Abstract
Streptococcus pneumoniae infections lead to high morbidity and mortality rates worldwide. Pneumococcal polysaccharide conjugate vaccines significantly reduce the burden of disease but have a limited range of protection, which encourages the development of a broadly protective protein-based alternative. We and others have shown that immunization with pneumococcal lipoproteins that lack the lipid anchor protects against colonization. Since immunity against S. pneumoniae is mediated through Toll-like receptor 2 signaling induced by lipidated proteins, we investigated the effects of a lipid modification on the induced immune responses in either intranasally or subcutaneously vaccinated mice. Here, we demonstrate that lipidation of recombinant lipoproteins DacB and PnrA strongly improves their immunogenicity. Mice immunized with lipidated proteins showed enhanced antibody concentrations and different induction kinetics. The induced humoral immune response was modulated by lipidation, indicated by increased IgG2/IgG1 subclass ratios related to Th1-type immunity. In a mouse model of colonization, immunization with lipidated antigens led to a moderate but consistent reduction of pneumococcal colonization as compared to the non-lipidated proteins, indicating that protein lipidation can improve the protective capacity of the coupled antigen. Thus, protein lipidation represents a promising approach for the development of a serotype-independent pneumococcal vaccine.
Highlights
Despite the implementation of pneumococcal polysaccharide conjugate vaccines (PCV), Streptococcus pneumoniae is still a major cause of morbidity and mortality worldwide, especially in young children, the elderly, and immune-compromised individuals [1,2]
We provide a detailed analysis of the lipidation-associated effects of pneumococcal lipoproteins on the mouse immune response and the protective capacity of these lipidated antigens
The genes were cloned downstream of the plasmid-encoded signal sequence of the gene coding for the outer surface protein A from Gram-negative Borrelia burgdorferi that enabled N-terminal lipidation of proteins [26]
Summary
Despite the implementation of pneumococcal polysaccharide conjugate vaccines (PCV), Streptococcus pneumoniae (pneumococcus) is still a major cause of morbidity and mortality worldwide, especially in young children, the elderly, and immune-compromised individuals [1,2]. The major disadvantages of PCVs include the high manufacturing costs and limited serotype coverage, which facilitates the replacement of vaccine serotypes by non-vaccine serotypes, requiring alternative immunization strategies in the near future [3,4]. Because of these shortcomings, efforts have been made to develop novel vaccines based on broadly representative, serotype-independent, highly conserved pneumococcal protein antigens. Pneumococcal lipoproteins might be promising candidates for a future protein-based vaccine as they represent the largest group of surface-exposed and conserved proteins of S. pneumoniae and contribute to pneumococcal pathogenesis [5,6,7]. Various pneumococcal lipoproteins have been shown to protect against pneumococcal infection in in vivo models [6,8,9].
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