Synthetic Double-Stranded RNAs Are Adjuvants for the Induction of T Helper 1 and Humoral Immune Responses to Human Papillomavirus in Rhesus Macaques

Abstract

Toll-like receptor (TLR) ligands are being considered as adjuvants for the induction of antigen-specific immune responses, as in the design of vaccines. Polyriboinosinic-polyribocytoidylic acid (poly I:C), a synthetic double-stranded RNA (dsRNA), is recognized by TLR3 and other intracellular receptors. Poly ICLC is a poly I:C analogue, which has been stabilized against the serum nucleases that are present in the plasma of primates. Poly I:C12U, another analogue, is less toxic but also less stable in vivo than poly I:C, and TLR3 is essential for its recognition. To study the effects of these compounds on the induction of protein-specific immune responses in an animal model relevant to humans, rhesus macaques were immunized subcutaneously (s.c.) with keyhole limpet hemocyanin (KLH) or human papillomavirus (HPV)16 capsomeres with or without dsRNA or a control adjuvant, the TLR9 ligand CpG-C. All dsRNA compounds served as adjuvants for KLH-specific cellular immune responses, with the highest proliferative responses being observed with 2 mg/animal poly ICLC (p = 0.002) or 6 mg/animal poly I:C12U (p = 0.001) when compared with immunization with KLH alone. Notably, poly ICLC—but not CpG-C given at the same dose—also helped to induce HPV16-specific Th1 immune responses while both adjuvants supported the induction of strong anti-HPV16 L1 antibody responses as determined by ELISA and neutralization assay. In contrast, control animals injected with HPV16 capsomeres alone did not develop substantial HPV16-specific immune responses. Injection of dsRNA led to increased numbers of cells producing the T cell–activating chemokines CXCL9 and CXCL10 as detected by in situ hybridization in draining lymph nodes 18 hours after injections, and to increased serum levels of CXCL10 (p = 0.01). This was paralleled by the reduced production of the homeostatic T cell–attracting chemokine CCL21. Thus, synthetic dsRNAs induce an innate chemokine response and act as adjuvants for virus-specific Th1 and humoral immune responses in nonhuman primates.

Decisions About Dendritic Cells: Past, Present, and Future

“…As a result of experiments with a consortium of investigators in Germany, including Klaus Uberla, Paul and Klara Racz, Christiane Stahl Hennig, and Ralf Ignatius, synthetic double-stranded RNA (poly IC) appeared to be promising adjuvant (126). Considerable research in mice by Paula Longhi came to the same conclusion and established that poly IC gained its potency as an adjuvant by being a strong inducer of innate interferon production (127).…”

Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A

“…The latter is poly IC formulated together with poly L-lysine and carboxymethylcellulose. Poly IC and poly ICLC are synthetic dsRNAs that are proving to be superior adjuvants for T-cell immune responses (40,41). Because both poly IC and poly ICLC were comparable in the response induced after primeboost, they were used interchangeably.…”

Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population

“…Even less is known about the effects of type I IFN inducers, such as Poly-ICLC, on latent tuberculosis, since the use of these compounds has been limited to clinical trials. Nevertheless, because of the promising effects seen with type I IFN inducers in immunotherapy of both cancer and viral infection and as adjuvants for vaccination (42)(43)(44), major new clinical applications for these drugs are likely to emerge. While the data presented here are confined to a specific murine experimental model of tuberculosis, they suggest that reactivation of latent M. tuberculosis should be evaluated as a possible side effect when testing type I IFN inducers or type I IFN treatment itself in clinical settings in which the treated population is heavily exposed and therefore at risk of tuberculosis.…”