title: Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines.
abstract: 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.
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA 02139, USA.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Chung
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.forename: Hannah
authors.initials: H
authors.lastname: Robinson
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.forename: Ickwon
authors.initials: I
authors.lastname: Choi
authors.forename: Sophie
authors.initials: S
authors.lastname: Lane
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dugast
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Schoen
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Suscovich
authors.forename: Alison E
authors.initials: AE
authors.lastname: Mahan
authors.forename: Larry
authors.initials: L
authors.lastname: Liao
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.forename: Charla
authors.initials: C
authors.lastname: Andrews
authors.forename: Supachai
authors.initials: S
authors.lastname: Rerks-Ngarm
authors.forename: Sorachai
authors.initials: S
authors.lastname: Nitayaphan
authors.forename: Mark S
authors.initials: MS
authors.lastname: de Souza
authors.forename: Jaranit
authors.initials: J
authors.lastname: Kaewkungwal
authors.forename: Punnee
authors.initials: P
authors.lastname: Pitisuttithum
authors.forename: Donald
authors.initials: D
authors.lastname: Francis
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Ackerman
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D006678:HIV / Q000502:physiology; D015483:HIV Antibodies / Q000096:biosynthesis; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G