CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization

Abstract

Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in nonhuman primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env. INTRODUCTIONBecause the majority of natural human immunodeficiency virus type 1 (HIV-1) transmissions occur via mucosal membranes an effective prophylactic vaccine should stimulate immune responses that are active at the portal site for viral entry (Gupta & Klasse, 2006;Mestecky et al., 2005). Vaccine-induced neutralizing antibodies (NAbs) that interfere with viral entry have been found to be the protective correlates of many other prophylactic antiviral vaccines (Parren et al., 2001;Wicker et al., 2007;Zignol et al., 2004). An HIV-1 vaccine that prevents or limits virus replication in the mucosa should reduce the risk of systemic viral dissemination (Haase, 2005;Maher et al., 2005;Mazanec et al., 1992) and may reduce the risk of human-to-human transmission (Kozlowski & Neutra, 2003;Mascola, 2003;Neutra & Kozlowski, 2006). However, the development of mucosal vaccines has been slow, owing mainly to the lack of safe and effective mucosal adjuvants. Furthermore, there is insufficient knowledge as to the best route for immunization of the genital tract: i.n., local vaginal, rectal or parenteral. Also, combinations of regimens, such as mucosal priming followed by systemic boost, or, systemic priming followed by mucosal boost, have not been exhaustively investigated (Vajdy et al., 2004). Finally, an overriding problem to ...

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

“…In preliminary experiments, we have also found that the adjuvant function of CTA1-DD was independent of TLR signaling, because GC reactions and augmented serum Ab levels were unimpaired in MyD88-and TLR4-deficient mice (J. Mattsson, unpublished observation). These observations confirm previous studies showing that CTA1-DD acted independently of TLR signaling and also had no polyclonal B cell-activating effect in vivo (13,19). In the current study, we consistently failed to demonstrate an effect of CTA1-DD on GC reactions or Ab responses to NP-Ficoll or NP-dextran, responses known to depend on extrafollicular Ab production primarily by B1b cells and possibly MZ B cells (63).…”

“…Although CT and related holotoxins are powerful adjuvants targeted to distinct ganglioside receptors present on all cells of the innate immune system, we do not yet know precisely which cells and how the CTA1-DD adjuvant augments an immune response (15). It improves immune responses to many infectious disease-relevant Ags and by enhancing a wide range of functions from an effective priming of CD8 and CD4 T cells to greatly augmented Ab responses in a TLR-independent manner (13,16). Hence, we have hypothesized that the adjuvant must critically affect key events or processes in the priming of an immune response, possibly through mechanisms that could be different from that of most adjuvants operating via TLR stimulation.…”

“…This adjuvant combines the ADP-ribosylating CTA1 subunit of CT with a D-dimer, derived from Staphylococcus aureus protein A (12). The fusion protein retains the strong adjuvant properties of CT, but contrary to CT, it cannot bind to the GM1-ganglioside receptor used by CT, and, hence, CTA1-DD has no adverse or toxic side effects when tested in mice or nonhuman primates (12)(13)(14). Although CT and related holotoxins are powerful adjuvants targeted to distinct ganglioside receptors present on all cells of the innate immune system, we do not yet know precisely which cells and how the CTA1-DD adjuvant augments an immune response (15).…”

CD4+ T‐cell immunity in the female genital tract is critically dependent on local mucosal immunization

“…However, a unique alternative strategy is the CTA1-DD adjuvant, which hosts the enzymatic activity of the A1 subunit of CT genetically fused to a dimer of the D-fragment of Staphylococcus aureus protein A, CTA1-DD [35]. The CTA1-DD adjuvant targets APCs and has been successfully used in a large number of infectious disease-related immunization protocols in mice and monkeys [36][37][38][39].…”

Is the choice of vaccine adjuvant critical for long-term memory development?

“…CTA1-DD has been found to host a broad range of adjuvant functions, greatly augmenting cell-mediated and humoral immune responses to admixed antigen [35]. This effect was TLR/MyD88-independent and comparable in strength to that of CT [36]. However, contrary to CT, CTA1-DD was found to be nontoxic and noninflammatory in mice and monkeys and a promising candidate for use in human vaccines.…”