Immune correlates analysis of the Imbokodo HIV-1 vaccine efficacy trial


BACKGROUND: In the phase 2b Imbokodo clinical trial (HVTN 705/HPX2008; NCT03060629), the investigational HIV vaccine regimen consisting of a vector-based vaccine (Ad26.Mos4.HIV) in combination with clade C gp140 protein was evaluated. Our analyses evaluated immune response markers as correlates of risk (CoR) for HIV-1 acquisition and protection (impact on VE).
METHODS: Immune markers were measured in samples from month 7 (4 weeks post-third vaccination) in a breakthrough case-control cohort (n=52 cases, 231 non-cases) from per-protocol vaccinees (HIV negative through month 7, received first 3 vaccinations within vaccination windows, without major protocol deviations). Binding and functional antibodies were measured in sera by ELISA, BAMA, ADCC, and ADCP; T-cell functionality was assessed via IFN-γ ELISpot and ICS. Forty-one markers (6 primary, 35 exploratory), including IgG and IgG3 magnitude-breadth and multi-epitope function scores, were assessed as univariate CoR and correlates of protection for HIV-1 acquisition over 550 days post-month 7 via Cox and nonparametric modelling adjusted for baseline prognostic factors. Multivariable CoR were assessed by Cox modelling (primary markers) and machine learning (all markers).
RESULTS: The analyses did not support statistically significant CoR (p-values for multivariable Cox model of primary markers: 0.11-0.72). There was a consistent trend toward IgG3 V1V2 breadth being associated with decreased HIV-1 acquisition, suggesting an immune correlate with a hazard ratio of 0.51 (p=0.11) in the multivariable analysis and 0.67 (p=0.24) in the univariable analysis per 10-fold increase, and increased VE with this marker (Figure). VE mediated through this marker was 25.3% (95% CI: 6.2%, 40.5%). The preclinical correlate combining ELISA and ELISpot responses was not recapitulated in this clinical trial.

CONCLUSIONS: Multiple statistical analyses revealed a trend of high IgG3 V1V2 BAMA breadth scores associated with lower infection risk and partial vaccine protection.