Serotype-Independent Protection Against Invasive Pneumococcal Infections Conferred by Live Vaccine With lgt Deletion

Abstract

Streptococcus pneumoniae is the most common respiratory bacterial pathogen among cases of community-acquired infection in young children, older adults, and individuals with underlying medical conditions. Although capsular polysaccharide-based pneumococcal vaccines have contributed to significant decrease in invasive pneumococcal infections, these vaccines have some limitations, including limited serotype coverage, lack of effective mucosal antibody responses, and high costs. In this study, we investigated the safety and immunogenicity of a live, whole-cell pneumococcal vaccine constructed by deleting the gene for prolipoprotein diacylglyceryl transferase ( lgt ) from the encapsulated pneumococcal strain TIGR4 (TIGR4Δ lgt ) for protection against heterologous pneumococcal strains. Pneumococcal strain TIGR4 was successfully attenuated by deletion of lgt , resulting in the loss of inflammatory activity and virulence. TIGR4Δ lgt colonized the nasopharynx long enough to induce strong mucosal IgA and IgG2b-dominant systemic antibody responses that were cross-reactive to heterologous pneumococcal serotypes. Finally, intranasal immunization with TIGR4Δ lgt provided serotype-independent protection against pneumococcal challenge in mice. Taken together, our results suggest that TIGR4Δ lgt is an avirulent and attractive broad-spectrum pneumococcal vaccine candidate. More broadly, we assert that modulation of such “master” metabolic genes represents an emerging strategy for developing more effective vaccines against numerous infectious agents.

Vaccination With the Commensal Streptococcus mitis Expressing Pneumococcal Serotype 5 Capsule Elicits IgG/IgA and Th17 Responses Against Streptococcus pneumoniae

“…Recently, we showed that intranasal immunization of mice with live S. mitis induces serotype-independent protection against infections with pneumococcal serotypes 2 and 4, which was associated with enhanced IgG and IgA responses (13). Likewise, vaccination with attenuated S. pneumoniae serotype 4 provided serotype-independent protection against invasive pneumococcal infections (22). The reason behind this serotype-independent immune response could be explained by the similarity between the nature of capsular and protein antigens of S. mitis and S. pneumoniae.…”

Enhanced biofilm formation of Streptococcus gordonii with lipoprotein deficiency

“…Especially, lgt converts pre‐prolipoprotein into prolipoprotein by adding diacyl lipid chains to lipoproteins (Wichgers Schreur et al., 2011). Thus, the deletion of lgt gene has been widely used to prepare lipoprotein‐deficient bacteria (Jang et al., 2019; Kang et al., 2018; Kim et al., 2018; Mohammad et al., 2020). However, lgt ‐deleted S. gordonii mutant strain still would have pre‐prolipoproteins in the cytoplasmic membrane.…”

Non-capsular based immunization approaches to prevent Streptococcus pneumoniae infection

“… Jang et al. (2019) developed a live attenuated vaccine with a strain TIGR4 lgt-mutant of S. pneumoniae.…”

“…(2019) developed a live attenuated vaccine with a strain TIGR4 lgt-mutant of S. pneumoniae. Lgt gene codifies the Lipoprotein diacylglyceryl transferase (Lgt) ( Jang et al., 2019 ), which participates in the production of lipoproteins in the bacterium. Lipoproteins are essential in several physiological roles in bacteria, for example, cell division, conjugation, adhesion, and immune evasion.…”