Peptide mimics of two pneumococcal capsular polysaccharide serotypes (6B and 9V) protect mice from a lethal challenge with Streptococcus pneumoniae

Abstract

Anti-polysaccharide immunity is a key facet of protection against several bacterial pathogens. Problems exist with current polysaccharide vaccines and alternative strategies that deliver a protective response are needed. We have identified immunological peptide mimics of type 6B and 9V pneumococcal capsular polysaccharides that could be used as vaccine antigens. Peptides mimicking antigenic properties of serotype 6B capsular polysaccharide were obtained from a phage-displayed peptide library expressing dodecameric peptides, using a human monoclonal antibody (Db3G9). A murine monoclonal antibody (206, F-5) against the serotype 9V capsular polysaccharide identified three peptide mimotopes from the dodecameric peptide library and one from a random pentadecameric peptide library. In ELISA, binding of 206, F-5 and Db3G9 to phage displaying the selected mimotopes was significantly inhibited by type-specific pneumococcal polysaccharide. Peptides were conjugated to keyhole limpet haemocyanin and were used to immunise mice. Two peptides, MP13 and MP7, induced specific anti-6B and 9V polysaccharide antibodies, respectively. Mice immunised with MP7-keyhole limpet hemocyanin or MP13-keyhole limpet hemocyanin conjugate were significantly and specifically protected against a lethal challenge with pneumococci of the appropriate serotype. This study provides strong in vivo evidence that peptide mimics are alternatives to polysaccharide vaccines.Key words: Mimotope . Peptide . Polysaccharide . Streptococcus pneumoniae .Vaccine IntroductionStreptococcus pneumoniae (the pneumococcus) remains a major cause of morbidity and mortality worldwide, causing diseases such as pneumonia, septicaemia, meningitis and otitis media [1]. It is well known that protective immunity to S. pneumoniae can result from the development of specific antibodies against pneumococcal capsular polysaccharides. In 1983 a vaccine (Pneumovax) composed of a mixture of 23 capsular serotypes was licensed for use [1]. Unfortunately, this vaccine has proved to be ineffective for the most at risk groups, particularly infants. Problems arise because polysaccharide antigens cannot be To circumvent the T-independence problem, major research efforts focused on a vaccine in which protein is chemically conjugated to polysaccharide. In this form the polysaccharide is converted to a T-dependent antigen. This increases its immunogenicity and stimulates immunological memory. Recently, a conjugate vaccine (Prevenar) composed of seven capsular serotypes was licensed for use in infants. Undoubtedly, the conjugate vaccine has been successful in reducing invasive pneumococcal disease in children [3][4][5]. However, the purification of polysaccharide, the need for multiple protein conjugations and the quality control issues make this a very expensive approach. Added to this is the question of the very restricted serotype coverage by the vaccine and the possibility that the low serotype coverage increases the opportunity for serotype replacement [6][7][8][9].An alternative approach is...

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