Background
Vaccine-induced HTI-specific T-cell responses have been associated with extended time off ART in early-treated PWH (etPWH) in 2 independent clinical trials, but with suboptimal viral control. We hypothesized that efficacy of T-cell vaccines could be improved with the support of vaccine-boosted humoral immunity.
Methods
BCN03 (NCT05208125) was a randomized, placebo-controlled trial testing the safety of ChAdOx1.HTI (C), MVA.HTI (M) and ConM.SOSIP.v7 (S) vaccines in 30 cis-gender men treated during chronic phase of HIV (ctPWH). HTI- and S-specific T-cells were evaluated by IFNγ-ELISpot, S-specific IgG by ELISA, and neutralization of 7 Tier1/2 pseudoviruses (one expressing S) by a TZM-bl assay. T/B/NKT cells were characterized by flow cytometry and sorted for transcriptome/methylome analyses. Near full-genome proviruses were amplified from isolated CD4+ T-cells to address vaccine coverage. In a 24-week ATI, ART was resumed if pVL >100,000 copies/mL once or >10,000 for 8 weeks.
Results
Related AEs were mostly mild and transient. Vaccinees significantly increased HTI-specific T cells, particularly in participants with pre-existing responses, from 113 (50-1,080) to 355 (50-2,265) SFC/106 PMBC from baseline to ATI-start (p=0.0082). At ATI-start, all 20 (100%) vaccinees vs. 3 (30%) placebo recipients had detectable anti-S IgG (p<0.0001), with levels correlating to neutralization (ID50) of the S-matched strain (ρ=0.69, p=0.0010), but minimally to other Tier-2 viruses. Magnitude of S-specific T-cells positively correlated with anti-S IgG levels. The magnitudes of HTI- and S-specific T-cells were not correlated, neither negatively nor positively. Frequencies of CD8+/PD1+, but not CD4+, T-cells were higher than in previous studies in etPWH and were associated with lower nadir CD4 counts (ρ=-0.38, p=0.0407). HTI coverage of proviral sequences was moderate. Viral rebound kinetics were similar between groups, not correlating with T or B-cell responses. Multi-omics analyses are ongoing.
Conclusions
CSSMS induced a lower magnitude of HTI T-cell responses in ctPWH compared to previous studies in etPWH receiving more complex T-cell vaccine regimens and did not improve ATI outcomes. Induced anti-S IgG correlated to S-specific T-cells and to neutralization of the S-matched strain, with no overt competition between T-/B-cell vaccine immunogens. BCN03 provides important insights into T-/B-cell collaboration on which further refined vaccine regimens can be built.