430 – Therapeutic HIV Vaccine ± TLR4 Adjuvant Impact on Monocyte Subsets in Early-Treated Youths With HIV

Background

Monocytes (MO) play a crucial role in restricting HIV replication and spread. After HIV acquisition, MO show increased activation and differentiation, altering subset distribution despite ART. MO enhance vaccine induced immune responses and contribute to trained immunity, boosting protection. We here investigated changes in MO phenotype in a therapeutic vaccine study.

Methods

HVRRICANE is the 1^st pediatric combined (HIVIS DNA + MVA-CMDR) therapeutic HIV vaccine ± Cervarix co-administration to provide TLR4 immunoadjuvant. 25 adolescents with perinatal HIV, suppressed on ART (since 6 months of age) were enrolled (Fig.1). Comprehensive phenotypic analysis of the MO populations was conducted across the entire cohort using a new gating strategy based on CD86, CCR2, HLA-DR, CD64, and CD33 expression. Data acquisition was performed using a BD Symphony A3 cell analyzer through multi-parametric approach. High dimensional analyses concatenating all participant events at baseline and weeks 16, 36, and 48 identified 8 cells clusters, analyzed via t-SNE for marker expression and temporal trends (Fig.1).

Results

Classical (CL, CD86+CD64^highCCR2+HLADR^low) MO showed a significant longitudinal increase (p=0.034) only in Arm 1 (no TLR4 agonist) from a baseline median of 38.4%, peaking at wk 8 (51.6%), and remained elevated at wk 48 (44.3%). This increase was accompanied by a waning trend in the Intermediate (ITM; CD86+CD64^highCCR2^lowHLADR^high), from a baseline of 2.57% and reaching 1.09% at wk 48. Arm 1 also showed significant (p=0.034) changes in CD93 geometric mean fluorescence intensity (gMFI) on CL MO over time. This subset presented lower CD49d gMFI at weeks 16 (p=0.045), 40 (p=0.031) and 48 (p=0.038) in Arm 1 than to Arm 2 (with TLR4 agonist), while CD11a gMFI was higher (p=0.037) in Arm 1 at wk 40. In contrast, Arm 3 (only TLR4 agonist) showed an increasing trend in non-classical (NC; CD86+CD64^lowCD33^low) MO, confirmed by higher (p=0.043) Ki67 gMFI at wk 36 than to Arm 1. Additionally, in the ITM subset, Arm 2 exhibited a substantial (p= 0.028) increase in CD11b gMFI, peaking at wk 48; while Arm 1 demonstrated a significant (p=0.009) decrease in CD11c gMFI above the on ITM MO over time.

Conclusions

We observed distinct MO subset distribution and integrin/receptor expression following DNA prime and MVA boost vaccination regimens with Cervarix® co-administration.