Intranasal c-di-GMP-adjuvanted plant-derived H5 influenza vaccine induces multifunctional Th1 CD4(+) cells and strong mucosal and systemic antibody responses in mice
ABSTRACT Vaccination is the best available measure of limiting the impact of the next influenza pandemic. Ideally, a candidate pandemic influenza vaccine should be easy to administer and should elicit strong mucosal and systemic immune responses. Production of influenza subunit antigen in transient plant expression systems is an alternative to overcome the bottleneck in vaccine supply during influenza pandemic. Furthermore, a needle-free intranasal influenza vaccine is an attractive approach, which may provide immunity at the portal of virus entry. The present study investigated the detailed humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with plant-derived influenza H5N1 (A/Anhui/1/05) antigen alone or formulated with bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) as adjuvant. The use of c-di-GMP as intramuscular adjuvant did not enhance the immune response to plant-derived influenza H5 antigen. However, intranasal c-di-GMP-adjuvanted vaccine induced strong mucosal and systemic humoral immune responses. Additionally, the intranasal vaccine elicited a balanced Th1/Th2 profile and, most importantly, high frequencies of multifunctional Th1 CD4(+) cells. Our results highlight that c-di-GMP is a promising mucosal adjuvant for pandemic influenza vaccine development.
SourceAvailable from: Mohamed Mahgoub Azooz[Show abstract] [Hide abstract]
ABSTRACT: Edible vaccine technology represents an alternative to fermentation based vaccine production system. Transgenic plants are used for the production of plant derived specific vaccines with native immunogenic properties stimulating both humoral and mucosal immune responses. Keeping in view the practical need of new technology for production and delivery of inexpensive vaccines, especially in developing world, plant derived edible vaccines is the best option in hand to combat infectious diseases. Plant derived vaccine is easy to administer, cost effective, readily acceptable, have increased safety, stability, versatility and efficacy. Several plant derived vaccines are under research, some are under clinical trials for commercial use. Like most biotechnology products, the IP situation for edible vaccines is complex as IP rights influence every stage of vaccine development.AFRICAN JOURNAL OF BIOTECHNOLOGY 11/2013; 12(43):6147-6158. DOI:10.5897/AJB2012.2925 · 0.57 Impact Factor
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ABSTRACT: An HIV vaccine capable of inducing high and durable levels of broadly neutralizing antibodies has thus far proven elusive. A promising antigen is the membrane-proximal external region (MPER) from gp41, a segment of the viral envelope recognized by a number of broadly neutralizing antibodies. Though an attractive vaccine target due to the linear nature of the epitope and its highly conserved sequence, MPER peptides are poorly immunogenic and may require display on membranes to achieve a physiological conformation matching the native virus. Here we systematically explored how the structure and composition of liposomes displaying MPER peptides impacts the strength and durability of humoral responses to this antigen as well as helper T-cell responses in mice. Administration of MPER peptides anchored to the surface of liposomes induced MPER-specific antibodies whereas MPER administered in oil-based emulsion adjuvants or alum did not, even when combined with Toll like receptor agonists. High-titer IgG responses to liposomal MPER required the inclusion of molecular adjuvants such as monophosphoryl lipid A. Anti-MPER humoral responses were further enhanced by incorporating high-Tm lipids in the vesicle bilayer and optimizing the MPER density to a mean distance of ∼10-15nm between peptides on the liposomes surfaces. Encapsulation of helper epitopes within the vesicles allowed efficient "intrastructural" T-cell help, which promoted IgG responses to MPER while minimizing competing B-cell responses against the helper sequence. These results define several key properties of liposome formulations that promote durable, high-titer antibody responses against MPER peptides, which will be a prerequisite for a successful MPER-targeting vaccine. Copyright © 2014. Published by Elsevier Ltd.Vaccine 01/2015; 33(7). DOI:10.1016/j.vaccine.2014.12.045 · 3.49 Impact Factor
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ABSTRACT: Effective mucosal adjuvants enhance the magnitude and quality of the vaccine response. Cyclic di-GMP is a promising mucosal vaccine adjuvant. However, its in vivo mechanisms are unclear. Here, we showed,in mice, that cyclic di-GMP elicits stronger Ab and TH responses than the mammalian 2'3'-cyclic GMP-AMP, and generated better protection against Streptococcus pneumoniae infection than 2'3'-cyclic GMP-AMP adjuvanted vaccine. We identified two in vivo mechanisms of cyclic di-GMP. First, intranasally administered cyclic di-GMP greatly enhances Ag uptake, including pinocytosis and receptor-mediated endocytosis in vivo. The enhancement depends on MPYS (STING, MITA) expression in CD11C(+) cells. Second, we found that cyclic di-GMP selectively activated pinocytosis-efficient-DCs, leading to TH polarizing cytokines IL-12p70, IFNγ, IL-5, IL-13, IL-23,and IL-6 production in vivo. Notably, cyclic di-GMP induces IFNλ, but not IFNβ, in vivo. Our study revealed previously unrecognized in vivo functions of MPYS and advanced our understanding of cyclic di-GMP as a mucosal vaccine adjuvant.eLife Sciences 04/2015; 4. DOI:10.7554/eLife.06670 · 8.52 Impact Factor