20 results on '"Sinoeun Touch"'
Search Results
2. Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys.
- Author
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Hualin Li, Cheryl Callahan, Michael Citron, Zhiyun Wen, Sinoeun Touch, Morgan A Monslow, Kara S Cox, Daniel J DiStefano, Kalpit A Vora, Andrew Bett, and Amy Espeseth
- Subjects
Medicine ,Science - Abstract
Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in young children and older adults throughout the world. Prevention of severe RSV disease through active immunization is optimal but no RSV vaccine has been licensed so far. Immune mechanisms of protection against RSV infection in humans have not been fully established, thus a comprehensive characterization of virus-specific immune responses in a relevant animal model will be beneficial in defining correlates of protection. In this study, we infected juvenile naive AGMs with RSV A2 strain and longitudinally assessed virus-specific humoral and cellular immune responses in both peripheral blood and the respiratory tract. RSV viral loads at nasopharyngeal surfaces and in the lung peaked at around day 5 following infection, and then largely resolved by day 10. Low levels of neutralizing antibody titers were detected in serum, with similar kinetics as RSV fusion (F) protein-binding IgG antibodies. RSV infection induced CD8+, but very little CD4+, T lymphocyte responses in peripheral blood. Virus-specific CD8+ T cell frequencies were ~10 fold higher in bronchoaveolar lavage (BAL) compared to peripheral blood and exhibited effector memory (CD95+CD28-) / tissue resident memory (CD69+CD103+) T (TRM) cell phenotypes. The kinetics of virus-specific CD8+ T cells emerging in peripheral blood and BAL correlated with declining viral titers, suggesting that virus-specific cellular responses contribute to the clearance of RSV infection. RSV-experienced AGMs were protected from subsequent exposure to RSV infection. Additional studies are underway to understand protective correlates in these seropositive monkeys.
- Published
- 2017
- Full Text
- View/download PDF
3. Characterization of humoral and cell-mediated immunity induced by mRNA vaccines expressing influenza hemagglutinin stem and nucleoprotein in mice and nonhuman primates
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Jessica A, Flynn, Teresa, Weber, Pedro J, Cejas, Kara S, Cox, Sinoeun, Touch, Lauren A, Austin, Yangsi, Ou, Michael P, Citron, Bin, Luo, Marian E, Gindy, Kapil, Bahl, Giuseppe, Ciaramella, Amy S, Espeseth, and Lan, Zhang
- Subjects
Primates ,Immunity, Cellular ,Vaccines, Synthetic ,General Veterinary ,General Immunology and Microbiology ,Public Health, Environmental and Occupational Health ,Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,Immunity, Humoral ,Mice ,Influenza A Virus, H1N1 Subtype ,Nucleoproteins ,Infectious Diseases ,Orthomyxoviridae Infections ,Influenza Vaccines ,Animals ,Molecular Medicine ,mRNA Vaccines - Abstract
In response to immune pressure, influenza viruses evolve, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response capable of recognizing multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the efficacy and immunogenicity of mRNA vaccines encoding either the conserved stem domain of a group 1 hemagglutinin (HA), a group 2 nucleoprotein (NP), or a combination of the two antigens in mice, as well as evaluated immunogenicity in naïve and influenza seropositive nonhuman primates (NHPs). HA stem-immunized animals developed a robust anti-stem antibody binding titer, and serum antibodies recognized antigenically distinct group 1 HA proteins. These antibodies showed little to no neutralizing activity in vitro but were active in an assay measuring induction of antibody-dependent cellular cytotoxicity. HA-directed cell-mediated immunity was weak following HA stem mRNA vaccination; however, robust CD4 and CD8 T cell responses were detected in both mice and NHPs after immunization with mRNA vaccines encoding NP. Both HA stem and NP mRNA vaccines partially protected mice from morbidity following lethal influenza virus challenge, and superior efficacy against two different H1N1 strains was observed when the antigens were combined. In vivo T cell depletion suggested that anti-NP cell-mediated immunity contributed to protection in the mouse model. Taken together, these data show that mRNA vaccines encoding conserved influenza antigens, like HA stem and NP in combination, induce broadly reactive humoral responses as well as cell-mediated immunity in mice and NHPs, providing protection against homologous and heterologous influenza infection in mice.
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- 2022
4. A Novel LNP-Based Chlamydia Subunit Vaccine Formulation That Induces Th1 Responses without Upregulating IL-17 Provides Equivalent Protection in Mice as Formulations That Induced IL-17 and Th1 Cytokines
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Bob J. Lucas, Deborah D. Nahas, Sinoeun Touch, Jinfu Xie, Kalpit A. Vora, Robin M. Kaufhold, Melissa A. Boddicker, Julie M. Skinner, Kara S. Cox, and Amy S. Espeseth
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0301 basic medicine ,education.field_of_study ,Chemistry ,medicine.medical_treatment ,Antibody titer ,Monophosphoryl Lipid A ,law.invention ,Microbiology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Antigen ,Membrane protein ,law ,medicine ,Recombinant DNA ,030212 general & internal medicine ,Dimethyldioctadecylammonium bromide ,education ,Bacterial outer membrane ,Adjuvant - Abstract
We evaluated novel Chlamydial vaccines, consisting of major outer membrane protein (MOMP) alone or in combination with polymorphic membrane proteins D (PmpD) and G (PmpG) using a C57BL/6 mouse model. Native MOMP (nMOMP) isolated from C. muridarum elementary bodies (EBs) and recombinant PmpD and PmpG proteins were adjuvanted with Monophosphoryl lipid A (MPLA), with either lipid nanoparticles (LNPs) or the cationic lipid dimethyldioctadecylammonium bromide (DDA). Antibody titers to C. muridarum nMOMP, and EBs were evaluated by ELISA, and T-cell responses were analyzed by intracellular cytokine staining (ICS). Protection from challenge was determined by qPCR. Vaccine immunized mice showed significantly higher antibody titers to nMOMP (P C. muridarum EBs (P C. muridarum EBs and PmpG. ICS analysis showed more robust CD4 + T-cell responses (IFN-γ/IL-2/TNF-a) in the DDA and LNP groups compared to the adjuvant alone group. The DDA + MPLA gave robust Th17 responses in comparison to MPLA and LNP group. Mice immunized with Chlamydia antigens also showed protection from C. muridarum challenge, by reduction in bacterial shedding for all groups (P < 0.003) compared to shedding from the adjuvant control. Both vaccine formulations generated robust immunological responses, and both were protective by reducing bacterial shedding after challenge. This data indicates equal protection can be achieved without the induction of Th17 responses.
- Published
- 2020
5. Upper and Lower Respiratory Tract Correlates of Protection Against RSV Following Vaccination of Non-Human Primates
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Michael P. Citron, Zhiyun Wen, Nickita Mehta, Galit Alter, Amy S. Espeseth, Daniel J. DiStefano, Jishnu Das, Sinoeun Touch, Cheryl Callahan, Jeffrey R. Sachs, Tomer Zohar, Paloma Cejas, Andrew J. Bett, Anush Devadhasan, Douglas A. Lauffenburger, and Wiktor Karpinski
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Innate immune system ,biology ,business.industry ,Virus ,Vaccination ,medicine.anatomical_structure ,Immunity ,Immunology ,biology.protein ,medicine ,Antibody ,Respiratory system ,business ,Viral load ,Respiratory tract - Abstract
Respiratory syncytial virus (RSV) infection is a major cause of severe respiratory illness in both young infants and the elderly. While antibodies represent key correlates of protection, the antibody mechanisms remain poorly understood. Emerging data point to additional humoral Fc-mediated mechanisms of action beyond neutralization. Therefore, to map the humoral correlates of immunity against RSV, antibody responses were profiled in a highly controlled non-human primate challenge model. Six different vaccine platforms were tested in African Green Monkeys, which post-challenge, yielded distinct antibody profiles and viral loads in both upper and lower respiratory tracts. Machine learning was then used to determine antibody features associated with protection. Upper respiratory control involved virus specific IgA levels, neutralization, and complement whereas lower respiratory control involved Fc-mediated mechanisms. These data highlight a collaborative Fab and Fc protective signature, induced selectively by distinct vaccine platforms, and provides mechanistic insights for the rational development of vaccines.
- Published
- 2021
6. Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection
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Andrew J. Bett, Dai Wang, Zhiyun Wen, Andrew H. Latham, Lan Zhang, Kalpit A. Vora, Michael P. Citron, Jeffrey S. Smith, Marian E. Gindy, Christine A. Shaw, Joseph M. Antonello, Jessica A. Flynn, Ryan Swoyer, Cheryl Callahan, Giuseppe Ciaramella, Paloma Cejas, Daniel J. DiStefano, Kapil Bahl, Daniel C. Freed, Kara S. Cox, Gregory O’ Donnell, Amy S. Espeseth, Sinoeun Touch, Jennifer D. Galli, and Daria J. Hazuda
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Protein subunit ,Immunology ,lcsh:RC254-282 ,Virus ,Epitope ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,RNA vaccines ,Virology ,Pharmacology (medical) ,030212 general & internal medicine ,Neutralizing antibody ,Pharmacology ,Vaccines ,biology ,Immunogenicity ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Vaccination ,030104 developmental biology ,Infectious Diseases ,biology.protein ,lcsh:RC581-607 - Abstract
The RSV Fusion (F) protein is a target for neutralizing antibody responses and is a focus for vaccine discovery; however, the process of RSV entry requires F to adopt a metastable prefusion form and transition to a more stable postfusion form, which displays less potent neutralizing epitopes. mRNA vaccines encode antigens that are translated by host cells following vaccination, which may allow conformational transitions similar to those observed during natural infection to occur. Here we evaluate a panel of chemically modified mRNA vaccines expressing different forms of the RSV F protein, including secreted, membrane associated, prefusion-stabilized, and non-stabilized structures, for conformation, immunogenicity, protection, and safety in rodent models. Vaccination with mRNA encoding native RSV F elicited antibody responses to both prefusion- and postfusion-specific epitopes, suggesting that this antigen may adopt both conformations in vivo. Incorporating prefusion stabilizing mutations further shifts the immune response toward prefusion-specific epitopes, but does not impact neutralizing antibody titer. mRNA vaccine candidates expressing either prefusion stabilized or native forms of RSV F protein elicit robust neutralizing antibody responses in both mice and cotton rats, similar to levels observed with a comparable dose of adjuvanted prefusion stabilized RSV F protein. In contrast to the protein subunit vaccine, mRNA-based vaccines elicited robust CD4+ and CD8+ T-cell responses in mice, highlighting a potential advantage of the technology for vaccines requiring a cellular immune response for efficacy.
- Published
- 2020
7. Upper and lower respiratory tract correlates of protection against respiratory syncytial virus following vaccination of nonhuman primates
- Author
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Tomer Zohar, Jeff C. Hsiao, Nickita Mehta, Jishnu Das, Anush Devadhasan, Wiktor Karpinski, Cheryl Callahan, Michael P. Citron, Daniel J. DiStefano, Sinoeun Touch, Zhiyun Wen, Jeffrey R. Sachs, Pedro J. Cejas, Amy S. Espeseth, Douglas A. Lauffenburger, Andrew J. Bett, and Galit Alter
- Subjects
Primates ,Vaccination ,Respiratory Syncytial Virus Infections ,Viral Load ,Antibodies, Viral ,Antibodies, Neutralizing ,Microbiology ,Immunity, Innate ,Immunoglobulin A ,Respiratory Syncytial Virus, Human ,Virology ,Chlorocebus aethiops ,Respiratory Syncytial Virus Vaccines ,Animals ,Humans ,Parasitology ,Lung ,Biomarkers - Abstract
Respiratory syncytial virus (RSV) infection is a major cause of respiratory illness in infants and the elderly. Although several vaccines have been developed, none have succeeded in part due to our incomplete understanding of the correlates of immune protection. While both T cells and antibodies play a role, emerging data suggest that antibody-mediated mechanisms alone may be sufficient to provide protection. Therefore, to map the humoral correlates of immunity against RSV, antibody responses across six different vaccines were profiled in a highly controlled nonhuman primate-challenge model. Viral loads were monitored in both the upper and lower respiratory tracts, and machine learning was used to determine the vaccine platform-agnostic antibody features associated with protection. Upper respiratory control was associated with virus-specific IgA levels, neutralization, and complement activity, whereas lower respiratory control was associated with Fc-mediated effector mechanisms. These findings provide critical compartment-specific insights toward the rational development of future vaccines.
- Published
- 2022
8. A novel method for strict intranasal delivery of non-replicating RSV vaccines in cotton rats and non-human primates
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Sinoeun Touch, Chinedu G. Orekie, Cameron M. Douglas, Walter Knapp, Jane Fontenot, Amy S. Espeseth, Zhiyun Wen, Michael P. Citron, Ioan Petrescu, Mona Purcell, Cheryl Callahan, Xiaoping Liang, Sai Prasanth Chamarthy, Manishkumar Patel, Paul McQuade, Daniel Rubins, Shu-An Lin, Alexa Gleason, and Matthew Pine
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0301 basic medicine ,Drug Evaluation, Preclinical ,Respiratory Syncytial Virus Infections ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,030225 pediatrics ,Chlorocebus aethiops ,Respiratory Syncytial Virus Vaccines ,medicine ,Animals ,Sigmodontinae ,Cotton rat ,Administration, Intranasal ,General Veterinary ,General Immunology and Microbiology ,biology ,business.industry ,Respiratory disease ,Public Health, Environmental and Occupational Health ,medicine.disease ,biology.organism_classification ,Vaccination ,Pneumonia ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Immunization ,Bronchiolitis ,Respiratory Syncytial Virus, Human ,Models, Animal ,Immunology ,Molecular Medicine ,Female ,business ,Respiratory tract - Abstract
Respiratory syncytial virus (RSV) is the most common viral cause of bronchiolitis and pneumonia in children twelve months of age or younger and a significant cause of lower respiratory disease in older adults. As various clinical and preclinical candidates advance, cotton rats (Sigmodon hispidus) and non-human primates (NHP) continue to play a valuable role in RSV vaccine development, since both animals are semi-permissive to human RSV (HRSV). However, appropriate utilization of the models is critical to avoid mis-interpretation of the preclinical findings. Using a multimodality imaging approach; a fluorescence based optical imaging technique for the cotton rat and a nuclear medicine based positron emission tomography (PET) imaging technique for monkeys, we demonstrate that many common practices for intranasal immunization in both species result in inoculum delivery to the lower respiratory tract, which can result in poor translation of outcomes from the preclinical to the clinical setting. Using these technologies we define a method to limit the distribution of intranasally administered vaccines solely to the upper airway of each species, which includes volume restrictions in combination with injectable anesthesia. We show using our newly defined methods for strict intranasal immunization that these methods impact the immune responses and efficacy observed when compared to vaccination methods resulting in distribution to both the upper and lower respiratory tracts. These data emphasize the importance of well-characterized immunization methods in the preclinical assessment of intranasally delivered vaccine candidates.
- Published
- 2018
9. Leveraging Automation to Miniaturize a Respiratory Syncytial Virus Neutralization Assay
- Author
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Radcliffe, Scott Wystan, Sinoeun Touch, Kinek, Keith, Riley, Daniel, Dubey, Sheri, Distefano, Daniel, Carroll, Steve, and Krosky, Paula
- Published
- 2019
- Full Text
- View/download PDF
10. Design and characterization of a fusion glycoprotein vaccine for Respiratory Syncytial Virus with improved stability
- Author
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Paloma Cejas, Paul Parmet, Amy S. Espeseth, Arthur Fridman, Jennifer D. Galli, Scott Cosmi, Lan Zhang, Sinoeun Touch, Andrew J. Bett, Bin Luo, and Eberhard Durr
- Subjects
0301 basic medicine ,Protein subunit ,Respiratory Syncytial Virus Infections ,Antibodies, Viral ,Virus ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immunogenicity, Vaccine ,Antigen ,Neutralization Tests ,Respiratory Syncytial Virus Vaccines ,Animals ,030212 general & internal medicine ,Neutralizing antibody ,Antigens, Viral ,chemistry.chemical_classification ,Mice, Inbred BALB C ,General Veterinary ,General Immunology and Microbiology ,biology ,Chemistry ,Immunogenicity ,Public Health, Environmental and Occupational Health ,Fusion protein ,Virology ,Antibodies, Neutralizing ,Cold Temperature ,030104 developmental biology ,Infectious Diseases ,Respiratory Syncytial Virus, Human ,biology.protein ,Molecular Medicine ,Female ,Antibody ,Glycoprotein ,Viral Fusion Proteins - Abstract
Respiratory Syncytial Virus (RSV) infection is the leading cause of lower respiratory tract infection in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. The infectious RSV particle is decorated with a type I viral fusion (F) glycoprotein that structurally rearranges from a metastable prefusion form to a highly stable postfusion form. In people naturally infected with RSV, the neutralizing antibodies primarily recognize the prefusion conformation. Therefore, engineered RSV F protein stabilized in its prefusion conformation has been an attractive strategy for developing RSV F vaccine antigens. Long-term stability at 4 °C or higher is a desirable attribute for a RSV F subunit vaccine antigen. We have previously shown that a prefusion stabilized RSV F construct, DS-Cav1, undergoes conformational changes and forms intermediate structures upon long-term storage at 4 °C. Structure-based design was performed to improve the stability of the RSV F subunit vaccine. We identified additional mutations that further stabilize RSV F protein in its prefusion conformation by using binding to a previously described antigenic site I antibody 4D7 as the screening tool. In addition, we designed and identified variants with increased expression levels, which is another desirable attribute for a subunit vaccine. Our data suggested that an RSV F variant F111 is properly folded, and has improved heat stability as well as stability upon long-term storage at 4 °C. A mouse immunogenicity study demonstrated that no compromise in immunogenicity (both binding and neutralizing antibody levels) was observed with the introduction of these additional mutations.
- Published
- 2018
11. Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys
- Author
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Michael P. Citron, Daniel J. DiStefano, Kara S. Cox, Cheryl Callahan, Zhiyun Wen, Hualin Li, Morgan A. Monslow, Andrew J. Bett, Sinoeun Touch, Amy S. Espeseth, and Kalpit A. Vora
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Pulmonology ,Physiology ,viruses ,Antibody Response ,lcsh:Medicine ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,Biochemistry ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,Chlorocebus aethiops ,Medicine and Health Sciences ,Enzyme-Linked Immunoassays ,lcsh:Science ,Immune Response ,Lung ,Immunity, Cellular ,Multidisciplinary ,Immune System Proteins ,biology ,T Cells ,respiratory system ,Body Fluids ,Respiratory Syncytial Viruses ,medicine.anatomical_structure ,Blood ,Antibody ,Cellular Types ,Anatomy ,Viral load ,Research Article ,T cell ,Immune Cells ,Immunology ,Cytotoxic T cells ,Respiratory Syncytial Virus Infections ,Research and Analysis Methods ,Antibodies ,03 medical and health sciences ,Immune system ,Antigen ,Immunity ,Antigens, CD ,medicine ,Animals ,Immunoassays ,Blood Cells ,business.industry ,lcsh:R ,Biology and Life Sciences ,Proteins ,Cell Biology ,Virology ,CD4 Lymphocyte Count ,030104 developmental biology ,Immunoglobulin G ,Respiratory Infections ,biology.protein ,Immunologic Techniques ,lcsh:Q ,business ,Immunologic Memory ,CD8 ,030215 immunology ,Respiratory tract - Abstract
Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in young children and older adults throughout the world. Prevention of severe RSV disease through active immunization is optimal but no RSV vaccine has been licensed so far. Immune mechanisms of protection against RSV infection in humans have not been fully established, thus a comprehensive characterization of virus-specific immune responses in a relevant animal model will be beneficial in defining correlates of protection. In this study, we infected juvenile naive AGMs with RSV A2 strain and longitudinally assessed virus-specific humoral and cellular immune responses in both peripheral blood and the respiratory tract. RSV viral loads at nasopharyngeal surfaces and in the lung peaked at around day 5 following infection, and then largely resolved by day 10. Low levels of neutralizing antibody titers were detected in serum, with similar kinetics as RSV fusion (F) protein-binding IgG antibodies. RSV infection induced CD8+, but very little CD4+, T lymphocyte responses in peripheral blood. Virus-specific CD8+ T cell frequencies were ~10 fold higher in bronchoaveolar lavage (BAL) compared to peripheral blood and exhibited effector memory (CD95+CD28-) / tissue resident memory (CD69+CD103+) T (TRM) cell phenotypes. The kinetics of virus-specific CD8+ T cells emerging in peripheral blood and BAL correlated with declining viral titers, suggesting that virus-specific cellular responses contribute to the clearance of RSV infection. RSV-experienced AGMs were protected from subsequent exposure to RSV infection. Additional studies are underway to understand protective correlates in these seropositive monkeys.
- Published
- 2017
12. 2729. mRNA Vaccines Encoding Conserved Influenza Antigens Induce Robust and Durable Immunity in Rhesus Macaques
- Author
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Kapil Bahl, Giuseppe Ciaramella, Yangsi Ou, Kara S. Cox, Lan Zhang, Teresa M. Weber, Michael P. Citron, Jessica A. Flynn, Amy S. Espeseth, and Sinoeun Touch
- Subjects
biology ,business.industry ,Immunogenicity ,Orthomyxoviridae ,biology.organism_classification ,Virology ,Nucleoprotein ,Vaccination ,Abstracts ,Infectious Diseases ,Immune system ,Oncology ,Antigen ,Immunity ,Aldesleukin ,Poster Abstracts ,Medicine ,business - Abstract
Background In response to immune pressure, influenza virus evolves, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response that can recognize multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the immunogenicity of mRNA vaccines encoding the stem domain of hemagglutinin (HA) or nucleoprotein (NP) in nonhuman primates (NHPs). Methods Rhesus macaques were immunized three times intramuscularly, at 28 day intervals, with lipid nanoparticle-encapsulated mRNA encoding either HA stem (Yassine et al, 2015) or NP. Serum and PBMCs were collected up to 14 or 24 weeks, respectively, after the last vaccination. The magnitude and durability of humoral and cell-mediated immunity were evaluated. ELISA, competition ELISA, an in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) reporter bioassay, and microneutralization assays were used to characterize serum immune responses. Intracellular cytokine staining (IFN-gamma and IL-2) was used to assess antigen-specific T-cell responses. Results HA stem-immunized NHPs developed a robust anti-stem binding titer after a single vaccine dose, and after two doses, serum antibodies recognized several antigenically distinct Group 1 HA proteins. This broad antibody response persisted for at least 14 weeks post-dose 3 (PD3). Serum antibodies showed ADCC activity and competed with a well-characterized broadly neutralizing antibody, CR9114, for binding to HA stem; however, the polyclonal serum had only minimal activity against a panel of H1N1 viruses in a microneutralization assay. HA-specific CD4+ T-cell responses were detectable PD3. A robust antibody binding response was also detected in NP-vaccinated NHPs, and titers remained high for at least 14 weeks PD3. Additionally, these animals developed robust NP-specific T-cell responses that persisted for at least 24 weeks PD3. On average, 0.5% of CD4+ and 4% of CD8+ T cells produced IFN-gamma in response to NP peptide stimulation at the peak of the response, 2 weeks after the last vaccine dose was administered. Conclusion Lipid nanoparticle-encapsulated mRNA vaccines encoding conserved influenza antigens induce a robust and durable immune response in NHPs. Disclosures All authors: No reported disclosures.
- Published
- 2019
13. Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptase
- Author
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Yuexia Liang, Daniel DeStefano, Samson M. Jolly, Georgia B. McGaughey, Joe P. Vacca, Bang-Lin Wan, Michael W. Miller, Robert P. Gomez, Youwei Yan, Sinoeun Touch, Neville J. Anthony, Robert M. Tynebor, Ming-Tain Lai, Rosa I. Sanchez, Vandna Munshi, Thomas J. Tucker, Theresa M. Williams, Peter J. Felock, and Brenda Paton
- Subjects
Pyridines ,Pyridones ,Stereochemistry ,Clinical Biochemistry ,Mutant ,Pharmaceutical Science ,Ether ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Protein structure ,Drug Discovery ,Humans ,Computer Simulation ,Binding site ,Molecular Biology ,Indazole ,Binding Sites ,Organic Chemistry ,HIV ,virus diseases ,HIV Reverse Transcriptase ,Reverse transcriptase ,Protein Structure, Tertiary ,Enzyme Activation ,chemistry ,Cell culture ,Drug Design ,Pyrazoles ,Reverse Transcriptase Inhibitors ,Molecular Medicine ,Nucleoside - Abstract
Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI's.
- Published
- 2011
14. Epsilon substituted lysinol derivatives as HIV-1 protease inhibitors
- Author
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Craig A. Coburn, Hua-Poo Su, Kristen G. Jones, Theresa M. Williams, Steven S. Carroll, M. Katharine Holloway, Christine Burlein, Joseph P. Vacca, Rosa I. Sanchez, Sinoeun Touch, and Daniel J. DiStefano
- Subjects
Models, Molecular ,Molecular model ,Stereochemistry ,medicine.medical_treatment ,Clinical Biochemistry ,Substituent ,Pharmaceutical Science ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,HIV-1 protease ,Drug Discovery ,medicine ,HIV Protease Inhibitor ,Structure–activity relationship ,Molecular Biology ,Protease ,biology ,Lysine ,Organic Chemistry ,HIV Protease Inhibitors ,Protease inhibitor (biology) ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-L-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket.
- Published
- 2010
15. Strategies towards improving the pharmacokinetic profile of ε-substituted lysinol-derived HIV protease inhibitors
- Author
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Abbas Walji, Aurpon W. Mitra, Daniel J. DiStefano, Alison R. Gregro, Sinoeun Touch, Keith P. Moore, Hemaka A. Rajapakse, Theresa M. Williams, Steven S. Carroll, Christine Burlein, Joseph P. Vacca, Hong Zhu, Philippe G. Nantermet, Jay A. Grobler, Ming-Tain Lai, Elizabeth Tinney, Rosa I. Sanchez, and Brenda Paton
- Subjects
Pharmacology ,Proteases ,Chemistry ,Lysine ,Organic Chemistry ,Human immunodeficiency virus (HIV) ,HIV Infections ,HIV Protease Inhibitors ,medicine.disease_cause ,Biochemistry ,Structure-Activity Relationship ,Pharmacokinetics ,Antiretroviral Therapy, Highly Active ,Drug Discovery ,medicine ,Molecular Medicine ,HIV Protease Inhibitor ,General Pharmacology, Toxicology and Pharmaceutics - Published
- 2010
16. Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif
- Author
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John T. Sisko, Kenneth D. Anderson, Meiquing Lu, Ming-Tain Lai, Theresa M. Williams, Vandna Munshi, Carolyn Bahnck, Yuexia Liang, Bang-Lin Wan, Gregory Moyer, Thomas J. Tucker, Michael W. Miller, Joe P. Vacca, Rebecca Perlow-Poehnelt, John Jin Lim, Daniel J. DiStefano, Rosa I. Sanchez, Peter J. Felock, Dai-Shi Su, Sinoeun Touch, Deanne Rudd, Elizabeth Tinney, Saggar Sandeep A, Neville J. Anthony, Mary Beth Young, and Jessica A. Flynn
- Subjects
Stereochemistry ,Anti-HIV Agents ,Pyridines ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Ether ,Pyrazole ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Dogs ,Allosteric Regulation ,Drug Discovery ,Pyrazolopyridine ,medicine ,Structure–activity relationship ,Animals ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Reverse-transcriptase inhibitor ,Organic Chemistry ,Reverse transcriptase ,HIV Reverse Transcriptase ,Rats ,Enzyme ,chemistry ,Mutation ,Molecular Medicine ,Pyrazoles ,Reverse Transcriptase Inhibitors ,medicine.drug ,Ethers - Abstract
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
- Published
- 2010
17. Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses
- Author
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Vandna Munshi, Joe P. Vacca, Sinoeun Touch, Gregory Moyer, Jessica A. Flynn, Peter J. Felock, Dai-Shi Su, Theresa M. Williams, Deanne Rudd, Neville J. Anthony, Meiquing Lu, Michael W. Miller, Carolyn Bahnck, Rebecca Perlow-Poehnelt, Daniel J. DiStefano, John Jin Lim, Rosa I. Sanchez, Bang-Lin Wan, Kenneth D. Anderson, Elizabeth Tinney, Ming-Tain Lai, Mary Beth Young, and Yuexia Liang
- Subjects
education ,Ether ,Nucleoside Reverse Transcriptase Inhibitor ,Cell Line ,chemistry.chemical_compound ,Structure-Activity Relationship ,Dogs ,Drug Discovery ,Pyrazolopyridine ,medicine ,Potency ,Structure–activity relationship ,Animals ,Humans ,Reverse-transcriptase inhibitor ,Chemistry ,Nucleosides ,Nucleotidyltransferase ,Macaca mulatta ,humanities ,Reverse transcriptase ,HIV Reverse Transcriptase ,Rats ,Biochemistry ,Mutation ,HIV-1 ,Molecular Medicine ,Reverse Transcriptase Inhibitors ,medicine.drug ,Ethers - Abstract
Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.
- Published
- 2009
18. Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants
- Author
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Ming-Tain Lai, Mary Beth Young, Michael W. Miller, Peter J. Felock, Theresa M. Williams, Carolyn Bahnck, Dai-Shi Su, Maricel Torrent, Vandna Munshi, Sinoeun Touch, Meiqing Lu, Rebecca Perlow-Poehnelt, Youwei Yan, Daniel J. DiStefano, Deanne Rudd, Kenneth D. Anderson, Joe P. Vacca, John Jin Lim, Rosa I. Sanchez, Bang-Lin Wan, Elizabeth Tinney, Yuexia Liang, Gregory Moyer, Sridhar Prasad, Jessica A. Flynn, and Neville J. Anthony
- Subjects
Anti-HIV Agents ,Clinical Biochemistry ,Mutant ,Allosteric regulation ,Molecular Conformation ,Pharmaceutical Science ,Crystallography, X-Ray ,Biochemistry ,Structure-Activity Relationship ,Thiocarbamates ,Drug Discovery ,medicine ,Structure–activity relationship ,Molecular Biology ,chemistry.chemical_classification ,Binding Sites ,Reverse-transcriptase inhibitor ,biology ,Organic Chemistry ,virus diseases ,Reverse transcriptase ,HIV Reverse Transcriptase ,Thiocarbamate ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Quinolines ,Molecular Medicine ,Reverse Transcriptase Inhibitors ,Mutant Proteins ,Allosteric Site ,medicine.drug - Abstract
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
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- 2009
19. Recombinant expression of Chlamydia trachomatis major outer membrane protein in E. Coli outer membrane as a substrate for vaccine research.
- Author
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Zhiyun Wen, Boddicker, Melissa A., Kaufhold, Robin M., Khandelwal, Puneet, Durr, Eberhard, Ping Qiu, Lucas, Bob J., Nahas, Debbie D., Cook, James C., Sinoeun Touch, Skinner, Julie M., Espeseth, Amy S., Przysiecki, Craig T., and Lan Zhang
- Subjects
CHLAMYDIA trachomatis ,MEMBRANE proteins ,ESCHERICHIA coli ,GENITALIA infections ,ANTIGENS ,RECOMBINANT antibodies ,VACCINATION - Abstract
Background: Chlamydia trachomatis is a human pathogen which causes a number of pathologies, including genital tract infections in women that can result in tubal infertility. Prevention of infection and disease control might be achieved through vaccination; however, a safe, efficacious and cost-effective vaccine against C. trachomatis infection remains an unmet medical need. C. trachomatis major outer membrane protein (MOMP), a β-barrel integral outer membrane protein, is the most abundant antigen in the outer membrane of the bacterium and has been evaluated as a subunit vaccine candidate. Recombinant MOMP (rMOMP) expressed in E. coli cytoplasm forms inclusion bodies and rMOMP extracted from inclusion bodies results in a reduced level of protection compared to the native MOMP in a mouse challenge model. Results: We sought to target the recombinant expression of MOMP to the E. coli outer membrane (OM). Successful surface expression was achieved with codon harmonization, utilization of low copy number vectors and promoters with moderate strength, suitable leader sequences and optimization of cell culture conditions. rMOMP was extracted from E. coli outer membrane, purified, and characterized biophysically. The OM expressed and purified rMOMP is immunogenic in mice and elicits antibodies that react to the native antigen, Chlamydia elementary body (EB). Conclusions: C. trachomatis MOMP was functionally expressed on the surface of E. coli outer membrane. The OM expressed and purified rMOMP elicits antibodies that react to the native antigen, Chlamydia EB, in a mouse immunogenicity model. Surface expression of MOMP could provide useful reagents for vaccine research, and the methodology could serve as a platform to produce other outer membrane proteins recombinantly. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
20. Biaryl Ethers as Novel Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Key Mutant Viruses.
- Author
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Dai-Shi Su, John J. Lim, Elizabeth Tinney, Bang-Lin Wan, Mary Beth Young, Kenneth D. Anderson, Deanne Rudd, Vandna Munshi, Carolyn Bahnck, Peter J. Felock, Meiquing Lu, Ming-Tain Lai, Sinoeun Touch, Gregory Moyer, Daniel J DiStefano, Jessica A. Flynn, Yuexia Liang, Rosa Sanchez, Rebecca Perlow-Poehnelt, and Mike Miller
- Published
- 2009
- Full Text
- View/download PDF
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