Serotype-specific protection against Streptococcus pneumoniae is an important limitation of the current polysaccharide-based vaccines. To prevent serotype replacement, reduce transmission, and limit the emergence of new variants, it is essential to induce broad protection and restrict pneumococcal colonization. In this study, we used a prototype vaccine formulation consisting of lipopolysaccharide (LPS)-detoxified outer membrane vesicles (OMVs) from Salmonella enterica serovar Typhimurium displaying the variable N terminus of PspA (␣1␣2) for intranasal vaccination, which induced strong Th17 immunity associated with a substantial reduction of pneumococcal colonization. Despite the variable nature of this protein, a common major histocompatibility complex class (MHC-II) epitope was identified, based on in silico prediction combined with ex vivo screening, and was essential for interleukin-17 A (IL-17A)-mediated cross-reactivity and associated with cross protection. Based on 1,352 PspA sequences derived from a pneumococcal carriage cohort, this OMV-based vaccine formulation containing a single ␣1␣2 type was estimated to cover 19.1% of strains, illustrating the potential of Th17-mediated cross protection.KEYWORDS intranasal vaccination, protein antigens, Streptococcus pneumoniae, PspA, colonization, Th17, broad protection, Salmonella outer membrane vesicle (OMV), antigen surface display, autotransporter Hbp R espiratory bacterial infections remain a major cause of severe morbidity and mortality worldwide in both infants and adults (1, 2). Vaccination is considered one of the most cost-effective strategies to reduce the global burden of infectious diseases, the associated health care costs, and the risk of emerging antibiotic-resistant strains (3). Vaccination against Streptococcus pneumoniae is implemented in different parts of the world. However, about 1 million children still die of pneumococcal disease every year (1, 2). Pneumococcal polysaccharide conjugate vaccines are designed based on epidemiological data from the Western world. These vaccines protect against serotypes that are the most prevalent and most frequently associated with severe invasive disease. They induce serotype-specific protection against 13 of the 97 identified serotypes that are circulating worldwide (4). This is an important limitation, and during the last decade, nonvaccine variants of S. pneumoniae that cause severe invasive disease have Citation Kuipers K, Jong WSP, van der Gaast-de Jongh CE, Houben D, van Opzeeland F, Simonetti E, van Selm S, de Groot R, Koenders MI, Azarian T, Pupo E, van der Ley P, Langereis JD, Zomer A, Luirink J, de Jonge MI. 2017. Th17-mediated cross protection against pneumococcal carriage by vaccination with a variable antigen. Infect Immun 85:e00281-17.
Nasopharyngeal colonization by Streptococcus pneumoniae is a prerequisite for pneumococcal transmission and disease. Current vaccines protect only against disease and colonization caused by a limited number of serotypes, consequently allowing serotype replacement and transmission. Therefore, the development of a broadly protective vaccine against colonization, transmission and disease is desired but requires a better understanding of pneumococcal adaptation to its natural niche. Hence, we measured the levels of free and protein-bound transition metals in human nasal fluid, to determine the effect of metal concentrations on the growth and proteome of S. pneumoniae. Pneumococci cultured in medium containing metal levels comparable to nasal fluid showed a highly distinct proteomic profile compared to standard culture conditions, including the increased abundance of nine conserved, putative surface-exposed proteins. AliA, an oligopeptide binding protein, was identified as the strongest protective antigen, demonstrated by the significantly reduced bacterial load in a murine colonization and a lethal mouse pneumonia model, highlighting its potential as vaccine antigen.
For many bacterial respiratory infections, development of (severe) disease is preceded by asymptomatic colonization of the upper airways. For Streptococcus pneumoniae, the transition to severe lower respiratory tract infection is associated with an increase in nasopharyngeal colonization density. Insight into how the mucosal immune system restricts colonization may provide new strategies to prevent clinical symptoms. Several studies have provided indirect evidence that the mucosal adjuvant cholera toxin subunit B (CTB) may confer nonspecific protection against respiratory infections. Here, we show that CTB reduces the pneumococcal load in the nasopharynx, which required activation of the caspase-1/11 inflammasome, mucosal T cells, and macrophages. Our findings suggest that CTB-dependent activation of the local innate response synergizes with noncognate T cells to restrict bacterial load. Our study not only provides insight into the immunological components required for containment and clearance of pneumococcal carriage, but also highlights an important yet often understudied aspect of adjuvants.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.