The impact of the classical, lectin and alternative pathways of complement activation on protective immunity against Streptococcus pneumoniae infection following vaccination with established pneumococcal vaccines

Streptococcus pneumoniae (S. pneumoniae) is a pathogen that can cause infectious disease, such as meningitis, septicaemia and pneumonia. As part of innate immunity, the complement system plays a major role in the immune response to S. pneumoniae. Given this, the aim was to determine the impact of selective deficiencies for classical, lectin and alternative pathways of complement activation on vaccination response using pneumococcal polysaccharide vaccines. All results were achieved using CRM197 (a non-toxic mutant of diphtheria toxin), which elicited a different immune response in comparison to pneumococcal polysaccharide vaccines (PneumovaxII and Prevenar13). WT mice, C1q-/-, MASP-2-/- and fB-/- mice were immunised subcutaneously or intraperitoneally (s.c./i.p.) with either 20μg of CRM197, 1μg of PneumovaxII (pneumococcal polysaccharide vaccine) or 1μg of Prevenar13 (pneumococcal polysaccharide conjugate vaccine). Mice received a single or three spaced dose of CRM197, PneumovaxII or Prevenar13 and then a final booster one week before the end of the experiment. Blood samples were taken at different time points and all mice responded with high antibody titres to CRM197, PneumovaxII and Prevenar13; showing, an increase in antibody response to CRM197 immediately after the third immunisation and after the first immunisation for PneumovaxII and Prevenar13. This suggested that the antibody response to CRM197 was independent from the presence or absence of C1q (classical pathway) and MASP-2 (lectin pathway), but was increased in C1q deficient mice for PneumovaxII and was completely independent for Prevenar13. Imperative to the effective treatment of pneumococcal infections, this project significantly aided in the understanding of the complement system and has highlighted the importance of activation pathways in protective responses. Overall, PneumovaxII showed that the classical complement pathway might play a negative regulatory role, whilst the lectin and the alternative pathways are involved in the positive regulation and minor positive regulation of immune responses.