Targeting the Mincle and TLR3 receptor using the dual agonist cationic adjuvant formulation 9 (CAF09) induces humoral and polyfunctional memory T cell responses in calves

Abstract

There is a need for the rational design of safe and effective vaccines to protect against chronic bacterial pathogens such as Mycobacterium tuberculosis and Mycobacterium avium subsp. paratuberculosis in a number of species. One of the main challenges for vaccine development is the lack of safe adjuvants that induce protective immune responses. Cationic Adjuvant Formulation 01 (CAF01)—an adjuvant based on trehalose dibehenate (TDB) and targeting the Mincle receptor—has entered human trials based on promising pre-clinical results in a number of species. However, in cattle CAF01 only induces weak systemic immune responses. In this study, we tested the ability of three pattern recognition receptors, either alone or in combination, to activate bovine monocytes and macrophages. We found that addition of the TLR3 agonist, polyinosinic:polycytidylic acid (Poly(I:C)) to either one of the Mincle receptor agonists, TDB or monomycoloyl glycerol (MMG), enhanced monocyte activation, and calves vaccinated with CAF09 containing MMG and Poly(I:C) had increased cell-mediated and humoral immune response compared to CAF01 vaccinated animals. In contrast to the highly reactogenic Montanide ISA 61 VG, CAF09-primed T cells maintained a higher frequency of polyfunctional CD4+ T cells (IFN-γ+ TNF-α+ IL-2+). In conclusion, CAF09 supports the development of antibodies along with a high-quality cell-mediated immune response and is a promising alternative to oil-in-water adjuvant in cattle and other ruminants.

Intrapulmonary (i.pulmon.) Pull Immunization With the Tuberculosis Subunit Vaccine Candidate H56/CAF01 After Intramuscular (i.m.) Priming Elicits a Distinct Innate Myeloid Response and Activation of Antigen-Presenting Cells Than i.m. or i.pulmon. Prime Immunization Alone

“…We envisage to use this strategy for immunization of adolescents and adults with H56/CAF01 vaccine. BCG is administered to newborns immediately after birth and has over 70% protective efficacy against tuberculous meningitis and miliary TB (46), while in adults, BCG vaccination fails to completely protect against pulmonary TB and has a very variable protective efficacy (0-80%) (47). BCG vaccination also reduces mortality in newborn and children because of non-specific cross-protection induced by this vaccine against other unrelated pathogens (48).…”

HCV p7 as a novel vaccine-target inducing multifunctional CD4+ and CD8+ T-cells targeting liver cells expressing the viral antigen

“…As the CAF09 adjuvant also supports induction of humoral responses, other effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), may also contribute to the clearance of target cells in vivo 84,85 . Although the contribution of ADCC in clearance of HCV remains to be studied in detail, ADCC represents an important asset in cancer immunotherapy and is also believed to contribute to clearance of HIV infection 86,87 .…”

Emerging glyco‐based strategies to steer immune responses

“…These nanoparticles were able to trigger Mincle activation in reporter cell lines and also evoked TNFα and IL‐6 secretion in mouse RAW264.7 and human PBMC, respectively. Combinations of Mincle ligands with other PPR stimuli, such as Poly I:C [ 110 ] or bis‐(3'‐5')‐cyclic dimeric guanosine monophosphate (c‐di‐GMP, a ligand for the STING receptor) [ 111 ], may even provide superior memory responses and long‐lasting cellular and humoral responses, as demonstrated in cattle and pigs. Incorporation of both TDB and monophosphoryl lipid A (MPLA) enhanced the efficacy of a Mycobacterium tuberculosis subunit vaccine, providing long‐term protection against a mycobacterial challenge [ 112 ].…”