title: First Phase I human clinical trial of a killed whole-HIV-1 vaccine: demonstration of its safety and enhancement of anti-HIV antibody responses.
abstract: BACKGROUND
  Vaccination with inactivated (killed) whole-virus particles has been used to prevent a wide range of viral diseases. However, for an HIV vaccine this approach has been largely negated due to inherent safety concerns, despite the ability of killed whole-virus vaccines to generate a strong, predominantly antibody-mediated immune response in vivo. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence for the Env signal peptide with that of honeybee melittin signal peptide to produce a less virulent and more replication efficient virus. This genetically modified virus (gmHIV-1NL4-3) was inactivated and formulated as a killed whole-HIV vaccine, and then used for a Phase I human clinical trial (Trial Registration: Clinical Trials NCT01546818). The gmHIV-1NL4-3was propagated in the A3.01 human T cell line followed by virus purification and inactivation with aldrithiol-2 and γ-irradiation. Thirty-three HIV-1 positive volunteers receiving cART were recruited for this observer-blinded, placebo-controlled Phase I human clinical trial to assess the safety and immunogenicity.
  
  
  RESULTS
  Genetically modified and killed whole-HIV-1 vaccine, SAV001, was well tolerated with no serious adverse events. HIV-1NL4-3-specific PCR showed neither evidence of vaccine virus replication in the vaccine virus-infected human T lymphocytes in vitro nor in the participating volunteers receiving SAV001 vaccine. Furthermore, SAV001 with adjuvant significantly increased the pre-existing antibody response to HIV-1 proteins. Antibodies in the plasma of vaccinees were also found to recognize HIV-1 envelope protein on the surface of infected cells as well as showing an enhancement of broadly neutralizing antibodies inhibiting tier I and II of HIV-1 B, D, and A subtypes.
  
  
  CONCLUSIONS
  The killed whole-HIV vaccine, SAV001, is safe and triggers anti-HIV immune responses. It remains to be determined through an appropriate trial whether this immune response prevents HIV infection.
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.|Sumagen Canada Inc., London, ON, Canada.
authors.forename: Eunsil
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Michalski
authors.affiliation: Sumagen Canada Inc., London, ON, Canada.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Choo
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Gyoung Nyoun
authors.initials: GN
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Banasikowska
authors.affiliation: Sumagen Canada Inc., London, ON, Canada.
authors.forename: Sangkyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Kunyu
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Hwa-Yong
authors.initials: HY
authors.lastname: An
authors.affiliation: Anthony M. Mills Internal Medicine, West Hollywood, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mills
authors.affiliation: Long Beach Education and Research Consultants, Long Beach, CA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Metropolis Medical PC, San Francisco, CA, USA.
authors.forename: U Fritz
authors.initials: UF
authors.lastname: Bredeek
authors.affiliation: Rockwood Clinics, P.C., Spokane, WA, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Coulston
authors.affiliation: Centre de Recherche du CHUM, Department of Microbiology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: Centre de Recherche du CHUM, Department of Microbiology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Tian
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Katja
authors.initials: K
authors.lastname: Klein
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Arts
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Jamie F S
authors.initials: JF
authors.lastname: Mann
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada. cykang@uwo.ca.
authors.forename: C Yong
authors.initials: CY
authors.lastname: Kang
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D001516:Bees / Q000235:genetics; D005260:Female; D015693:Gene Products, nef / Q000235:genetics; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics; D006801:Humans; D000071497:Immunogenicity, Vaccine; D008297:Male; D008875:Middle Aged; D021382:Protein Sorting Signals; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D055815:Young Adult; D000086082:Viroporin Proteins
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015693:Gene Products, nef; D015483:HIV Antibodies; D054298:Human Immunodeficiency Virus Proteins; D021382:Protein Sorting Signals; D015164:Vaccines, Inactivated; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
keywords: AIDS; Clinical trial; HIV; Immune responses; Killed whole-HIV vaccine; Neutralizing antibodies; Safety