Primate immune responses to HIV-1 Env formulated in the saponin-based adjuvant AbISCO-100 in the presence or absence of TLR9 co-stimulation

Abstract

Protein-based vaccines require adjuvants to achieve optimal responses. Toll-like receptor (TLR) 9 agonists were previously shown to improve responses to protein-based vaccines, such as the Hepatitis B virus vaccine formulated in alum. Here, we used CpG-C together with the clinically relevant saponin-based adjuvant AbISCO-100/Matrix-M (AbISCO), to assess if TLR9 co-stimulation would quantitatively or qualitatively modulate HIV-1 envelope glycoprotein (Env)-specific B and T cell responses in rhesus macaques. The macaques were inoculated with soluble Env trimers in AbISCO, with or without the addition of CpG-C, using an interval similar to the Hepatitis B virus vaccine. Following a comprehensive evaluation of antigen-specific responses in multiple immune compartments, we show that the Env-specific circulating IgG, memory B cells and plasma cells displayed similar kinetics and magnitude in the presence or absence of CpG-C and that there was no apparent difference between the two groups in the elicited HIV-1 neutralizing antibody titers or antigen-specific CD4+ T cell responses. Importantly, the control of SHIV viremia was significantly improved in animals from both Env-immunized groups relative to adjuvant alone controls, demonstrating the potential of AbISCO to act as a stand-alone adjuvant for Env-based vaccines.

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

“…In our view, data from the A3R5 assay provide another comparative evaluation tool of the Ab responses elicited in vaccinated macaques. The neutralization breadth generated by these vaccines is as potent and comparable to that reported in a recent Env-based vaccine study using similar virus panels (13) and notably more potent than others (15,21,70), including the immunogenicity results of the studies using native-like trimers (58,71). Importantly, this study is unique because we show that the Env-specific vaccine-induced macaque polyclonal IgG was biased toward the same regions of Env mapped to NAb breadth in human subject plasma verified in our earlier studies.…”

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

“…Previously, we performed an immunogenicity study in nonhuman primates (NHPs) using YU2gp140-F, an early-generation HIV-1 Env trimer immunogen, administered three times in adjuvant (21) (Fig. 1A, upper panel).…”

“…Upper panel, immunization/sampling schedule. Rhesus macaques were inoculated with HIV-1 Env YU2gp140-F trimer 3 times (black arrows) using a 6-month interval between the second and the third immunizations (21). Plasma and PBMCs from animal K17 were collected 2 weeks after the third inoculation and subjected to virus neutralization assay and FACS sorting (red arrow).…”

“…The plasma of the immunized animals displayed robust tier 1 virus neutralizing responses but also low titer neutralizing responses against the autologous tier 2 virus (YU2) and several heterologous (cross-reactive) tier 2 viruses (21). In the present study, we set out to define the cross-reactive tier 2 virus NAb response elicited by this vaccination at the MAb level to guide future vaccine design.…”

“…Previously we conducted an HIV-1 Env immunogenicity experiment in rhesus macaques, using gp140-F trimers derived from clade B primary isolate YU2 as a model immunogen to examine the adjuvant effect of saponin-based AbISCO in combination with Toll-like receptor 9 (TLR9) agonist CpG-C ODN (21). The plasma of the immunized animals displayed robust tier 1 virus neutralizing responses but also low titer neutralizing responses against the autologous tier 2 virus (YU2) and several heterologous (cross-reactive) tier 2 viruses (21).…”