A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils

Abstract

Mucosally active subunit vaccines are an unmet clinical need due to lack of licensed immunostimulants suitable for vaccine antigens. Here, we show that intranasal administration of liposomes incorporating: the Streptococcus pyogenes peptide antigen, J8; diphtheria toxoid as a source of T cell help; and the immunostimulatory glycolipid, 3D(6-acyl) PHAD (PHAD), is able to induce long-lived humoral and cellular immunity. Mice genetically deficient in either mucosal antibodies or total antibodies are protected against S. pyogenes respiratory tract infection. Utilizing IL-17-deficient mice or depleting cellular subsets using antibodies, shows that the cellular responses encompassing, CD4+ T cells, IL-17, macrophages and neutrophils have important functions in vaccine-mediated mucosal immunity. Overall, these data demonstrate the utility of a mucosal vaccine platform to deliver multi-pronged protective responses against a highly virulent pathogen.

Disruption of IL-17-mediated immunosurveillance in the respiratory mucosa results in invasive Streptococcus pyogenes infection

“…This explains the high incidence of streptococcal skin and mucosal infections in children under the age of 10, which decreases in early adulthood (41). Furthermore, we have previously demonstrated age-related acquisition of antibodies to the conserved region of S. pyogenes M-protein in teenagers and adults residing in endemic areas (42) and demonstrated that vaccination of mice with conserved region peptides can induce protection from both mucosal and skin challenges (43)(44)(45).…”

“…This was paralleled by an increase in effector/memory CD4 + T cells in the lungs. This population contains both long-lived lung resident memory T cells that mediate immunity against S. pyogenes mucosal infection ( 44 , 58 ) and short-lived effector T cells, which recirculate between the blood, lymphatics, or other peripheral tissues and die after acute infections ( 59 , 60 ). The markers used to identify EM CD4 + T cells in this study were not sufficient to distinguish short-lived effector T cells without memory potential from long-lived memory cells.…”

Conserved molecular chaperone PrsA stimulates protective immunity against group A Streptococcus

“…Recently, novel adjuvant formulations and delivery methods have emerged to enhance vaccine efficacy. The utilization of liposomal adjuvant CAF ® 01 60 , self-assembled poly (methyl acrylate) polymer nanoparticles 61 , immunostimulatory 3D(6-acyl) PHAD glycolipid 62 , biopolymer particles derived from endotoxin-free E. coli 63 , and high-density microarray patch 64 on J8 and P*17 peptide vaccines has demonstrated a significant enhancement in the magnitude and duration of mucosal immunity or a preference for driving Th1-prone immune responses following immunization. The incorporation of potent immune-stimulants like saponin QS21 and TLR4 agonist 3D-(6-acyl) PHAD 16 or TLR9 agonist CpG 30 in non-M protein vaccines can induce Th1- or Th17-related immune responses to promote bacterial clearance.…”