Intranasal Immunization with Multivalent Group A Streptococcal Vaccines Protects Mice against Intranasal Challenge Infections

Abstract

We have previously shown that a hexavalent group A streptococcal M protein-based vaccine evoked bactericidal antibodies after intramuscular injection. In the present study, we show that the hexavalent vaccine formulated with several different mucosal adjuvants and delivered intranasally induced serum and salivary antibodies that protected mice from intranasal challenge infections with virulent group A streptococci. The hexavalent vaccine was formulated with liposomes with or without monophosphorylated lipid A (MPL), cholera toxin B subunit with or without holotoxin, or proteosomes from Neisseria meningitidis outer membrane proteins complexed with lipopolysaccharide from Shigella flexneri. Intranasal immunization with the hexavalent vaccine mixed with these adjuvants resulted in significant levels of antibodies in serum 2 weeks after the final dose. Mean serum antibody titers were equivalent in all groups of mice except those that were immunized with hexavalent protein plus liposomes without MPL, which were significantly lower. Salivary antibodies were also detected in mice that received the vaccine formulated with the four strongest adjuvants. T-cell proliferative assays and cytokine assays using lymphocytes from cervical lymph nodes and spleens from mice immunized with the hexavalent vaccine formulated with proteosomes indicated the presence of hexavalent protein-specific T cells and a Th1-weighted mixed Th1-Th2 cytokine profile. Intranasal immunization with adjuvanted formulations of the hexavalent vaccine resulted in significant levels of protection (80 to 100%) following intranasal challenge infections with type 24 group A streptococci. Our results indicate that intranasal delivery of adjuvanted multivalent M protein vaccines induces protective antibody responses and may provide an alternative to parenteral vaccine formulations.

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…Several recent M-protein-based studies have investigated the protective efficacy of the N-terminal hypervariable region (338,444,(534)(535)(536)(537)(538)(539), as this region may not be involved in autoimmune disease. Two N-terminal M protein vaccine preparations have reached human clinical trials to date: a hexavalent preparation (444,539,540) and a 26-valent preparation (541,542). These preparations were well tolerated in adult volunteers.…”

M Protein Gene ( emm Type) Analysis of Group A Beta-Hemolytic Streptococci from Ethiopia Reveals Unique Patterns

“…Hence, a vaccine targeting this highly variable region of M protein needs to be multivalent, consisting of several types. Currently, such multivalent vaccines composed of the most common emm types in Australia and United States are in development (9,20,23).…”

A Novel Live Vector Group A StreptococcalemmType 9 Vaccine Delivered Intranasally Protects Mice against Challenge Infection withemmType 9 Group A Streptococci

“…The serum antibody titer after 3 immunizations was similar to that obtained with multivalent fusion protein vaccines (20)(21)(22). Although we did not determine mucosal levels of IgA in saliva, we were unable to recover GAS from the oropharynx of vaccinated mice, suggesting that immunization impacted GAS colonization or infection at the level of the mucosa.…”

“…In fact, clinical and microbiological responses to Streptococcus gordonii, a commensal LAB, have already been assessed in healthy volunteers, which demonstrated that its use as a live mucosal vaccine vector is feasible (27). LAB vaccines can be administered intranasally, which may prove to be the optimal immunization route for a GAS vaccine (20,28). The vaccine candidate presented here can be produced inexpensively and easily delivered without the need for a syringe or highly skilled personnel.…”