Systemic immunization with CCL27/CTACK modulates immune responses at mucosal sites in mice and macaques

Abstract

Plasmid DNA is a promising vaccine platform as it is has been shown to be safe and able to be administered repeatedly without vector interference. Enhancing the potency of DNA vaccination through co-delivery of molecular adjuvants is one strategy currently under investigation. Here we describe the use of the novel chemokine adjuvant CCL27/CTACK to enhance immune responses to an HIV-1 or SIV antigen in mice and rhesus macaques. CCL27 has been shown to play a role in inflammatory responses through Chemotaxis of CCR10+ cells and we hypothesized that CCL27 may modulate adaptive immune responses. Immunizations in mice with HIV-1gag/CCL27 enhanced immune responses both at peripheral and surprisingly mucosal sites. To confirm these findings in a large animal model, we created optimized CCL27 and SIV antigenic plasmid constructs for rhesus macaques. 10 macaques (n=5/group) were immunized intramuscularly with 1mg/construct of antigenic plasmids +/- CCL27 with electroporation. We observed significant IFN-γ secretion and CD8+ T cell proliferation in peripheral blood. Interestingly, CCL27 co-immunized macaques exhibited a trend toward greater effector CD4+T cells in the bronchiolar lavage (BAL). CCL27 co-delivery also elicited greater antigen specific IgA at unique sites including BAL and fecal samples, but not in the periphery. Future studies incorporating CCL27 adjuvant in vaccine or therapy models where eliciting immune responses in the lung are warranted.

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

“…CCL27 binds to T cells expressing CCR10 and is thought to be important in attracting these cells to the skin during inflammatory responses (45). It is possible that CCL27 is associated with more vigorous HIV-specific immune responses in ECs (15) as vaccination studies using CCL27 plasmid DNA as an adjuvant demonstrated enhanced T cell and antibody responses, including at mucosal sites (46,47).…”

Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines

“…Recent studies found that systemic immunization of animals with the CCR10 ligand CCL27 or CCL28 as an adjuvant increased titers of antigen-specific IgA antibodies in mucosal tissues such as intestines, suggesting that manipulating the CCR10/ligand axis could be useful in enhancing the vaccination efficacy against mucosal pathogens (28,29). It will be interesting to study how CCR10/ligands increase the mucosal IgA memory in this setting.…”

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

“…The intranasal delivery of genetic vaccines has been shown to be limited to induce adequate mucosal antibody responses, thus requiring the use of adjuvants, such as the chemokine adjuvant CCL27/CTACK (Kraynyak et al 2010), lipid adjuvant (Brave et al 2008), ligants of TLR (Deml et al 1999;Kojima et al 2002), cytokines, or cytokine genes (Dale et al 2004;Rollman et al 2004). We have shown herein that the chimeric vaccine LAMP/gag was able to efficiently induce systemic and mucosal antibody responses; this vaccine efficiently enhanced anti-GAG antibody productionas a consequence of the appropriate antigen presentation -and activated CD4+ T cells, stimulating a broad clonal expansion of B cells.…”