Background:
Natural CD8+ T cell responses are ineffective at intercepting rebounding reservoirs after antiretroviral therapy (ART) release until after systemic viral replication and spread. Here, we evaluated whether a nucleoside unmodified mRNA vaccine (RNActive®) expressing full length SIV Gag and formulated in lipid nanoparticles (LNP) can be used to enhance Gag-specific CD8+ T cells in SIVmac239-infected rhesus macaques (RM) on ART. We hypothesized that vaccination during ART followed by a boost just prior to ART interruption (ATI) will enhance the immune intercept of reactivating SIV infections and facilitate post-ART viral control.
Methods:
16 RMs were infected with 5000IU of SIVmac239M and started on ART 9 days post-infection. Following viral suppression, RM were divided into 2 balanced groups that received 5 intramuscular injections at 100µg each of the SIV-Gag (n=8) or control mRNA/LNP vectors (n=8) at 59-, 62-, 65-, 79- and 106-weeks post-infection (wpi). SIV-specific T cell responses were assessed by intracellular cytokine stimulation assay. Two weeks after the last immunization, at 108wpi, ART was stopped to assess the impact of vaccine-induced immune responses on post-ART viral replication using RT-PCR.
Results:
SIV-Gag mRNA/LNP increased Gag-specific CD8+ T cells in multiple tissues, particularly the bronchoalveolar lavage (BAL), which saw responses peak to 25% (mean ± 4.4% SEM) of CD8+ T cells. Indeed, overall frequencies of Gag-specific CD8+ T cells in BAL were higher in SIV-Gag mRNA/LNP vaccinated RM relative to controls after 47 weeks (AUC, p=0.0002). A boost SIV-Gag mRNA/LNP at 16 days prior to ATI significantly increased frequencies of Gag-specific CD8+ T cells in blood (p=0.0002), BAL (p=0.0002), lymph node (p=0.0003), bone marrow (p=0.0002), spleen (p=0.0002), rectum (p=0.02) and liver (0.0002) relative to controls. Upon ART cessation, time to viral rebound was delayed in RM that received the SIV-Gag mRNA/LNP (median 20 vs. 11.5 days, p=0.0005) (Figure 1A). Additionally, SIV-Gag mRNA/LNP RM had lower post-ART peak viremia (p=0.002) and lower viral burden up to 5 weeks after rebound (AUC, p=0.002) (Figure 1B).
Conclusions:
Collectively, these data suggest that a T cell-targeted vaccination strategy that systemically increases the frequencies of SIV-specific CD8+ T cells immediately prior to ATI can restrict early viral spread and facilitate enhanced post-ART viral control.
