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
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...
Saved in:
Published in | PLoS pathogens Vol. 13; no. 2; p. e1006182 |
---|---|
Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
01.02.2017
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-News-2 ObjectType-Feature-3 content type line 23 Duke Center for AIDS Research Duke University Interdisciplinary Research Training Program in HIV/AIDS OPP1033098; OPP1114721; OPP1032144; AI 064518; Al102691; 1F32AI116355; GM62580 National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH) US Army Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bill and Melinda Gates Foundation USDOD Conceptualization: BFH.Data curation: DE DF HC MA MAM JP NV SMA GF DCM GDT SCH BFH.Formal analysis: NV.Funding acquisition: BFH.Investigation: DE DF HC RP.Methodology: MAM MA RP HXL GF DCM GDT.Project administration: DE MAM MA KW KOS RP SMA HXL GF MSS DCM GDT SCH BFH.Resources: JKi NLM RJO JLE MLR SV SN JKa PP SRN FS JT SP TBK.Software: TBK.Supervision: MAM MA KOS SMA GF MSS DCM GDT SCH BFH.Validation: DE DF MAM HC MA JP RP SMA GF MSS DCM GDT SCH BFH.Visualization: DE DF JP GF.Writing – original draft: DE BFH.Writing – review & editing: DE DF HC MA KW RJO JP NLM MLR GF MSS SCH BFH. Current address: International Vaccine Institute, Seoul, Republic of Korea The ALVAC-HIV canarypox vector is a Sanofi Pasteur patented product. JT and SP are employed by Sanofi Pasteur. |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1006182 |