title: Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial.
abstract: The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1-uninfected RV144 vaccine recipients were reimmunized 6-8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VH mutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports. While post-boost plasma did not have bnAb activity, the vaccine boosts expanded a pool of envelope CD4 binding site (bs)-reactive memory B cells with long third heavy chain complementarity determining regions (HCDR3) whose germline precursors and affinity matured B cell clonal lineage members neutralized the HIV-1 CRF01 AE tier 2 (difficult to neutralize) primary isolate, CNE8. Electron microscopy of two of these antibodies bound with near-native gp140 trimers showed that they recognized an open conformation of the Env trimer. Although late boosting of RV144 vaccinees expanded a novel pool of neutralizing B cell clonal lineages, we hypothesize that boosts with stably closed trimers would be necessary to elicit antibodies with greater breadth of tier 2 HIV-1 strains.
  
  
  
  ClinicalTrials.gov NCT01435135.
authors.affiliation: Duke University, Durham, North Carolina, United States of America.
authors.forename: David
authors.identifier: 0000-0001-5223-3277
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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authors.identifier: 0000-0002-3890-5855
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authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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authors.identifier: 0000-0002-1706-9288
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authors.affiliation: Dartmouth College, Hanover, New Hampshire, United States of America.
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authors.identifier: 0000-0002-5368-3613
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authors.affiliation: Dartmouth College, Hanover, New Hampshire, United States of America.
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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authors.identifier: 0000-0001-9933-9618
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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authors.identifier: 0000-0003-0461-6438
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authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
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authors.affiliation: U.S. Army Medical Directorate, AFRIMS, Bangkok, Thailand.
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authors.initials: RJ
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authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.|The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America.
authors.forename: Jean-Louis
authors.identifier: 0000-0002-6462-5101
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authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
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authors.affiliation: Thai Ministry of Public Health, Nonthaburi, Thailand.
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authors.affiliation: Mahidol University, Bangkok, Thailand.
authors.forename: Jaranit
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authors.affiliation: Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
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authors.affiliation: Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
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authors.affiliation: GSID, South San Francisco, California, United States of America.
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authors.initials: F
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authors.affiliation: Sanofi Pasteur, Swiftwater, Pennsylvania, United States of America.
authors.forename: James
authors.identifier: 0000-0001-5196-8001
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authors.lastname: Tartaglia
authors.affiliation: Sanofi Pasteur, Swiftwater, Pennsylvania, United States of America.
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authors.affiliation: Boston University, Boston, Massachusetts, United States of America.
authors.forename: Thomas B
authors.identifier: 0000-0002-1383-6865
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Duke University, Durham, North Carolina, United States of America.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Duke University, Durham, North Carolina, United States of America.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke University, Durham, North Carolina, United States of America.
authors.forename: Guido
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authors.lastname: Ferrari
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Duke University, Durham, North Carolina, United States of America.
authors.forename: David C
authors.initials: DC
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
authors.forename: Georgia D
authors.identifier: 0000-0001-8076-1931
authors.initials: GD
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authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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authors.initials: SC
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authors.affiliation: Duke University, Durham, North Carolina, United States of America.
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mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D002469:Cell Separation; D022801:Complementarity Determining Regions / Q000276:immunology; D018360:Crystallography, X-Ray; D004311:Double-Blind Method; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007117:Immunization, Secondary / Q000379:methods*; D008854:Microscopy, Electron; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D020349:Surface Plasmon Resonance
chemical_list: D016915:AIDS Vaccines; C574872:AIDSVAX B-E; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120