Abstract
The upper respiratory tract (URT) is the major entry site for human pathogens and strategies to activate this network could lead to new vaccines capable of preventing infection with many pathogens. Group A streptococcus (GAS) infections, causing rheumatic fever, rheumatic heart disease, and invasive disease, are responsible for substantial morbidity and mortality. We describe an innovative vaccine strategy to induce mucosal antibodies of significant magnitude against peptide antigens of GAS using a novel biocompatible liposomal platform technology. The approach is to encapsulate free diphtheria toxoid (DT), a standard vaccine antigen, within liposomes as a source of helper T-cell stimulation while lipidated peptide targets for B-cells are separately displayed on the liposome surface. As DT is not physically conjugated to the peptide, it is possible to develop modular epitopic constructs that simultaneously activate IgA-producing B-cells of different and complementary specificity and function that together neutralize distinct virulence factors. An inflammatory cellular immune response is also induced. The immune response provides profound protection against streptococcal infection in the URT. The study describes a new vaccine platform for humoral and cellular immunity applicable to the development of vaccines against multiple mucosal pathogens.
Highlights
Strains[6,13]
Mice were challenged with the M1 Group A streptococcus (GAS) strain and we observed limited reduction in GAS colonies from nasal secretions, in throat, and in Nasal Associated Lymphoid Tissue (NALT; a murine functional homolog to human tonsils)[25], which did not reach statistical significance (Supplemental Fig. 1C–H)
Given our evidence that protection against the highly virulent Control of Virulence Regulatory Sensor (CovR/S) mutant GAS required the induction of antibodies capable of neutralizing two complementary virulence factors[12], we developed a modular vaccine that could present more than one peptide simultaneously
Summary
Strains[6,13]. S2 is a 20-amino acid peptide from SpyCEP12. Liposomes are spherical vesicles composed of biocompatible phospholipid bilayers[22] in which multiple lipophilic constructs can be incorporated within the lipid bilayers They should be ideal platforms to induce peptide-specific antibody responses of multiple specificities. The question that we addressed was whether a carrier protein contained within a liposome, but not physically conjugated to the peptide, would be able to induce T-cell help to B-cells responding to different surface peptide epitopes of GAS and induce protection against this mucosal pathogen. If successful, such liposomes would transform vaccine development by allowing modular design of multiple peptide immunogens effective against many mucosal pathogens
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