Membrane-anchored CCL20 augments HIV Env-specific mucosal immune responses

Abstract

BackgroundInduction of broad immune responses at mucosal site remains a primary goal for most vaccines against mucosal pathogens. Abundance of evidence indicates that the co-delivery of mucosal adjuvants, including cytokines, is necessary to induce effective mucosal immunity. In the present study, we set out to evaluate the role of a chemokine, CCL20, as an effective mucosal adjuvant for HIV vaccine.MethodsTo evaluate the role of CCL20 as a potent adjuvant for HIV vaccine, we examined its effects on antigen-specific antibody responses, level of antibody-secreting cells, cytokine production and intestinal homing of plasma cells in vaccine immunized mice.ResultsCCL20-incorporated VLP administered by mucosal route (intranasal (n = 10, p = 0.0085) or intravaginal (n = 10, p = 0.0091)) showed much higher potency in inducing Env-specific IgA antibody response than those administered by intramuscular route (n = 10). For intranasal administration, the HIV Env-specific IFN-γ(751 pg/ml), IL-4 (566 pg/ml), IL-5 (811 pg/ml) production and IgA-secreting plasma cells (62 IgA-secreting plasma cells/106 cells) in mucosal lamina propria were significantly augmented in CCL20-incorporated VLP immunized mice as compared to those immunized with Env only VLPs (p = 0.0332, 0.0398, 0.033, 0.0302 for IFN-γ, IL-4, IL-5, and IgA-secreting plasma cells, respectively).Further, anti-CCL20 mAb partially suppressed homing of Env-specific IgA ASCs into small intestine in mice immunized with CCL20-incorporated VLP by intranasal (62 decreased to 16 IgA- secreting plasma cells/106 cells, p = 0.0341) or intravaginal (52 decreased to 13 IgA- secreting plasma cells/106 cells, p = 0.0332) routes.ConclusionOur data indicated that the VLP-incorporated CCL20 can enhance HIV Env-specific immune responses in mice, especially those occurring in the mucosal sites. We also found that i.m. prime followed by mucosal boost is critical and required for CCL20 to exert its full function as an effective mucosal adjuvant. Therefore, co-incorporation of CCL20 into Env VLPs when combined with mucosal administration could represent a novel and promising HIV vaccine candidate.

Chemokine-Adjuvanted Plasmid DNA Induces Homing of Antigen-Specific and Non–Antigen-Specific B and T Cells to the Intestinal and Genital Mucosae

“…Eliciting an appropriate immune response at mucosal sites is likely necessary to protect from sexually transmitted pathogens such as HIV and Chlamydia, respiratory pathogens like influenza and RSV, or gastrointestinal infections caused by rotavirus, clostridium, and Salmonella. To induce mucosal immunity, strategies involving systemic and topical immunizations with chemokine adjuvants have been tested with the aim to recruit and program immune cells (8,9,11,18,28). In this study, we developed a DNA platform which allows bicistronic expression of the Ag of interest and a chosen chemokine/cytokine using an EMCV IRES.…”

“…route and trigger high levels of systemic immunity, this delivery route is much less efficient at directing protective immune responses toward mucosal sites (7). Therefore, approaches to induce effective mucosal responses have generally focused on the use of chemokines and cytokines as molecular adjuvants for vaccines with the aim to recruit cells from the systemic compartment and program them for homing to mucosal surfaces (8)(9)(10)(11).…”

Parenterally Administered Porcine Epidemic Diarrhea Virus-Like Particle-Based Vaccine Formulated with CCL25/28 Chemokines Induces Systemic and Mucosal Immune Protectivity in Pigs

“…On the other hand, the use of the soluble chemokines may also contribute to the ineffective stimulation of immune responses. Several studies have indicated that chemokine-incorporated VLPs can stimulate robust antigen-specific immune responses, while modest immune responses are noted in VLPs with soluble chemokines [ 76 , 77 ], highlighting the influence of co-delivery of an antigen and chemokine on promoting effective immune stimulation. Hence, the adequate regimens of VLP and CCL or even co-delivery of all the components still need further optimization and should also be applied to sows to evaluate the protection for litters via lactogenic immunity.…”

Oral Immunization with AttenuatedSalmonellaCholeraesuis Expressing the P42 and P97 Antigens Protects Mice againstMycoplasma hyopneumoniaeChallenge

“…In addition, the use of Salmonella as a vector allows the placement of heterologous antigens directly into the lymphoid tissues, thereby permitting the maximum stimulation of the relevant lymphoid cells for the formation of sIgA ( 25 , 26 ). This increases the possibility of developing vaccines that can elicit significant immune responses at mucosal sites beyond those achievable by other means ( 27 ). In a previous study, the delivery of the NrdF antigen of Mhp with an attenuated Salmonella vector (Δ aroA ) induced significant cellular immune responses and sIgA responses and ameliorated lung pathological damage and daily weight gain in pigs, indicating that the delivery of the Mhp protective antigen with attenuated Salmonella is a feasible approach ( 28 ).…”