Background
At CROI 2024 (abstract 180), we reported that mRNA/SIV-Gag vaccination during ART and with boost prior to ART interruption (ATI) delayed time to rebound and induced early virologic control in SIV-infected rhesus macaques (RM). In this study, we explored whether the latency-reversing agent AZD5582 can be used to enhance efficacy of the mRNA/SIV-Gag vaccine.
Methods
All RM were intravenously (IV) inoculated with 5000 IU SIVmac239M and started ART 9 days post-infection (dpi). After ART suppression (>200 dpi), RM were divided into treatment groups: (A) mRNA/SIV-Gag alone (n=8), (B) mRNA/control alone (n=8), (C) mRNA/SIV-Gag + AZD5582 (n=6) and (D) mRNA/Control + AZD5582 (n=5). Vaccine was administered intramuscularly (100ug/dose) at weeks 0, 3, 6, 20, plus a final immunization 2 weeks before ATI (week 34+). AZD5582 was administered IV as 15 weekly doses of 100ug/kg each between weeks 10-19 and 24-28. SIV-specific T cell responses were assessed by intracellular cytokine stimulation (ICS) assay and plasma viral loads (pVL) were quantified by ddPCR.
Results
Prior to AZD5582, Gag-specific CD8+ T cells in bronchoalveolar lavage (BAL) peaked at week 6 (prior to AZD5582) to a mean of 18.1 ± 6% in group C and 25.0 ± 4.4% in group A (p=0.35) (Figure 1A). However, at week 15, after 5 doses of AZD5582, responses sharply declined to a mean of 0.2 ± 0.2% in group C compared to 7.2 ± 2.6% in group A (p=0.0013). By week 18, lymph node responses were also lower in group C compared to group A (mean 0.10 ± 0.09% vs 0.56 ± 0.03%, respectively, p=0.02). After the 4th vaccination, responses in BAL (AUC weeks 21-26) were lower in group C compared with group A (p=0.048). Upon ATI, viral rebound was delayed in group A compared to group B controls (median 20 vs 11.5 days, p=0.005) (Figure 1B). However, there was no difference in time to SIV rebound between groups C and D (median 13 vs 11.5 days, p=0.86). While post-ART peak pVL and viral burden (pVL AUC 0-8 weeks post-rebound) were lower in group A compared to group B (p=0.002 and p=0.049, respectively), no difference was observed between groups C and D (p=0.29 and p=0.55, respectively).
Conclusions
Collectively, these data suggests that AZD5582 diminished mRNA/SIV-Gag vaccine-induced CD8+ T cell responses and abrogated vaccine-enhanced early intercept of rebounding infections following ATI. This highlights the need for novel latency-reversal agents that do not disrupt the effector activity of CD8+ T cell responses.