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Judith Spijkerman

Thursday 10 October 2013

Pneumococcal conjugate vaccines; impact on nasopharyngeal bacterial carriage and optimizing current vaccination strategies.

Promotor: Prof. dr. E.A.M. Sanders
Defence: 10 October 2013

The aims of the thesis were first to assess nasopharyngeal carriage to evaluate long-term population effects on the nasopharyngeal bacterial population in children and parents after PCV-7 introduction in the Dutch NIP in 2006 and to assess potential impact of PCV-10 as introduced in 2011 on carriage of NTHi in a randomized trial (Part 1), and second to assess immunogenicity of vaccines to guide optimimalization of current PCV vaccination strategies (Part 2).

In summary, the major findings of this thesis were:
1. Already three years after introduction of a 3+1 dose schedule of PCV-7 without a catch-up campaign in the Dutch NIP, VT pneumococci were largely replaced by NVT pneumococci in the nasopharynx of vaccinated children but also in their unvaccinated parents. This finding illustrates the major role of infants in transmission of pneumococci within families, ultimately affecting the whole population (Chapter 2). In the fifth year after PCV-7 implementation in the NIP, VT pneumococci had virtually disappeared, but serotype 19A showed a steady rise in carriage followed by serotypes 6C, 15BC and 11A (Chapter 3).
2. In addition to large shifts in pneumococcal serotypes, progressively higher nasopharyngeal prevalence rates of S. aureus (tripled at 12 months of age) and H. influenzae were found among both young children and their parents 3 and 4.5 years after PCV-7 implementation. These findings may have implications for disease incidence caused by these bacteria and for antibiotic treatment in particular for respiratory infections (otitis and pneumonia) in the post-PCV era but also for invasive or skin infections. This indicates that monitoring should not be restricted to pneumococcal disease, but should also include other bacterial infections (Chapter 3).
3. PCV-10 had no differential effect compared to PCV-7 on nasopharyngeal NTHi colonization or H. influenzae density in healthy Dutch children up to 2 years of age. This finding implies that de PD carrier protein of the vaccine and induced anti-PD antibodies did not affect carriage and no herd effects for NTHi are not to be expected after introduction of PCV-10 (Chapter 4).
4. Based on PCV-13 induced immune responses when compared in different primary schedules the 2-4-6 schedule is superior with respect to post-primary IgG antibody induction but the reduced 3-5 schedule offers an attractive alternative as primary immunisation schedule, in particular in times of herd immunity. Both the 2-4-6 and 3-5 schedules were superior to the 2-3-4 (for 9 and 5 serotypes, respectively) and 2-4 schedules (for 11 serotypes) with respect to post-primary IgG levels. Functional assays showed a similar pattern as the IgG levels except for a lower avidity of the 2-3-4 schedule for most serotypes and a higher OPA GMT in 2-3-4 schedule for 6B. Differences in antibody levels persist between the primary and booster dose, but have disappeared after the booster dose. Our results demonstrate that optimal timing of the primary series (i.e. higher age at vaccinations and larger interval between doses) is highly relevant for optimal antibody induction (Chapter 5)
5. Post-primary antibody responses to PCV-10 and DTaP-IPV-Hib when co-administered were non-inferior compared with PCV-10 / DTaP-HBV-IPV/Hib (except for serotype 18C) or compared with co-administration of PCV-7 / DTaP-IPV-Hib after the primary series (Chapter 6). PCV-10 and DTaP-IPV-Hib were immunogenic and well-tolerated when co-administered as a 3+1-dose vaccination schedule in infants and negative effects on vaccine-induced immunity through interference were not observed (Chapter 7).