RT Journal Article SR Electronic T1 Polyfunctional Fc-Effector Profiles Mediated by IgG Subclass Selection Distinguish RV144 and VAX003 Vaccines JF Science Translational Medicine FD American Association for the Advancement of Science SP 228ra38 OP 228ra38 DO 10.1126/scitranslmed.3007736 VO 6 IS 228 A1 Chung, Amy W. A1 Ghebremichael, Musie A1 Robinson, Hannah A1 Brown, Eric A1 Choi, Ickwon A1 Lane, Sophie A1 Dugast, Anne-Sophie A1 Schoen, Matthew K. A1 Rolland, Morgane A1 Suscovich, Todd J. A1 Mahan, Alison E. A1 Liao, Larry A1 Streeck, Hendrik A1 Andrews, Charla A1 Rerks-Ngarm, Supachai A1 Nitayaphan, Sorachai A1 de Souza, Mark S. A1 Kaewkungwal, Jaranit A1 Pitisuttithum, Punnee A1 Francis, Donald A1 Michael, Nelson L. A1 Kim, Jerome H. A1 Bailey-Kellogg, Chris A1 Ackerman, Margaret E. A1 Alter, Galit YR 2014 UL http://stm.sciencemag.org/content/6/228/228ra38.abstract AB The human phase 2B RV144 ALVAC-HIV vCP1521/AIDSVAX B/E vaccine trial, held in Thailand, resulted in an estimated 31.2% efficacy against HIV infection. By contrast, vaccination with VAX003 (consisting of only AIDSVAX B/E) was not protective. Because protection within RV144 was observed in the absence of neutralizing antibody activity or cytotoxic T cell responses, we speculated that the specificity or qualitative differences in Fc-effector profiles of nonneutralizing antibodies may have accounted for the efficacy differences observed between the two trials. We show that the RV144 regimen elicited nonneutralizing antibodies with highly coordinated Fc-mediated effector responses through the selective induction of highly functional immunoglobulin G3 (IgG3). By contrast, VAX003 elicited monofunctional antibody responses influenced by IgG4 selection, which was promoted by repeated AIDSVAX B/E protein boosts. Moreover, only RV144 induced IgG1 and IgG3 antibodies targeting the crown of the HIV envelope V2 loop, albeit with limited coverage of breakthrough viral sequences. These data suggest that subclass selection differences associated with coordinated humoral functional responses targeting strain-specific protective V2 loop epitopes may underlie differences in vaccine efficacy observed between these two vaccine trials.