Nanoformulation of synergistic TLR ligands to enhance vaccination against Entamoeba histolytica

Abstract

Diarrheal infectious diseases represent a major cause of global morbidity and mortality. There is an urgent need for vaccines against diarrheal pathogens, especially parasites. Modern subunit vaccines rely on combining a highly purified antigen with an adjuvant to increase their efficacy. In the present study, we evaluated the ability of a nanoliposome adjuvant system to trigger a strong mucosal immune response to the Entamoeba histolytica Gal/GalNAc lectin LecA antigen. CBA/J mice were immunized with alum, emulsion or liposome based formulations containing synthetic TLR agonists. A liposome formulation containing TLR4 and TLR7/8 agonists was selected based on its ability to generate intestinal IgA, plasma IgG2a/IgG1, IFN-γ and IL-17A. Immunization with a mucosal prime followed by a parenteral boost generated a high mucosal IgA response that inhibited adherence of parasites to mammalian cells. Inclusion of the immune potentiator all-trans retinoic acid in the regimen further improved the mucosal IgA response. Immunization protected from infection with up to 55% efficacy. Our results show that a nanoliposome delivery system coupled to TLR agonists is a promising prospect for the development of vaccines against enteric pathogens, especially when a multifaceted immune response is desired.

Adjuvant composition and delivery route shape immune response quality and protective efficacy of a recombinant vaccine for Entamoeba histolytica

“… 19 – 21 In previous work, we screened various adjuvant formulations for their ability to generate a Th1-indicating IgG2a/IgG1 ratio in mice after subcutaneous administration with LecA, thus identifying a PEGylated liposomal formulation containing a combination of synthetic TLR4 (GLA) and TLR7/8 (3M-052) ligands as a promising candidate. 22 Further evaluation demonstrated that this adjuvant formulation upregulated production of IFN-γ and IL-17A, 22 cytokines shown to be protective in a mouse model, after subcutaneous administration with adjuvanted LecA. 11 , 23 When administered via alternating intranasal and subcutaneous routes with LecA, the GLA-3M-052 liposome formulation generated functional fecal IgA and 34% protective efficacy as assessed by culturing of parasites from cecal contents in a mouse challenge model of amebic colitis.…”

“… 11 , 23 When administered via alternating intranasal and subcutaneous routes with LecA, the GLA-3M-052 liposome formulation generated functional fecal IgA and 34% protective efficacy as assessed by culturing of parasites from cecal contents in a mouse challenge model of amebic colitis. 22 …”

TLR-Mediated Host Immune Response to Parasitic Infectious Diseases

“…In the amebiasis model, the nanoliposome adjuvant containing synergistic TLR4 and TLR7/8 agonists successfully elicited balanced systemic humoral and cellular immune responses. The immunization protected against infection with up to 55% efficacy [115].…”

Liposomal vaccine formulations as prophylactic agents: design considerations for modern vaccines

“…Currently these kinds of vaccines are facing challenges with variabilities in immune response induction [ 57 , 58 ]. Modern vaccination strategies are emphasizing the study of subunit vaccines and proving their effectiveness in immune response modulation [ 59 , 60 ]. Subunit vaccines are characterized by the co-delivery of adjuvants and antigens for immunostimulatory purposes (Fig.…”

“…Finally, a research paper dealing with parasitic infections present us the incorporation of Entamoeba histolytica Gal/GalNAc lectin LecA antigen in liposomal, emulsion and alum formulations containing synthetic TLR agonists adjuvants [ 59 ]. E. histolytica is an anaerobic amoeba and is the etiological agent of amoebiasis, or diarrheal disease commonly transmitted through contaminated water and food sources [ 119 ].…”