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Rappaport AR, Kyi C, Lane M, Hart MG, Johnson ML, Henick BS, Liao CY, Mahipal A, Shergill A, Spira AI, Goldman JW, Scallan CD, Schenk D, Palmer CD, Davis MJ, Kounlavouth S, Kemp L, Yang A, Li YJ, Likes M, Shen A, Boucher GR, Egorova M, Veres RL, Espinosa JA, Jaroslavsky JR, Kraemer Tardif LD, Acrebuche L, Puccia C, Sousa L, Zhou R, Bae K, Hecht JR, Carbone DP, Johnson B, Allen A, Ferguson AR, Jooss K. A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results. Nat Med 2024; 30:1013-1022. [PMID: 38538867 DOI: 10.1038/s41591-024-02851-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/29/2024] [Indexed: 04/21/2024]
Abstract
Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .
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Affiliation(s)
| | - Chrisann Kyi
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | | | | | - Brian S Henick
- Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Chih-Yi Liao
- University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA
| | | | - Ardaman Shergill
- University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - David P Carbone
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
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Miner MD, deCamp A, Grunenberg N, De Rosa SC, Fiore-Gartland A, Bar K, Spearman P, Allen M, Yu PC, Manso B, Frahm N, Kalams S, Baden L, Keefer MC, Scott HM, Novak R, Van Tieu H, Tomaras GD, Kublin JG, McElrath MJ, Corey L, Frank I. Polytopic fractional delivery of an HIV vaccine alters cellular responses and results in increased epitope breadth in a phase 1 randomized trial. EBioMedicine 2024; 100:104987. [PMID: 38306894 PMCID: PMC10847480 DOI: 10.1016/j.ebiom.2024.104987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/20/2023] [Accepted: 01/15/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Elicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination. METHODS We randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine. FINDINGS CD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group. INTERPRETATION This study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans. FUNDING National Institute of Allergy and Infectious Diseases, NIH.
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Affiliation(s)
- Maurine D Miner
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA.
| | - Allan deCamp
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Nicole Grunenberg
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Stephen C De Rosa
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA
| | | | | | - Paul Spearman
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mary Allen
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pei-Chun Yu
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Bryce Manso
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Nicole Frahm
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Spyros Kalams
- Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Michael C Keefer
- Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA
| | - Hyman M Scott
- San Francisco Department of Public Health, San Francisco, CA, USA
| | | | - Hong Van Tieu
- Laboratory of Infectious Disease Prevention, Lindsley F. Kimball Research Institute, New York Blood Center, New York City, NY, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York City, NY, USA
| | | | - James G Kublin
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - M Juliana McElrath
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Lawrence Corey
- Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
| | - Ian Frank
- University of Pennsylvania, Philadelphia, PA, USA
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3
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Erez N, Achdout H, Yahalom-Ronen Y, Adutler-Lieber S, Bar-On L, Bar-Haim E, Politi B, Vitner EB, Tamir H, Melamed S, Paran N, Israely T. Identification of T-Cell Epitopes Using a Combined In-Silico and Experimental Approach in a Mouse Model for SARS-CoV-2. Curr Issues Mol Biol 2023; 45:7944-7955. [PMID: 37886945 PMCID: PMC10605721 DOI: 10.3390/cimb45100502] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/28/2023] Open
Abstract
Following viral infection, T-cells are crucial for an effective immune response to intracellular pathogens, including respiratory viruses. During the COVID-19 pandemic, diverse assays were required in pre-clinical trials to evaluate the immune response following vaccination against SARS-CoV-2 and assess the response following exposure to the virus. To assess the nature and potency of the cellular response to infection or vaccination, a reliable and specific activity assay was needed. A cellular activity assay based on the presentation of short peptides (epitopes) allows the identification of T cell epitopes displayed on different alleles of the MHC, shedding light on the strength of the immune response towards antigens and aiding in antigen design for vaccination. In this report, we describe two approaches for scanning T cell epitopes on the surface glycoprotein of the SARS-CoV-2 (spike), which is utilized for attachment and entry and serves as an antigen in many vaccine candidates. We demonstrate that epitope scanning is feasible using peptide libraries or computational scanning combined with a cellular activity assay. Our scans identified four CD8 T cell epitopes, including one novel undescribed epitope. These epitopes enabled us to establish a reliable T-cell response assay, which was examined and used in various experimental mouse models for SARS-CoV-2 infection and vaccination. These approaches could potentially aid in future antigen design for vaccination and establish cellular activity assays against uncharacterized antigens of emerging pathogens.
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Affiliation(s)
- Noam Erez
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Hagit Achdout
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Yfat Yahalom-Ronen
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Shimrit Adutler-Lieber
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Liat Bar-On
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (L.B.-O.); (E.B.-H.)
| | - Erez Bar-Haim
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (L.B.-O.); (E.B.-H.)
| | - Boaz Politi
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Einat B. Vitner
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Hadas Tamir
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Sharon Melamed
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Nir Paran
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
| | - Tomer Israely
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel; (H.A.); (Y.Y.-R.); (S.A.-L.); (B.P.); (E.B.V.); (H.T.); (S.M.); (N.P.)
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4
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Muraduzzaman AKM, Illing PT, Mifsud NA, Purcell AW. Understanding the Role of HLA Class I Molecules in the Immune Response to Influenza Infection and Rational Design of a Peptide-Based Vaccine. Viruses 2022; 14:2578. [PMID: 36423187 PMCID: PMC9695287 DOI: 10.3390/v14112578] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Influenza A virus is a respiratory pathogen that is responsible for regular epidemics and occasional pandemics that result in substantial damage to life and the economy. The yearly reformulation of trivalent or quadrivalent flu vaccines encompassing surface glycoproteins derived from the current circulating strains of the virus does not provide sufficient cross-protection against mismatched strains. Unlike the current vaccines that elicit a predominant humoral response, vaccines that induce CD8+ T cells have demonstrated a capacity to provide cross-protection against different influenza strains, including novel influenza viruses. Immunopeptidomics, the mass spectrometric identification of human-leukocyte-antigen (HLA)-bound peptides isolated from infected cells, has recently provided key insights into viral peptides that can serve as potential T cell epitopes. The critical elements required for a strong and long-living CD8+ T cell response are related to both HLA restriction and the immunogenicity of the viral peptide. This review examines the importance of HLA and the viral immunopeptidome for the design of a universal influenza T-cell-based vaccine.
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Affiliation(s)
| | | | - Nicole A. Mifsud
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Anthony W. Purcell
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
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5
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Hon C, Friesen J, Ingmundson A, Scheppan D, Hafalla JCR, Müller K, Matuschewski K. Conservation of S20 as an Ineffective and Disposable IFNγ-Inducing Determinant of Plasmodium Sporozoites Indicates Diversion of Cellular Immunity. Front Microbiol 2021; 12:703804. [PMID: 34421862 PMCID: PMC8377727 DOI: 10.3389/fmicb.2021.703804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/07/2021] [Indexed: 11/19/2022] Open
Abstract
Despite many decades of research to develop a malaria vaccine, only one vaccine candidate has been explored in pivotal phase III clinical trials. This candidate subunit vaccine consists of a portion of a single Plasmodium antigen, circumsporozoite protein (CSP). This antigen was initially identified in the murine malaria model and shown to contain an immunodominant and protective CD8+ T cell epitope specific to the H-2Kd (BALB/c)-restricted genetic background. A high-content screen for CD8+ epitopes in the H2Kb/Db (C57BL/6)-restricted genetic background, identified two distinct dominant epitopes. In this study, we present a characterization of one corresponding antigen, the Plasmodium sporozoite-specific protein S20. Plasmodium berghei S20 knockout sporozoites and liver stages developed normally in vitro and in vivo. This potent infectivity of s20(-) sporozoites permitted comparative analysis of knockout and wild-type parasites in cell-based vaccination. Protective immunity of irradiation-arrested s20(-) sporozoites in single, double and triple immunizations was similar to irradiated unaltered sporozoites in homologous challenge experiments. These findings demonstrate the presence of an immunogenic Plasmodium pre-erythrocytic determinant, which is not essential for eliciting protection. Although S20 is not needed for colonization of the mammalian host and for initiation of a blood infection, it is conserved amongst Plasmodium species. Malarial parasites express conserved, immunogenic proteins that are not required to establish infection but might play potential roles in diverting cellular immune responses.
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Affiliation(s)
- Calvin Hon
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany
| | - Johannes Friesen
- Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.,Medical Care Unit Labor 28 GmbH, Berlin, Germany
| | - Alyssa Ingmundson
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.,Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Diana Scheppan
- Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Julius C R Hafalla
- Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Katja Müller
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.,Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Kai Matuschewski
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.,Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany
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6
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Lopez E, van Heerden J, Bosch-Camós L, Accensi F, Navas MJ, López-Monteagudo P, Argilaguet J, Gallardo C, Pina-Pedrero S, Salas ML, Salt J, Rodriguez F. Live Attenuated African Swine Fever Viruses as Ideal Tools to Dissect the Mechanisms Involved in Cross-Protection. Viruses 2020; 12:v12121474. [PMID: 33371460 PMCID: PMC7767464 DOI: 10.3390/v12121474] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/03/2022] Open
Abstract
African swine fever (ASF) has become the major threat for the global swine industry. Furthermore, the epidemiological situation of African swine fever virus (ASFV) in some endemic regions of Sub-Saharan Africa is worse than ever, with multiple virus strains and genotypes currently circulating in a given area. Despite the recent advances on ASF vaccine development, there are no commercial vaccines yet, and most of the promising vaccine prototypes available today have been specifically designed to fight the genotype II strains currently circulating in Europe, Asia, and Oceania. Previous results from our laboratory have demonstrated the ability of BA71∆CD2, a recombinant LAV lacking CD2v, to confer protection against homologous (BA71) and heterologous genotype I (E75) and genotype II (Georgia2007/01) ASFV strains, both belonging to same clade (clade C). Here, we extend these results using BA71∆CD2 as a tool trying to understand ASFV cross-protection, using phylogenetically distant ASFV strains. We first observed that five out of six (83.3%) of the pigs immunized once with 106 PFU of BA71∆CD2 survived the tick-bite challenge using Ornithodoros sp. soft ticks naturally infected with RSA/11/2017 strain (genotype XIX, clade D). Second, only two out of six (33.3%) survived the challenge with Ken06.Bus (genotype IX, clade A), which is phylogenetically more distant to BA71∆CD2 than the RSA/11/2017 strain. On the other hand, homologous prime-boosting with BA71∆CD2 only improved the survival rate to 50% after Ken06.Bus challenge, all suffering mild ASF-compatible clinical signs, while 100% of the pigs immunized with BA71∆CD2 and boosted with the parental BA71 virulent strain survived the lethal challenge with Ken06.Bus, without almost no clinical signs of the disease. Our results confirm that cross-protection is a multifactorial phenomenon that not only depends on sequence similarity. We believe that understanding this complex phenomenon will be useful for designing future vaccines for ASF-endemic areas.
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Affiliation(s)
- Elisabeth Lopez
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
| | - Juanita van Heerden
- Agricultural Research Council-Onderstepoort Veterinary Research, Pretoria 0110, South Africa;
| | - Laia Bosch-Camós
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
| | - Francesc Accensi
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
- Departament de Sanitat i d’Anatomia Animals, Facultat de Veterinària, UAB, 08193 Bellaterra, Spain
| | - Maria Jesus Navas
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
| | - Paula López-Monteagudo
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
| | - Jordi Argilaguet
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
| | - Carmina Gallardo
- Centro de Investigación en Sanidad Animal (CISA-INIA), 28130 Madrid, Spain;
| | - Sonia Pina-Pedrero
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
| | - Maria Luisa Salas
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autònoma de Madrid, 28049 Madrid, Spain;
| | - Jeremy Salt
- GALVmed, Doherty Building, Pentlands Science Park, Bush Loan, Penicuik Edinburgh EH26 0PZ, UK;
| | - Fernando Rodriguez
- IRTA, Centre de Recerca en Sanitat Animal (IRTA-CReSA), Campus de la Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; (E.L.); (L.B.-C.); (F.A.); (M.J.N.); (P.L.-M.); (J.A.); (S.P.-P.)
- Correspondence:
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7
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Park S, Wang X, Lim J, Xiao G, Lu T, Wang T. Bayesian multiple instance regression for modeling immunogenic neoantigens. Stat Methods Med Res 2020; 29:3032-3047. [PMID: 32401701 DOI: 10.1177/0962280220914321] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The relationship between tumor immune responses and tumor neoantigens is one of the most fundamental and unsolved questions in tumor immunology, and is the key to understanding the inefficiency of immunotherapy observed in many cancer patients. However, the properties of neoantigens that can elicit immune responses remain unclear. This biological problem can be represented and solved under a multiple instance learning framework, which seeks to model multiple instances (neoantigens) within each bag (patient specimen) with the continuous response (T cell infiltration) observed for each bag. To this end, we develop a Bayesian multiple instance regression method, named BMIR, using a Gaussian distribution to address continuous responses and latent binary variables to model primary instances in bags. By means of such Bayesian modeling, BMIR can learn a function for predicting the bag-level responses and for identifying the primary instances within bags, as well as give access to Bayesian statistical inference, which are elusive in existing works. We demonstrate the superiority of BMIR over previously proposed optimization-based methods for multiple instance regression through simulation and real data analyses. Our method is implemented in R package entitled "BayesianMIR" and is available at https://github.com/inmybrain/BayesianMIR.
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Affiliation(s)
- Seongoh Park
- Department of Statistics, Seoul National University, Seoul, Korea
| | - Xinlei Wang
- Department of Statistical Science, Southern Methodist University, Dallas, TX, USA
| | - Johan Lim
- Department of Statistics, Seoul National University, Seoul, Korea
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tianshi Lu
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tao Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA
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8
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Poh CM, Zheng J, Channappanavar R, Chang ZW, Nguyen THO, Rénia L, Kedzierska K, Perlman S, Poon LLM. Multiplex Screening Assay for Identifying Cytotoxic CD8 + T Cell Epitopes. Front Immunol 2020; 11:400. [PMID: 32218786 PMCID: PMC7078160 DOI: 10.3389/fimmu.2020.00400] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/20/2020] [Indexed: 11/13/2022] Open
Abstract
The cytotoxicity of epitope-specific CD8+ T cells is usually measured indirectly through IFNγ production. Existing assays that directly measure this activity are limited mainly to measurements of up to two specificities in a single reaction. Here, we develop a multiplex cytotoxicity assay that allows direct, simultaneous measurement of up to 23 different specificities of CD8+ T cells in a single reaction. This can greatly reduce the amount of starting clinical materials for a systematic screening of CD8+ T cell epitopes. In addition, this greatly enhanced capacity enables the incorporation of irrelevant epitopes for determining the non-specific killing activity of CD8+ T cells, thereby allowing to measure the actual epitope-specific cytotoxicity activities. This technique is shown to be useful to study both human and mouse CD8+ T cells. Besides, our results from human PBMCs and three independent infectious animal models (MERS, influenza and malaria) further reveal that IFNγ expression by epitope-specific CD8+ T cells does not always correlate with their cell-killing potential, highlighting the need for using cytotoxicity assays in specific contexts (e.g., evaluating vaccine candidates). Overall, our approach opens up new possibilities for comprehensive analyses of CD8+ T cell cytotoxicity in a practical manner.
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Affiliation(s)
- Chek Meng Poh
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jian Zheng
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Rudragouda Channappanavar
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Zi Wei Chang
- Singapore Immunology Network, Agency of Science, Technology and Research, Singapore, Singapore
| | - Thi H. O. Nguyen
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Laurent Rénia
- Singapore Immunology Network, Agency of Science, Technology and Research, Singapore, Singapore
| | - Katherine Kedzierska
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Stanley Perlman
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Leo L. M. Poon
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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9
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Gonzalez-Nieto L, Castro IM, Bischof GF, Shin YC, Ricciardi MJ, Bailey VK, Dang CM, Pedreño-Lopez N, Magnani DM, Ejima K, Allison DB, Gil HM, Evans DT, Rakasz EG, Lifson JD, Desrosiers RC, Martins MA. Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. PLoS Pathog 2019; 15:e1008015. [PMID: 31568531 PMCID: PMC6791558 DOI: 10.1371/journal.ppat.1008015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 10/14/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023] Open
Abstract
A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)-a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy.
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Affiliation(s)
- Lucas Gonzalez-Nieto
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Isabelle M. Castro
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Georg F. Bischof
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Young C. Shin
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Michael J. Ricciardi
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Varian K. Bailey
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Christine M. Dang
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Nuria Pedreño-Lopez
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Diogo M. Magnani
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Keisuke Ejima
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, United States of America
| | - David B. Allison
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, United States of America
| | - Hwi Min Gil
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, United States of America
| | - David T. Evans
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, United States of America
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Eva G. Rakasz
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Jeffrey D. Lifson
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America
| | - Ronald C. Desrosiers
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Mauricio A. Martins
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
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10
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Impact of epitope density on CD8+ T cell development and function. Mol Immunol 2019; 113:120-125. [DOI: 10.1016/j.molimm.2019.03.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/17/2019] [Accepted: 03/21/2019] [Indexed: 11/23/2022]
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11
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Schøller AS, Fonnes M, Nazerai L, Christensen JP, Thomsen AR. Local Antigen Encounter Is Essential for Establishing Persistent CD8 + T-Cell Memory in the CNS. Front Immunol 2019; 10:351. [PMID: 30886617 PMCID: PMC6409353 DOI: 10.3389/fimmu.2019.00351] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 02/11/2019] [Indexed: 12/11/2022] Open
Abstract
While the brain is considered an immune-privileged site, the CNS may nevertheless be the focus of immune mediated inflammation in the case of infection and certain autoimmune diseases, e.g., multiple sclerosis. As in other tissues, it has been found that acute T-cell infiltration may be followed by establishment of persistent local T-cell memory. To improve our understanding regarding the regulation of putative tissue resident memory T (Trm) cells in CNS, we devised a new model system for studying the generation of Trm cells in this site. To this purpose, we exploited the fact that the CNS may be a sanctuary for adenoviral infection, and to minimize virus-induced disease, we chose replication-deficient adenoviruses for infection of the CNS. Non-replicating adenoviruses are known to be highly immunogenic, and our studies demonstrate that intracerebral inoculation causes marked local T-cell recruitment, which is followed by persistent infiltration of the CNS parenchyma by antigen specific CD8+ T cells. Phenotypical analysis of CNS infiltrating antigen specific CD8+ T cells was consistent with these cells being Trms. Regarding the long-term stability of the infiltrate, resident CD8+ T cells expressed high levels of the anti-apoptotic molecule Bcl-2 as well as the proliferation marker Ki-67 suggesting that the population is maintained through steady homeostatic proliferation. Functionally, memory CD8+ T cells from CNS matched peripheral memory cells with regard to capacity for ex vivo cytotoxicity and cytokine production. Most importantly, our experiments revealed a key role for local antigen encounter in the establishment of sustained CD8+ T-cell memory in the brain. Inflammation in the absence of cognate antigen only led to limited and transient infiltration by antigen specific CD8+ T cells. Together these results indicate that memory CD8+ T cells residing in the CNS predominantly mirror previous local infections and immune responses to local autoantigens.
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Affiliation(s)
- Amalie S Schøller
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Masja Fonnes
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Loulieta Nazerai
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jan P Christensen
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Allan R Thomsen
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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12
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Martins MA, Bischof GF, Shin YC, Lauer WA, Gonzalez-Nieto L, Watkins DI, Rakasz EG, Lifson JD, Desrosiers RC. Vaccine protection against SIVmac239 acquisition. Proc Natl Acad Sci U S A 2019; 116:1739-1744. [PMID: 30642966 PMCID: PMC6358712 DOI: 10.1073/pnas.1814584116] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The biological characteristics of HIV pose serious difficulties for the success of a preventive vaccine. Molecularly cloned SIVmac239 is difficult for antibodies to neutralize, and a variety of vaccine approaches have had great difficulty achieving protective immunity against it in rhesus monkey models. Here we report significant protection against i.v. acquisition of SIVmac239 using a long-lasting approach to vaccination. The vaccine regimen includes a replication-competent herpesvirus engineered to contain a near-full-length SIV genome that expresses all nine SIV gene products, assembles noninfectious SIV virion particles, and is capable of eliciting long-lasting effector-memory cellular immune responses to all nine SIV gene products. Vaccinated monkeys were significantly protected against acquisition of SIVmac239 following repeated marginal dose i.v. challenges over a 4-month period. Further work is needed to define the critical components necessary for eliciting this protective immunity, evaluate the breadth of the protection against a variety of strains, and explore how this approach may be extended to human use.
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Affiliation(s)
- Mauricio A Martins
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Georg F Bischof
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Young C Shin
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - William A Lauer
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Lucas Gonzalez-Nieto
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - David I Watkins
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Eva G Rakasz
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715
| | - Jeffrey D Lifson
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701
| | - Ronald C Desrosiers
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136;
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13
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Lauron EJ, Yang L, Elliott JI, Gainey MD, Fremont DH, Yokoyama WM. Cross-priming induces immunodomination in the presence of viral MHC class I inhibition. PLoS Pathog 2018; 14:e1006883. [PMID: 29444189 PMCID: PMC5812664 DOI: 10.1371/journal.ppat.1006883] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 01/17/2018] [Indexed: 01/07/2023] Open
Abstract
Viruses have evolved mechanisms of MHCI inhibition in order to evade recognition by cytotoxic CD8+ T cells (CTLs), which is well-illustrated by our prior studies on cowpox virus (CPXV) that encodes potent MHCI inhibitors. Deletion of CPXV viral MHCI inhibitors markedly attenuated in vivo infection due to effects on CTL effector function, not priming. However, the CTL response to CPXV in C57BL/6 mice is dominated by a single peptide antigen presented by H-2Kb. Here we evaluated the effect of viral MHCI inhibition on immunodominant (IDE) and subdominant epitopes (SDE) as this has not been thoroughly examined. We found that cross-priming, but not cross-dressing, is the main mechanism driving IDE and SDE CTL responses following CPXV infection. Secretion of the immunodominant antigen was not required for immunodominance. Instead, immunodominance was caused by CTL interference, known as immunodomination. Both immunodomination and cross-priming of SDEs were not affected by MHCI inhibition. SDE-specific CTLs were also capable of exerting immunodomination during primary and secondary responses, which was in part dependent on antigen abundance. Furthermore, CTL responses directed solely against SDEs protected against lethal CPXV infection, but only in the absence of the CPXV MHCI inhibitors. Thus, both SDE and IDE responses can contribute to protective immunity against poxviruses, implying that these principles apply to poxvirus-based vaccines. The use of vaccinia virus (VACV) to eradicate smallpox is the arguably the most successful demonstration of vaccination. The VACV vaccine also provides cross-protection against related zoonotic orthopoxviruses, including monkey poxvirus (MXPV) and CPXV, which circulate between various animal hosts and humans. Interestingly, Edward Jenner first demonstrated the concept of vaccination against smallpox in the late 1700s using CPXV. He also made the curious observation that CPXV vaccination did not always protect against recurrent exposure to CPXV. Jenner’s observations may be explained by the ability for CPXV to evade antiviral CD8+ T cell immune responses. To evade CD8+ T cells, CPXV inhibits MHCI antigen presentation, which is required to prime CD8+ T cells. Importantly, CPXV is the only orthopoxvirus that inhibits MHCI and thus provides a unique opportunity to investigate the effects of viral MHCI inhibition on CD8+ T cell priming. Here, we examine the factors that contribute to priming of CPXV-specific CD8+ T cells and show that viral MHCI inhibition does not affect CD8+ T cell priming, but prior CPXV immunization does inhibit priming during subsequent exposure to CPXV. The effects of pre-existing poxvirus immunity are therefore important to consider if poxvirus-based vaccines against various diseases are to be widely used.
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Affiliation(s)
- Elvin J. Lauron
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Liping Yang
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Jabari I. Elliott
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Maria D. Gainey
- Department of Biology, Western Carolina University, Cullowhee, North Carolina, United States of America
| | - Daved H. Fremont
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Wayne M. Yokoyama
- Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- * E-mail:
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14
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Donaldson B, Al-Barwani F, Pelham SJ, Young K, Ward VK, Young SL. Multi-target chimaeric VLP as a therapeutic vaccine in a model of colorectal cancer. J Immunother Cancer 2017; 5:69. [PMID: 28806910 PMCID: PMC5556368 DOI: 10.1186/s40425-017-0270-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 07/21/2017] [Indexed: 02/08/2023] Open
Abstract
Background Colorectal cancer is responsible for almost 700,000 deaths annually worldwide. Therapeutic vaccination is a promising alternative to conventional treatment for colorectal cancer, using vaccines to induce targeted immune responses against tumour-associated antigens. In this study, we have developed chimaeric virus-like particles (VLP), a form of non-infectious non-replicative subunit vaccine consisting of rabbit haemorrhagic disease virus (RHDV) VP60 capsid proteins containing recombinantly inserted epitopes from murine topoisomerase IIα and survivin. These vaccines were developed in mono- (T.VP60, S.VP60) and multi-target (TS.VP60) forms, aiming to elucidate the potential benefits from multi-target vaccination. Methods Chimaeric RHDV VLP were developed by recombinantly inserting immune epitopes at the N-terminus of VP60. Vaccines were tested against a murine model of colorectal cancer by establishing MC38-OVA tumours subcutaneously. Unmethylated CpG DNA oligonucleotides (CpGs) were used as a vaccine adjuvant. Statistical tests employed included the Mantel-Cox log-rank test, ANOVA and unpaired t-tests depending on the data analysed, with a post hoc Bonferroni adjustment for multiple measures. Results Chimaeric RHDV VLP were found to form a composite particle in the presence of CpGs. Overall survival was significantly improved amongst mice bearing MC38-OVA tumours following vaccination with T.VP60 (60%, 9/15), S.VP60 (60%, 9/15) or TS.VP60 (73%, 11/15). TS.VP60 significantly prolonged the vaccine-induced remission period in comparison to each mono-therapy. Conclusions Chimaeric VLP containing multiple epitopes were found to confer an advantage for therapeutic vaccination in a model of colorectal cancer based on the prolongation of remission prior to tumour escape. Electronic supplementary material The online version of this article (doi:10.1186/s40425-017-0270-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Braeden Donaldson
- Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand
| | - Farah Al-Barwani
- Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand
| | - Simon J Pelham
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand
| | - Katie Young
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand
| | - Vernon K Ward
- Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Sarah L Young
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand.
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15
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Abdul-Jawad S, Ondondo B, van Hateren A, Gardner A, Elliott T, Korber B, Hanke T. Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. Mol Ther 2016; 24:375-384. [PMID: 26581160 PMCID: PMC4817818 DOI: 10.1038/mt.2015.210] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 11/09/2015] [Indexed: 12/19/2022] Open
Abstract
The biggest roadblock in development of effective vaccines against human immunodeficiency virus type 1 (HIV-1) is the virus genetic diversity. For T-cell vaccine, this can be tackled by focusing the vaccine-elicited T-cells on the highly functionally conserved regions of HIV-1 proteins, mutations in which typically cause a replicative fitness loss, and by computing multivalent mosaic proteins, which maximize the coverage of potential 9-mer T-cell epitopes of the input viral sequences. Our first conserved region vaccines HIVconsv employed clade alternating consensus sequences and showed promise in the initial clinical trials in terms of magnitude and breadth of elicited CD8(+) T-cells. Here, monitoring T-cells restricted by HLA-A*02:01 in transgenic mice, we assessed whether or not the tHIVconsv design (HIVconsv with a tissue plasminogen activator leader sequence) benefits from combining with a complementing conserved mosaic immunogen tHIVcmo, and compared the bivalent immunization to that with trivalent conserved mosaic vaccines. A hierarchy of tHIVconsv ≤ tHIVconsv+tHIVcmo < tCmo1+tCmo2+tCmo3 vaccinations for induction of CD8(+) T-cell responses was observed in terms of recognition of tested peptide variants. Thus, our HLA-A*02:01-restricted epitope data concur with previously published mouse and macaque observations and suggest that even conserved region vaccines benefit from oligovalent mosaic design.
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Affiliation(s)
| | | | - Andy van Hateren
- Faculty of Medicine and Institute for Life Science, University of Southampton, Southampton, UK
| | | | - Tim Elliott
- Faculty of Medicine and Institute for Life Science, University of Southampton, Southampton, UK
| | - Bette Korber
- Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, New Mexico, USA; The New Mexico Consortium, Los Alamos, New Mexico, USA
| | - Tomáš Hanke
- The Jenner Institute, University of Oxford, Oxford, UK; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
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16
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Yang Y, Sun W, Guo J, Zhao G, Sun S, Yu H, Guo Y, Li J, Jin X, Du L, Jiang S, Kou Z, Zhou Y. In silico design of a DNA-based HIV-1 multi-epitope vaccine for Chinese populations. Hum Vaccin Immunother 2015; 11:795-805. [PMID: 25839222 DOI: 10.1080/21645515.2015.1012017] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The development of an HIV-1 vaccine that is capable of inducing effective and broadly cross-reactive humoral and cellular immune responses remains a challenging task because of the extensive diversity of HIV-1, the difference of virus subtypes (clades) in different geographical regions, and the polymorphism of human leukocyte antigens (HLA). We performed an in silico design of 3 DNA vaccines, designated pJW4303-MEG1, pJW4303-MEG2 and pJW4303-MEG3, encoding multi-epitopes that are highly conserved within the HIV-1 subtypes most prevalent in China and can be recognized through HLA alleles dominant in China. The pJW4303-MEG1-encoded protein consisted of one Th epitope in Env, and one, 2, and 6 epitopes in Pol, Env, and Gag proteins, respectively, with a GGGS linker sequence between epitopes. The pJW4303-MEG2-encoded protein contained similar epitopes in a different order, but with the same linker as pJW4303-MEG1. The pJW4303-MEG3-encoded protein contained the same epitopes in the same order as that of pJW4303-MEG2, but with a different linker sequence (AAY). To evaluate immunogenicity, mice were immunized intramuscularly with these DNA vaccines. Both pJW4303-MEG1 and pJW4303-MEG2 vaccines induced equally potent humoral and cellular immune responses in the vaccinated mice, while pJW4303-MEG3 did not induce immune responses. These results indicate that both epitope and linker sequences are important in designing effective epitope-based vaccines against HIV-1 and other viruses.
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Affiliation(s)
- Yi Yang
- a State Key Laboratory of Pathogen and Biosecurity ; Beijing Institute of Microbiology and Epidemiology ; Beijing , China
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17
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Lacasta A, Monteagudo PL, Jiménez-Marín Á, Accensi F, Ballester M, Argilaguet J, Galindo-Cardiel I, Segalés J, Salas ML, Domínguez J, Moreno Á, Garrido JJ, Rodríguez F. Live attenuated African swine fever viruses as ideal tools to dissect the mechanisms involved in viral pathogenesis and immune protection. Vet Res 2015; 46:135. [PMID: 26589145 PMCID: PMC4654842 DOI: 10.1186/s13567-015-0275-z] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/12/2015] [Indexed: 11/10/2022] Open
Abstract
African swine fever virus (ASFV) is the causal agent of African swine fever, a hemorrhagic and often lethal porcine disease causing enormous economical losses in affected countries. Endemic for decades in most of the sub-Saharan countries and Sardinia, the risk of ASFV-endemicity in Europe has increased since its last introduction into Europe in 2007. Live attenuated viruses have been demonstrated to induce very efficient protective immune responses, albeit most of the time protection was circumscribed to homologous ASFV challenges. However, their use in the field is still far from a reality, mainly due to safety concerns. In this study we compared the course of the in vivo infection caused by two homologous ASFV strains: the virulent E75 and the cell cultured adapted strain E75CV1, obtained from adapting E75 to grow in the CV1 cell-line. Interestingly, the kinetics of both viruses not only differed on the clinical signs that they caused and in the virus loads found, but also in the immunological pathways activated throughout the infections. Furthermore, E75CV1 confirmed its protective potential against the homologous E75 virus challenge and allowed the demonstration of poor cross-protection against BA71, thus defining it as heterologous. The in vitro specificity of the CD8(+) T-cells present at the time of lethal challenge showed a clear activation against the homologous virus (E75) but not against BA71. These findings will be of utility for a better understanding of ASFV pathogenesis and for the rational designing of safe and efficient vaccines against this virus.
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Affiliation(s)
- Anna Lacasta
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain. .,International Livestock Research Intitute (ILRI), 00100, Nairobi, Kenya.
| | - Paula L Monteagudo
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain.
| | - Ángeles Jiménez-Marín
- Instituto de Agricultura Sostenible, Campus Alameda del Obispo, 14080 CSIC, Córdoba, Spain.
| | - Francesc Accensi
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain. .,Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193, Barcelona, Spain.
| | - María Ballester
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain. .,INRA, UMR, 1313, Génétique Animale et Biologie Intégrative, 78352, Jouy-en-Josas, France.
| | | | - Iván Galindo-Cardiel
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain. .,WorldPathol Ltd. Co., 50005, Saragossa, Spain.
| | - Joaquim Segalés
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain. .,Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193, Barcelona, Spain.
| | - María L Salas
- Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28049, Madrid, Spain.
| | | | - Ángela Moreno
- Instituto de Agricultura Sostenible, Campus Alameda del Obispo, 14080 CSIC, Córdoba, Spain. .,Grupo de Genómica y Mejora Animal, Departamento de Genética, Facultad de Veterinaria, Universidad de Córdoba, Campus de Rabanales, Ed. C-5, 14071, Córdoba, Spain.
| | - Juan J Garrido
- Instituto de Agricultura Sostenible, Campus Alameda del Obispo, 14080 CSIC, Córdoba, Spain.
| | - Fernando Rodríguez
- Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain.
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18
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Epigenetic control of interferon-gamma expression in CD8 T cells. J Immunol Res 2015; 2015:849573. [PMID: 25973438 PMCID: PMC4418004 DOI: 10.1155/2015/849573] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 12/02/2014] [Indexed: 11/18/2022] Open
Abstract
Interferon- (IFN-) γ is an essential cytokine for immunity against intracellular pathogens and cancer. IFN-γ expression by CD4 T lymphocytes is observed only after T helper (Th) 1 differentiation and there are several studies about the molecular mechanisms that control Ifng expression in these cells. However, naïve CD8 T lymphocytes do not produce large amounts of IFN-γ, but after TCR stimulation there is a progressive acquisition of IFN-γ expression during differentiation into cytotoxic T lymphocytes (CTL) and memory cells, which are capable of producing high levels of this cytokine. Differential gene expression can be regulated from the selective action of transcriptional factors and also from epigenetic mechanisms, such as DNA CpG methylation or posttranslational histone modifications. Recently it has been recognized that epigenetic modification is an integral part of CD8 lymphocyte differentiation. This review will focus on the chromatin status of Ifng promoter in CD8 T cells and possible influences of epigenetic modifications in Ifng gene and conserved noncoding sequences (CNSs) in regulation of IFN-γ production by CD8 T lymphocytes.
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19
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Short conserved sequences of HIV-1 are highly immunogenic and shift immunodominance. J Virol 2014; 89:1195-204. [PMID: 25378501 DOI: 10.1128/jvi.02370-14] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
UNLABELLED Cellular immunity is pivotal in HIV-1 pathogenesis but is hampered by viral sequence diversity. An approach to minimize this diversity is to focus immunity on conserved proteome sequences; therefore, we selected four relatively conserved regions (Gag amino acids 148 to 214 and 250 to 335, Env amino acids 521 to 606, and Nef amino acids 106 to 148), each created in three mosaics, to provide better coverage of M-group HIV-1 sequences. A conserved-region vaccine (CRV) delivering genes for these four regions as equal mixtures of three mosaics each (each region at a separate injection site) was compared to a whole-protein vaccine (WPV) delivering equimolar amounts of genes for whole Gag, Env, and Nef as clade B consensus sequences (separate injection sites). Three rhesus macaques were vaccinated via three DNA primes and a recombinant adenovirus type 5 boost (weeks 0, 4, 8, and 24, respectively). Although CRV inserts were about one-fifth that of WPV, the CRV generated comparable-magnitude blood CD4+ and CD8+ T lymphocyte responses against Gag, Env, and Nef. WPV responses preferentially targeted proteome areas outside the selected conserved regions in direct proportion to sequence lengths, indicating similar immunogenicities for the conserved regions and the outside regions. The CRV yielded a conserved-region targeting density that was approximately 5-fold higher than that of the WPV. A similar pattern was seen for bronchoalveolar lymphocytes, but with quadruple the magnitudes seen in blood. Overall, these findings demonstrate that the selected conserved regions are highly immunogenic and that anatomically isolated vaccinations with these regions focus immunodominance compared to the case for full-length protein vaccination. IMPORTANCE HIV-1 sequence diversity is a major barrier limiting the capability of cellular immunity to contain infection and the ability of vaccines to match circulating viral sequences. To date, vaccines tested in humans have delivered whole proteins or genes for whole proteins, and it is unclear whether including only conserved sequences would yield sufficient cellular immunogenicity. We tested a vaccine delivering genes for four small conserved HIV-1 regions compared to a control vaccine with genes for whole Gag, Env, and Nef. Although the conserved regions ranged from 43 to 86 amino acids and comprised less than one-fifth of the whole Gag/Env/Nef sequence, the vaccines elicited equivalent total magnitudes of both CD4+ and CD8+ T lymphocyte responses. These data demonstrate the immunogenicity of these small conserved regions and the potential for a vaccine to steer immunodominance toward conserved epitopes.
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Abstract
While advances have been made in some areas, more often than not attempts at vaccine development against the human immunodeficiency virus only serve to highlight gaps in our knowledge of host immunity. While numerous approaches have been explored, to control infection, an HIV vaccine will need to be able to induce production of neutralizing antibodies and a cytotoxic T cell response in order to prevent the formation of the CD4+ T cell viral reservoir. However, challenges still remain for the development of an HIV vaccine. Incomplete knowledge of host immunity lies at the core of the tribulations lying in the face of effective vaccine development.
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Affiliation(s)
- David Rhys Alchin
- Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, University of Melbourne, Parkville, Australia,
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21
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Dalla Santa S, Merlo A, Bobisse S, Ronconi E, Boldrin D, Milan G, Barbieri V, Marin O, Facchinetti A, Biasi G, Dolcetti R, Zanovello P, Rosato A. Functional avidity-driven activation-induced cell death shapes CTL immunodominance. THE JOURNAL OF IMMUNOLOGY 2014; 193:4704-11. [PMID: 25246498 DOI: 10.4049/jimmunol.1303203] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Immunodominance is a complex phenomenon that relies on a mere numerical concept, while being potentially influenced at every step of the immune response. We investigated the mechanisms leading to the establishment of CTL immunodominance in a retroviral model and found that the previously defined subdominant Env-specific CD8(+) T cells are endowed with an unexpectedly higher functional avidity than is the immunodominant Gag-recognizing counterpart. This high avidity, along with the Env Ag overload, results in a supraoptimal TCR engagement. The overstimulation makes Env-specific T lymphocytes more susceptible to apoptosis, thus hampering their expansion and leading to an unintentional "immune kamikazing." Therefore, Ag-dependent, hyperactivation-induced cell death can be regarded as a novel mechanism in the establishment of the immunodominance that restrains and opposes the expansion of high-avidity T cells in favor of lower-affinity populations.
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Affiliation(s)
| | - Anna Merlo
- Veneto Institute of Oncology, 35128 Padua, Italy
| | - Sara Bobisse
- Ludwig Center for Cancer Research, University of Lausanne, Biopôle III, 1066 Epalinges, Lausanne, Switzerland
| | - Elisa Ronconi
- Excellence Centre for Research, Transfer, and High Education, University of Florence, 50139 Florence, Italy
| | | | - Gabriella Milan
- Department of Medicine, University of Padua, 35128 Padua, Italy
| | - Vito Barbieri
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy
| | - Oriano Marin
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
| | - Antonella Facchinetti
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy
| | - Giovanni Biasi
- Department of Molecular Pathology, University of Marche, 60126 Ancona, Italy; and
| | | | - Paola Zanovello
- Veneto Institute of Oncology, 35128 Padua, Italy; Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy
| | - Antonio Rosato
- Veneto Institute of Oncology, 35128 Padua, Italy; Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy;
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22
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Expression library immunization can confer protection against lethal challenge with African swine fever virus. J Virol 2014; 88:13322-32. [PMID: 25210179 DOI: 10.1128/jvi.01893-14] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED African swine fever is one of the most devastating pig diseases, against which there is no vaccine available. Recent work from our laboratory has demonstrated the protective potential of DNA vaccines encoding three African swine fever viral antigens (p54, p30, and the hemagglutinin extracellular domain) fused to ubiquitin. Partial protection was afforded in the absence of detectable antibodies prior to virus challenge, and survival correlated with the presence of a large number of hemagglutinin-specific CD8(+) T cells in blood. Aiming to demonstrate the presence of additional CD8(+) T-cell determinants with protective potential, an expression library containing more than 4,000 individual plasmid clones was constructed, each one randomly containing a Sau3AI restriction fragment of the viral genome (p54, p30, and hemagglutinin open reading frames [ORFs] excluded) fused to ubiquitin. Immunization of farm pigs with the expression library yielded 60% protection against lethal challenge with the virulent E75 strain. These results were further confirmed by using specific-pathogen-free pigs after challenging them with 10(4) hemadsorbing units (HAU) of the cell culture-adapted strain E75CV1. On this occasion, 50% of the vaccinated pigs survived the lethal challenge, and 2 out of the 8 immunized pigs showed no viremia or viral excretion at any time postinfection. In all cases, protection was afforded in the absence of detectable specific antibodies prior to challenge and correlated with the detection of specific T-cell responses at the time of sacrifice. In summary, our results clearly demonstrate the presence of additional protective determinants within the African swine fever virus (ASFV) genome and open up the possibility for their future identification. IMPORTANCE African swine fever is a highly contagious disease of domestic and wild pigs that is endemic in many sub-Saharan countries, where it causes important economic losses and is currently in continuous expansion across Europe. Unfortunately, there is no treatment nor an available vaccine. Early attempts using attenuated vaccines demonstrated their potential to protect pigs against experimental infection. However, their use in the field remains controversial due to safety issues. Although inactive and subunit vaccines did not confer solid protection against experimental ASFV infection, our DNA vaccination results have generated new expectations, confirming the key role of T-cell responses in protection and the existence of multiple ASFV antigens with protective potential, more of which are currently being identified. Thus, the future might bring complex and safe formulations containing more than a single viral determinant to obtain broadly protective vaccines. We believe that obtaining the optimal vaccine formulation it is just a matter of time, investment, and willingness.
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23
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Martins MA, Wilson NA, Piaskowski SM, Weisgrau KL, Furlott JR, Bonaldo MC, Veloso de Santana MG, Rudersdorf RA, Rakasz EG, Keating KD, Chiuchiolo MJ, Piatak M, Allison DB, Parks CL, Galler R, Lifson JD, Watkins DI. Vaccination with Gag, Vif, and Nef gene fragments affords partial control of viral replication after mucosal challenge with SIVmac239. J Virol 2014; 88:7493-516. [PMID: 24741098 PMCID: PMC4054456 DOI: 10.1128/jvi.00601-14] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 04/14/2014] [Indexed: 01/12/2023] Open
Abstract
UNLABELLED Broadly targeted cellular immune responses are thought to be important for controlling replication of human and simian immunodeficiency viruses (HIV and SIV). However, eliciting such responses by vaccination is complicated by immunodominance, the preferential targeting of only a few of the many possible epitopes of a given antigen. This phenomenon may be due to the coexpression of dominant and subdominant epitopes by the same antigen-presenting cell and may be overcome by distributing these sequences among several different vaccine constructs. Accordingly, we tested whether vaccinating rhesus macaques with "minigenes" encoding fragments of Gag, Vif, and Nef resulted in broadened cellular responses capable of controlling SIV replication. We delivered these minigenes through combinations of recombinant Mycobacterium bovis BCG (rBCG), electroporated recombinant DNA (rDNA) along with an interleukin-12 (IL-12)-expressing plasmid (EP rDNA plus pIL-12), yellow fever vaccine virus 17D (rYF17D), and recombinant adenovirus serotype 5 (rAd5). Although priming with EP rDNA plus pIL-12 increased the breadth of vaccine-induced T-cell responses, this effect was likely due to the improved antigen delivery afforded by electroporation rather than modulation of immunodominance. Indeed, Mamu-A*01(+) vaccinees mounted CD8(+) T cells directed against only one subdominant epitope, regardless of the vaccination regimen. After challenge with SIVmac239, vaccine efficacy was limited to a modest reduction in set point in some of the groups and did not correlate with standard T-cell measurements. These findings suggest that broad T-cell responses elicited by conventional vectors may not be sufficient to substantially contain AIDS virus replication. IMPORTANCE Immunodominance poses a major obstacle to the generation of broadly targeted, HIV-specific cellular responses by vaccination. Here we attempted to circumvent this phenomenon and thereby broaden the repertoire of SIV-specific cellular responses by vaccinating rhesus macaques with minigenes encoding fragments of Gag, Vif, and Nef. In contrast to previous mouse studies, this strategy appeared to minimally affect monkey CD8(+) T-cell immundominance hierarchies, as seen by the detection of only one subdominant epitope in Mamu-A*01(+) vaccinees. This finding underscores the difficulty of inducing subdominant CD8(+) T cells by vaccination and demonstrates that strategies other than gene fragmentation may be required to significantly alter immunodominance in primates. Although some of the regimens tested here were extremely immunogenic, vaccine efficacy was limited to a modest reduction in set point viremia after challenge with SIVmac239. No correlates of protection were identified. These results reinforce the notion that vaccine immunogenicity does not predict control of AIDS virus replication.
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Affiliation(s)
- Mauricio A Martins
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Nancy A Wilson
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Shari M Piaskowski
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kim L Weisgrau
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jessica R Furlott
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Myrna C Bonaldo
- Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Richard A Rudersdorf
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Eva G Rakasz
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Karen D Keating
- Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Maria J Chiuchiolo
- International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, USA
| | - Michael Piatak
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA
| | - David B Allison
- Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Christopher L Parks
- International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, USA
| | - Ricardo Galler
- Instituto de Tecnologia em Imunobiológicos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Jeffrey D Lifson
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA
| | - David I Watkins
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
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24
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Pavlenko M, Leder C, Pisa P. Plasmid DNA vaccines against cancer: cytotoxic T-lymphocyte induction against tumor antigens. Expert Rev Vaccines 2014; 4:315-27. [PMID: 16026247 DOI: 10.1586/14760584.4.3.315] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In recent years, a number of tumor vaccination strategies have been developed. Most of these rely on the identification of tumor antigens that can be recognized by the immune system. DNA vaccination represents one such approach for the induction of both humoral and cellular immune responses against tumor antigens. Studies in animal models have demonstrated the feasibility of utilizing DNA vaccination to elicit protective antitumor immune responses. However, most tumor antigens expressed by cancer cells in humans are weakly immunogenic, and therefore require the development of strategies to potentiate DNA vaccine efficacy in the clinical setting. This review focuses on recent advances in understanding of the immunology of DNA vaccines, as well as strategies used to increase DNA vaccine potency with respect to cytotoxic T-lymphocyte activity.
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Affiliation(s)
- Maxim Pavlenko
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm S-171 76, Sweden.
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25
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Kraft ARM, Wlodarczyk MF, Kenney LL, Selin LK. PC61 (anti-CD25) treatment inhibits influenza A virus-expanded regulatory T cells and severe lung pathology during a subsequent heterologous lymphocytic choriomeningitis virus infection. J Virol 2013; 87:12636-47. [PMID: 24049180 PMCID: PMC3838166 DOI: 10.1128/jvi.00936-13] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 09/06/2013] [Indexed: 12/19/2022] Open
Abstract
Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 H1N1 pandemic. This pathology is induced by IAV-specific memory CD8(+) T cells cross-reactive with LCMV. Here, we discovered that IAV-immune mice have enhanced CD4(+) Foxp3(+) T-regulatory (Treg) cells in their lungs, leading us to question whether a modulation in the normal balance of Treg and effector T-cell responses also contributes to enhancing lung pathology upon LCMV infection of IAV-immune mice. Treg cell and interleukin-10 (IL-10) levels remained elevated in the lungs and mediastinal lymph nodes (mLNs) throughout the acute LCMV response of IAV-immune mice. PC61 treatment, used to decrease Treg cell levels, did not change LCMV titers but resulted in a surprising decrease in lung pathology upon LCMV infection in IAV-immune but not in naive mice. Associated with this decrease in pathology was a retention of Treg in the mLN and an unexpected partial clonal exhaustion of LCMV-specific CD8(+) T-cell responses only in IAV-immune mice. PC61 treatment did not affect cross-reactive memory CD8(+) T-cell proliferation. These results suggest that in the absence of IAV-expanded Treg cells and in the presence of cross-reactive memory, the LCMV-specific response was overstimulated and became partially exhausted, resulting in a decreased effector response. These studies suggest that Treg cells generated during past infections can influence the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. Thus, in humans with complex infection histories, PC61 treatment may lead to unexpected results.
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Affiliation(s)
- Anke R. M. Kraft
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Myriam F. Wlodarczyk
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
- Centre de Physiopathologie de Toulouse-Purpan INSERM UMR1043, CNRS UMR5282, Université Toulouse III CHU Purpan, Toulouse, France
| | - Laurie L. Kenney
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Liisa K. Selin
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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Cook R, Leroux C, Issel C. Equine infectious anemia and equine infectious anemia virus in 2013: A review. Vet Microbiol 2013; 167:181-204. [DOI: 10.1016/j.vetmic.2013.09.031] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 09/16/2013] [Accepted: 09/21/2013] [Indexed: 10/26/2022]
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Chapman R, Stutz H, Jacobs W, Shephard E, Williamson AL. Priming with recombinant auxotrophic BCG expressing HIV-1 Gag, RT and Gp120 and boosting with recombinant MVA induces a robust T cell response in mice. PLoS One 2013; 8:e71601. [PMID: 23977084 PMCID: PMC3748047 DOI: 10.1371/journal.pone.0071601] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 07/08/2013] [Indexed: 11/23/2022] Open
Abstract
In previous studies we have shown that a pantothenate auxotroph of Myocbacterium bovis BCG (BCGΔpanCD) expressing HIV-1 subtype C Gag induced Gag-specific immune responses in mice and Chacma baboons after prime-boost immunization in combination with matched rMVA and VLP vaccines respectively. In this study recombinant BCG (rBCG) expressing HIV-1 subtype C reverse transcriptase and a truncated envelope were constructed using both the wild type BCG Pasteur strain as a vector and the pantothenate auxotroph. Mice were primed with rBCG expressing Gag and RT and boosted with a recombinant MVA, expressing a polyprotein of Gag, RT, Tat and Nef (SAAVI MVA-C). Priming with rBCGΔpanCD expressing Gag or RT rather than the wild type rBCG expressing Gag or RT resulted in higher frequencies of total HIV-specific CD8+ T cells and increased numbers of T cells specific to the subdominant Gag and RT epitopes. Increasing the dose of rBCG from 105 cfu to 107 cfu also led to an increase in the frequency of responses to subdominant HIV epitopes. A mix of the individual rBCGΔpanCD vaccines expressing either Gag, RT or the truncated Env primed the immune system for a boost with SAAVI MVA-C and generated five-fold higher numbers of HIV-specific IFN-γ-spot forming cells than mice primed with rBCGΔpanCD containing an empty vector control. Priming with the individual rBCGΔpanCD vaccines or the mix and boosting with SAAVI MVA-C also resulted in the generation of HIV-specific CD4+ and CD8+ T cells producing IFN-γ and TNF-α and CD4+ cells producing IL-2. The rBCG vaccines tested in this study were able to prime the immune system for a boost with rMVA expressing matching antigens, inducing robust, HIV-specific T cell responses to both dominant and subdominant epitopes in the individual proteins when used as individual vaccines or in a mix.
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Affiliation(s)
- Rosamund Chapman
- Institute of Infectious Disease and Molecular Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Division of Medical Virology, Department of Clinical Laboratory Science, Albert Einstein College of Medicine, Bronx, New York, United States of America
- * E-mail:
| | - Helen Stutz
- Institute of Infectious Disease and Molecular Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Division of Medical Virology, Department of Clinical Laboratory Science, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - William Jacobs
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Enid Shephard
- Institute of Infectious Disease and Molecular Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Medical Research Council, Cape Town, South Africa
| | - Anna-Lise Williamson
- Institute of Infectious Disease and Molecular Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Division of Medical Virology, Department of Clinical Laboratory Science, Albert Einstein College of Medicine, Bronx, New York, United States of America
- National Health Laboratory Service, Cape Town, South Africa
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28
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Lin LCW, Flesch IEA, Tscharke DC. Immunodomination during peripheral vaccinia virus infection. PLoS Pathog 2013; 9:e1003329. [PMID: 23633956 PMCID: PMC3635974 DOI: 10.1371/journal.ppat.1003329] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 03/14/2013] [Indexed: 11/20/2022] Open
Abstract
Immunodominance is a fundamental property of CD8(+) T cell responses to viruses and vaccines. It had been observed that route of administration alters immunodominance after vaccinia virus (VACV) infection, but only a few epitopes were examined and no mechanism was provided. We re-visited this issue, examining a panel of 15 VACV epitopes and four routes, namely intradermal (i.d.), subcutaneous (s.c.), intraperitoneal (i.p.) and intravenous (i.v.) injection. We found that immunodominance is sharpened following peripheral routes of infection (i.d. and s.c.) compared with those that allow systemic virus dissemination (i.p. and i.v.). This increased immunodominance was demonstrated with native epitopes of VACV and with herpes simplex virus glycoprotein B when expressed from VACV. Responses to some subdominant epitopes were altered by as much as fourfold. Tracking of virus, examination of priming sites, and experiments restricting virus spread showed that priming of CD8(+) T cells in the spleen was necessary, but not sufficient to broaden responses. Further, we directly demonstrated that immunodomination occurs more readily when priming is mainly in lymph nodes. Finally, we were able to reduce immunodominance after i.d., but not i.p. infection, using a VACV expressing the costimulators CD80 (B7-1) and CD86 (B7-2), which is notable because VACV-based vaccines incorporating these molecules are in clinical trials. Taken together, our data indicate that resources for CD8(+) T cell priming are limiting in local draining lymph nodes, leading to greater immunodomination. Further, we provide evidence that costimulation can be a limiting factor that contributes to immunodomination. These results shed light on a possible mechanism of immunodomination and highlight the need to consider multiple epitopes across the spectrum of immunogenicities in studies aimed at understanding CD8(+) T cell immunity to viruses.
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Affiliation(s)
- Leon C. W. Lin
- Division of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Inge E. A. Flesch
- Division of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - David C. Tscharke
- Division of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory, Australia
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29
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Zhou HF, Yan H, Cannon JL, Springer LE, Green JM, Pham CTN. CD43-mediated IFN-γ production by CD8+ T cells promotes abdominal aortic aneurysm in mice. THE JOURNAL OF IMMUNOLOGY 2013; 190:5078-85. [PMID: 23585675 DOI: 10.4049/jimmunol.1203228] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CD43 is a glycosylated surface protein abundantly expressed on lymphocytes. Its role in immune responses has been difficult to clearly establish, with evidence supporting both costimulatory and inhibitory functions. In addition, its contribution to disease pathogenesis remains elusive. Using a well-characterized murine model of elastase-induced abdominal aortic aneurysm (AAA) that recapitulates many key features of the human disease, we established that the presence of CD43 on T cells is required for AAA formation. Moreover, we found that IFN-γ-producing CD8(+) T cells, but not CD4(+) T cells, promote the development of aneurysm by enhancing cellular apoptosis and matrix metalloprotease activity. Reconstitution with IFN-γ-producing CD8(+) T cells or recombinant IFN-γ promotes the aneurysm phenotype in CD43(-/-) mice, whereas IFN-γ antagonism abrogates disease in wild-type animals. Furthermore, we showed that the presence of CD43 with an intact cytoplasmic domain capable of binding to ezrin-radixin-moesin cytoskeletal proteins is essential for optimal in vivo IFN-γ production by T cells and aneurysm formation. We have thus identified a robust physiologic role for CD43 in a relevant animal model and established an important in vivo function for CD43-dependent regulation of IFN-γ production. These results further suggest that IFN-γ antagonism or selective blockade of CD43(+)CD8(+) T cell activities merits further investigation for immunotherapy in AAA.
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Affiliation(s)
- Hui-fang Zhou
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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30
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Schotsaert M, Ysenbaert T, Neyt K, Ibañez LI, Bogaert P, Schepens B, Lambrecht BN, Fiers W, Saelens X. Natural and long-lasting cellular immune responses against influenza in the M2e-immune host. Mucosal Immunol 2013; 6:276-87. [PMID: 22806098 DOI: 10.1038/mi.2012.69] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Influenza is a global health concern. Licensed influenza vaccines induce strain-specific virus-neutralizing antibodies but hamper the induction of possibly cross-protective T-cell responses upon subsequent infection.(1) In this study, we compared protection induced by a vaccine based on the conserved extracellular domain of matrix 2 protein (M2e) with that of a conventional whole inactivated virus (WIV) vaccine using single as well as consecutive homo- and heterosubtypic challenges. Both vaccines protected against a primary homologous (with respect to hemagglutinin and neuraminidase in WIV) challenge. Functional T-cell responses were induced after primary challenge of M2e-immune mice but were absent in WIV-vaccinated mice. M2e-immune mice displayed limited inducible bronchus-associated lymphoid tissue, which was absent in WIV-immune animals. Importantly, M2e- but not WIV-immune mice were protected from a primary as well as a secondary, severe heterosubtypic challenge, including challenge with pandemic H1N1 2009 virus. Our findings advocate the use of infection-permissive influenza vaccines, such as those based on M2e, in immunologically naive individuals. The combined immune response induced by M2e-vaccine and by clinically controlled influenza virus replication results in strong and broad protection against pandemic influenza. We conclude that the challenge of the M2e-immune host induces strong and broadly reactive immunity against influenza virus infection.
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Affiliation(s)
- M Schotsaert
- Department for Molecular Biomedical Research, VIB, Ghent, Belgium
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31
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Martins MA, Bonaldo MC, Rudersdorf RA, Piaskowski SM, Rakasz EG, Weisgrau KL, Furlott JR, Eernisse CM, Veloso de Santana MG, Hidalgo B, Friedrich TC, Chiuchiolo MJ, Parks CL, Wilson NA, Allison DB, Galler R, Watkins DI. Immunogenicity of seven new recombinant yellow fever viruses 17D expressing fragments of SIVmac239 Gag, Nef, and Vif in Indian rhesus macaques. PLoS One 2013; 8:e54434. [PMID: 23336000 PMCID: PMC3545953 DOI: 10.1371/journal.pone.0054434] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 12/11/2012] [Indexed: 12/31/2022] Open
Abstract
An effective vaccine remains the best solution to stop the spread of human immunodeficiency virus (HIV). Cellular immune responses have been repeatedly associated with control of viral replication and thus may be an important element of the immune response that must be evoked by an efficacious vaccine. Recombinant viral vectors can induce potent T-cell responses. Although several viral vectors have been developed to deliver HIV genes, only a few have been advanced for clinical trials. The live-attenuated yellow fever vaccine virus 17D (YF17D) has many properties that make it an attractive vector for AIDS vaccine regimens. YF17D is well tolerated in humans and vaccination induces robust T-cell responses that persist for years. Additionally, methods to manipulate the YF17D genome have been established, enabling the generation of recombinant (r)YF17D vectors carrying genes from unrelated pathogens. Here, we report the generation of seven new rYF17D viruses expressing fragments of simian immunodeficiency virus (SIV)mac239 Gag, Nef, and Vif. Studies in Indian rhesus macaques demonstrated that these live-attenuated vectors replicated in vivo, but only elicited low levels of SIV-specific cellular responses. Boosting with recombinant Adenovirus type-5 (rAd5) vectors resulted in robust expansion of SIV-specific CD8+ T-cell responses, particularly those targeting Vif. Priming with rYF17D also increased the frequency of CD4+ cellular responses in rYF17D/rAd5-immunized macaques compared to animals that received rAd5 only. The effect of the rYF17D prime on the breadth of SIV-specific T-cell responses was limited and we also found evidence that some rYF17D vectors were more effective than others at priming SIV-specific T-cell responses. Together, our data suggest that YF17D – a clinically relevant vaccine vector – can be used to prime AIDS virus-specific T-cell responses in heterologous prime boost regimens. However, it will be important to optimize rYF17D-based vaccine regimens to ensure maximum delivery of all immunogens in a multivalent vaccine.
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MESH Headings
- AIDS Vaccines/genetics
- AIDS Vaccines/immunology
- Animals
- CD8-Positive T-Lymphocytes/immunology
- Epitopes, T-Lymphocyte/immunology
- Female
- Gene Order
- Gene Products, gag/genetics
- Gene Products, gag/immunology
- Gene Products, nef/genetics
- Gene Products, nef/immunology
- Gene Products, vif/genetics
- Gene Products, vif/immunology
- Genetic Vectors/genetics
- Humans
- Immunization
- Immunization, Secondary
- Kinetics
- Macaca mulatta
- Male
- Simian Immunodeficiency Virus/genetics
- Simian Immunodeficiency Virus/immunology
- T-Lymphocytes/immunology
- Vaccines, Synthetic/genetics
- Vaccines, Synthetic/immunology
- Virus Replication
- Yellow fever virus/genetics
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Affiliation(s)
- Mauricio A. Martins
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Myrna C. Bonaldo
- Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz – FIOCRUZ, Rio de Janeiro, Brazil
| | - Richard A. Rudersdorf
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Shari M. Piaskowski
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Eva G. Rakasz
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Kim L. Weisgrau
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Jessica R. Furlott
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Christopher M. Eernisse
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | | | - Bertha Hidalgo
- Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Thomas C. Friedrich
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Maria J. Chiuchiolo
- International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, United States of America
| | - Christopher L. Parks
- International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn Army Terminal, Brooklyn, New York, United States of America
| | - Nancy A. Wilson
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - David B. Allison
- Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Ricardo Galler
- Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz – FIOCRUZ, Rio de Janeiro, Brazil
| | - David I. Watkins
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- * E-mail:
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Karlsson I, Kløverpris H, Jensen KJ, Stryhn A, Buus S, Karlsson A, Vinner L, Goulder P, Fomsgaard A. Identification of conserved subdominant HIV Type 1 CD8(+) T Cell epitopes restricted within common HLA Supertypes for therapeutic HIV Type 1 vaccines. AIDS Res Hum Retroviruses 2012; 28:1434-43. [PMID: 22747336 DOI: 10.1089/aid.2012.0081] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The high HIV-1 prevalence, up to 4.6% in Guinea-Bissau, West Africa, makes it a relevant location for testing of therapeutic vaccines. With the aim of performing a clinical study in Guinea-Bissau, after first testing the vaccine for safety in Denmark, Europe, we here describe the design of a universal epitope peptide-based T cell vaccine with relevance for any geographic locations. The two major obstacles when designing such a vaccine are the high diversities of the HIV-1 genome and of the human major histocompatibility complex (MHC) class I. We selected 15 CD8-restricted epitopes predicted from conserved regions of HIV-1 that were subdominant (i.e., infrequently targeted) within natural infections. Moreover, the epitopes were predicted to be restricted to at least one of the five common HLA supertypes (HLA-A01, A02, A03, B07, and B44). Here, we validated the resulting peptide-specific, HLA-restricted T cell specificities using peptide-MHC class I tetramer labeling of CD8(+) T cells from HIV-1-infected individuals. The selected vaccine epitopes are infrequently targeted in HIV-1-infected individuals from both locations. Moreover, we HLA-typed HIV-1-infected individuals and demonstrated that the selected vaccine epitopes, when targeted, are restricted to the five most common HLA supertypes at both locations. Thus, the HLA supertype-directed approach achieved HLA coverage of 95% and 100% of the examined cohorts in Guinea-Bissau and Denmark, respectively. In conclusion, the selected vaccine epitopes match the host populations and HIV-1 strains of these two distant geographic regions, justifying clinical testing in both locations.
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Affiliation(s)
- Ingrid Karlsson
- Department of Virology, Statens Serum Institut, Copenhagen, Denmark
| | - Henrik Kløverpris
- Department of Virology, Statens Serum Institut, Copenhagen, Denmark
- Department of Paediatrics, University of Oxford, Oxford, United Kingdom
| | - Kristoffer Jarlov Jensen
- Department of Virology, Statens Serum Institut, Copenhagen, Denmark
- The Bandim Health Project, Bissau, Guinea-Bissau
| | - Anette Stryhn
- Department of International Health, Immunology and Microbiology, Panum Institut, University of Copenhagen, Copenhagen, Denmark
| | - Søren Buus
- Department of International Health, Immunology and Microbiology, Panum Institut, University of Copenhagen, Copenhagen, Denmark
| | - Annika Karlsson
- Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Lasse Vinner
- Department of Virology, Statens Serum Institut, Copenhagen, Denmark
| | - Philip Goulder
- Department of Paediatrics, University of Oxford, Oxford, United Kingdom
| | - Anders Fomsgaard
- Department of Virology, Statens Serum Institut, Copenhagen, Denmark
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Gamma interferon and perforin control the strength, but not the hierarchy, of immunodominance of an antiviral CD8+ T cell response. J Virol 2011; 85:12578-84. [PMID: 21917955 DOI: 10.1128/jvi.05334-11] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The two major antiviral effector mechanisms of CD8(+) T cells are thought to be perforin (Prf)-mediated cell lysis and gamma interferon (IFN-γ)-mediated induction of an antiviral state. By affecting the expression of proteins involved in antigen presentation, IFN-γ is also thought to shape the magnitude and specificity of the CD8(+) T cell response. Here we studied the roles of Prf and IFN-γ in shaping the effector and memory CD8(+) T cell responses to vaccinia virus (VACV). IFN-γ deficiency resulted in increased numbers of anti-VACV effector and memory CD8(+) T cells, which were partly dependent on increased virus loads. On the other hand, Prf-deficient mice showed an increase in the number of VACV-specific CD8(+) T cells only in the memory phase. Treatment of the mice with the antiviral drug cidofovir reduced the numbers of effector and memory cells closer to wild-type levels in IFN-γ-deficient mice and reduced the numbers of memory CD8(+) T cells to wild-type levels in Prf-deficient mice. These data suggest that virus loads are the main reason for the increased strength of the CD8 response in IFN-γ- and Prf-deficient mice. Neither Prf deficiency nor IFN-γ deficiency had an effect on the immunodominance hierarchy of five K(b)-restricted CD8(+) T cell determinants either during acute infection or after recovery. Thus, our work shows that CD8(+) T cell immunodominance during VACV infection is not affected by the effects of IFN-γ on the antigen presentation machinery.
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Vojnov L, Bean AT, Peterson EJ, Chiuchiolo MJ, Sacha JB, Denes FS, Sandor M, Fuller DH, Fuller JT, Parks CL, McDermott AB, Wilson NA, Watkins DI. DNA/Ad5 vaccination with SIV epitopes induced epitope-specific CD4⁺ T cells, but few subdominant epitope-specific CD8⁺ T cells. Vaccine 2011; 29:7483-90. [PMID: 21839132 DOI: 10.1016/j.vaccine.2011.07.048] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 07/14/2011] [Accepted: 07/16/2011] [Indexed: 02/07/2023]
Abstract
The goals of a T cell-based vaccine for HIV are to reduce viral peak and setpoint and prevent transmission. While it has been relatively straightforward to induce CD8(+) T cell responses against immunodominant T cell epitopes, it has been more difficult to broaden the vaccine-induced CD8(+) T cell response against subdominant T cell epitopes. Additionally, vaccine regimens to induce CD4(+) T cell responses have been studied only in limited settings. In this study, we sought to elicit CD8(+) T cells against subdominant epitopes and CD4(+) T cells using various novel and well-established vaccine strategies. We vaccinated three Mamu-A*01(+) animals with five Mamu-A*01-restricted subdominant SIV-specific CD8(+) T cell epitopes. All three vaccinated animals made high frequency responses against the Mamu-A*01-restricted Env TL9 epitope with one animal making a low frequency CD8(+) T cell response against the Pol LV10 epitope. We also induced SIV-specific CD4(+) T cells against several MHC class II DRBw*606-restricted epitopes. Electroporated DNA with pIL-12 followed by a rAd5 boost was the most immunogenic vaccine strategy. We induced responses against all three Mamu-DRB*w606-restricted CD4 epitopes in the vaccine after the DNA prime. Ad5 vaccination further boosted these responses. Although we successfully elicited several robust epitope-specific CD4(+) T cell responses, vaccination with subdominant MHC class I epitopes elicited few detectable CD8(+) T cell responses. Broadening the CD8(+) T cell response against subdominant MHC class I epitopes was, therefore, more difficult than we initially anticipated.
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Affiliation(s)
- Lara Vojnov
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 555 Science Drive, Madison, WI 53711, USA
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35
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Brun A, Bárcena J, Blanco E, Borrego B, Dory D, Escribano JM, Le Gall-Reculé G, Ortego J, Dixon LK. Current strategies for subunit and genetic viral veterinary vaccine development. Virus Res 2011; 157:1-12. [PMID: 21316403 DOI: 10.1016/j.virusres.2011.02.006] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 02/03/2011] [Accepted: 02/04/2011] [Indexed: 12/24/2022]
Abstract
Developing vaccines for livestock provides researchers with the opportunity to perform efficacy testing in the natural hosts. This enables the evaluation of different strategies, including definition of effective antigens or antigen combinations, and improvement in delivery systems for target antigens so that protective immune responses can be modulated or potentiated. An impressive amount of knowledge has been generated in recent years on vaccine strategies and consequently a wide variety of antigen delivery systems is now available for vaccine research. This paper reviews several antigen production and delivery strategies other than those based on the use of live viral vectors. Genetic and protein subunit vaccines as well as alternative production systems are considered in this review.
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Affiliation(s)
- Alejandro Brun
- Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, 28130 Madrid, Spain.
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Ruckwardt TJ, Luongo C, Malloy AMW, Liu J, Chen M, Collins PL, Graham BS. Responses against a subdominant CD8+ T cell epitope protect against immunopathology caused by a dominant epitope. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:4673-80. [PMID: 20833834 PMCID: PMC4144756 DOI: 10.4049/jimmunol.1001606] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CD8(+) T cell responses are critical for the control of virus infections. Following infection, epitope-specific responses establish an unpredictable but reproducible pattern of dominance that is dictated by a large number of both positive and negative factors. Immunodomination, or diminution of subdominant epitope-specific responses by dominant epitopes, can play a substantial role in the establishment of epitope hierarchy. To determine the role of a dominant (K(d)M2(82-90)) and a subdominant (D(b)M(187-195)) epitope of respiratory syncytial virus in viral control and immunodomination, MHC-binding anchor residues in the two epitopes were mutated individually in recombinant infectious viruses, greatly reducing or deleting the epitope-specific CD8(+) T cell responses. Neither mutation negatively affected viral clearance in mice, and compensation by the unmutated epitope was seen in both cases, whereas compensation by five other subdominant epitopes was minimal. Mutation of the dominant K(d)M2(82-90) response resulted in effective viral clearance by the subdominant epitope with less illness, whereas mutation of the subdominant D(b)M(187-195) response resulted in overcompensation of the already dominant K(d)M2(82-90) epitope, and increased severity of illness. Increased illness was associated with poor functionality of the abundant population of CD8(+) T cells specific to the dominant K(d)M2(82-90) epitope, as measured by the percentage and magnitude of IFN-γ production. These data demonstrate efficient viral clearance, and a protective effect of subdominant CD8(+) T cell responses.
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Affiliation(s)
- Tracy J. Ruckwardt
- Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
| | - Cindy Luongo
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
| | - Allison M. W. Malloy
- Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
| | - Jie Liu
- Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
| | - Man Chen
- Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
| | - Peter L. Collins
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
| | - Barney S. Graham
- Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
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Irvine K, Bennink J. Factors influencing immunodominance hierarchies in TCD8+ -mediated antiviral responses. Expert Rev Clin Immunol 2010; 2:135-47. [PMID: 20477094 DOI: 10.1586/1744666x.2.1.135] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
CD8(+) T-lymphocytes (T(CD8+)) perform a critical role in immunity against tumors and virus infections. A central feature of T(CD8+) immune responses is immunodominance: the observation that T(CD8+) responses consist of a limited collection of specificities with a structured hierarchy. These immunodominance hierarchies result from a complex combination of factors. Major roles are played by peptide binding affinity, T-cell repertoire, and antigen processing and presentation. While the bulk of our information comes from mouse model systems, an increasing number of human studies suggest that immunodominance will be even more complicated. This review outlines current knowledge of T(CD8+ )immunodominance to viral antigens and discusses the relevance and importance of a thorough understanding for the rational design of vaccines that elicit effective T(CD8+) responses.
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Affiliation(s)
- Kari Irvine
- National Institute for Allergy & Infectious Diseases, Cell Biology Section/Viral Immunology Section, Laboratory of Viral Diseases, Room 209, Building 44 Center Drive, Bethesda, MD 20892-0440, USA.
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Lambeck AJ, Nijman HW, Hoogeboom BN, Regts J, de Mare A, Wilschut J, Daemen T. Role of T cell competition in the induction of cytotoxic T lymphocyte activity during viral vector-based immunization regimens. Vaccine 2010; 28:4275-82. [DOI: 10.1016/j.vaccine.2010.04.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 03/31/2010] [Accepted: 04/14/2010] [Indexed: 10/19/2022]
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Mechanism of protection of live attenuated simian immunodeficiency virus: coevolution of viral and immune responses. AIDS 2010; 24:637-48. [PMID: 20186034 DOI: 10.1097/qad.0b013e328337795a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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40
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Flesch IEA, Woo WP, Wang Y, Panchanathan V, Wong YC, La Gruta NL, Cukalac T, Tscharke DC. Altered CD8(+) T cell immunodominance after vaccinia virus infection and the naive repertoire in inbred and F(1) mice. THE JOURNAL OF IMMUNOLOGY 2009; 184:45-55. [PMID: 19949110 DOI: 10.4049/jimmunol.0900999] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Previous studies of CD8(+) T cell immunodominance after primary virus infection of F(1) mice compared with their inbred parents have generally concluded that no dramatic changes occur. In this study, we revisit this issue using vaccinia virus (VACV), which has a large genome, a recently defined immunodominance hierarchy in mice, and is a candidate vector for vaccines. We found that immunogenicity of VACV peptides defined using inbred mice was highly variable in F(1) progeny: some peptides were equally immunogenic in F(1) and inbred, whereas others elicited responses that were reduced by >90% in F(1) mice. Furthermore, the dominance of a peptide in the relevant inbred parent did not predict whether it would be poorly immunogenic in F(1) mice. This result held using F(1) hybrids of MHC-congenic mice, suggesting that MHC differences alone were responsible. It was also extended to foreign epitopes expressed by an rVACV vaccine. F(1) mice were less able to mount responses to the poorly immunogenic peptides when used as a sole immunogen, ruling out immunodomination. In addition, conserved TCR Vbeta usage between inbred and F(1) mice did not always correlate with strong responses in F(1) mice. However, direct estimation of naive precursor numbers showed that these were reduced in F(1) compared with inbred mice for specificities that were poorly immunogenic in the hybrids. These data have implications for our understanding of the extent to which MHC diversity alters the range of epitopes that are immunogenic in outbred populations.
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Affiliation(s)
- Inge E A Flesch
- Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia
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41
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Candidate vaccine sequences to represent intra- and inter-clade HIV-1 variation. PLoS One 2009; 4:e7388. [PMID: 19812689 PMCID: PMC2753653 DOI: 10.1371/journal.pone.0007388] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Accepted: 09/04/2009] [Indexed: 11/24/2022] Open
Abstract
A likely key factor in the failure of a HIV-1 vaccine based on cytotoxic T lymphocytes (CTL) is the natural immunodominance of epitopes that fall in variable regions of the proteome, which both increases the chance of epitope sequence mismatch with the incoming challenge strain and replicates the pathogenesis of early CTL failure due to epitope escape mutation during natural infection. To identify potential vaccine sequences to focus the CTL response on highly conserved epitopes, the whole proteomes of HIV-1 clades A1, B, C, and D were assessed for Shannon entropy at each amino acid position. Highly conserved regions in Gag (cGag-1, Gag 148–214, and cGag-2, Gag 253–331), Env (cEnv, Env 521–606), and Nef (cNef, Nef 106–148) were identified across clades. Inter- and intra-clade variability of amino acids within the regions tended to overlap, suggesting that polyvalent representation of consensus sequences for the four clades would allow broad HIV-1 strain representation. These four conserved regions were rich in both known and predicted CTL epitopes presented by a breadth of HLA types, and screening of 54 persons with chronic HIV-1 infection revealed that these regions are commonly immunogenic in the context of natural infection. These data suggest that vaccine delivery of a 16-valent mixture of these regions could focus the CTL response against conserved epitopes that are broadly representative of circulating HIV-1 strains.
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42
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Raué HP, Slifka MK. CD8+ T cell immunodominance shifts during the early stages of acute LCMV infection independently from functional avidity maturation. Virology 2009; 390:197-204. [PMID: 19539966 PMCID: PMC2728041 DOI: 10.1016/j.virol.2009.05.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Revised: 05/14/2009] [Accepted: 05/16/2009] [Indexed: 02/01/2023]
Abstract
Virus-specific T cell responses are often directed to a small subset of possible epitopes and their relative magnitude defines their hierarchy. We determined the size and functional avidity of 4 representative peptide-specific CD8(+) T cell populations in C57BL/6 mice at different time points after lymphocytic choriomeningitis virus (LCMV) infection. We found that the frequency of different peptide-specific T cell populations in the spleen changed independently over the first 8 days after infection. These changes were not associated with a larger or more rapid increase in functional avidity and yet still resulted in a shift in the final immunodominance hierarchy. Thus, the immunodominance observed at the peak of an antiviral T cell response is not necessarily determined by the initial size or rate of functional avidity maturation of peptide-specific T cell populations.
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Affiliation(s)
- Hans-Peter Raué
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185 Avenue, Beaverton, OR 97006, USA
| | - Mark K. Slifka
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185 Avenue, Beaverton, OR 97006, USA
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Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes. AIDS 2009; 23:1329-40. [PMID: 19528789 DOI: 10.1097/qad.0b013e32832d9b00] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To investigate the potential to induce additional cytotoxic T-lymphocyte (CTL) immunity during chronic HIV-1 infection. DESIGN We selected infrequently targeted or subdominant but conserved HLA-A*0201-binding epitopes in Gag, Pol, Env, Vpu and Vif. These relatively immune silent epitopes were modified as anchor-optimized peptides to improve immunogenicity and delivered on autologous monocyte-derived dendritic cells (MDDCs). METHODS Twelve treatment-naïve HLA-A*0201 HIV-1-infected Danish individuals received 1 x 10 MDDCs subcutaneously (s.c.) (weeks 0, 2, 4 and 8), pulsed with seven CD8 T-cell epitopes and three CD4 T-cell epitopes. Epitope-specific responses were evaluated by intracellular cytokine staining for interferon-gamma, tumor necrosis factor alpha and interleukin-2 and/or pentamer labeling 3 weeks prior to, 10 weeks after and 32 weeks after the first immunization. RESULTS Previously undetected T-cell responses specific for one or more epitopes were induced in all 12 individuals. Half of the participants had sustained CD4 T-cell responses 32 weeks after immunization. No severe adverse effects were observed. No overall or sustained change in viral load or CD4 T-cell counts was observed. CONCLUSION These data show that it is possible to generate new T-cell responses in treatment-naive HIV-1-infected individuals despite high viral loads, and thereby redirect immunity to target new multiple and rationally selected subdominant CTL epitopes. Further optimization could lead to stronger and more durable cellular responses to selected epitopes with the potential to control viral replication and prevent disease in HIV-1-infected individuals.
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Turnbull EL, Wong M, Wang S, Wei X, Jones NA, Conrod KE, Aldam D, Turner J, Pellegrino P, Keele BF, Williams I, Shaw GM, Borrow P. Kinetics of expansion of epitope-specific T cell responses during primary HIV-1 infection. THE JOURNAL OF IMMUNOLOGY 2009; 182:7131-45. [PMID: 19454710 DOI: 10.4049/jimmunol.0803658] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Multiple lines of evidence support a role for CD8(+) T cells in control of acute/early HIV replication; however, features of the primary HIV-specific CD8(+) T cell response that may impact on the efficiency of containment of early viral replication remain poorly defined. In this study, we performed a novel, comprehensive analysis of the kinetics of expansion of components of the HIV-specific CD8(+) T cell response in 21 acutely infected individuals. Epitope-specific T cell responses expanded asynchronously during primary infection in all subjects. The most rapidly expanded responses peaked as early as 5 days following symptomatic presentation and were typically of very limited epitope breadth. Responses of additional specificities expanded and contracted in subsequent waves, resulting in successive shifts in the epitope immunodominance hierarchy over time. Sequence variation and escape were temporally associated with the decline in magnitude of only a subset of T cell responses, suggesting that other factors such as Ag load and T cell exhaustion may play a role in driving the contraction of HIV-specific T cell responses. These observations document the preferential expansion of CD8(+) T cells recognizing a subset of epitopes during the viral burst in acute HIV-1 infection and suggest that the nature of the initial, very rapidly expanded T cell response may influence the efficiency with which viral replication is contained in acute/early HIV infection.
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Affiliation(s)
- Emma L Turnbull
- Viral Immunology Group, Jenner Institute, University of Oxford, Compton, United Kingdom.
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Vaccinia virus CD8+ T-cell dominance hierarchies cannot be altered by prior immunization with individual peptides. J Virol 2009; 83:9008-12. [PMID: 19535449 DOI: 10.1128/jvi.00410-09] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Heterologous prime-boost is a common vaccination strategy to elicit CD8(+) T cells (T(CD8+)), and vaccinia virus (VACV) has been widely used as a boosting vector. Studies with other viruses have suggested that priming may reduce responses to native epitopes in boosting vectors as well as improve responses to primed epitopes. We explored this possibility with a VACV model in mice and find that irrespective of an epitope's dominance, prior priming was able to double T(CD8+) responses. More surprisingly, and in contrast to findings for other viruses, responses to remaining epitopes were undisturbed, leaving the overall dominance hierarchy unchanged.
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Neller MA, López JA, Schmidt CW. Antigens for cancer immunotherapy. Semin Immunol 2008; 20:286-95. [DOI: 10.1016/j.smim.2008.09.006] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2008] [Accepted: 09/05/2008] [Indexed: 01/19/2023]
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Mok H, Lee S, Wright DW, Crowe JE. Enhancement of the CD8+ T cell response to a subdominant epitope of respiratory syncytial virus by deletion of an immunodominant epitope. Vaccine 2008; 26:4775-82. [PMID: 18662734 PMCID: PMC2561208 DOI: 10.1016/j.vaccine.2008.07.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2008] [Revised: 06/30/2008] [Accepted: 07/08/2008] [Indexed: 11/17/2022]
Abstract
Cytotoxic T lymphocytes (CTLs) are critical for the control of respiratory syncytial virus infection (RSV) in humans and mice. Recently, we identified a new H-2K(d)-restricted subdominant epitope in the respiratory syncytial virus M2 protein. In this study, we investigated if modification of anchor residues at positions 2 and 9 in the dominant M2(82-90) epitope in the M2 protein would alter the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 proteins. We showed that immunogenicity of the subdominant epitope M2(127-135) was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to the subdominant epitope.
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Affiliation(s)
- Hoyin Mok
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
- The Program for Vaccine Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Sujin Lee
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
- The Program for Vaccine Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
| | - David W. Wright
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Chemistry, Vanderbilt University, Nashville, TN 37232
| | - James E. Crowe
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
- Departments of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
- The Program for Vaccine Sciences, Vanderbilt University Medical Center, Nashville, TN 37232
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Walker EB, Haley D, Petrausch U, Floyd K, Miller W, Sanjuan N, Alvord G, Fox BA, Urba WJ. Phenotype and functional characterization of long-term gp100-specific memory CD8+ T cells in disease-free melanoma patients before and after boosting immunization. Clin Cancer Res 2008; 14:5270-83. [PMID: 18698047 PMCID: PMC2756994 DOI: 10.1158/1078-0432.ccr-08-0022] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE Effective cancer vaccines must both drive a strong CTL response and sustain long-term memory T cells capable of rapid recall responses to tumor antigens. We sought to characterize the phenotype and function of gp100 peptide-specific memory CD8+ T cells in melanoma patients after primary gp100(209-2M) immunization and assess the anamnestic response to boosting immunization. EXPERIMENTAL DESIGN Eight-color flow cytometry analysis of gp100-specific CD8+ T cells was done on peripheral blood mononuclear cells collected shortly after the primary vaccine regimen, 12 to 24 months after primary vaccination, and after boosting immunization. The anamnestic response was assessed by comparing the frequency of circulating gp100-specific T cells before and after boosting. Gp100 peptide-induced in vitro functional avidity and proliferation responses and melanoma-stimulated T-cell CD107 mobilization were compared for cells from all three time points for multiple patients. RESULTS The frequency of circulating gp100-specific memory CD8+ T cells was comparable with cytomegalovirus-specific and FLU-specific T cells in the same patients, and the cells exhibited anamnestic proliferation after boosting. Their phenotypes were not unique, and individual patients exhibited one of two distinct phenotype signatures that were homologous to either cytomegalovirus-specific or FLU-specific memory T cells. Gp100-specific memory T cells showed some properties of competent memory T cells, such as heightened in vitro peptide-stimulated proliferation and increase in central memory (TCM) differentiation when compared with T-cell responses measured after the primary vaccine regimen. However, they did not acquire enhanced functional avidity usually associated with competent memory T-cell maturation. CONCLUSIONS Although vaccination with class I-restricted melanoma peptides alone can break tolerance to self-tumor antigens, it did not induce fully competent memory CD8+ T cells--even in disease-free patients. Data presented suggest other vaccine strategies will be required to induce functionally robust long-term memory T cells.
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Affiliation(s)
- Edwin B Walker
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon 97213, USA.
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Watkins DI, Burton DR, Kallas EG, Moore JP, Koff WC. Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans. Nat Med 2008; 14:617-21. [PMID: 18535579 PMCID: PMC3697853 DOI: 10.1038/nm.f.1759] [Citation(s) in RCA: 209] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge-rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector-based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4+ T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.
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Affiliation(s)
- David I Watkins
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, Wisconsin 53715, USA.
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Watkins DI. The hope for an HIV vaccine based on induction of CD8+ T lymphocytes--a review. Mem Inst Oswaldo Cruz 2008; 103:119-29. [PMID: 18425263 PMCID: PMC2997999 DOI: 10.1590/s0074-02762008000200001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Accepted: 03/21/2008] [Indexed: 01/29/2023] Open
Abstract
The only long-term and cost-effective solution to the human immunodeficiency virus (HIV) epidemic in the developing world is a vaccine that prevents individuals from becoming infected or, once infected, from passing the virus on to others. There is currently little hope for an AIDS vaccine. Conventional attempts to induce protective antibody and CD8(+) lymphocyte responses against HIV and simian immunodeficiency virus (SIV) have failed. The enormous diversity of the virus has only recently been appreciated by vaccinologists, and our assays to determine CD8(+) lymphocyte antiviral efficacy are inadequate. The central hypothesis of a CTL-based vaccine is that particularly effective CD8(+) lymphocytes directed against at least five epitopes that are derived from regions under functional and structural constraints will control replication of pathogenic SIV. This would be somewhat analogous to control of virus replication by triple drug therapy or neutralizing antibodies.
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Affiliation(s)
- David I Watkins
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
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