title: First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens.
abstract: BACKGROUND
  We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.
  
  
  METHODS
  Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH).
  
  
  RESULTS
  All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASHgroup. In contrast, the highest Gag-specific antibody titers were seen in the ASHgroup. Mucosal antibody responses were sporadic.
  
  
  CONCLUSIONS
  SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated.
  
  
  BACKGROUND
  NCT01705990.
authors.affiliation: Projet San Francisco, Kigali, Rwanda.
authors.forename: Julien
authors.initials: J
authors.lastname: Nyombayire
authors.affiliation: Kenya AIDS Vaccine Initiative Institute of Clinical Research, Nairobi.
authors.forename: Omu
authors.initials: O
authors.lastname: Anzala
authors.affiliation: Chelsea and Westminster Healthcare NHS Foundation Trust.
authors.forename: Brian
authors.initials: B
authors.lastname: Gazzard
authors.affiliation: Projet San Francisco, Kigali, Rwanda.
authors.forename: Etienne
authors.initials: E
authors.lastname: Karita
authors.affiliation: Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Bergin
authors.affiliation: Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Hayes
authors.affiliation: Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom.
authors.forename: Jakub
authors.initials: J
authors.lastname: Kopycinski
authors.affiliation: Kenya AIDS Vaccine Initiative Institute of Clinical Research, Nairobi.
authors.forename: Gloria
authors.initials: G
authors.lastname: Omosa-Manyonyi
authors.affiliation: Chelsea and Westminster Healthcare NHS Foundation Trust.
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Projet San Francisco, Kigali, Rwanda.
authors.forename: Jean
authors.initials: J
authors.lastname: Bizimana
authors.affiliation: Kenya AIDS Vaccine Initiative Institute of Clinical Research, Nairobi.
authors.forename: Bashir
authors.initials: B
authors.lastname: Farah
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Eddy
authors.initials: E
authors.lastname: Sayeed
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Parks
authors.affiliation: ID Pharma, Tsukuba.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.affiliation: ID Pharma, Tsukuba.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hironaka
authors.affiliation: ID Pharma, Tsukuba.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hara
authors.affiliation: ID Pharma, Tsukuba.
authors.forename: Tsugumine
authors.initials: T
authors.lastname: Shu
authors.affiliation: University of Tokyo.|National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matano
authors.affiliation: Emmes Corporation, Rockville, Maryland.
authors.forename: Len
authors.initials: L
authors.lastname: Dally
authors.affiliation: Emmes Corporation, Rockville, Maryland.
authors.forename: Burc
authors.initials: B
authors.lastname: Barin
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Harriet
authors.initials: H
authors.lastname: Park
authors.affiliation: Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Angela
authors.initials: A
authors.lastname: Lombardo
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Excler
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fast
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Dagna S
authors.initials: DS
authors.lastname: Laufer
authors.affiliation: International AIDS Vaccine Initiative, New York, New York.
authors.forename: Josephine H
authors.initials: JH
authors.lastname: Cox
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D000281:Administration, Intranasal; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005814:Genes, Viral / Q000276:immunology; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007117:Immunization, Secondary; D000071497:Immunogenicity, Vaccine; D007630:Kenya; D008297:Male; D008875:Middle Aged; D012432:Rwanda; D029082:Sendai virus / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006113:United Kingdom; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D014779:Virus Replication
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D019444:Vaccines, DNA
keywords: HIV-1 vaccine; Sendai virus vector; adenovirus 35; immunogenicity; intranasal delivery; mucosal responses; prime-boost; replication competent