Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

Abstract

Globally, 1.8 million children are living with HIV-1. While antiretroviral therapy (ART) has improved disease outcomes, it does not eliminate the latent HIV-1 reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial for HIV-1-infected children who now must remain on daily ART throughout their lifespan. Here, we evaluated therapeutic Ad48-SIV prime, MVA-SIV boost immunization in combination with the TLR-7 agonist GS-986 in rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen beginning 4 weeks after infection. We hypothesized immunization would enhance SIV-specific T cell responses during ART-mediated suppression of viremia. Compared to controls, vaccinated infants had greater magnitude SIV-specific T cell responses (mean of 3475 vs 69 IFN-γ spot forming cells (SFC) per 106 PBMCs, respectively, P = 0.01) with enhanced breadth of epitope recognition and increased CD8+ and CD4+ T cell polyfunctionality (P = 0.004 and P = 0.005, respectively). Additionally, SIV-specific gp120 antibodies against challenge and vaccine virus strains were significantly elevated following MVA boost (P = 0.02 and P < 0.001, respectively). GS-986 led to expected immune stimulation demonstrated by activation of monocytes and T cells 24 hours post-dose. Despite the vaccine-induced immune responses, levels of SIV DNA in peripheral and lymph node CD4+ T cells were not significantly different from controls and a similar time to viral rebound and viral load set point were observed following ART interruption in both groups. We demonstrate infant RMs mount a robust immunological response to this immunization, but vaccination alone was not sufficient to impact viral reservoir size or modulate rebound dynamics following ART release. Our findings hold promise for therapeutic vaccination as a part of a combination cure approach in children and highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.

Predictive Markers of Immunogenicity and Efficacy for Human Vaccines

“…Infant NHPs have been frequently used in studies to evaluate vaccines against Mycobacterium tuberculosis [229][230][231] and HIV [232][233][234]. Recently, Han et al used highthroughput technologies, including single-cell RNA sequencing of PBMCs, to perform an in-depth comparison of neonatal and adult immune responses to HIV immunization in macaques [235].…”

Understanding Viral and Immune Interplay During Vertical Transmission of HIV: Implications for Cure

“…However, presently over half of new infections occur postnatally through breast milk (9). As this route has become predominant in perinatal HIV infection, a nonhuman primate model has been established to better understand virologic and immunologic features of lentivirus infection following postpartum transmission, more precisely define anatomic sites of virus persistence, and test strategies to promote reservoir eradication or remission (46,47,(222)(223)(224). These and other ongoing studies may inform the design of future cure-directed clinical trials in children with HIV infection acquired through breast milk.…”

Latency Reversal 2.0: Giving the Immune System a Seat at the Table

“…Furthermore, 2/9 RM treated with GS-9620 did not show viral rebound after ART interruption and adoptive transfer of peripheral blood mononuclear cells (PBMCs) and lymph node mononuclear cells from these two RM to two uninfected animals did not result in establishment of infection. However, these exciting results showing virus reactivation were not reproduced in multiple additional studies in RM infected with SIV or simian human immunodeficiency virus (SHIV) [ 30 •, 31 •, 32 •, 33 , 34 ] nor in PLWH. Vesatolimod (formerly GS-9620) was assessed in a phase 1b, randomized, double-blind, placebo-controlled clinical trial, and only isolated viral load elevations above 20 copies/ml (highest 69 copies/ml) were observed [ 35 ].…”