title: Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial.
abstract: A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA).
  
  
  
  Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart.
  
  
  
  The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding antibodies to subtype C Env (included in HIV-DNA and protein boost), subtype B Env (included only in HIV-DNA) and CRF01_AE Env (included only in HIV-MVA) were significantly boosted by the CN54rgp140/GLA-AF immunizations. Functional antibodies detected using an infectious molecular clone virus/peripheral blood mononuclear cell neutralization assay, a pseudovirus/TZM-bl neutralization assay or by assays for antibody-dependent cellular cytotoxicity (ADCC) were not significantly boosted. In contrast, T-cell proliferative responses to subtype B MN antigen and IFN-γ ELISpot responses to Env peptides were significantly enhanced. Four volunteers not primed with HIV-DNA and HIV-MVA before the CN54rgp140/GLA-AF immunizations mounted an antibody response, while cell-mediated responses were rare. After the two Env subtype C protein immunizations, a trend towards higher median subtype C Env binding antibody titers was found in vaccinees who had received HIV-DNA and HIV-MVA prior to the two Env protein immunizations as compared to unprimed vaccinees (p = 0.07).
  
  
  
  We report excellent tolerability, enhanced binding antibody responses and Env-specific cell-mediated immune responses but no ADCC antibody increase after two immunizations with a subtype C rgp140 protein adjuvanted in GLA-AF in healthy volunteers previously immunized with HIV-DNA and HIV-MVA.
  
  
  
  International Clinical Trials Registry PACTR2010050002122368.
authors.affiliation: Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Agricola
authors.identifier: 0000-0001-6639-5293
authors.initials: A
authors.lastname: Joachim
authors.affiliation: National Institute for Medical Research-Mbeya, Medical Research Center, Mbeya, Tanzania.|Department of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
authors.forename: Asli
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Joseph
authors.affiliation: Department of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.|German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Geldmacher
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Munseri
authors.affiliation: Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Said
authors.initials: S
authors.lastname: Aboud
authors.affiliation: National Institute for Medical Research-Mbeya, Medical Research Center, Mbeya, Tanzania.
authors.forename: Marco
authors.initials: M
authors.lastname: Missanga
authors.affiliation: National Institute for Medical Research-Mbeya, Medical Research Center, Mbeya, Tanzania.
authors.forename: Philipp
authors.initials: P
authors.lastname: Mann
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Britta
authors.initials: B
authors.lastname: Wahren
authors.affiliation: Department of Surgery and Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: The Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Polonis
authors.affiliation: The Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.|The Military HIV Research Program, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weber
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Roger
authors.initials: R
authors.lastname: Tatoud
authors.affiliation: National Institute for Medical Research-Mbeya, Medical Research Center, Mbeya, Tanzania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Maboko
authors.affiliation: National Institute for Medical Research-Mbeya, Medical Research Center, Mbeya, Tanzania.|Department of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.|German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Eligius F
authors.initials: EF
authors.lastname: Lyamuya
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gunnel
authors.initials: G
authors.lastname: Biberfeld
authors.affiliation: Venhälsan, Karolinska Insitutet at Södersjukhuset, Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Sandström
authors.affiliation: National Institute for Medical Research-Mbeya, Medical Research Center, Mbeya, Tanzania.|Department of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.|German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Kroidl
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Bakari
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.|The Public Health Agency of Sweden, Solna, Sweden.|Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Nilsson
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom.
authors.forename: Sheena
authors.initials: S
authors.lastname: McCormack
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic; D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D005260:Female; D005960:Glucosides; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D064368:Healthy Volunteers; D006801:Humans; D007115:Immunization Schedule; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D008050:Lipid A; D008213:Lymphocyte Activation; D008297:Male; D009500:Neutralization Tests; D013636:Tanzania; D014611:Vaccination; D019444:Vaccines, DNA / Q000009:adverse effects / Q000276:immunology*; D014765:Viral Vaccines; D055815:Young Adult; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D005960:Glucosides; D015483:HIV Antibodies; D007074:Immunoglobulin G; D008050:Lipid A; C560489:MVA vaccine; D019444:Vaccines, DNA; D014765:Viral Vaccines; D054299:env Gene Products, Human Immunodeficiency Virus; C000608161:glucopyranosyl lipid-A; C097729:gp140 envelope protein, Human immunodeficiency virus 1; D007371:Interferon-gamma