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1. Phase I trial of viral vector based personalized vaccination elicits robust neoantigen specific antitumor T cell responses

Author

D'Alise, Anna Morena., primary, Leoni, Guido, additional, Cotugno, Gabriella, additional, Siani, Loredana, additional, Vitale, Rosa, additional, Ruzza, Valentino, additional, Garzia, Irene, additional, Antonucci, Laura, additional, Micarelli, Elisa, additional, Venafra, Veronica, additional, Gogov, Sven, additional, Capone, Alessia, additional, Runswick, Sarah, additional, Martin-Liberal, Juan, additional, Calvo, Emiliano, additional, Moreno, Victor, additional, Symeonides, Stefan N., additional, Scarselli, Elisa, additional, and Bechter, Oliver, additional

Published
2024
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2. Development of a Potency Assay for Nous-209, a Multivalent Neoantigens-Based Genetic Cancer Vaccine

Author

Bartolomeo, Rosa, primary, Troise, Fulvia, additional, Allocca, Simona, additional, Sdruscia, Giulia, additional, Vitale, Rosa, additional, Bignone, Veronica, additional, Petrone, Anna Maria, additional, Romano, Giuseppina, additional, D’Alise, Anna Morena, additional, Ruzza, Valentino, additional, Garzia, Irene, additional, Leoni, Guido, additional, Merone, Rossella, additional, Lanzaro, Francesca, additional, Colloca, Stefano, additional, Siani, Loredana, additional, Scarselli, Elisa, additional, and Cotugno, Gabriella, additional

Published
2024
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4. 1526 Nous-209 genetic vaccine encoding shared cancer neoantigens is safe and elicits robust immune response in healthy Lynch syndrome carriers: interim results from Phase 1 cancer interception trial

Author

D’Alise, Morena, primary, Willis, Jason, additional, Leoni, Guido, additional, Cruz-Correa, Marcia, additional, Hall, Michael J, additional, Idos, Gregory E, additional, Garzia, Irene, additional, Antonucci, Laura, additional, Cotugno, Gabriella, additional, Siani, Loredana, additional, Gogov, Sven, additional, Liu, Diane, additional, Lee, Jack, additional, Vornik, Lana A, additional, Uribe, Laura Reyes, additional, Garcia-Gonzalez, Araceli, additional, Richmond, Ellen, additional, Umar, Asad, additional, Brown, Powel H, additional, Rodriguez, Luz Maria, additional, Scarselli, Elisa, additional, and Vilar, Eduardo, additional

Published
2023
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5. Abstract LB196: NOUS-PEV, a personalized cancer immunotherapy targeting neoantigens, induces long lasting, tumor infiltrating memory T cells

Author

Bechter, Oliver, primary, D'Alise, Anna Morena, additional, Leoni, Guido, additional, Cotugno, Gabriella, additional, Siani, Loredana, additional, Vitale, Rosa, additional, Ruzza, Valentino, additional, Garzia, Irene, additional, Antonucci, Laura, additional, Micarelli, Elisa, additional, Gogov, Sven, additional, Capone, Alessia, additional, Martin-Liberal, Juan, additional, Calvo, Emiliano, additional, Moreno, Victor, additional, Symeonides, Stefan, additional, and Scarselli, Elisa, additional

Published
2023
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6. 706 NOUS-PEV, a novel personalized viral-based prime/boost cancer immunotherapy targeting patient-specific neoantigens: interim results from the first subjects in the phase 1b study

Author

Bechter, Oliver, primary, Martin-Liberal, Juan, additional, D’Alise, Anna, additional, Leoni, Guido, additional, Cotugno, Gabriella, additional, Siani, Loredana, additional, Vitale, Rosa, additional, Ruzza, Valentino, additional, Micarelli, Elisa, additional, Garzia, Irene, additional, Faivre, Thea, additional, Gogov, Sven, additional, Delaite, Patricia, additional, Colloca, Stefano, additional, Ambrosio, Maria, additional, Merone, Rossella, additional, Scarselli, Elisa, additional, and Symeonides, Stefan, additional

Published
2022
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7. Clinical Assessment of a Recombinant Simian Adenovirus ChAd63: A Potent New Vaccine Vector

Author

O'Hara, Geraldine A., Duncan, Christopher J. A., Ewer, Katie J., Collins, Katharine A., Elias, Sean C., Halstead, Fenella D., Goodman, Anna L., Edwards, Nick J., Reyes-Sandoval, Arturo, Bird, Prudence, Rowland, Rosalind, Sheehy, Susanne H., Poulton, Ian D., Hutchings, Claire, Todryk, Stephen, Andrews, Laura, Folgori, Antonella, Berrie, Eleanor, Moyle, Sarah, Nicosia, Alfredo, Colloca, Stefano, Cortese, Riccardo, Siani, Loredana, Lawrie, Alison M., Gilbert, Sarah C., and Hill, Adrian V. S.

Published
2012
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8. Chronic hepatitis C viral infection subverts vaccine-induced T-cell immunity in humans

Author

Kelly, Christabel, Swadling, Leo, Capone, Stefania, Brown, Anthony, Richardson, Rachel, Halliday, John, von Delft, Annette, Oo, Ye, Mutimer, David, Kurioka, Ayako, Hartnell, Felicity, Collier, Jane, Ammendola, Virginia, Sorbo, Mariarosaria Del, Grazioli, Fabiana, Esposito, Maria Luisa, Marco, Stefania Di, Siani, Loredana, Traboni, Cinzia, Hill, Adrian V.S., Colloca, Stefano, Nicosia, Alfredo, Cortese, Riccardo, Folgori, Antonella, Klenerman, Paul, and Barnes, Eleanor

Published
2016
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9. A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA

Author

Ewer, Katie, Rampling, Tommy, Venkatraman, Navin, Bowyer, Georgina, Wright, Danny, Lambe, Teresa, Imoukhuede, Egeruan B., Payne, Ruth, Fehling, Sarah Katharina, Strecker, Thomas, Biedenkopf, Nadine, Krähling, Verena, Tully, Claire M., Edwards, Nick J., Bentley, Emma M., Samuel, Dhanraj, Labbé, Geneviève, Jin, Jing, Gibani, Malick, Minhinnick, Alice, Wilkie, Morven, Poulton, Ian, Lella, Natalie, Roberts, Rachel, Hartnell, Felicity, Bliss, Carly, Sierra-Davidson, Kailan, Powlson, Jonathan, Berrie, Eleanor, Tedder, Richard, Roman, Francois, De Ryck, Iris, Nicosia, Alfredo, Sullivan, Nancy J., Stanley, Daphne A., Mbaya, Olivier T., Ledgerwood, Julie E., Schwartz, Richard M., Siani, Loredana, Colloca, Stefano, Folgori, Antonella, Di Marco, Stefania, Cortese, Riccardo, Wright, Edward, Becker, Stephan, Graham, Barney S., Koup, Richard A., Levine, Myron M., Volkmann, Ariane, Chaplin, Paul, Pollard, Andrew J., Draper, Simon J., Ballou, Ripley W., Lawrie, Alison, Gilbert, Sarah C., and Hill, Adrian V.S.

Published
2016
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10. MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans

Author

Esposito, Ilaria, Cicconi, Paola, D'Alise, Anna Morena, Brown, Anthony, Esposito, Marialuisa, Swadling, Leo, Holst, Peter Johannes, Bassi, Maria Rosaria, Stornaiuolo, Mariano, Mori, Federica, Vassilev, Ventzislav, Li, Wenqin, Donnison, Timothy, Gentile, Chiara, Turner, Bethany, von Delft, Annette, Del Sorbo, Mariarosaria, Barra, Federica, Contino, Alessandra Maria, Abbate, Adele, Novellino, Ettore, Thomsen, Allan Randrup, Christensen, Jan Pravsgaard, Lahm, Armin, Grazioli, Fabiana, Ammendola, Virginia, Siani, Loredana, Colloca, Stefano, Klenerman, Paul, Nicosia, Alfredo, Dorrell, Lucy, Folgori, Antonella, Capone, Stefania, Barnes, Eleanor, Esposito, Ilaria, Cicconi, Paola, D'Alise, Anna Morena, Brown, Anthony, Esposito, Marialuisa, Swadling, Leo, Holst, Peter Johannes, Bassi, Maria Rosaria, Stornaiuolo, Mariano, Mori, Federica, Vassilev, Ventzislav, Li, Wenqin, Donnison, Timothy, Gentile, Chiara, Turner, Bethany, von Delft, Annette, Del Sorbo, Mariarosaria, Barra, Federica, Contino, Alessandra Maria, Abbate, Adele, Novellino, Ettore, Thomsen, Allan Randrup, Christensen, Jan Pravsgaard, Lahm, Armin, Grazioli, Fabiana, Ammendola, Virginia, Siani, Loredana, Colloca, Stefano, Klenerman, Paul, Nicosia, Alfredo, Dorrell, Lucy, Folgori, Antonella, Capone, Stefania, and Barnes, Eleanor

Abstract

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.

Published
2020

13. GS-05-MHC-II invariant chain adjuvanted chimpanzee adenoviral and MVA hepatitis C vaccines elicit unprecedented levels of anti-viral T-cell immune responses in humans

Author

Esposito, Ilaria, primary, Cicconi, Paola, additional, Capone, Stefania, additional, Brown, Anthony, additional, Esposito, Maria Luisa, additional, Mori, Federica, additional, Vassilev, Ventzislav, additional, Siani, Loredana, additional, Ghaffari, Emma, additional, Gardiner, Claire, additional, Mitton, Celia, additional, Delft, Annette von, additional, Li, Lan, additional, Li, Wenqin, additional, Klenerman, Paul, additional, Colloca, Stefano, additional, Nicosia, Alfredo, additional, Dorrell, Lucy, additional, Folgori, Antonella, additional, and Barnes, Ellie, additional

Published
2019
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14. A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis : First-in-human trial of ChAd63-KH

Author

Osman, Mohamed, Mistry, Anoop, Keding, Ada, Gabe, Rhian, Cook, Elizabeth, Forrester, Sarah, Wiggins, Rebecca, Di Marco, Stefania, Colloca, Stefano, Siani, Loredana, Cortese, Riccardo, Smith, Deborah F, Aebischer, Toni, Kaye, Paul M, and Lacey, Charles J

Subjects
Male, Enzyme-Linked Immunospot Assay, CD8-Positive T-Lymphocytes, White Blood Cells, Animal Cells, Zoonoses, Medicine and Health Sciences, Public and Occupational Health, Enzyme-Linked Immunoassays, Leishmaniasis, Immune Response, Leishmania, Vaccines, Drug Carriers, Vaccines, Synthetic, T Cells, lcsh:Public aspects of medicine, Middle Aged, Flow Cytometry, Vaccination and Immunization, Healthy Volunteers, Infectious Diseases, Leishmaniasis, Visceral, Female, Cellular Types, Research Article, Neglected Tropical Diseases, Adult, lcsh:Arctic medicine. Tropical medicine, Infectious Disease Control, Adolescent, lcsh:RC955-962, Immune Cells, Immunology, Leishmaniasis, Cutaneous, Cytotoxic T cells, Antigens, Protozoan, Research and Analysis Methods, Injections, Intramuscular, Interferon-gamma, Young Adult, Vaccine Development, parasitic diseases, Parasitic Diseases, Humans, Immunoassays, Leishmaniasis Vaccines, Blood Cells, Protozoan Infections, Biology and Life Sciences, lcsh:RA1-1270, Cell Biology, Tropical Diseases, Immunologic Techniques, Adenoviruses, Simian, Preventive Medicine
Abstract

Background Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells. Methods We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry. Findings ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects. Conclusion The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. Trial registration This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359)., Author summary Leishmaniasis is a neglected disease of poverty with global public health impact. Caused by species of the Leishmania parasite, it may manifest itself as slow to heal skin ulcers, metastatic disease affecting the mouth and nose or systemic disease affecting internal organs (kala azar or visceral leishmaniasis). In common with other poverty-related neglected diseases, there have been few incentives for pharma to develop new drugs and vaccines. The few drugs currently available may cause serious side effects and/or only work well in some settings. No vaccines are available for prevention (prophylactic vaccines) or treatment (therapeutic vaccines). The clinical development of vaccines requires a series of clinical trials (Phases I–IV). Phase I studies assess primarily safety and are conducted in healthy volunteers. Later phase trials then involve either more healthy subjects (for prophylactic vaccines) or patients (for therapeutic vaccines) and provide additional safety data as well as preliminary data on efficacy. Here, we describe the results from a Phase I first-in-human trial of a new vaccine for leishmaniasis. Our vaccine is novel compared to those previously tested in that it is designed to target induction of a specific type of immune response (CD8+ T cells). We show here that the vaccine is safe in healthy volunteers and induces robust CD8+ T cell responses. The study represents an important step towards the development of a leishmaniasis vaccine.

Published
2017

15. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Author

Payne, Ruth O., primary, Silk, Sarah E., additional, Elias, Sean C., additional, Miura, Kazutoyo, additional, Diouf, Ababacar, additional, Galaway, Francis, additional, de Graaf, Hans, additional, Brendish, Nathan J., additional, Poulton, Ian D., additional, Griffiths, Oliver J., additional, Edwards, Nick J., additional, Jin, Jing, additional, Labbé, Geneviève M., additional, Alanine, Daniel G.W., additional, Siani, Loredana, additional, Di Marco, Stefania, additional, Roberts, Rachel, additional, Green, Nicky, additional, Berrie, Eleanor, additional, Ishizuka, Andrew S., additional, Nielsen, Carolyn M., additional, Bardelli, Martino, additional, Partey, Frederica D., additional, Ofori, Michael F., additional, Barfod, Lea, additional, Wambua, Juliana, additional, Murungi, Linda M., additional, Osier, Faith H., additional, Biswas, Sumi, additional, McCarthy, James S., additional, Minassian, Angela M., additional, Ashfield, Rebecca, additional, Viebig, Nicola K., additional, Nugent, Fay L., additional, Douglas, Alexander D., additional, Vekemans, Johan, additional, Wright, Gavin J., additional, Faust, Saul N., additional, Hill, Adrian V.S., additional, Long, Carole A., additional, Lawrie, Alison M., additional, and Draper, Simon J., additional

Published
2017
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16. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Author

Payne, Ruth O, Silk, Sarah E, Elias, Sean C, Miura, Kazutoyo, Diouf, Ababacar, Galaway, Francis, de Graaf, Hans, Brendish, Nathan J, Poulton, Ian D, Griffiths, Oliver J, Edwards, Nick J, Jin, Jing, Labbé, Geneviève M, Alanine, Daniel Gw, Siani, Loredana, Di Marco, Stefania, Roberts, Rachel, Green, Nicky, Berrie, Eleanor, Ishizuka, Andrew S, Nielsen, Carolyn M, Bardelli, Martino, Partey, Frederica D, Ofori, Michael F, Barfod, Lea, Wambua, Juliana, Murungi, Linda M, Osier, Faith H, Biswas, Sumi, McCarthy, James S, Minassian, Angela M, Ashfield, Rebecca, Viebig, Nicola K, Nugent, Fay L, Douglas, Alexander D, Vekemans, Johan, Wright, Gavin J, Faust, Saul N, Hill, Adrian Vs, Long, Carole A, Lawrie, Alison M, Draper, Simon J, Payne, Ruth O, Silk, Sarah E, Elias, Sean C, Miura, Kazutoyo, Diouf, Ababacar, Galaway, Francis, de Graaf, Hans, Brendish, Nathan J, Poulton, Ian D, Griffiths, Oliver J, Edwards, Nick J, Jin, Jing, Labbé, Geneviève M, Alanine, Daniel Gw, Siani, Loredana, Di Marco, Stefania, Roberts, Rachel, Green, Nicky, Berrie, Eleanor, Ishizuka, Andrew S, Nielsen, Carolyn M, Bardelli, Martino, Partey, Frederica D, Ofori, Michael F, Barfod, Lea, Wambua, Juliana, Murungi, Linda M, Osier, Faith H, Biswas, Sumi, McCarthy, James S, Minassian, Angela M, Ashfield, Rebecca, Viebig, Nicola K, Nugent, Fay L, Douglas, Alexander D, Vekemans, Johan, Wright, Gavin J, Faust, Saul N, Hill, Adrian Vs, Long, Carole A, Lawrie, Alison M, and Draper, Simon J

Abstract

The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen - a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers. We utilized established viral vectors, the replication-deficient chimpanzee adenovirus serotype 63 (ChAd63), and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding RH5 from the 3D7 clone of P. falciparum. Vaccines were administered i.m. in a heterologous prime-boost regimen using an 8-week interval and were well tolerated. Vaccine-induced anti-RH5 serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. This is the first time to our knowledge that substantial RH5-specific responses have been induced by immunization in humans, with levels greatly exceeding the serum antibody responses observed in African adults following years of natural malaria exposure. These data support the progression of RH5-based vaccines to human efficacy testing.

Published
2017

17. A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH

Author

Osman, Mohamed, primary, Mistry, Anoop, additional, Keding, Ada, additional, Gabe, Rhian, additional, Cook, Elizabeth, additional, Forrester, Sarah, additional, Wiggins, Rebecca, additional, Di Marco, Stefania, additional, Colloca, Stefano, additional, Siani, Loredana, additional, Cortese, Riccardo, additional, Smith, Deborah F., additional, Aebischer, Toni, additional, Kaye, Paul M., additional, and Lacey, Charles J., additional

Published
2017
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19. Results of phase I-II bridging study for Nous-209, a neoantigen cancer immunotherapy, in combination with pembrolizumab as first line treatment in patients with advanced dMMR/MSI-h colorectal cancer.

Author

Overman, Michael J., Maurel, Joan, Oberstein, Paul Eliezer, Roselló-Keränen, Susana, Le, Dung T., Pedersen, Katrina Sophia, Mukherjee, Sarbajit, D'Alise, Anna Morena, Leoni, Guido, Siani, Loredana, Scarselli, Elisa, Faivre, Théa, Delaite, Patricia, Gogov, Sven, and Fakih, Marwan

Published
2023
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20. Chimpanzee adenovirus– and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults

Author

Green, Christopher A., primary, Scarselli, Elisa, additional, Sande, Charles J., additional, Thompson, Amber J., additional, de Lara, Catherine M., additional, Taylor, Kathryn S., additional, Haworth, Kathryn, additional, Del Sorbo, Mariarosaria, additional, Angus, Brian, additional, Siani, Loredana, additional, Di Marco, Stefania, additional, Traboni, Cinzia, additional, Folgori, Antonella, additional, Colloca, Stefano, additional, Capone, Stefania, additional, Vitelli, Alessandra, additional, Cortese, Riccardo, additional, Klenerman, Paul, additional, Nicosia, Alfredo, additional, and Pollard, Andrew J., additional

Published
2015
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21. Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates

Author

Pierantoni, Angiolo, primary, Esposito, Maria Luisa, additional, Ammendola, Virginia, additional, Napolitano, Federico, additional, Grazioli, Fabiana, additional, Abbate, Adele, additional, del Sorbo, Mariarosaria, additional, Siani, Loredana, additional, D'Alise, Anna Morena, additional, Taglioni, Alessandra, additional, Perretta, Gemma, additional, Siccardi, Antonio, additional, Soprana, Elisa, additional, Panigada, Maddalena, additional, Thom, Michelle, additional, Scarselli, Elisa, additional, Folgori, Antonella, additional, Colloca, Stefano, additional, Taylor, Geraldine, additional, Cortese, Riccardo, additional, Nicosia, Alfredo, additional, Capone, Stefania, additional, and Vitelli, Alessandra, additional

Published
2015
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22. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory

Author

Swadling, Leo, primary, Capone, Stefania, additional, Antrobus, Richard D., additional, Brown, Anthony, additional, Richardson, Rachel, additional, Newell, Evan W., additional, Halliday, John, additional, Kelly, Christabel, additional, Bowen, Dan, additional, Fergusson, Joannah, additional, Kurioka, Ayako, additional, Ammendola, Virginia, additional, Del Sorbo, Mariarosaria, additional, Grazioli, Fabiana, additional, Esposito, Maria Luisa, additional, Siani, Loredana, additional, Traboni, Cinzia, additional, Hill, Adrian, additional, Colloca, Stefano, additional, Davis, Mark, additional, Nicosia, Alfredo, additional, Cortese, Riccardo, additional, Folgori, Antonella, additional, Klenerman, Paul, additional, and Barnes, Eleanor, additional

Published
2014
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23. Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation

Author

Ewer, Katie J., primary, O’Hara, Geraldine A., additional, Duncan, Christopher J. A., additional, Collins, Katharine A., additional, Sheehy, Susanne H., additional, Reyes-Sandoval, Arturo, additional, Goodman, Anna L., additional, Edwards, Nick J., additional, Elias, Sean C., additional, Halstead, Fenella D., additional, Longley, Rhea J., additional, Rowland, Rosalind, additional, Poulton, Ian D., additional, Draper, Simon J., additional, Blagborough, Andrew M., additional, Berrie, Eleanor, additional, Moyle, Sarah, additional, Williams, Nicola, additional, Siani, Loredana, additional, Folgori, Antonella, additional, Colloca, Stefano, additional, Sinden, Robert E., additional, Lawrie, Alison M., additional, Cortese, Riccardo, additional, Gilbert, Sarah C., additional, Nicosia, Alfredo, additional, and Hill, Adrian V. S., additional

Published
2013
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24. Clinical Assessment of a Recombinant Simian Adenovirus ChAd63: A Potent New Vaccine Vector

Author

O’Hara, Geraldine A., primary, Duncan, Christopher J. A., additional, Ewer, Katie J., additional, Collins, Katharine A., additional, Elias, Sean C., additional, Halstead, Fenella D., additional, Goodman, Anna L., additional, Edwards, Nick J., additional, Reyes-Sandoval, Arturo, additional, Bird, Prudence, additional, Rowland, Rosalind, additional, Sheehy, Susanne H., additional, Poulton, Ian D., additional, Hutchings, Claire, additional, Todryk, Stephen, additional, Andrews, Laura, additional, Folgori, Antonella, additional, Berrie, Eleanor, additional, Moyle, Sarah, additional, Nicosia, Alfredo, additional, Colloca, Stefano, additional, Cortese, Riccardo, additional, Siani, Loredana, additional, Lawrie, Alison M., additional, Gilbert, Sarah C., additional, and Hill, Adrian V. S., additional

Published
2012
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25. Novel Adenovirus-Based Vaccines Induce Broad and Sustained T Cell Responses to HCV in Man

Author

Barnes, Eleanor, primary, Folgori, Antonella, additional, Capone, Stefania, additional, Swadling, Leo, additional, Aston, Stephen, additional, Kurioka, Ayako, additional, Meyer, Joel, additional, Huddart, Rachel, additional, Smith, Kira, additional, Townsend, Rachel, additional, Brown, Anthony, additional, Antrobus, Richard, additional, Ammendola, Virginia, additional, Naddeo, Mariarosaria, additional, O’Hara, Geraldine, additional, Willberg, Chris, additional, Harrison, Abby, additional, Grazioli, Fabiana, additional, Esposito, Maria Luisa, additional, Siani, Loredana, additional, Traboni, Cinzia, additional, Oo, Ye, additional, Adams, David, additional, Hill, Adrian, additional, Colloca, Stefano, additional, Nicosia, Alfredo, additional, Cortese, Riccardo, additional, and Klenerman, Paul, additional

Published
2012
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26. Vaccine Vectors Derived from a Large Collection of Simian Adenoviruses Induce Potent Cellular Immunity Across Multiple Species

Author

Colloca, Stefano, primary, Barnes, Eleanor, additional, Folgori, Antonella, additional, Ammendola, Virginia, additional, Capone, Stefania, additional, Cirillo, Agostino, additional, Siani, Loredana, additional, Naddeo, Mariarosaria, additional, Grazioli, Fabiana, additional, Esposito, Maria Luisa, additional, Ambrosio, Maria, additional, Sparacino, Angela, additional, Bartiromo, Marta, additional, Meola, Annalisa, additional, Smith, Kira, additional, Kurioka, Ayako, additional, O’Hara, Geraldine A., additional, Ewer, Katie J., additional, Anagnostou, Nicholas, additional, Bliss, Carly, additional, Hill, Adrian V. S., additional, Traboni, Cinzia, additional, Klenerman, Paul, additional, Cortese, Riccardo, additional, and Nicosia, Alfredo, additional

Published
2012
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28. Transgene Optimization, Immunogenicity and In Vitro Efficacy of Viral Vectored Vaccines Expressing Two Alleles of Plasmodium falciparum AMA1

Author

Biswas, Sumi, primary, Dicks, Matthew D. J., additional, Long, Carole A., additional, Remarque, Edmond J., additional, Siani, Loredana, additional, Colloca, Stefano, additional, Cottingham, Matthew G., additional, Holder, Anthony A., additional, Gilbert, Sarah C., additional, Hill, Adrian V. S., additional, and Draper, Simon J., additional

Published
2011
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29. Prime-Boost Immunization with Adenoviral and Modified Vaccinia Virus Ankara Vectors Enhances the Durability and Polyfunctionality of Protective Malaria CD8+T-Cell Responses

Author

Reyes-Sandoval, Arturo, primary, Berthoud, Tamara, additional, Alder, Nicola, additional, Siani, Loredana, additional, Gilbert, Sarah C., additional, Nicosia, Alfredo, additional, Colloca, Stefano, additional, Cortese, Riccardo, additional, and Hill, Adrian V. S., additional

Published
2011
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30. Immune responses against a liver-stage malaria antigen induced by simian adenoviral vector AdCh63 and MVA prime–boost immunisation in non-human primates

Author

Capone, Stefania, primary, Reyes-Sandoval, Arturo, additional, Naddeo, Mariarosaria, additional, Siani, Loredana, additional, Ammendola, Virginia, additional, Rollier, Christine S., additional, Nicosia, Alfredo, additional, Colloca, Stefano, additional, Cortese, Riccardo, additional, Folgori, Antonella, additional, and Hill, Adrian V.S., additional

Published
2010
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31. Prime-Boost Immunization with Adenoviral and Modified Vaccinia Virus Ankara Vectors Enhances the Durability and Polyfunctionality of Protective Malaria CD8 + T-Cell Responses

Author

Reyes-Sandoval, Arturo, primary, Berthoud, Tamara, additional, Alder, Nicola, additional, Siani, Loredana, additional, Gilbert, Sarah C., additional, Nicosia, Alfredo, additional, Colloca, Stefano, additional, Cortese, Riccardo, additional, and Hill, Adrian V. S., additional

Published
2010
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33. Preventing spontaneous genetic rearrangements in the transgene cassettes of adenovirus vectors.

Author

Cottingham, Matthew G., Carroll, Fionnadh, Morris, Susan J., Turner, Alison V., Vaughan, Aisling M., Kapulu, Melissa C., Colloca, Stefano, Siani, Loredana, Gilbert, Sarah C., and Hill, Adrian V.S.

Abstract

First-generation, E1/E3-deleted adenoviral vectors with diverse transgenes are produced routinely in laboratories worldwide for development of novel prophylactics and therapies for a variety of applications, including candidate vaccines against important infectious diseases, such as HIV/AIDS, tuberculosis, and malaria. Here, we show, for two different transgenes (both encoding malarial antigens) inserted at the E1 locus, that rare viruses containing a transgene-inactivating mutation exhibit a selective growth advantage during propagation in E1-complementing HEK293 cells, such that they rapidly become the major or sole species in the viral population. For one of these transgenes, we demonstrate that viral yield and cytopathic effect are enhanced by repression of transgene expression in the producer cell line, using the tetracycline repressor system. In addition to these transgene-inactivating mutations, one of which occurred during propagation of the pre-viral genomic clone in bacteria, and the other after viral reconstitution in HEK293 cells, we describe two other types of mutation, a small deletion and a gross rearranging duplication, in one of the transgenes studied. These were of uncertain origin, and the effects on transgene expression and viral growth were not fully characterized. We demonstrate that, together with minor protocol modifications, repression of transgene expression in HEK293 cells during viral propagation enables production of a genetically stable chimpanzee adenovirus vector expressing a malarial antigen which had previously been impossible to derive. These results have important implications for basic and pre-clinical studies using adenoviral vectors and for derivation of adenoviral vector products destined for large-scale amplification during biomanufacture. Biotechnol. Bioeng. 2012; 109:719-728. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2012
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34. Prime-Boost Immunization with Adenoviral and Modified Vaccinia Virus Ankara Vectors Enhances the Durability and Polyfunctionality of Protective Malaria CD8+T-Cell Responses

Author

Reyes-Sandoval, Arturo, Berthoud, Tamara, Alder, Nicola, Siani, Loredana, Gilbert, Sarah C., Nicosia, Alfredo, Colloca, Stefano, Cortese, Riccardo, and Hill, Adrian V. S.

Abstract

ABSTRACTProtection against liver-stage malaria relies on the induction of high frequencies of antigen-specific CD8+T cells. We have previously reported high protective levels against mouse malaria, albeit short-lived, by a single vaccination with adenoviral vectors coding for a liver-stage antigen (ME.TRAP). Here, we report that prime-boost regimens using modified vaccinia virus Ankara (MVA) and adenoviral vectors encoding ME.TRAP can enhance both short- and long-term sterile protection against malaria. Protection persisted for at least 6 months when simian adenoviruses AdCh63 and AdC9 were used as priming vectors. Kinetic analysis showed that the MVA boost made the adenoviral-primed T cells markedly more polyfunctional, with the number of gamma interferon (INF-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) triple-positive and INF-γ and TNF-α double-positive cells increasing over time, while INF-γ single-positive cells declined with time. However, IFN-γ production prevailed as the main immune correlate of protection, while neither an increase of polyfunctionality nor a high integrated mean fluorescence intensity (iMFI) correlated with protection. These data highlight the ability of optimized viral vector prime-boost regimens to generate more protective and sustained CD8+T-cell responses, and our results encourage a more nuanced assessment of the importance of inducing polyfunctional CD8+T cells by vaccination.

Published
2010
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35. Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation.

Author

Ewer, Katie J., O'Hara, Geraldine A., Duncan, Christopher J. A., Collins, Katharine A., Sheehy, Susanne H., Reyes-Sandoval, Arturo, Goodman, Anna L., Edwards, Nick J., Elias, Sean C., Halstead, Fenella D., Longley, Rhea J., Rowland, Rosalind, Poulton, Ian D., Draper, Simon J., Blagborough, Andrew M., Berrie, Eleanor, Moyle, Sarah, Williams, Nicola, Siani, Loredana, and Folgori, Antonella

Published
2013
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36. Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults

Author

K Haworth, Stefano Colloca, Elisa Scarselli, Paul Klenerman, C de Lara, Stefania Capone, Loredana Siani, Cinzia Traboni, Alfredo Nicosia, M Del Sorbo, Riccardo Cortese, Alessandra Vitelli, Kathryn Mary Taylor, Antonella Folgori, A J Thompson, Christopher A Green, Charles J. Sande, S Di Marco, Brian Angus, Andrew J. Pollard, Green, Christopher A., Scarselli, Elisa, Sande, Charles J., Thompson, Amber J., De Lara, Catherine M., Taylor, Kathryn S., Haworth, Kathryn, Del Sorbo, Mariarosaria, Angus, Brian, Siani, Loredana, Di Marco, Stefania, Traboni, Cinzia, Folgori, Antonella, Colloca, Stefano, Capone, Stefania, Vitelli, Alessandra, Cortese, Riccardo, Klenerman, Paul, Nicosia, Alfredo, and Pollard, Andrew J.

Subjects
CD4-Positive T-Lymphocytes, viruses, CD8-Positive T-Lymphocytes, Antibodies, Viral, Body Temperature, chemistry.chemical_compound, 0302 clinical medicine, HEK293 Cell, 030212 general & internal medicine, 0303 health sciences, Immunogenicity, Medicine (all), Pan troglodyte, Vaccination, virus diseases, Respiratory infection, General Medicine, T helper cell, respiratory system, Healthy Volunteer, Healthy Volunteers, 3. Good health, Respiratory Syncytial Viruses, medicine.anatomical_structure, Editorial, CD4-Positive T-Lymphocyte, Respiratory Syncytial Virus Vaccine, Genetic Vector, Respiratory Syncytial Viruse, Human, Adult, Pan troglodytes, Genetic Vectors, Dose-Response Relationship, Immunologic, Immunization, Secondary, Vaccinia virus, Respiratory Syncytial Virus Infections, Biology, complex mixtures, Article, Virus, Viral vector, 03 medical and health sciences, Interferon-gamma, medicine, Respiratory Syncytial Virus Vaccines, Animals, Humans, 030304 developmental biology, Respiratory Syncytial Virus Infection, Animal, CD8-Positive T-Lymphocyte, Virology, Antibodies, Neutralizing, Vaccinia viru, HEK293 Cells, chemistry, Immunology, Adenoviruses, Simian, Vaccinia
Abstract

Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4(+) and CD8(+) T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease.

Published
2016

37. A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA

Author

Katie Ewer, Tommy Rampling, Navin Venkatraman, Georgina Bowyer, Danny Wright, Teresa Lambe, Egeruan B. Imoukhuede, Ruth Payne, Sarah Katharina Fehling, Thomas Strecker, Nadine Biedenkopf, Verena Krähling, Claire M. Tully, Nick J. Edwards., Emma M. Bentley, Dhanraj Samuel, Geneviève Labbé, Jing Jin, Malick Gibani., Alice Minhinnic, Morven Wilkie, Ian Poulton, Natalie Lella, Rachel Roberts, Felicity Hartnell, Carly Bliss, Kailan Sierra-Davidson, Jonathan Powlson, Eleanor Berrie, Richard Tedder, B. Chir., Francois Roman, Iris De Ryck, Alfredo Nicosia, Nancy J. Sullivan, Daphne A. Stanley, Olivier T. Mbaya, Julie E. Ledgerwood, Richard M. Schwartz, Loredana Siani, Stefano Colloca, Antonella Folgori, Stefania Di Marco, Riccardo Cortese, Edward Wright, Stephan Becker, Barney S. Graham, Richard A. Koup, Myron M. Levine, Ariane Volkmann, Paul Chaplin, Andrew J. Pollard, Simon J. Draper, D. Phil., W. Ripley Ballou, Alison Lawrie, Sarah C. Gilbert, and Adrian V. S. Hill, Ewer, Katie, Rampling, Tommy, Venkatraman, Navin, Bowyer, Georgina, Wright, Danny, Lambe, Teresa, Imoukhuede, Egeruan B., Payne, Ruth, Katharina Fehling, Sarah, Strecker, Thoma, Biedenkopf, Nadine, Krähling, Verena, Tully, Claire M., J. Edwards., Nick, Bentley, Emma M., Samuel, Dhanraj, Labbé, Geneviève, Jin, Jing, Gibani., Malick, Minhinnic, Alice, Wilkie, Morven, Poulton, Ian, Lella, Natalie, Roberts, Rachel, Hartnell, Felicity, Bliss, Carly, Sierra-Davidson, Kailan, Powlson, Jonathan, Berrie, Eleanor, Tedder, Richard, Chir., B., Roman, Francoi, De Ryck, Iri, Nicosia, Alfredo, Sullivan, Nancy J., Stanley, Daphne A., Mbaya, Olivier T., Ledgerwood, Julie E., Schwartz, Richard M., Siani, Loredana, Colloca, Stefano, Folgori, Antonella, Di Marco, Stefania, Cortese, Riccardo, Wright, Edward, Becker, Stephan, Graham, Barney S., Koup, Richard A., Levine, Myron M., Volkmann, Ariane, Chaplin, Paul, Pollard, Andrew J., Draper, Simon J., Phil., D., Ripley Ballou, W., Lawrie, Alison, Gilbert, Sarah C., and Hill, and Adrian V. S.

Subjects
0301 basic medicine, Zaire ebolavirus, Male, T-Lymphocytes, viruses, medicine.disease_cause, Antibodies, Viral, chemistry.chemical_compound, 0302 clinical medicine, INFECTION, Vaccinia, 030212 general & internal medicine, 11 Medical and Health Sciences, B-Lymphocytes, Immunity, Cellular, PROTECTS NONHUMAN-PRIMATES, biology, ELISPOT, General Medicine, Middle Aged, Ebolavirus, 3. Good health, VIRUS, Cytokines, Female, Antibody, Life Sciences & Biomedicine, Adult, Pan troglodytes, Immunization, Secondary, IMMUNITY, Article, 03 medical and health sciences, Young Adult, Medicine, General & Internal, Immunity, General & Internal Medicine, medicine, Animals, Humans, Ebola Vaccines, QR355, Ebola virus, Science & Technology, Ebola vaccine, business.industry, Hemorrhagic Fever, Ebola, Virology, 030104 developmental biology, chemistry, Immunology, biology.protein, Adenoviruses, Simian, business, CHALLENGE
Abstract

BACKGROUND\ud The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak.\ud \ud METHODS\ud In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels — 1×1010 viral particles, 2.5×1010 viral particles, and 5×1010 viral particles — with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime–boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus–based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability.\ud \ud RESULTS\ud No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P

Published
2016

38. Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates

Author

Angiolo Pierantoni1, Maria Luisa Esposito1, Virginia Ammendola1, Federico Napolitano1, Fabiana Grazioli1, Adele Abbate1, Mariarosaria del Sorbo1, Loredana Siani1, Anna Morena D'Alise1, Alessandra Taglioni3, Gemma Perretta3, Antonio Siccardi4, Elisa Soprana4, Maddalena Panigada4, Michelle Thom2, Elisa Scarselli1, Antonella Folgori1, Stefano Colloca1, Geraldine Taylor2, Riccardo Cortese1, 7, Alfredo Nicosia1, 5, 6, Stefania Capone1, Alessandra Vitelli1, Pierantoni, Angiolo, Esposito, Maria Luisa, Ammendola, Virginia, Napolitano, Federico, Grazioli, Fabiana, Abbate, Adele, del Sorbo, Mariarosaria, Siani, Loredana, D'Alise, Anna Morena, Taglioni, Alessandra, Perretta, Gemma, Siccardi, Antonio, Soprana, Elisa, Panigada, Maddalena, Thom, Michelle, Scarselli, Elisa, Folgori, Antonella, Colloca, Stefano, Taylor, Geraldine, Cortese, Riccardo, Nicosia, Alfredo, Capone, Stefania, and Vitelli, Alessandra

Subjects
Cellular immunity, Modified vaccinia Ankara, lcsh:QH426-470, viruses, Virus, Article, Lower respiratory tract infection, medicine, Genetics, lcsh:QH573-671, Neutralizing antibody, Molecular Biology, biology, business.industry, lcsh:Cytology, Immunogenicity, virus diseases, respiratory system, medicine.disease, Virology, 3. Good health, Vaccination, lcsh:Genetics, medicine.anatomical_structure, Immunology, biology.protein, Molecular Medicine, business, Respiratory tract
Abstract

Respiratory Syncytial Virus (RSV) is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV) and Modified Vaccinia Ankara RSV (MVA-RSV) encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing.

Published
2015

39. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory

Author

Rachel Richardson, Loredana Siani, Antonella Folgori, Riccardo Cortese, Evan W. Newell, Joannah R. Fergusson, Fabiana Grazioli, Cinzia Traboni, Alfredo Nicosia, Mark M. Davis, Adrian V. S. Hill, Leo Swadling, Maria Luisa Esposito, Richard D Antrobus, Dan Hameiri Bowen, Stefania Capone, John Halliday, Virginia Ammendola, Eleanor Barnes, Christabel Kelly, Anthony Brown, Mariarosaria Del Sorbo, Stefano Colloca, Ayako Kurioka, Paul Klenerman, Swadling, Leo, Capone, Stefania, Antrobus, Richard D., Brown, Anthony, Richardson, Rachel, Newell, Evan W., Halliday, John, Kelly, Christabel, Bowen, Dan, Fergusson, Joannah, Kurioka, Ayako, Ammendola, Virginia, Del Sorbo, Mariarosaria, Grazioli, Fabiana, Esposito, Maria Luisa, Siani, Loredana, Traboni, Cinzia, Hill, Adrian, Colloca, Stefano, Davis, Mark, Nicosia, Alfredo, Cortese, Riccardo, Folgori, Antonella, Klenerman, Paul, and Barnes, Eleanor

Subjects
CD4-Positive T-Lymphocytes, Modified vaccinia Ankara, Enzyme-Linked Immunospot Assay, Time Factors, viruses, Hepacivirus, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Interferon-gamma Release Test, Vaccines, DNA, Vector (molecular biology), Cells, Cultured, Viral Vaccine, Medicine (all), Pan troglodyte, Vaccination, virus diseases, General Medicine, Healthy Volunteer, Hepatitis C, Healthy Volunteers, medicine.anatomical_structure, Treatment Outcome, England, CD4-Positive T-Lymphocyte, Human, Viral Hepatitis Vaccines, Pan troglodytes, Time Factor, T cell, Biology, Article, Viral vector, Adenoviridae, Antigen, medicine, Animals, Humans, Cell Proliferation, Hepaciviru, Animal, Histocompatibility Antigens Class I, Viral Vaccines, CD8-Positive T-Lymphocyte, biochemical phenomena, metabolism, and nutrition, Hepatitis C Antibodies, Virology, digestive system diseases, Immunology, Hepatitis C Antibodie, Immunologic Memory, Interferon-gamma Release Tests, CD8, Viral Hepatitis Vaccine
Abstract

A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.

Published
2014

40. MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans.

Author

Esposito I, Cicconi P, D'Alise AM, Brown A, Esposito M, Swadling L, Holst PJ, Bassi MR, Stornaiuolo M, Mori F, Vassilev V, Li W, Donnison T, Gentile C, Turner B, von Delft A, Del Sorbo M, Barra F, Contino AM, Abbate A, Novellino E, Thomsen AR, Christensen JP, Lahm A, Grazioli F, Ammendola V, Siani L, Colloca S, Klenerman P, Nicosia A, Dorrell L, Folgori A, Capone S, and Barnes E

Subjects
Antigens, Differentiation, B-Lymphocyte genetics, CD8-Positive T-Lymphocytes, Hepacivirus genetics, Histocompatibility Antigens Class II, Humans, Viral Vaccines
Abstract

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4 + T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8 + and CD4 + responses were induced with up to 30% of CD3 + CD8 + cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2020
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41. Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates.

Author

Pierantoni A, Esposito ML, Ammendola V, Napolitano F, Grazioli F, Abbate A, Del Sorbo M, Siani L, D'Alise AM, Taglioni A, Perretta G, Siccardi A, Soprana E, Panigada M, Thom M, Scarselli E, Folgori A, Colloca S, Taylor G, Cortese R, Nicosia A, Capone S, and Vitelli A

Abstract

Respiratory Syncytial Virus (RSV) is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV) and Modified Vaccinia Ankara RSV (MVA-RSV) encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing.

Published
2015
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42. Prime-boost immunization with adenoviral and modified vaccinia virus Ankara vectors enhances the durability and polyfunctionality of protective malaria CD8+ T-cell responses.

Author

Reyes-Sandoval A, Berthoud T, Alder N, Siani L, Gilbert SC, Nicosia A, Colloca S, Cortese R, and Hill AV

Subjects
Adenoviridae, Animals, CD8-Positive T-Lymphocytes immunology, Female, Immunization Schedule, Mice, Mice, Inbred BALB C, Protozoan Proteins immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic immunology, Vaccinia virus classification, CD8-Positive T-Lymphocytes physiology, Immunization, Secondary, Malaria Vaccines administration & dosage, Malaria Vaccines immunology, Malaria, Falciparum prevention & control
Abstract

Protection against liver-stage malaria relies on the induction of high frequencies of antigen-specific CD8+ T cells. We have previously reported high protective levels against mouse malaria, albeit short-lived, by a single vaccination with adenoviral vectors coding for a liver-stage antigen (ME.TRAP). Here, we report that prime-boost regimens using modified vaccinia virus Ankara (MVA) and adenoviral vectors encoding ME.TRAP can enhance both short- and long-term sterile protection against malaria. Protection persisted for at least 6 months when simian adenoviruses AdCh63 and AdC9 were used as priming vectors. Kinetic analysis showed that the MVA boost made the adenoviral-primed T cells markedly more polyfunctional, with the number of gamma interferon (INF-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-2 (IL-2) triple-positive and INF-gamma and TNF-alpha double-positive cells increasing over time, while INF-gamma single-positive cells declined with time. However, IFN-gamma production prevailed as the main immune correlate of protection, while neither an increase of polyfunctionality nor a high integrated mean fluorescence intensity (iMFI) correlated with protection. These data highlight the ability of optimized viral vector prime-boost regimens to generate more protective and sustained CD8+ T-cell responses, and our results encourage a more nuanced assessment of the importance of inducing polyfunctional CD8(+) T cells by vaccination.

Published
2010
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