19 results on '"Hokey D"'
Search Results
2. Screw pulsation generation and control: a shock tube mechanism
- Author
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Huang, P.X., primary, Yonkers, S., additional, Hokey, D., additional, and Olenick, D., additional
- Published
- 2013
- Full Text
- View/download PDF
3. Developing whole mycobacteria cell vaccines for tuberculosis: Workshop proceedings, Max Planck Institute for Infection Biology, Berlin, Germany, July 9, 2014
- Author
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Kaufmann, S H E, Bloom, B, Brosch, R, Cardona, P-J, Dockrell, H, Fritzell, B, Grode, L, Hanekom, W, Hokey, D, Levin, M, Martin, C, Sander, P, Scriba, T, Shaligram, U, Tameris, M, von Reyn, F, Walker, B, Weiner, J, White, R G, Schrager, L, Kaufmann, S H E, Bloom, B, Brosch, R, Cardona, P-J, Dockrell, H, Fritzell, B, Grode, L, Hanekom, W, Hokey, D, Levin, M, Martin, C, Sander, P, Scriba, T, Shaligram, U, Tameris, M, von Reyn, F, Walker, B, Weiner, J, White, R G, and Schrager, L
- Abstract
On July 9, 2014, Aeras and the Max Planck Institute for Infection Biology convened a workshop entitled "Whole Mycobacteria Cell Vaccines for Tuberculosis" at the Max Planck Institute for Infection Biology on the grounds of the Charité Hospital in Berlin, Germany, close to the laboratory where, in 1882, Robert Koch first identified Mycobacterium tuberculosis (Mtb) as the pathogen responsible for tuberculosis (TB). The purpose of the meeting was to discuss progress in the development of TB vaccines based on whole mycobacteria cells. Live whole cell TB vaccines discussed at this meeting were derived from Mtb itself, from Bacille Calmette-Guérin (BCG), the only licensed vaccine against TB, which was genetically modified to reduce pathogenicity and increase immunogenicity, or from commensal non-tuberculous mycobacteria. Inactivated whole cell TB and non-tuberculous mycobacterial vaccines, intended as immunotherapy or as safer immunization alternatives for HIV+ individuals, also were discussed. Workshop participants agreed that TB vaccine development is significantly hampered by imperfect animal models, unknown immune correlates of protection and the absence of a human challenge model. Although a more effective TB vaccine is needed to replace or enhance the limited effectiveness of BCG in all age groups, members of the workshop concurred that an effective vaccine would have the greatest impact on TB control when administered to adolescents and adults, and that use of whole mycobacteria cells as TB vaccine candidates merits greater support, particularly given the limited understanding of the specific Mtb antigens necessary to generate an immune response capable of preventing Mtb infection and/or disease.
- Published
- 2015
4. The origin of gas pulsations in rotary PD compressors: ΔP or ΔU?
- Author
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Huang, P X, primary, Yonkers, S, additional, and Hokey, D, additional
- Published
- 2015
- Full Text
- View/download PDF
5. P16-36. Functional genomic immune profile of SIV DNA vaccines delivered by electroporation and combined with molecular adjuvants
- Author
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Boyer, JD, primary, Yin, J, additional, Dai, A, additional, Belisle, S, additional, Hirao, L, additional, Palermo, R, additional, Hokey, D, additional, Yan, J, additional, and Weiner, D, additional
- Published
- 2009
- Full Text
- View/download PDF
6. P19-49. Modulation of vaccine induced responses through CTLA-4 and 41BB enhances protection in macaques following SIVmac251 challenge
- Author
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Jure-Kunkel MN, Lewis M, Anderson H, Dai A, Boyer JD, Yan J, Weber J, Hokey DA, Hirao LA, and Weiner DB
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
- Full Text
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7. Increased immunogenicity of HIV vaccination with constant-current electroporation and molecular adjuvants in mice and rhesus macaques
- Author
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Weiner David B, Draghia-Akli Ruxandra, Hokey David, Khan Amir, Wu Ling, and Hirao Lauren
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2006
- Full Text
- View/download PDF
8. The origin of gas pulsations in rotary PD compressors: ?P or ?U?
- Author
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Huang, P X, Yonkers, S, and Hokey, D
- Abstract
This paper is a continuing work from the same authors on the same topic by analogizing the transient shock tube process to the gas pulsation phenomena [1, 2]. It has been demonstrated in the previous theoretical investigation that gas pulsations can be generated either by a sudden velocity change (DU) say from a piston or lobe movement, or by the sudden opening of a pressure difference (Dp4i) such as during the discharge phase of a rotary PD (Positive Displacement) compressor (screw, scroll or Roots) under UC (Under-Compression) or OC (Over-Compression) conditions. It is further reasoned that the more dominant pulsation source should be from the Ap41 induced source, but without backing from experiments.This paper is aimed at validating the theoretical predictions through experimental investigation conducted on a Roots blower, a special 100% UC case. This further clarification is important not only to prove the theory, but would pave the way for potential gas pulsation control methods if exact origin and nature of gas pulsations can be located and understood. Two schemes of tests under different load and speed conditions were carried out and results confirm the previous analytical conclusion that the dominant source of the gas pulsations for the 100% UC case is mainly from the sudden release of a pressure difference (Dp41) while the non-uniform rotor movement (DU) induced pulsation is about one order of magnitude lower. More experimental work on other types of rotary compressors such as screw or scroll is desirable in the future.
- Published
- 2015
9. Safety and immunogenicity of the H56:IC31 tuberculosis vaccine candidate in adults successfully treated for drug-susceptible pulmonary TB: a phase 1 randomized trial.
- Author
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Tait D, Diacon A, Borges ÁH, van Brakel E, Hokey D, Rutkowski KT, Hunt DJ, Russell M, Andersen PL, Kromann I, Ruhwald M, Churchyard G, and Dawson R
- Abstract
Background: H56:IC31 is a candidate vaccine against tuberculosis (TB) with the potential to reduce TB recurrence rate. It is thus important for future clinical trials to demonstrate safety and immunogenicity of H56:IC31 in individuals treated for TB., Methods: 22 adults confirmed to be Mtb negative (by 2 GeneXpert tests or 2 sputum cultures) after four-five months of TB treatment, and not more than 28 days after completion of TB treatment, were randomized to receive two doses of H56:IC31 (5 mg H56:500 nmol IC31; N=16) or placebo (N=6) 56 days apart. Participants were followed for 420 days for safety and immunogenicity., Results: H56:IC31 vaccination was associated with an acceptable safety profile, consisting mostly of mild self-limited injection site reactions. No serious adverse events, and no vaccine-related severe adverse events, were reported. H56:IC31 induced a CD4+ T-cell response for Ag85B and ESAT-6, with ESAT-6 being immunodominant, which persisted through six months after the last vaccination. There was some evidence of CD8+ T-cell responses for both Ag85B and ESAT-6, but to a lesser extent than CD4+ responses., Conclusions: H56:IC31 was associated with an acceptable safety profile, and induced a predominant CD4+ T-cell response, in adults recently treated for drug-susceptible, uncomplicated pulmonary TB., Trial Registration: ClinicalTrials.gov, NCT02375698., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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10. A 2-Dose AERAS-402 Regimen Boosts CD8 + Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients.
- Author
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Sivakumaran D, Blatner G, Bakken R, Hokey D, Ritz C, Jenum S, and Grewal HMS
- Subjects
- Adolescent, Adult, BCG Vaccine immunology, Double-Blind Method, Humans, India, Male, Middle Aged, Vaccines, DNA, Young Adult, CD8-Positive T-Lymphocytes immunology, Immunization, Secondary methods, Tuberculosis prevention & control, Tuberculosis Vaccines immunology
- Abstract
Despite the widespread use of BCG, tuberculosis (TB) remains a global threat. Existing vaccine candidates in clinical trials are designed to replace or boost BCG which does not provide satisfying long-term protection. AERAS-402 is a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis (Mtb) antigens 85A, 85B, and TB10.4. The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India - a highly TB-endemic area. Healthy male participants aged 18-45 years with a negative QuantiFERON-TB Gold in-tube test (QFT) were recruited. Enrolled participants (n=12) were randomized 2:1 to receive two intramuscular injections of either AERAS-402 (3 x 10
10 viral particles [vp]); (n=8) or placebo (n=4) on study days 0 and 28. Safety and immunogenicity parameters were evaluated for up to 182 days post the second injection. Immunogenicity was assessed by a flow cytometry-based intracellular cytokine staining (ICS) assay and transcriptional profiling. The latter was examined using dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA) assay. AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine-induced CD8+ T-cell responses were dominated by cells co-expressing IFN-γ, TNF-α, and IL-2 ("polyfunctional" cells) and were more robust than CD4+ T-cell responses. Five genes ( CXCL10, GNLY, IFI35, IL1B and PTPRCv2 ) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes ( CLEC7A, PTPRCv1 and TAGAP) were consistently up-regulated following two doses of vaccination in the AERAS-402-group. No safety concerns were observed for AERAS-402 in healthy Indian adult males. The vaccine-induced predominantly polyfunctional CD8+ T cells in response to Ag85B, humoral immunity, and altered gene expression profiles in peripheral blood mononuclear cells (PBMCs) indicative of activation of various immunologically relevant biological pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sivakumaran, Blatner, Bakken, Hokey, Ritz, Jenum and Grewal.)- Published
- 2021
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11. Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, Placebo-controlled, Dose-Selection Trial.
- Author
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Suliman S, Luabeya AKK, Geldenhuys H, Tameris M, Hoff ST, Shi Z, Tait D, Kromann I, Ruhwald M, Rutkowski KT, Shepherd B, Hokey D, Ginsberg AM, Hanekom WA, Andersen P, Scriba TJ, and Hatherill M
- Subjects
- Acyltransferases immunology, Acyltransferases therapeutic use, Adolescent, Adult, Antigens, Bacterial immunology, Antigens, Bacterial therapeutic use, Bacterial Proteins immunology, Bacterial Proteins therapeutic use, Dose-Response Relationship, Drug, Double-Blind Method, Drug Combinations, Female, Humans, Male, Middle Aged, Oligodeoxyribonucleotides immunology, Oligodeoxyribonucleotides therapeutic use, Oligopeptides immunology, Oligopeptides therapeutic use, South Africa, Treatment Outcome, Tuberculosis immunology, Tuberculosis Vaccines immunology, Young Adult, Tuberculosis prevention & control, Tuberculosis Vaccines therapeutic use
- Abstract
Rationale: Global tuberculosis (TB) control requires effective vaccines in TB-endemic countries, where most adults are infected with Mycobacterium tuberculosis (M.tb)., Objectives: We sought to define optimal dose and schedule of H56:IC31, an experimental TB vaccine comprising Ag85B, ESAT-6, and Rv2660c, for M.tb-infected and M.tb-uninfected adults., Methods: We enrolled 98 healthy, HIV-uninfected, bacillus Calmette-Guérin-vaccinated, South African adults. M.tb infection was defined by QuantiFERON-TB (QFT) assay. QFT-negative participants received two vaccinations of different concentrations of H56 in 500 nmol of IC31 to enable dose selection for further vaccine development. Subsequently, QFT-positive and QFT-negative participants were randomized to receive two or three vaccinations to compare potential schedules. Participants were followed for safety and immunogenicity for 292 days., Measurements and Main Results: H56:IC31 showed acceptable reactogenicity profiles irrespective of dose, number of vaccinations, or M.tb infection. No vaccine-related severe or serious adverse events were observed. The three H56 concentrations tested induced equivalent frequencies and functional profiles of antigen-specific CD4 T cells. ESAT-6 was only immunogenic in QFT-negative participants who received three vaccinations., Conclusions: Two or three H56:IC31 vaccinations at the lowest dose induced durable antigen-specific CD4 T-cell responses with acceptable safety and tolerability profiles in M.tb-infected and M.tb-uninfected adults. Additional studies should validate applicability of vaccine doses and regimens to both QFT-positive and QFT-negative individuals. Clinical trial registered with www.clinicaltrials.gov (NCT01865487).
- Published
- 2019
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12. The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: first-in-human trial.
- Author
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Coler RN, Day TA, Ellis R, Piazza FM, Beckmann AM, Vergara J, Rolf T, Lu L, Alter G, Hokey D, Jayashankar L, Walker R, Snowden MA, Evans T, Ginsberg A, and Reed SG
- Abstract
Tuberculosis (TB) is the leading cause of infectious death worldwide. Development of improved TB vaccines that boost or replace BCG is a major global health goal. ID93 + GLA-SE is a fusion protein TB vaccine candidate combined with the Toll-like Receptor 4 agonist adjuvant, GLA-SE. We conducted a phase 1, randomized, double-blind, dose-escalation clinical trial to evaluate two dose levels of the ID93 antigen, administered intramuscularly alone or in combination with two dose levels of the GLA-SE adjuvant, in 60 BCG-naive, QuantiFERON-negative, healthy adults in the US (ClinicalTrials.gov identifier: NCT01599897). When administered as 3 injections, 28 days apart, all dose levels of ID93 alone and ID93 + GLA-SE demonstrated an acceptable safety profile. All regimens elicited vaccine-specific humoral and cellular responses. Compared with ID93 alone, vaccination with ID93 + GLA-SE elicited higher titers of ID93-specific antibodies, a preferential increase in IgG1 and IgG3 subclasses, and a multifaceted Fc-mediated effector function response. The addition of GLA-SE also enhanced the magnitude and polyfunctional cytokine profile of CD4
+ T cells. The data demonstrate an acceptable safety profile and indicate that the GLA-SE adjuvant drives a functional humoral and T-helper 1 type cellular response., Competing Interests: S.G.R. is a founder of, and holds an equity interest in, Immune Design Corp., a licensee of certain rights associated with GLA. The remaining authors declare no competing interests.- Published
- 2018
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13. Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine.
- Author
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Nyendak M, Swarbrick GM, Duncan A, Cansler M, Huff EW, Hokey D, Evans T, Barker L, Blatner G, Sadoff J, Douoguih M, Pau MG, Lewinsohn DA, and Lewinsohn DM
- Subjects
- Adult, Double-Blind Method, Female, Humans, Male, Tuberculosis Vaccines immunology, Vaccination, Vaccines, DNA, Young Adult, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Mycobacterium tuberculosis immunology, Tuberculosis Vaccines administration & dosage
- Abstract
The development of a vaccine for Mycobacterium tuberculosis (Mtb) has been impeded by the absence of correlates of protective immunity. One correlate would be the ability of cells induced by vaccination to recognize the Mtb-infected cell. AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA expressing a fusion protein of Mtb antigens 85A, 85B and TB10.4. We undertook a phase I double-blind, randomized placebo controlled trial of vaccination with AERAS-402 following BCG. Analysis of the vaccine-induced immune response revealed strong antigen-specific polyfunctional CD4
+ and CD8+ T cell responses. However, analysis of the vaccine-induced CD8+ T cells revealed that in many instances these cells did not recognize the Mtb-infected cell. Our findings highlight the measurement of vaccine-induced, polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying the Mtb-infected cell and correspondingly, the value of detailed experimental medicine studies early in vaccine development., Competing Interests: Aeras TB Vaccine Foundation has licensed technology (not the subject of this research) from OHSU of which Dr. David Lewinsohn and Dr. Deborah Lewinsohn are inventors. OHSU, Dr. David Lewinsohn, and Dr. Deborah Lewinsohn and Dr. Melissa Nyendak have a financial interest in ViTi, Inc., a company that may have a commercial interest in some research results reported herein. These potential conflicts of interest have been reviewed and managed by OHSU.- Published
- 2016
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14. The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial.
- Author
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Geldenhuys H, Mearns H, Miles DJ, Tameris M, Hokey D, Shi Z, Bennett S, Andersen P, Kromann I, Hoff ST, Hanekom WA, Mahomed H, Hatherill M, Scriba TJ, van Rooyen M, Bruce McClain J, Ryall R, and de Bruyn G
- Subjects
- Adolescent, Adult, Antigens, Bacterial administration & dosage, Cytokines analysis, Double-Blind Method, Drug Combinations, Enzyme-Linked Immunospot Assay, Female, Humans, Injections, Intramuscular, Male, Middle Aged, Oligodeoxyribonucleotides adverse effects, Oligopeptides adverse effects, Placebos administration & dosage, South Africa, Staining and Labeling, Tuberculosis Vaccines administration & dosage, Tuberculosis Vaccines adverse effects, Young Adult, Antigens, Bacterial immunology, CD4-Positive T-Lymphocytes immunology, Mycobacterium tuberculosis immunology, Oligodeoxyribonucleotides administration & dosage, Oligopeptides administration & dosage, Tuberculosis Vaccines immunology
- Abstract
Background: New, more effective vaccines to prevent tuberculosis (TB) disease are needed urgently. H4:IC31 is an investigational vaccine that contains a fusion protein of the immunodominant antigens TB10.4 and Ag85B, formulated in IC31 adjuvant. We assessed the safety and immunogenicity of H4:IC31 in South African adults from a TB endemic setting., Methods: In this double blind, placebo controlled, phase I trial, Mycobacterium tuberculosis-uninfected, HIV-uninfected, healthy adults with a history of childhood BCG vaccination were randomly allocated to two intramuscular vaccinations with 5, 15, 50 or 150 μg H4 formulated in 500nmol IC31, two months apart. Vaccinees were followed for six months to assess safety; immunogenicity was measured by ELISpot and intracellular cytokine staining assays., Results: Thirty-two participants received H4:IC31 and 8 received placebo. Injection site adverse events were common but mild; mild fatigue was the most common systemic adverse event. Frequencies of adverse events did not differ between dosage groups. Detectable antigen-specific CD4 T cell responses were induced by all doses of H4:IC31, but doses below 50 μg induced the highest frequencies of CD4 T cells, comprised predominantly of IFN-γ(+)TNF-α(+)IL-2(+) or TNF-α(+)IL-2(+) cells. These memory responses persisted up to the end of follow up, on study day 182., Conclusions: H4:IC31 demonstrated an acceptable safety profile and was immunogenic in South African adults. In this trial, the 15 μg dose appeared to induce the most optimal immune response., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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15. A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.
- Author
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Tameris M, Hokey DA, Nduba V, Sacarlal J, Laher F, Kiringa G, Gondo K, Lazarus EM, Gray GE, Nachman S, Mahomed H, Downing K, Abel B, Scriba TJ, McClain JB, Pau MG, Hendriks J, Dheenadhayalan V, Ishmukhamedov S, Luabeya AK, Geldenhuys H, Shepherd B, Blatner G, Cardenas V, Walker R, Hanekom WA, Sadoff J, Douoguih M, Barker L, and Hatherill M
- Subjects
- Acyltransferases immunology, Adult, Africa South of the Sahara, Antibodies, Bacterial blood, Antigens, Bacterial immunology, BCG Vaccine administration & dosage, BCG Vaccine immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Dose-Response Relationship, Immunologic, Double-Blind Method, Female, Healthy Volunteers, Humans, Immunity, Humoral, Infant, Interferon-gamma immunology, Male, Tuberculosis prevention & control, Tuberculosis Vaccines adverse effects, Tuberculosis Vaccines immunology, Vaccination, Vaccines, DNA, Tuberculosis Vaccines administration & dosage
- Abstract
Background: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design., Methods: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years., Results: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses., Conclusions: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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16. The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV-infected, BCG-vaccinated adults with CD4(+) T cell counts >350 cells/mm(3).
- Author
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Churchyard GJ, Snowden MA, Hokey D, Dheenadhayalan V, McClain JB, Douoguih M, Pau MG, Sadoff J, and Landry B
- Subjects
- Adult, Antibodies, Bacterial blood, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes, Double-Blind Method, Female, Humans, Injections, Intramuscular, Interferon-gamma immunology, Interleukin-2 immunology, Male, Middle Aged, Mycobacterium tuberculosis immunology, South Africa, Tuberculosis Vaccines administration & dosage, Tumor Necrosis Factor-alpha immunology, Vaccination, Vaccines, DNA, Viral Load, Young Adult, Antigens, Bacterial immunology, BCG Vaccine immunology, HIV Infections immunology, Tuberculosis prevention & control, Tuberculosis Vaccines adverse effects, Tuberculosis Vaccines immunology
- Abstract
Background: The safety and immunogenicity of a replication deficient adenovirus serotype 35 tuberculosis (TB) vaccine containing gene inserts for Antigens (Ag) 85A, Ag85B and TB10.4 (AERAS-402/AD35.TB-S) was evaluated in previously BCG vaccinated, HIV-infected South African adults with baseline CD4 counts >350 cells/mm(3)., Methods: Subjects were randomized (1:1) to receive two doses of either intramuscular AERAS-402/AD35.TB-S or placebo at month 0 and at month 1. Participants were monitored for adverse events 28 days after each vaccination and for serious adverse events over 12 months. CD4(+) and CD8(+) T-cell and antibody responses to vaccine antigens were evaluated post first and second vaccination., Results: 26 subjects were randomly assigned to receive AERAS-402/AD35.TB-S (N=13) or placebo (N=13). The mean age was 29.0 years, all were Black-African, 88.5% were female, 46.2% were QuantiFERON Test (QFT) positive at baseline, and the median CD4 count was 559.5 cells/mm(3), all similar by treatment group. All subjects received their first vaccination and 24 subjects received their second vaccination. Injection site reactions and some systemic reactions were reported more commonly in the AERAS-402/AD35.TB-S versus placebo recipients. AERAS-402/AD35.TB-S did not appear to influence CD4 counts and HIV-1 viral load over the course of study follow-up. AERAS-402/AD35.TB-S induced a mixed CD4(+) T-cell and CD8(+) T-cell responses to Ag85B. The CD4(+) T-cell responses peaked to Ag85A and Ag85B 14 days after the second vaccination and had declined by Day 182. AERAS-402/AD35.TB-S predominantly induced CD4(+) T-cells expressing three (IFN-γ, TNF, IL-2) or two (IL-2 and TNF) cytokines, two weeks after the last vaccination, which did not differ by baseline Quantiferon test status. AERAS-402/AD35.TB-S induced strong Ag85A and Ag85B specific antibody responses, particularly after the second vaccination., Conclusion: AERAS-402/AD35.TB-S was well tolerated, safe and induced predominantly polyfunctional CD4(+) and CD8(+) T-cell responses to vaccine., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
17. Tuberculosis vaccine development: Shifting focus amid increasing development challenges.
- Author
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Graves AJ and Hokey DA
- Subjects
- Animals, Biomarkers analysis, Biomedical Research trends, Disease Models, Animal, Drug Discovery trends, Humans, Tuberculosis immunology, Mycobacterium tuberculosis immunology, Tuberculosis prevention & control, Tuberculosis Vaccines immunology, Tuberculosis Vaccines isolation & purification
- Abstract
A new tuberculosis vaccine is needed to replace or enhance BCG, which induces variable protection against Mycobacterium tuberculosis pulmonary infections in adults. Development of new TB vaccine candidates is severely hampered by the lack of a correlate of immunity, unproven animal models, and limited funding opportunities. One candidate, MVA85A, recently failed to meet its efficacy endpoint goals despite promising early-phase trial data. As a result, some in the field believe we should now shift our focus away from product development and toward a research-oriented approach. Here, we outline our suggestions for this research-oriented strategy including diversification of the candidate pipeline, expanding measurements of immunity, improving pre-clinical animal models, and investing in combination pre-clinical/experimental medicine studies. As with any evolution, this change in strategy comes at a cost but may also represent an opportunity for advancing the field.
- Published
- 2015
- Full Text
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18. Mycobacterium tuberculosis Erdman infection of rhesus macaques of Chinese origin.
- Author
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Zhang J, Xian Q, Guo M, Huang Z, Rao Y, Wang Y, Wang X, Bao R, Evans TG, Hokey D, Sizemore D, and Ho WZ
- Subjects
- Acute Disease, Animals, Blood Sedimentation, Bronchoscopy, C-Reactive Protein metabolism, Colony Count, Microbial, Disease Susceptibility, Female, Macaca mulatta, Male, Mycobacterium tuberculosis classification, Radiography, Survival Analysis, Tuberculin Test, Tuberculosis, Pulmonary diagnostic imaging, Tuberculosis, Pulmonary pathology, Virulence, Disease Models, Animal, Mycobacterium tuberculosis pathogenicity, Tuberculosis, Pulmonary microbiology
- Abstract
Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of mycobacterium Bacille Calmette-Guérin (BCG) emphasize the need for improved vaccines and drugs against TB, which require clinically relevant animal models for evaluation. We infected a total of 24 Chinese rhesus macaques with varying doses (CFU of 25, 100 and 500) of Mycobacterium tuberculosis (M.tb) Erdman strain via bronchoscopy. Regardless of the M.tb doses, all animals were infected successfully with minor differences in clinical progression; as evidenced by clinical manifestations, laboratory analyses, bacterial burden in infected tissues and histopathology evaluations. Rhesus macaques of Chinese origin are highly susceptible to infection with M.tb Erdman strain and develop acute TB disease, which is similar to that in humans. Pathologically, Chinese rhesus macaques recapitulated the complete spectrum of granulomatous lesions seen in human TB disease. These data indicate that low-dose infection of rhesus macaques of Chinese origin is a suitable model for acute M.tb infection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
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19. Nonclinical Development of BCG Replacement Vaccine Candidates.
- Author
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Velmurugan K, Grode L, Chang R, Fitzpatrick M, Laddy D, Hokey D, Derrick S, Morris S, McCown D, Kidd R, Gengenbacher M, Eisele B, Kaufmann SH, Fulkerson J, and Brennan MJ
- Abstract
The failure of current Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccines, given to neonates to protect against adult tuberculosis and the risk of using these live vaccines in HIV-infected infants, has emphasized the need for generating new, more efficacious and safer replacement vaccines. With the availability of genetic techniques for constructing recombinant BCG (rBCG) strains containing well-defined gene deletions or insertions, new vaccine candidates are under evaluation at both the preclinical and clinical stages of development. Since most BCG vaccines in use today were evaluated in clinical trials decades ago and are produced by outdated processes, the development of new BCG vaccines offers a number of advantages that include a modern well-defined manufacturing process along with state-of-the-art evaluation of safety and efficacy in target populations. We provide a description of the preclinical development of two novel rBCGs, VPM1002 that was constructed by adding a modified hly gene coding for the protein listeriolysin O (LLO) from Listeria monocytogenes and AERAS-422, which carries a modified pfoA gene coding for the protein perfringolysin O (PFO) from Clostridium perfringens, and three genes from Mycobacterium tuberculosis. Novel approaches like these should be helpful in generating stable and effective rBCG vaccine candidates that can be better characterized than traditional BCG vaccines.
- Published
- 2013
- Full Text
- View/download PDF
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