The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults.

RATIONALE AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine. OBJECTIVES We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a tuberculosis-endemic region of South Africa. METHODS Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4(+) and CD8(+) T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells. MEASUREMENTS AND MAIN RESULTS AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4(+) T-cell response dominated by cells coexpressing IFN-gamma, tumor necrosis factor-alpha, and IL-2 ("polyfunctional" cells). AERAS-402 also induced a potent CD8(+) T-cell response, characterized by cells expressing IFN-gamma and/or tumor necrosis factor-alpha, which persisted for the duration of the study. CONCLUSIONS Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8(+) T cells are also important. AERAS-402 induced a robust and durable CD8(+) T-cell response, which appears extremely promising. Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381).

[1]  J. Dietrich,et al.  Protection and Polyfunctional T Cells Induced by Ag85B-TB10.4/IC31® against Mycobacterium tuberculosis Is Highly Dependent on the Antigen Dose , 2009, PloS one.

[2]  H. McShane,et al.  Safety and Immunogenicity of Boosting BCG Vaccinated Subjects with BCG: Comparison with Boosting with a New TB Vaccine, MVA85A , 2009, PloS one.

[3]  A. Lemckert,et al.  Heterologous prime–boost vaccinations for poverty-related diseases: advantages and future prospects , 2009, Expert review of vaccines.

[4]  D. H. Young,et al.  Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. , 2009, Blood.

[5]  William R. Jacobs,et al.  A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis , 2009, PLoS pathogens.

[6]  D. Mehrotra,et al.  Safety and immunogenicity of adenovirus-vectored near-consensus HIV type 1 clade B gag vaccines in healthy adults. , 2009, AIDS research and human retroviruses.

[7]  J. Andersson,et al.  rBCG Induces Strong Antigen-Specific T Cell Responses in Rhesus Macaques in a Prime-Boost Setting with an Adenovirus 35 Tuberculosis Vaccine Vector , 2008, PloS one.

[8]  H. Dockrell,et al.  A comparison of IFNgamma detection methods used in tuberculosis vaccine trials. , 2008, Tuberculosis.

[9]  A. Hill,et al.  Multifunctional, High-Level Cytokine-Producing Th1 Cells in the Lung, but Not Spleen, Correlate with Protection against Mycobacterium tuberculosis Aerosol Challenge in Mice , 2008, The Journal of Immunology.

[10]  D. Woodland,et al.  Early T‐cell responses in tuberculosis immunity , 2008, Immunological reviews.

[11]  T. Lang,et al.  Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa. , 2008, The Journal of infectious diseases.

[12]  R. Adegbola,et al.  Safety and Immunogenicity of the Candidate Tuberculosis Vaccine MVA85A in West Africa , 2008, PloS one.

[13]  V. A. Stewart,et al.  Adenovirus 5 and 35 vectors expressing Plasmodium falciparum circumsporozoite surface protein elicit potent antigen-specific cellular IFN-gamma and antibody responses in mice. , 2008, Vaccine.

[14]  R. Wilkinson,et al.  Distinct, Specific IL-17- and IL-22-Producing CD4+ T Cell Subsets Contribute to the Human Anti-Mycobacterial Immune Response1 , 2008, The Journal of Immunology.

[15]  David A. Price,et al.  Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover , 2007, The Journal of experimental medicine.

[16]  S. Kaufmann,et al.  Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis , 2007, Proceedings of the National Academy of Sciences.

[17]  Mario Roederer,et al.  Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major , 2007, Nature Medicine.

[18]  T. van der Poll,et al.  Protective Immune Responses to a Recombinant Adenovirus Type 35 Tuberculosis Vaccine in Two Mouse Strains: CD4 and CD8 T-Cell Epitope Mapping and Role of Gamma Interferon , 2007, Infection and Immunity.

[19]  N. Letvin,et al.  Effect of Preexisting Immunity to Adenovirus Human Serotype 5 Antigens on the Immune Responses of Nonhuman Primates to Vaccine Regimens Based on Human- or Chimpanzee-Derived Adenovirus Vectors , 2007, Journal of Virology.

[20]  B. Ryffel,et al.  Tumor necrosis factor is critical to control tuberculosis infection. , 2007, Microbes and infection.

[21]  S. Nakae,et al.  IL-17-Mediated Regulation of Innate and Acquired Immune Response against Pulmonary Mycobacterium bovis Bacille Calmette-Guérin Infection1 , 2007, The Journal of Immunology.

[22]  V. A. Stewart,et al.  Priming with an Adenovirus 35-Circumsporozoite Protein (CS) Vaccine followed by RTS,S/AS01B Boosting Significantly Improves Immunogenicity to Plasmodium falciparum CS Compared to That with Either Malaria Vaccine Alone , 2007, Infection and Immunity.

[23]  M. Havenga,et al.  Immunogenicity of Heterologous Recombinant Adenovirus Prime-Boost Vaccine Regimens Is Enhanced by Circumventing Vector Cross-Reactivity , 2006, Journal of Virology.

[24]  M. Havenga,et al.  Novel replication-incompetent adenoviral B-group vectors: high vector stability and yield in PER.C6 cells. , 2006, The Journal of general virology.

[25]  Mario Roederer,et al.  HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. , 2006, Blood.

[26]  A. Tyznik,et al.  Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells , 2006, Nature.

[27]  J. Sadoff,et al.  Advances in tuberculosis vaccine strategies , 2006, Nature Reviews Microbiology.

[28]  C. Dye,et al.  Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness , 2006, The Lancet.

[29]  B. Berkhout,et al.  Immunogenicity and Protection of a Recombinant Human Adenovirus Serotype 35-Based Malaria Vaccine against Plasmodium yoelii in Mice , 2006, Infection and Immunity.

[30]  H. Vordermeier,et al.  Recent advances in the development of adenovirus- and poxvirus-vectored tuberculosis vaccines. , 2005, Current gene therapy.

[31]  M. Lifton,et al.  Immunogenicity of Heterologous Prime-Boost Regimens Involving Recombinant Adenovirus Serotype 11 (Ad11) and Ad35 Vaccine Vectors in the Presence of Anti-Ad5 Immunity , 2005, Journal of Virology.

[32]  Z. Xing,et al.  Single Mucosal, but Not Parenteral, Immunization with Recombinant Adenoviral-Based Vaccine Provides Potent Protection from Pulmonary Tuberculosis1 , 2004, The Journal of Immunology.

[33]  H. McShane,et al.  Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans , 2004, Nature Medicine.

[34]  P. Haslett,et al.  Novel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studies. , 2004, Journal of immunological methods.

[35]  B. Berkhout,et al.  Adenovirus types 5 and 35 seroprevalence in AIDS risk groups supports type 35 as a vaccine vector , 2004, AIDS.

[36]  S. Kostense,et al.  Immunogenicity of Recombinant Adenovirus Serotype 35 Vaccine in the Presence of Pre-Existing Anti-Ad5 Immunity1 , 2004, The Journal of Immunology.

[37]  Jaap Goudsmit,et al.  Quantifying Adenovirus-Neutralizing Antibodies by Luciferase Transgene Detection: Addressing Preexisting Immunity to Vaccine and Gene Therapy Vectors , 2003, Journal of Clinical Microbiology.

[38]  H. McShane,et al.  Enhanced Immunogenicity of CD4+ T-Cell Responses and Protective Efficacy of a DNA-Modified Vaccinia Virus Ankara Prime-Boost Vaccination Regimen for Murine Tuberculosis , 2001, Infection and Immunity.

[39]  P. Andersen,et al.  Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells , 2000, European journal of immunology.

[40]  J. Sedgwick,et al.  Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. , 1999, Journal of immunology.

[41]  J. Casanova,et al.  Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria. , 1998, Immunology today.

[42]  S. Kaufmann,et al.  Mycobacterium bovis Bacille Calmette-Guérin strains secreting listeriolysin of Listeria monocytogenes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  C. Lowenstein,et al.  Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. , 1995, Immunity.

[44]  V. Diwan,et al.  Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. , 1993, International journal of epidemiology.

[45]  J. Flynn,et al.  An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection , 1993, The Journal of experimental medicine.

[46]  J. Abrams,et al.  Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection. , 1993, Journal of immunology.

[47]  S. Kaufmann,et al.  Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. , 2006, Immunity.

[48]  S. Behar,et al.  Mycobacterium tuberculosis-specific CD8+ T cells and their role in immunity. , 2006, Critical reviews in immunology.

[49]  P. Fine,et al.  Issues relating to the use of BCG in immunization programmes A discussion document , 1999 .

[50]  G. Kaplan,et al.  rhuIL-2 adjunctive therapy in multidrug resistant tuberculosis: a comparison of two treatment regimens and placebo. , 1997, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.