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

• Published in: PLoS pathogens Vol. 13; no. 2; p. e1006182
• Main Authors: Easterhoff, David, Moody, M Anthony, Fera, Daniela, Cheng, Hao, Ackerman, Margaret, Wiehe, Kevin, Saunders, Kevin O, Pollara, Justin, Vandergrift, Nathan, Parks, Rob, Kim, Jerome, Michael, Nelson L, O'Connell, Robert J, Excler, Jean-Louis, Robb, Merlin L, Vasan, Sandhya, Rerks-Ngarm, Supachai, Kaewkungwal, Jaranit, Pitisuttithum, Punnee, Nitayaphan, Sorachai, Sinangil, Faruk, Tartaglia, James, Phogat, Sanjay, Kepler, Thomas B, Alam, S Munir, Liao, Hua-Xin, Ferrari, Guido, Seaman, Michael S, Montefiori, David C, Tomaras, Georgia D, Harrison, Stephen C, Haynes, Barton F
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2017; Public Library of Science (PLoS)
• Subjects: 60 APPLIED LIFE SCIENCES; Acquired immune deficiency syndrome; AIDS; AIDS Vaccines - administration & dosage; AIDS Vaccines - immunology; Antibodies; Armed forces; B cells; Biology and Life Sciences; CD4 Antigens - immunology; Cell Separation; Clinical trials; Colleges & universities; Complementarity Determining Regions - immunology; Crystallography, X-Ray; Double-Blind Method; Electron microscopy; Enzyme-linked immunoassays; HIV Antibodies - immunology; HIV Envelope Protein gp120 - immunology; HIV Infections - immunology; HIV Infections - prevention & control; HIV vaccines; HIV-1; HIV-1 - immunology; Humans; Image Processing, Computer-Assisted; Immunization, Secondary - methods; Immunoglobulins; Medical schools; Medicine and Health Sciences; Memory B cells; Microscopy; Microscopy, Electron; Neutralization Tests; Polymerase Chain Reaction; Research and Analysis Methods; Surface Plasmon Resonance; Vaccines; North Carolina; South Korea; United States > US; Massachusetts; New Hampshire; Maryland; Bangkok Thailand
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006182

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.