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 (TIGR4Δlgt) 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. TIGR4Δlgt 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 TIGR4Δlgt provided serotype-independent protection against pneumococcal challenge in mice. Taken together, our results suggest that TIGR4Δlgt 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.
Highlights
Streptococcus pneumoniae (Sp, known as pneumococcus) is the most common bacterial pathogen causing human diseases such as otitis media, pneumonia, and life-threatening invasive pneumococcal diseases, including meningitis and sepsis
To investigate its potential clinical use as a pneumococcal live attenuated vaccine, an lgt-deficient pneumococcal strain was constructed from the pneumococcal strain TIGR4 (TIGR4 lgt)
The expression of PsaA was detected in the cell lysate of wild-type (WT) TIGR4, while PsaA accumulated in the culture supernatant of TIGR4 lgt, indicating its improper anchoring in the membrane
Summary
Streptococcus pneumoniae (Sp, known as pneumococcus) is the most common bacterial pathogen causing human diseases such as otitis media, pneumonia, and life-threatening invasive pneumococcal diseases, including meningitis and sepsis. A protein-conjugated capsular polysaccharide vaccine (PCV) was initially developed to provide protection against the seven most prevalent serotypes causing invasive pneumococcal disease in young children This was later expanded to include 10 or 13 of the most invasive pneumococcal serotypes and is highly immunogenic in both adults and infants [8]. The overall incidence of invasive pneumococcal disease has declined by 47% as a result of the introduction of PCVs, the prevalence of non-vaccine serotypes (21, 23B, 33F, and 35F) has significantly increased among asymptomatic carriers and invasive pneumococcal diseases in countries in which a PCV is used nationwide [3, 14] Both PPVs and PCVs have recently been reported to produce diminished mucosal immune responses, especially in the production of immunoglobulin A (IgA), a predominant Ig isotype at the respiratory surface commonly colonized by pneumococcus [15]. The development of inactivated whole-cell-based vaccines for pneumococcus has been ongoing in both clinical and preclinical trials since 1911, and recent meta-analyses have affirmed their efficacy [18, 20]
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