Current Progress and Challenges in the Study of Adjuvants for Oral Vaccines

Abstract

Over the past 20 years, a variety of potential adjuvants have been studied to enhance the effect of oral vaccines in the intestinal mucosal immune system; however, no licensed adjuvant for clinical application in oral vaccines is available. In this review, we systematically updated the research progress of oral vaccine adjuvants over the past 2 decades, including biogenic adjuvants, non-biogenic adjuvants, and their multi-type composite adjuvant materials, and introduced their immune mechanisms of adjuvanticity, aiming at providing theoretical basis for developing feasible and effective adjuvants for oral vaccines. Based on these insights, we briefly discussed the challenges in the development of oral vaccine adjuvants and prospects for their future development.

Fig. 1

Concise mechanisms of oral adjuvants at intestinal mucosal sites. a Bacterial enterotoxin (dmLT, mmCT) targets GM1 receptors, promotes Th17 response, and subsequently induces antigen-specific IgA antibodies. b Bacterial flagellin increases TLR5 stimulation that activates the production of inflammatory cytokines and subsequently augments innate and adaptive immune responses. c1 M cell-targeting peptides (CKS9, Co1) specifically target and bind to M cells. c2 RANKL, increasing the number of M cells. c3 DC-targeting ligand (DCpep), specifically targets and binds to dendritic cells. d Small molecular immunomodulatory proteins (cytokines and Tα1) directly stimulate, attract immune cells, and induce immune response. e1 PLG and PLGA protect antigens from degradation in GIT, allow the sustained and extended release of encapsulated antigens, and enhance antigen uptake by APCs, and subsequently the delivery of these microparticle-containing APCs to specific lymphoid compartments. e2 CS and its derivatives (TMC, HACC) and e3 PAHs possess mucoadhesive properties and permeation-enhancing effects. e4 ALG possesses mucoadhesive properties. f UEA-1 specifically targets and binds to M cells. g α-GalCer activates the iNKT-cell. h CpG-ODN activates TLR9 on B-lymphocytes and DCs, stimulates antigen presentation and induction of antigen-specific immune response towards the Th1 phenotype. CS chitosan, PAHs polyanhydrides, ALG alginate, iNKT-cell invariant natural killer T cell

Fig. 2

List of oral adjuvant candidates developed and their corresponding in vivo tests. According to the physicochemical properties, oral adjuvants could be divided into biogenic, non-biogenic, and a biogenic and non-biogenic combined composite. In vivo tests for oral adjuvant development have involved humans, rabbits, fish, rodents, pigs, primates, canines, and chickens. No connection means the in vivo test has not yet been carried out. α-GalCer alpha-Galactosylceramide, c-di-AMP 3′5′-cyclic di-adenosine monophosphate, CKS9 M cell-targeting peptide, Co1 M cell-specific peptide ligands, CpG-ODN CpG oligodeoxynucleotides, DCpep dendritic cell-targeting peptide, dmLT double-mutant heat-labile toxin, FnBPA fibronectin binding protein A, GM-CSF granulocyte-macrophage colony-stimulating factor, MCS NPs mannosylated chitosan nanoparticles, MDP muramyl dipeptide, mmCT multiple mutant cholera toxin, MPL monophosphoryl lipid A, O-2′-HACC O-2′-hydroxypropyltrimethyl ammonium chloride chitosan, PLG poly(d,l-lactide-co-glycolide), PLGA poly(d,l-lactic-co-glycolic acid), RANKL receptor activator of NF-kB ligand, RCK Salmonella resistance to complement killing, SMIPs small molecular immunomodulatory proteins, TMC trimethyl chitosan, UEA-1 ulex europaeus agglutinin-1