Clinical and microbiological response of mice to intranasal inoculation with Lactococcus lactis expressing Group A Streptococcus antigens, to be used as an anti‐streptococcal vaccine

Abstract

Protein subunit vaccines are often preferred because of their protective efficacy and safety. Lactic acid bacteria expressing heterologous antigens constitute a promising approach to vaccine development. However, their safety in terms of toxicity and bacterial clearance must be evaluated. Anti-Streptococcus pyogenes (S. pyogenes) vaccines face additional safety concerns because they may elicit autoimmune responses. The assessment of toxicity, clearance and autoimmunity of an antistreptococcal vaccine based on Lactococcus lactis (L. lactis) expressing 10 different M protein fragments from S. pyogenes (L. lactis-Mx10) is here reported. Clearance of L. lactis from the oropharynges of immunocompetent mice and mice devoid of T/B lymphocytes mice was achieved without using antibiotics. The absence of autoimmune responses against human tissues was demonstrated with human brain, heart and kidney. Assessment of toxicity showed that leucocyte counts and selected serum biochemical factors were not affected in L. lactis-Mx10-immunized mice. In contrast, mice immunized with L. lactis wild type vector (L. lactis-WT) showed increased neutrophil and monocyte counts and altered histopathology of lymph nodes, lungs and nasal epithelium. Two days after immunization, L. lactis-Mx10-immunized and L. lactis-WT-immunized mice weighed significantly less than unimmunized mice. However, both groups of immunized mice recovered their body weights by Day 6. Our results demonstrate that L. lactis-WT, but not the vaccine L. lactis-Mx10, induces alterations in certain hematologic and histopathological variables. We consider these data a major contribution to data on L. lactis as a bacterial vector for vaccine delivery.Despite ongoing efforts, no vaccine for preventing infections caused by S. pyogenes (Group A Streptococcus) and their complications is currently available. We are developing an intranasal bacterial-vectored vaccine based on 10 strains of Lactococcus lactis, each expressing a different M protein fragment from S. pyogenes. We have previously reported the immunogenicity and efficacy of an L. lactis strain expressing M9 antigen (1) Correspondence

Development of an implantable three-dimensional model of a functional pathogenic multispecies biofilm to study infected wounds

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Development of fluorescence-labeled antibody for immune checkpoint inhibitor using engineered probiotics

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Mucosal Immunization Has Benefits over Traditional Subcutaneous Immunization with Group A Streptococcus Antigens in a Pilot Study in a Mouse Model

“…Studies have shown that the sublingual route with CTB or heat-labile toxin can generate IgA at mucosal sites and serum IgG to protective levels against other species of Streptococci [10,11]. Several studies have demonstrated intranasal immunization can generate a mucosal immune response against GAS [14,16,25], but ours is the first study to show that a response can also be generated through immunization with a subunit vaccine by the sublingual route, which has potential safety benefits over intranasal immunization.…”

“…Whole cell vectors such as Lactococcus lactis, or cell-like structures could potentially bypass the need for adjuvant systems. A study with L. lactis expressing M-protein units was able to produce serum IgG and pharyngeal IgA without the need for adjuvant through the intranasal route [25]. Oral gavage of L. lactis expressing pilin proteins was also able to stimulate a bronchial IgA response as well as a serum IgG response, demonstrating the benefit of cellular structures in mucosal immunity [15].…”