Identifying Novel Pneumococcal Pneumonia Vaccine Candidates

Abstract

The burden of pneumococcal pneumonia remains high worldwide. The disease disproportionately affects infants, the elderly and the immunocompromised. Nasopharyngeal colonisation with S. pneumoniae is the pre-requisite for disease but also, paradoxically, an immunising event. Current pneumococcal vaccines offer limited protection against pneumonia and do not offer serotype-independent coverage. Serotype replacement is particularly concerning. Identification of serotype-independent correlates of protection against S. pneumoniae infection will accelerate development of vaccines with broad coverage. Protein vaccines are a particularly promising way to confer serotype-independent protection.

The experimental human pneumococcal challenge (EHPC) model enables us to investigate correlates of protection against experimental colonisation with S. pneumoniae and study protein-directed immune responses to nasopharyngeal colonisation with the bacteria. A multiplex Luminex assay was developed and used to measure serum IgG against 75 conserved pneumococcal antigens pre- and post-intranasal inoculation with two serotypes of pneumococcus (6B and 15B) in EHPC volunteers. Peripheral blood mononuclear cells taken pre- and post-challenge with serotype 6B pneumococcus were used to evaluate correlation between protein-specific IgG+ memory B-cell responses and protection against experimental colonisation as well as memory B-cell responses to pneumococcal challenge by ELISpot. Memory B-cell responses to six selected proteins and the novel PnuBioVax vaccine were investigated. The results of this work showed that colonisation with serotype 6B pneumococcus induces significant systemic protein-mediated antibody and memory B-cell responses. No single protein antigen correlated with protection against experimental colonisation with S. pneumoniae. However, whilst not significant, there was a trend that PnuBioVax-specific memory B-cells conferred protection against experimental pneumococcal colonisation. Five novel nanoparticle-based vaccines were also investigated to determine their effects on dendritic cell maturation and support of T-cell activation. One of these nanoparticles was subsequently loaded with pneumococcal protein PspA to investigate antigen-specific response. Further work is needed to ascertain the immune response to these novel vaccines, though they are a promising method of serotype-independent vaccine delivery.

It is likely that for a novel pneumococcal protein vaccine to confer serotype-independent protection against pneumococcal pneumonia, a combination of protein antigens will need to be included in vaccine formulations. Mucosal vaccination in particular will likely be needed to induce robust immunity