Abstract
Detoxified pneumolysin, PlyD1, is a protein vaccine candidate that induces protection against infections with Streptococcus pneumoniae in mouse models. Despite extensive knowledge on antibody responses against PlyD1, limited information is available about PlyD1 induced T cell recognition. Here we interrogated epitope breadth and functional characteristics of the T cell response to PlyD1 in two mouse strains. BALB/c (H-2d) and C57BL/6 (H-2b) mice were vaccinated with Al(OH)3-adjuvanted or non-adjuvanted PlyD1, or placebo, on day 0, 21 and 42 and were sacrificed at day 56 for collection of sera and spleens. Vaccination with adjuvanted and non-adjuvanted PlyD1 induced anti-pneumolysin IgG antibodies with neutralizing capacity in both mouse strains. Adjuvantation of PlyD1 enhanced the serological responses in both strains. In vitro restimulation of splenocytes with PlyD1 and 18-mer synthetic peptides derived from pneumolysin revealed specific proliferative and cytokine responses. For both mouse strains, one immunodominant and three subdominant natural epitopes were identified. Overlap between H-2d and H-2b restricted T cell epitopes was limited, yet similarities were found between epitopes processed in mice and predicted to be immunogenic in humans. H-2d restricted T cell epitopes were localized in pneumolysin domains 2 and 3, whereas H-2b epitopes were scattered over the protein. Cytokine responses show mostly a Th2 profile, with low levels of Th1 cytokines, in both mouse strains. In conclusion, PlyD1 evokes T cell responses in mice directed against multiple epitope regions, that is dependent on Major Histocompatibility Complex (MHC) background. These results are important to understand human PlyD1 T cell immunogenicity, to guide cell mediated immunity studies in the context of vaccine development.
Highlights
Streptococcus pneumoniae is a main cause of pneumonia, sepsis and meningitis in young children, which can be prevented by vaccination
Non-adjuvanted PlyD1 induced high levels of total IgG antibodies directed against Ply in both BALB/c and C57BL/6 mice
PlyD1 alone was capable of inducing comparable IgG levels in BALB/c and C57BL/6 mice
Summary
Streptococcus pneumoniae is a main cause of pneumonia, sepsis and meningitis in young children, which can be prevented by vaccination. Alternative pneumococcal vaccine candidates include conserved protein antigens that confer serotype-independent protection. Killed whole cell vaccines are an example of these alternative pneumococcal vaccines, and have been shown to induce a humoral and a Th17-type cell-mediated response in mice [2, 3]. This Th17-type response is thought to be important for protection against carriage, by promoting neutrophilic infiltration in nasopharyngeal mucosa [4, 5]. Serotype-independent coverage can be induced by conserved proteins, when they are used as a protein vaccine by itself or as a pneumococcal specific carrier protein in PCVs. Several conserved, mainly surface exposed, proteins are under investigation as vaccine candidates [6]
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