ABSTRACT
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
Subject(s)
Adjuvants, Immunologic/pharmacology , Antigens, Viral/immunology , Candida albicans/chemistry , Mannans/immunology , Aluminum Hydroxide/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibody Specificity/immunology , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Epitopes/immunology , Immunity, Innate , Immunization , Inflammation/pathology , Interferons/metabolism , Lectins, C-Type/metabolism , Ligands , Lung/immunology , Lung/pathology , Lung/virology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Macrophages/metabolism , Mice, Inbred C57BL , Paranasal Sinuses/metabolism , Protein Subunits/metabolism , Sialic Acid Binding Ig-like Lectin 1/metabolism , Solubility , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , Transcription Factor RelB/metabolism , Vero Cells , beta-Glucans/metabolismABSTRACT
Introduction: Adjuvants are essential to vaccines for immunopotentiation in the elicitation of protective immunity. However, classical and widely used aluminum-based adjuvants have limited capacity to induce cellular response. There are increasing needs for appropriate adjuvants with improved profiles for vaccine development toward emerging pathogens. Carbohydrate-containing nanoparticles (NPs) with immunomodulatory activity and particulate nanocarriers for effective antigen presentation are capable of eliciting a more balanced humoral and cellular immune response.Areas covered: We reviewed several carbohydrates with immunomodulatory properties. They include chitosan, ß-glucan, mannan, and saponins, which have been used in vaccine formulations. The mode of action, the preparation methods, characterization of these carbohydrate-containing NPs and the corresponding vaccines are presented.Expert opinion: Several carbohydrate-containing NPs have entered the clinical stage or have been used in licensed vaccines for human use. Saponin-containing NPs are being evaluated in a vaccine against SARS-CoV-2, the pathogen causing the on-going worldwide pandemic. Vaccines with carbohydrate-containing NPs are in different stages of development, from preclinical studies to late-stage clinical trials. A better understanding of the mode of action for carbohydrate-containing NPs as vaccine carriers and as immunostimulators will likely contribute to the design and development of new generation vaccines against cancer and infectious diseases.