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Background: Heterologous prime-boost strategies are considered among the most promising HIV vaccine strategies. We hypothesized that the priming component is important for induction of strong immune responses and that an innovative trial design allows for rapid selection of promising strategies.
Methods: ANRS/INSERM VRI01 is an open-label randomized multicenter trial of 3 candidate vaccines administered as prime or boost: MVA HIV-B (coding for Gag, Pol, Nef); LIPO-5 (lipopeptides from Gag, Pol, Nef); and GTUÒ-MultiHIV B (DNA coding for Rev, Nef, Tat, Gag, gp160 clade B). Healthy volunteers were randomized 1:1:1:1 to four parallel groups: G1 (M2L2): MVA HIV-B (Wks 0, 8) then LIPO-5 (Wks 20, 28); G2 (L2M2): LIPO-5 (Wks 0, 8) then MVA HIV-B (Wks 20, 28); G3 (D3L2): GTUÒ-MultiHIV B (Wks 0, 4, 12) then LIPO-5 (Wks 20, 28); G4 (D3M2): GTUÒ-MultiHIV B (Wks 0, 4, 12) then MVA HIV-B (Wks 20, 28). Vaccine responders were defined by a positive IFN-γ-ELISPOT to ≥1 HIV peptide pool measured 2 Wks after each injection. Co-primary endpoints were safety and the proportion of IFN-γ-ELISPOT responders at Wk30, aiming to discard strategies with ≤ 50% responders.
Results: Nighty-two volunteers were randomized (mean age 30 years, 54% male) and received ≥1 injection. Four, 0, 6 and 1 SAEs possibly related to vaccination were reported in G1, G2, G3, G4, respectively, including one myelitis possibly related to LIPO-5.
Frequency of IFN-γ-ELISPOT responders and median SFC/106 PBMC among responders post-prime were: 59% and 328 SFC (G1 post-prime MVA); 5% and 323 SFC (G2 post-prime LIPO-5), 0% (pooled G3+4 post-prime GTUÒ-MultiHIV B). Following boosting, at Wk30 (primary endpoint, ITT analysis) these responses were 33% and 250 SFC (M2L2); 43% and 528 SFC (L2M2), 0% (D3L2); and 67% (P=0. 06 for superiority to 50% threshold) and 324 SFC (D3M2). In Wk30 per protocol analyses D3M2 was significantly above the predefined minimum immunogenicity level: 74% responders (P=0.02 for superiority to 50% threshold).
Conclusions: This optimized trial design helped to identify MVAHIV-B as a safe and immunogenic T-cell vaccine given as either prime or boost in various combinations. GTUÒ-MultiHIVB/MVA HIV-B met the pre-defined minimum immunogenicity criterion to pursue clinical development.

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