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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

Journal Article · · PLoS Pathogens
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  1. Duke Univ., Durham, NC (United States)
  2. Harvard Medical School, Boston, MA (United States)
  3. Dartmouth College, Hanover, NH (United States)
  4. Walter Reed Army Inst. of Research, Silver Spring, MD (United States). US Military HIV Research Program
  5. The Armed Forces Research Inst. of Medical Sciences (AFRIMS), Bangkok (Thailand). U.S. Army Medical Directorate
  6. Walter Reed Army Inst. of Research, Silver Spring, MD (United States). US Military HIV Research Program; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD (United States)
  7. Thai Ministry of Public Health, Nonthaburi (Thailand)
  8. Mahidol Univ., Bangkok (Thailand)
  9. The Armed Forces Research Inst. of Medical Sciences (AFRIMS), Bangkok (Thailand). Royal Thai Army Component
  10. Global Solutions for Infectious Diseases (GSID), South San Francisco, CA (United States)
  11. Sanofi Pasteur, Swiftwater, PA (United States)
  12. Boston Univ., MA (United States)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Bill and Melinda Gates Foundation; Duke University Interdisciplinary Research Training Program in HIV/AIDS; Duke Center for AIDS Research; National Institutes of Health (NIH); Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.; USDOD; National Institute of Allergy and Infectious Diseases (NIAID); US Army
Grant/Contract Number:
OPP1033098; OPP1114721; OPP1032144; AI 064518; Al102691; 1F32AI116355; GM62580
OSTI ID:
1430312
Journal Information:
PLoS Pathogens, Vol. 13, Issue 2; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 30 works
Citation information provided by
Web of Science

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Novel prime-boost vaccine strategies against HIV-1 journal July 2019
Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity posted_content May 2019
Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa journal September 2019
Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency journal November 2019
HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions journal January 2020
Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site journal March 2018
Robotic selection for the rapid development of stable CHO cell lines for HIV vaccine production journal August 2018
Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection journal February 2018
HIV Vaccination: A Roadmap among Advancements and Concerns journal April 2018
Novel Concepts for HIV Vaccine Vector Design journal December 2017
Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines journal February 2020

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