The Impact of Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease

Oligbu, Godwin (2019) The Impact of Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national childhood immunisation programme in 2006, which was replaced with the 13-valent PCV (PCV13) in 2010. The published articles presented in this thesis assessed the impact of PCVs on invasive pneumococcal disease (IPD) especially in children and those with underlying comorbidities, particularly sickle cell disease (SCD). The systematic review of PCV failures found a low incidence of vaccine failures irrespective of the PCV used in the national immunisation programme. After PCV7 introduction, serotypes 19F and 6B were responsible for more than two-thirds of vaccine failure cases. In keeping with published studies, these serotypes were also responsible for most cases of vaccine failure in the national surveillance of PCV failures in England and wales before the introduction of PCV13. After PCV7 was replaced with PCV13, serotypes 3 and 19A were over-represented among the vaccine failure cases. Overall case fatality rate (CFR) in children with PCV failure was low, with only six of 161 children (4%) dying, including five (83%) who had significant underlying comorbidities. A review of IPD in children with SCD however identified continued increased risk of IPD in children with SCD. The overall CFR among published cases was 11.5%. More than half of the serotypes associated with IPD were not included in the PCV13, of which more than half were due to serogroup 15. Similarly, in the enhanced national surveillance of IPD in children with SCD, in England, it was identified that there were 881 IPD cases, including eleven children homozygote for haemoglobin S (HbSS) and one double heterozygote for haemoglobin S and C (HbSC). Children with SCD remained 49 times more likely to develop IPD and 5 times more likely to die of their infection compared to their healthy peers. Most IPD cases in SCD were also due to serotypes that were not covered by PCV13, particularly serogroup 15, and this finding was found to be consistent with published literatures. Research was also carried out to determine the epidemiology of pneumococcal meningitis following the introduction of PCV in England and Wales. The incidence of pneumococcal meningitis did not change after PCV7 introduction, but declined by 48% after the vaccine was replaced with PCV13 in keeping with large reductions in cases due to the additional PCV13 serotypes 7F and 19A. Currently, meningitis due to PCV13 serotypes is rare and the 6 non-PCV13 serotypes 8 and 12F are the predominant causes of pneumococcal meningitis. Additionally, while the incidence of pneumococcal meningitis has declined, the CFR has remained high at 17.5%. However, childhood CFR for IPD remained low at 4.8%, with more than half (59%) of deaths occurring in infants, mainly in those aged <3 months who accounted for 28% of all fatal cases. Overall, 35% of children who died had underlying risk factors for IPD while meningitis was responsible for 47% of IPD-related deaths. In summary, this thesis has demonstrated that the rate of PCV failure, irrespective of the vaccine used or schedule, was very low, as was CFR in children with PCV failure. Most children with PCV13 failure were healthy, developed LRTI, and survived their infection without long-term complications. The continuing low prevalence of PCV7 failures after PCV13 introduction is reassuring and it is likely that PCV13 failure will also decline in the coming years. However, children with SCD remained at risk of IPD and death despite these measures of daily penicillin prophylaxis as well as pneumococcal vaccination. The majority of serotypes causing IPD in SCD are no longer vaccine preventable, therefore every effort should be made to ensure that these children adhere to penicillin prophylaxis and pneumococcal vaccines. Thus, in conclusion, PCVs are highly effective in preventing IPD due to the respective vaccine serotypes. The childhood pneumococcal vaccination programme has led to a significant reduction in the incidence of IPD, including meningitis. However, compared to other clinical presentations, there was a lower than expected impact on pneumococcal meningitis, with case fatality rates due to meningitis remaining relatively unchanged across the age groups. Given that most IPD cases, including meningitis are now due to non-PCV13 serotypes, including most fatal IPD cases, additional strategies need to be introduced to reduce childhood pneumococcal deaths in countries with established pneumococcal vaccination programmes.