The catalytic A1 domains of cholera toxin and heat-labile enterotoxin are potent DNA adjuvants that evoke mixed Th1/Th17 cellular immune responses

Abstract

DNA encoded adjuvants are well known for increasing the magnitude of cellular and/or humoral immune responses directed against vaccine antigens. DNA adjuvants can also tune immune responses directed against vaccine antigens to better protect against infection of the target organism. Two potent DNA adjuvants that have unique abilities to tune immune responses are the catalytic A1 domains of Cholera Toxin (CTA1) and Heat-Labile Enterotoxin (LTA1). Here, we have characterized the adjuvant activities of CTA1 and LTA1 using HIV and SIV genes as model antigens. Both of these adjuvants enhanced the magnitude of antigen-specific cellular immune responses on par with those induced by the well-characterized cytokine adjuvants IL-12 and GM-CSF. CTA1 and LTA1 preferentially enhanced cellular responses to the intracellular antigen SIVmac239-gag over those for the secreted HIVBaL-gp120 antigen. IL-12, GM-CSF and electroporation did the opposite suggesting differences in the mechanisms of actions of these diverse adjuvants. Combinations of CTA1 or LTA1 with IL-12 or GM-CSF generated additive and better balanced cellular responses to both of these antigens. Consistent with observations made with the holotoxin and the CTA1-DD adjuvant, CTA1 and LTA1 evoked mixed Th1/Th17 cellular immune responses. Together, these results show that CTA1 and LTA1 are potent DNA vaccine adjuvants that favor the intracellular antigen gag over the secreted antigen gp120 and evoke mixed Th1/Th17 responses against both of these antigens. The results also indicate that achieving a balanced immune response to multiple intracellular and extracellular antigens delivered via DNA vaccination may require combining adjuvants that have different and complementary mechanisms of action.

Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs

“…The control group (N = 4) received mock DNA immunizations via PMED consisting of the vaccine plasmid backbone, without SIV antigens or adjuvants. The MAG + LT group (N = 5) received the MAG vaccine, a plasmid that encodes SIV/17E-Fr Gag-Pol-Env and expresses virus-like particles [ 40 ] co-delivered with plasmids encoding SIV/17E-Fr p57 Gag and the LT adjuvant we previously showed induces mucosal T cell responses [ 15 , 27 ], also via PMED. A PMED group was included as a comparator because of its previously demonstrated therapeutic efficacy with another DNA vaccine [ 15 ].…”

“…Our adjuvant combination (AC) consisted of co-delivered DNA plasmids encoding the catalytic subunit of LT (LTA1), the cytokines IL-12 and IL-33, the enzyme retinaldehyde dehydrogenase 2 (RALDH2), soluble PD-1 (sPD-1), and soluble CD80 (sCD80). LTA1 is a potent adjuvant that performs similarly to LT, through the recruitment and activation of dendritic cells [ 26 , 27 ]. The IL-12 adjuvant has been widely used in both NHP and human clinical trials [ 28 , 29 ] and promotes differentiation of naïve CD4 + and CD8 + T cells to Th1 and cytotoxic T lymphocytes (CTLs), respectively.…”

Protection from viral rebound after therapeutic vaccination with an adjuvanted DNA vaccine is associated with SIV-specific polyfunctional CD8 T cells in the blood and mesenteric lymph nodes

“…The control group (N = 4) received mock DNA immunizations via particle-mediated epidermal delivery (PMED) consisting of the vaccine plasmid backbone, without SIV antigens or adjuvants. The MAG + LT group (N = 5) received the MAG vaccine, a plasmid that encodes Gag-Pol-Env and expresses virus-like particles as described previously [37] co-delivered with plasmids encoding p57 Gag and the LT adjuvant that we previously showed induces mucosal T cell responses [15, 25], also via PMED. The MAG + AC group (N = 5) received DNA immunizations via intradermal injection followed by electroporation.…”

“…Our adjuvant combination (AC) consisted of co-delivered plasmids encoding the catalytic subunit of LT (LTA1), the cytokines IL-12 and IL-33, the enzyme retinaldehyde dehydrogenase 2 (RALDH2), soluble PD-1 (sPD-1), and soluble CD80 (sCD80). LTA1 is a potent adjuvant that performs similarly to LT, through the recruitment and activation of dendritic cells [24, 25]. The IL-12 adjuvant has been widely used in both NHP and human clinical trials [26, 27] and promotes differentiation of naïve CD4 + and CD8 + T cells to Th1 and cytotoxic T lymphocytes (CTLs), respectively.…”