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

Abstract

The aim of this thesis was to first assess nasopharyngeal bacterial carriage to evaluate population effects after introduction of PCV7 in the NIP in 2006 and to assess the potential impact of PCV10 as introduced in 2011 on carriage of NTHi in a randomized trial (Part One) and second, to assess immunogenicity of vaccines to guide optimization of current PCV vaccination strategies (Part Two). In summary, the major findings of this thesis were: Part One: •Three years after introduction of a 3+1 dose schedule of PCV7 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 PCV7 implementation in the NIP, VT pneumococci had virtually disappeared, but NVT 19A showed a steady rise in carriage followed by serotypes 6C, 15B/C and 11A (Chapter 3). •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 PCV7 implementation. These findings may have implications for disease incidence caused by these bacteria and for antibiotic treatment in the vaccinated and non-vaccinated population in the post-PCV7 era. This indicates that monitoring should not be restricted to pneumococcal disease only, but should also include other bacterial infections (Chapter 3). •PCV10 had no differential effect compared to PCV7 on nasopharyngeal NTHi colonization or H. influenzae density in healthy Dutch children up to 2 years of age. This finding implies that anti-PD induced antibodies did not affect carriage. In consequence, herd effects for NTHi are not to be expected after introduction of PCV10 (Chapter 4). Part Two: •Based on PCV13 induced immune responses when compared in different primary schedules, the 2-4-6 schedule is superior but the reduced 3-5 schedule offers an attractive alternative as primary immunization schedule particularly in times of herd immunity. With respect to post-primary IgG antibody induction, 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 (both for 11 serotypes). 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 and avidity indices 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). •Post-primary antibody responses to PCV10 and DTaP-IPV-Hib when co-administered were non-inferior compared with PCV10 / DTaP-HBV-IPV/Hib (except for serotype 18C) or compared with co-administration of PCV7 / DTaP-IPV-Hib after the primary series (Chapter 6). PCV10 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).