Streptococcus pneumoniae infections before and after the introduction of a conjugated pneumococcal vaccine

Pneumococcal infections are among the leading causes of death in children in developing countries. In developed countries the main burden of severe infections, such as invasive pneumococcal disease (IPD) is carried by the immunocomprised and the elderly. Different pneumococcal serotypes vary widely in their ability to colonize the nasopharynx and cause diseases such as Acute Otitis Media (AOM) and IPD. Introduction of pneumococcal conjugated vaccines (PCV) for children marks a new era in the battle against the pathogen. This thesis aims to examine changes in pneumococcal epidemiology in relation to the introduction of PCV in southern Sweden and to explore the immunogenicity and virulence of serotypes included in the vaccine. We monitored the prevalence of clinical nasopharyngeal samples positive for Streptococcus pneumoniae and two related pathogens before and after PCV introduction. IPD incidence is continously evaluated by the Swedish National Board of Health. But less is known about the ability of individual serotypes to cause severe infections. To determine whether serotypes are associated to clinical outcome we conducted a retrospective investigation on IPD cases in Skåne. In order to protect itself the human host develops a strong antibody response to pneumococcal antigens. However, in some settings vaccination with polysaccharides has led to a suboptimal hyporesponse. Can natural immunization by S. pnuemoniae lead to a weakened immune response and is serotype a determining factor? In immunological assays on sera from sepsis survivors we investigated the antibody response after IPD and pneumonia caused by different serotypes. Bacterial cultures from the upper respiratory tract referred to Clinical Microbiology at the University hospital of Skåne were analyzed. 14,473 cultures from the years 2004-2017 were included . Serotyping of S. pneumoniae was performed with Quellung technique. In order to determine disease severeness in cases of IPD, medical history of 513 patient sepsis patients were retrospectively reviewed. Quantification of antibodies in patient sera was performed with ELISA and an Opsonophagocytic assay was used to test their functionality in inducing opsonization of live bacteria. We found serotype-dependent variations in disease severity in patients with IPD. For instance, serotype 3 was significantly associated to septic shock. In parallel, sera from sepsis survivors had serotype dependent differences in their antibody response after disease. According to our data, some serotypes induce a poorer antibody response in the host compared to other serotypes. A poor immune response was found predominantly in IPD patients, compared to patients suffering from pneumonia without sepsis. In two observational studies of PCV effects in the southern county of Skåne, we found that nasopharyngeal cultures of vaccine type S. pneumoniae decreased markedly, while non-vaccine types increased. The net result was a steady decrease in pneumococcal infections during the years investigated (2004-2017). Interestingly, nasopharyngeal cultures of H. influenzae and M. catarrhalis also decreased in prevalence following introduction of PCV. Relative to total cultures taken, however, H. influenzae prevalance appeared unaffected. The reduction of M. catarrhalis, may partly be attributed to a positive association between PCV serotypes and M. catarrhalis discovered by us. In summary, we have found evidence for a change in prevalence of positive bacterial cultures from the nasopharynx of symtomatic children post PCV. There was a relative increase in prevalence of non-vaccine serotypes and other pathogens. Vaccine serotypes were, however, not completely eradicated. Some of them, such as serotype 3, was associated to a worse clinical outcome and to induce a poor antobody response. These findings are important for the evaluation of PCV.