expressing the glycoprotein genes of CCHFV elicits protective immunity against CCHFV.
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- 2017
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40. Immunogenicity and malaria transmission reducing potency of Pfs48/45 and Pfs25 encoded by DNA vaccines administered by intramuscular electroporation.
- Author
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Datta D, Bansal GP, Gerloff DL, Ellefsen B, Hannaman D, and Kumar N
- Subjects
- Animals, Antibodies, Protozoan blood, Antigens, Protozoan genetics, Antigens, Protozoan immunology, Disease Transmission, Infectious prevention & control, Electroporation, Female, Malaria, Falciparum transmission, Membrane Glycoproteins genetics, Mice, Inbred BALB C, Protozoan Proteins genetics, Malaria Vaccines administration & dosage, Malaria Vaccines immunology, Malaria, Falciparum prevention & control, Membrane Glycoproteins immunology, Protozoan Proteins immunology, Vaccines, DNA administration & dosage, Vaccines, DNA immunology
- Abstract
Pfs48/45 and Pfs25 are leading candidates for the development of Plasmodium falciparum transmission blocking vaccines (TBV). Expression of Pfs48/45 in the erythrocytic sexual stages and presentation to the immune system during infection in the human host also makes it ideal for natural boosting. However, it has been challenging to produce a fully folded, functionally active Pfs48/45, using various protein expression platforms. In this study, we demonstrate that full-length Pfs48/45 encoded by DNA plasmids is able to induce significant transmission reducing immune responses. DNA plasmids encoding Pfs48/45 based on native (WT), codon optimized (SYN), or codon optimized and mutated (MUT1 and MUT2), to prevent any asparagine (N)-linked glycosylation were compared with or without intramuscular electroporation (EP). EP significantly enhanced antibody titers and transmission blocking activity elicited by immunization with SYN Pfs48/45 DNA vaccine. Mosquito membrane feeding assays also revealed improved functional immunogenicity of SYN Pfs48/45 (N-glycosylation sites intact) as compared to MUT1 or MUT2 Pfs48/45 DNA plasmids (all N-glycosylation sites mutated). Boosting with recombinant Pfs48/45 protein after immunization with each of the different DNA vaccines resulted in significant boosting of antibody response and improved transmission reducing capabilities of all four DNA vaccines. Finally, immunization with a combination of DNA plasmids (SYN Pfs48/45 and SYN Pfs25) also provides support for the possibility of combining antigens targeting different life cycle stages in the parasite during transmission through mosquitoes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
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- 2017
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41. A phase 1, randomized, controlled dose-escalation study of EP-1300 polyepitope DNA vaccine against Plasmodium falciparum malaria administered via electroporation.
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Spearman P, Mulligan M, Anderson EJ, Shane AL, Stephens K, Gibson T, Hartwell B, Hannaman D, Watson NL, and Singh K
- Subjects
- Adolescent, Adult, Africa, Antibodies, Protozoan biosynthesis, Antibodies, Protozoan blood, Dose-Response Relationship, Immunologic, Electroporation, Epitopes, T-Lymphocyte administration & dosage, Epitopes, T-Lymphocyte immunology, Female, Humans, Malaria Vaccines adverse effects, Malaria, Falciparum epidemiology, Male, Plasmodium falciparum immunology, Protozoan Proteins immunology, Vaccines, DNA adverse effects, Vaccines, DNA chemistry, Young Adult, Immunogenicity, Vaccine, Malaria Vaccines administration & dosage, Malaria Vaccines immunology, Malaria, Falciparum prevention & control, Vaccines, DNA administration & dosage, Vaccines, DNA immunology
- Abstract
Plasmodium falciparum malaria is one of the leading infectious causes of childhood mortality in Africa. EP-1300 is a polyepitope plasmid DNA vaccine expressing 38 cytotoxic T cell epitopes and 16 helper T cell epitopes derived from P. falciparum antigens expressed predominantly in the liver phase of the parasite's life cycle. We performed a phase 1 randomized, placebo-controlled, dose escalation clinical trial of the EP-1300 DNA vaccine administered via electroporation using the TriGrid Delivery System device (Ichor Medical Systems). Although the delivery of the EP-1300 DNA vaccine via electroporation was safe, tolerability was less than that usually observed with standard needle and syringe intramuscular administration. This was primarily due to acute local discomfort at the administration site during electroporation. Despite the use of electroporation, the vaccine was poorly immunogenic. The reasons for the poor immunogenicity of this polyepitope DNA vaccine remain uncertain., Clinical Trials Registration: ClinicalTrials.gov NCT01169077., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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42. Broad HIV-1 inhibition in vitro by vaccine-elicited CD8(+) T cells in African adults.
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Mutua G, Farah B, Langat R, Indangasi J, Ogola S, Onsembe B, Kopycinski JT, Hayes P, Borthwick NJ, Ashraf A, Dally L, Barin B, Tillander A, Gilmour J, De Bont J, Crook A, Hannaman D, Cox JH, Anzala O, Fast PE, Reilly M, Chinyenze K, Jaoko W, Hanke T, and Hiv-Core 004 Study Group T
- Abstract
We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8(+) T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy.
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- 2016
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43. A Phase 1 clinical trial of a DNA vaccine for Venezuelan equine encephalitis delivered by intramuscular or intradermal electroporation.
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Hannaman D, Dupuy LC, Ellefsen B, and Schmaljohn CS
- Subjects
- Adolescent, Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, Double-Blind Method, Electroporation, Encephalitis Virus, Venezuelan Equine, Female, Humans, Immunogenicity, Vaccine, Injections, Intradermal, Injections, Intramuscular, Male, Middle Aged, Vaccines, DNA therapeutic use, Viral Vaccines therapeutic use, Young Adult, Encephalomyelitis, Venezuelan Equine prevention & control, Vaccines, DNA administration & dosage, Viral Vaccines administration & dosage
- Abstract
Venezuelan equine encephalitis virus (VEEV), a mosquito-borne alphavirus, causes periodic epizootics in equines and is a recognized biological defense threat for humans. There are currently no FDA-licensed vaccines against VEEV. We developed a candidate DNA vaccine expressing the E3-E2-6K-E1 genes of VEEV (pWRG/VEE) and performed a Phase 1 clinical study to assess the vaccine's safety, reactogenicity, tolerability, and immunogenicity when administered by intramuscular (IM) or intradermal (ID) electroporation (EP) using the Ichor Medical Systems TriGrid™ Delivery System. Subjects in IM-EP groups received 0.5mg (N=8) or 2.0mg (N=9) of pWRG/VEE or a saline placebo (N=4) in a 1.0ml injection. Subjects in ID-EP groups received 0.08mg (N=8) or 0.3mg (N=8) of DNA or a saline placebo (N=4) in a 0.15ml injection. Subjects were monitored for a total period of 360 days. No vaccine- or device-related serious adverse events were reported. Based on the results of a subject questionnaire, the IM- and ID-EP procedures were both considered to be generally acceptable for prophylactic vaccine administration, with the acute tolerability of ID EP delivery judged to be greater than that of IM-EP delivery. All subjects (100%) in the high and low dose IM-EP groups developed detectable VEEV-neutralizing antibodies after two or three administrations of pWRG/VEE, respectively. VEEV-neutralizing antibody responses were detected in seven of eight subjects (87.5%) in the high dose and five of eight subjects (62.5%) in the low dose ID-EP groups after three vaccine administrations. There was a correlation between the DNA dose and the magnitude of the resulting VEEV-neutralizing antibody responses for both IM and ID EP delivery. These results indicate that pWRG/VEE delivered by either IM- or ID-EP is safe, tolerable, and immunogenic in humans at the evaluated dose levels. Clinicaltrials.gov registry number NCT01984983., (Published by Elsevier Ltd.)
- Published
- 2016
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44. The improved antibody response against HIV-1 after a vaccination based on intrastructural help is complemented by functional CD8+ T cell responses.
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Storcksdieck genannt Bonsmann M, Niezold T, Hannaman D, Überla K, and Tenbusch M
- Subjects
- Animals, Antibody Formation, Cytokines immunology, Electroporation, HIV Antibodies blood, HIV-1, Immunization, Secondary, Immunoglobulin G blood, Mice, Mice, Inbred BALB C, Vaccines, DNA immunology, Vaccines, Virus-Like Particle immunology, Vaccinia virus, env Gene Products, Human Immunodeficiency Virus immunology, gag Gene Products, Human Immunodeficiency Virus immunology, pol Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines immunology, CD8-Positive T-Lymphocytes immunology, HIV Infections prevention & control, Immunity, Cellular, Immunity, Humoral, Vaccination methods
- Abstract
Despite more than three decades of intense research, a prophylactic HIV-1 vaccine remains elusive. Four vaccine modalities have been evaluated in clinical efficacy studies, but only one demonstrated at least modest efficacy, which correlated with polyfunctional antibody responses to the HIV surface protein Env. To be most effective, a HIV-1 vaccine probably has to induce both, functional antibody and CD8(+) T cell responses. We therefore analyzed DNA/DNA and DNA/virus-like particle (VLP) regimens for their ability to induce humoral and cellular immune responses. Here, DNA vaccination of mice induced strong CD8(+) responses against Env and Gag. However, the humoral response to Env was dominated by IgG1, a subclass known for its low functionality. In contrast, priming only with the Gag-encoding plasmid followed by a boost with VLPs consisting of Gag and Env improved the quality of the anti-Env antibody response via intrastructural help (ISH) provided by Gag-specific T cells to Env-specific B cells. Furthermore, the Gag-specific CD8(+) T cells induced by the DNA prime immunization could still protect from a lethal infection with recombinant vaccinia virus encoding HIV Gag. Therefore, this immunization regimen represents a promising approach to combine functional antibody responses toward HIV Env with strong CD8(+) responses controlling early viral replication., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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45. Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells.
- Author
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Storcksdieck genannt Bonsmann M, Niezold T, Temchura V, Pissani F, Ehrhardt K, Brown EP, Osei-Owusu NY, Hannaman D, Hengel H, Ackerman ME, Streeck H, Nabi G, Tenbusch M, and Überla K
- Subjects
- AIDS Vaccines administration & dosage, Animals, Cell Line, Tumor, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred BALB C, AIDS Vaccines immunology, HIV Antibodies immunology, HIV-1 immunology, T-Lymphocytes, Helper-Inducer immunology, env Gene Products, Human Immunodeficiency Virus immunology, gag Gene Products, Human Immunodeficiency Virus immunology, pol Gene Products, Human Immunodeficiency Virus immunology
- Abstract
The importance of Fc-dependent effector functions of Abs induced by vaccination is increasingly recognized. However, vaccination of mice against HIV envelope (Env) induced a skewed Th cell response leading to Env-specific Abs with reduced effector function. To overcome this bias, GagPol-specific Th cells were harnessed to provide intrastructural help for Env-specific B cells after immunization with virus-like particles containing GagPol and Env. This led to a balanced Env-specific humoral immune response with a more inflammatory Fc glycan profile. The increased quality in the Ab response against Env was confirmed by FcγR activation assays. Because the Env-specific Th cell response was also biased in human vaccinees, intrastructural help is an attractive novel approach to increase the efficacy of prophylactic HIV Env-based vaccines and may also be applicable to other particulate vaccines., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
- Full Text
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46. Human Polyclonal Antibodies Produced through DNA Vaccination of Transchromosomal Cattle Provide Mice with Post-Exposure Protection against Lethal Zaire and Sudan Ebolaviruses.
- Author
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Bounds CE, Kwilas SA, Kuehne AI, Brannan JM, Bakken RR, Dye JM, Hooper JW, Dupuy LC, Ellefsen B, Hannaman D, Wu H, Jiao JA, Sullivan EJ, and Schmaljohn CS
- Subjects
- Animals, Animals, Genetically Modified, Antibodies, Neutralizing immunology, Cattle genetics, Cattle immunology, Chromosomes, Artificial, Human genetics, Democratic Republic of the Congo, Ebola Vaccines immunology, Female, Hemorrhagic Fever, Ebola virology, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptor, Interferon alpha-beta genetics, Sudan, Vaccination methods, Antibodies, Viral metabolism, Ebolavirus immunology, Hemorrhagic Fever, Ebola prevention & control, Post-Exposure Prophylaxis methods, Vaccines, DNA immunology
- Abstract
DNA vaccination of transchromosomal bovines (TcBs) with DNA vaccines expressing the codon-optimized (co) glycoprotein (GP) genes of Ebola virus (EBOV) and Sudan virus (SUDV) produce fully human polyclonal antibodies (pAbs) that recognize both viruses and demonstrate robust neutralizing activity. Each TcB was vaccinated by intramuscular electroporation (IM-EP) a total of four times and at each administration received 10 mg of the EBOV-GPco DNA vaccine and 10 mg of the SUDV-GPco DNA vaccine at two sites on the left and right sides, respectively. After two vaccinations, robust antibody responses (titers > 1000) were detected by ELISA against whole irradiated EBOV or SUDV and recombinant EBOV-GP or SUDV-GP (rGP) antigens, with higher titers observed for the rGP antigens. Strong, virus neutralizing antibody responses (titers >1000) were detected after three vaccinations when measured by vesicular stomatitis virus-based pseudovirion neutralization assay (PsVNA). Maximal neutralizing antibody responses were identified by traditional plaque reduction neutralization tests (PRNT) after four vaccinations. Neutralizing activity of human immunoglobulins (IgG) purified from TcB plasma collected after three vaccinations and injected intraperitoneally (IP) into mice at a 100 mg/kg dose was detected in the serum by PsVNA up to 14 days after administration. Passive transfer by IP injection of the purified IgG (100 mg/kg) to groups of BALB/c mice one day after IP challenge with mouse adapted (ma) EBOV resulted in 80% protection while all mice treated with non-specific pAbs succumbed. Similarly, interferon receptor 1 knockout (IFNAR(-/-)) mice receiving the purified IgG (100 mg/kg) by IP injection one day after IP challenge with wild type SUDV resulted in 89% survival. These results are the first to demonstrate that filovirus GP DNA vaccines administered to TcBs by IM-EP can elicit neutralizing antibodies that provide post-exposure protection. Additionally, these data describe production of fully human IgG in a large animal system, a system which is capable of producing large quantities of a clinical grade therapeutic product.
- Published
- 2015
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47. Evaluation of the Impact of Codon Optimization and N-Linked Glycosylation on Functional Immunogenicity of Pfs25 DNA Vaccines Delivered by In Vivo Electroporation in Preclinical Studies in Mice.
- Author
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Datta D, Bansal GP, Kumar R, Ellefsen B, Hannaman D, and Kumar N
- Subjects
- Animals, Antibodies, Protozoan blood, Antibodies, Protozoan immunology, Drug Evaluation, Preclinical, Enzyme-Linked Immunosorbent Assay, Female, Glycosylation, Malaria prevention & control, Malaria Vaccines administration & dosage, Mice, Inbred BALB C, Plasmodium berghei immunology, Plasmodium berghei pathogenicity, Protozoan Proteins genetics, Vaccines, DNA administration & dosage, Codon, Electroporation, Malaria Vaccines immunology, Protozoan Proteins immunology, Vaccines, DNA immunology
- Abstract
Plasmodium falciparum sexual stage surface antigen Pfs25 is a well-established candidate for malaria transmission-blocking vaccine development. Immunization with DNA vaccines encoding Pfs25 has been shown to elicit potent antibody responses in mice and nonhuman primates. Studies aimed at further optimization have revealed improved immunogenicity through the application of in vivo electroporation and by using a heterologous prime-boost approach. The goal of the studies reported here was to systematically evaluate the impact of codon optimization, in vivo electroporation, and N-linked glycosylation on the immunogenicity of Pfs25 encoded by DNA vaccines. The results from this study demonstrate that while codon optimization and in vivo electroporation greatly improved functional immunogenicity of Pfs25 DNA vaccines, the presence or absence of N-linked glycosylation did not significantly impact vaccine efficacy. These findings suggest that N-glycosylation of Pfs25 encoded by DNA vaccines is not detrimental to overall transmission-blocking efficacy., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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48. A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of Electroporated HIV DNA with or without Interleukin 12 in Prime-Boost Combinations with an Ad35 HIV Vaccine in Healthy HIV-Seronegative African Adults.
- Author
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Mpendo J, Mutua G, Nyombayire J, Ingabire R, Nanvubya A, Anzala O, Karita E, Hayes P, Kopycinski J, Dally L, Hannaman D, Egan MA, Eldridge JH, Syvertsen K, Lehrman J, Rasmussen B, Gilmour J, Cox JH, Fast PE, and Schmidt C
- Subjects
- AIDS Vaccines immunology, Adenoviridae metabolism, Adult, CD8-Positive T-Lymphocytes immunology, Demography, Double-Blind Method, Enzyme-Linked Immunospot Assay, Female, Flow Cytometry, HIV Antibodies immunology, Humans, Immunity, Cellular, Immunity, Humoral, Immunization, Interferon-gamma metabolism, Male, Middle Aged, Placebos, Young Adult, AIDS Vaccines adverse effects, DNA, Viral adverse effects, DNA, Viral immunology, Electroporation, HIV Infections immunology, Immunization, Secondary, Interleukin-12 immunology
- Abstract
Background: Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study., Methods: Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM., Results: All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected., Conclusion: The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected., Trial Registration: ClinicalTrials.gov NCT01496989.
- Published
- 2015
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49. DNA vaccines encoding DEC205-targeted antigens: immunity or tolerance?
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Niezold T, Storcksdieck Genannt Bonsmann M, Maaske A, Temchura V, Heinecke V, Hannaman D, Buer J, Ehrhardt C, Hansen W, Überla K, and Tenbusch M
- Subjects
- Animals, Antigens, Viral genetics, Antigens, Viral immunology, Antigens, Viral pharmacology, Asthma immunology, Asthma prevention & control, Female, HEK293 Cells, Histocompatibility Antigens Class II immunology, Humans, Influenza A virus genetics, Influenza Vaccines genetics, Influenza Vaccines immunology, Mice, Minor Histocompatibility Antigens, Orthomyxoviridae Infections prevention & control, Vaccines, DNA genetics, Vaccines, DNA immunology, Antigens, CD immunology, CD4-Positive T-Lymphocytes immunology, Immune Tolerance drug effects, Immunity, Cellular drug effects, Influenza A virus immunology, Influenza Vaccines pharmacology, Lectins, C-Type immunology, Orthomyxoviridae Infections immunology, Receptors, Cell Surface immunology, Vaccines, DNA pharmacology
- Abstract
Targeting of antigens to the endocytic uptake receptor DEC205 resulted in enhanced antigen presentation by dendritic cells (DCs). In combination with adjuvants for DC maturation, proteins coupled to an antibody against DEC205 induced strong pathogen-specific immune responses, whereas without additional adjuvant tolerance could be induced. As less is known about DNA vaccines encoding DEC205-targeted antigens, we explored the immunogenicity and efficacy of a dendritic cell-targeted DNA vaccine against influenza A virus (IAV) delivered by electroporation. Although coupling of haemagglutinin to a single-chain antibody against DEC205 enhanced antigen presentation on MHC class II and activation of T-cell receptor-transgenic CD4 T cells, the T-cell responses induced by the targeted DNA vaccine in wild-type BALB/c mice were significantly reduced compared with DNA encoding non-targeted antigens. Consistently, these mice were less protected against an IAV infection. Adoptive transfer experiments were performed to assess the fate of the antigen-specific T cells in animals vaccinated with DNA encoding DEC205-targeted antigens. By this, we could exclude the general deletion of antigen-specific T cells as cause for the reduced efficacy, but observed a local expansion of antigen-specific regulatory T cells, which could suppress the activation of effector cells. In conclusion, DNA vaccines encoding DEC205-targeted antigens induce peripheral tolerance rather than immunity in our study. Finally, we evaluated our DNA vaccines as prophylactic or therapeutic treatment in an allergen-induced asthma mouse model., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2015
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50. Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges.
- Author
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Grant-Klein RJ, Altamura LA, Badger CV, Bounds CE, Van Deusen NM, Kwilas SA, Vu HA, Warfield KL, Hooper JW, Hannaman D, Dupuy LC, and Schmaljohn CS
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Codon, Disease Models, Animal, Drug Evaluation, Preclinical, Enzyme-Linked Immunosorbent Assay, Enzyme-Linked Immunospot Assay, Female, Filoviridae genetics, Glycoproteins genetics, Glycoproteins immunology, Immunoglobulin G blood, Injections, Intramuscular, Interferon-gamma metabolism, Leukocytes, Mononuclear immunology, Macaca fascicularis, Male, Neutralization Tests, Plasmids, Survival Analysis, Treatment Outcome, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Electroporation, Filoviridae immunology, Hemorrhagic Fever, Ebola prevention & control, Marburg Virus Disease prevention & control, Vaccines, DNA immunology
- Abstract
Cynomolgus macaques were vaccinated by intramuscular electroporation with DNA plasmids expressing codon-optimized glycoprotein (GP) genes of Ebola virus (EBOV) or Marburg virus (MARV) or a combination of codon-optimized GP DNA vaccines for EBOV, MARV, Sudan virus and Ravn virus. When measured by ELISA, the individual vaccines elicited slightly higher IgG responses to EBOV or MARV than did the combination vaccines. No significant differences in immune responses of macaques given the individual or combination vaccines were measured by pseudovirion neutralization or IFN-γ ELISpot assays. Both the MARV and mixed vaccines were able to protect macaques from lethal MARV challenge (5/6 vs. 6/6). In contrast, a greater proportion of macaques vaccinated with the EBOV vaccine survived lethal EBOV challenge in comparison to those that received the mixed vaccine (5/6 vs. 1/6). EBOV challenge survivors had significantly higher pre-challenge neutralizing antibody titers than those that succumbed.
- Published
- 2015
- Full Text
- View/download PDF
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