Cross-sectional surveillance study on pneumococcal serotypes and other pathogens in nasopharyngeal samples from children and parents performed in the tenth year after introduction of pneumococcal vaccination in The Netherlands

The current OKIDOKI-4 study is part of an ongoing surveillance program intended
to monitor the carriage of Streptococcus pneumoniae (pneumococcus) serotypes
through collection of nasopharyngeal swabs in children and their parents. S.
pneumoniae is the leading cause of invasive pneumococcal disease (IPD) like
meningitis, sepsis and bacteremic pneumonia as well as of respiratory
infections like community acquired pneumonia and otitis media. The highest
disease incidence is observed in children below two years of age and in elderly
>65 years of age. Diseases caused by S. pneumoniae are preceded by asymptomatic
nasopharyngeal acquisition and colonization. Vaccination with a 7-valent
pneumococcal vaccine (Prevenar-7, PCV-7) was introduced in the Dutch National
Immunization Program (NIP) for children in 2006 and replaced in 2011, by a
10-valent vaccine (PCV-10). PCV vaccination reduced acquisition and density of
colonization of vaccine-serotype pneumococci in the nasopharynx of vaccinated
children and subsequent transmission to others leading to an indirect
protection of the community (herd effect). The vacant niche in the nasopharynx
of vaccinated children is however immediately filled by non-vaccine pneumococci
and possibly other potential pathogens that may be involved in respiratory or
invasive disease. Surveillance of nasopharyngeal carriage of pneumococci is
important to evaluate shifts in circulation of specific serotypes after
pneumococcal conjugate vaccine introduction as a measure for vaccine
effectiveness and impact (Pneumocarr). This surveillance information is used to
determine whether adjustments in the vaccination program/strategy are needed.
Previous carriage surveillance studies were performed immediately before
introduction of pneumococcal conjugate vaccination and 3, 4.5 and 6.5 years
after introduction, i.e. respectively the MINOES, OKIDOKI-1, OKIDOKI-2 and
OKIDOKI-3 studies. The nasopharyngeal swabs collected during current study will
be used to assess concurrent presence of S. aureus, H. influenzae, M.
catarrhalis and shifts in respiratory microbioom composition as has been done
in the previous trials. In addition, the nasopharyngeal swabs will be evaluated
for presence of other respiratory bacteria and viruses. The occurrence rates of
these pathogens in nasopharyngeal swabs obtained from asymptomatic children and
their parents in this surveillance will be compared to the frequency rates in
the previous studies performed in the same region by the same investigators.
Blood and saliva samples will be collected to measure the immune response
against the different pathogens and to assess S. pneumoniae presence in saliva
with molecular methods.

Primary
• To determine changes over time, since introduction of PCV vaccination in
National Immunization Program, in nasopharyngeal colonization frequencies of
total vaccine- and non-vaccine serotypes of S. pneumoniae in healthy
24-month-old and 46-month-old children
Secondary
• Longitudinal analysis of colonization using data from 11-months of age
subjects (OKIDOKI-3) and their 46-months of age data (OKIDOKI-4)
• To determine changes over time in nasopharyngeal pneumococcal colonization
with total vaccine- and non-vaccine serotypes in the parents of healthy
24-month-old children
• To determine changes over time in presence of other nasopharyngeal
respiratory non-pneumococcal bacteria and of respiratory viruses*
• To determine changes over time in individual pneumococcal serotype
colonization
• To determine pneumococcal specific B and T cell immunity in relation to
carriage
• To determine humoral and cellular immunity against bacterial pathogens as
well as against viruses circulating in the autumn-winter season, including but
not limited to influenza and RSV
• To compare data on pneumococcal presence and serotype specific carriage in
nasopharyngeal and saliva samples when tested using molecular methods with data
obtained using conventional culturing method
• To relate the immune response against relevant nasopharyngeal respiratory
viruses and bacteria, measured in saliva, to responses measured in serum
• To explore pneumococcal density and multi-serotype carriage analysis using
molecular methods
• To establish the bacterial microbiome (defined as of a wide range of *non-
pathogenic* bacteria like viridans streptococci together with potential
pathogens like S. pneumoniae, H. influenzae, and S. aureus i.e. the ecological
community of commensal, symbiotic, and pathogenic microbes that share the
nasopharyngeal niche with pneumococci)
• To establish antibiotic non-susceptibility of pathogens, including but not
limited to pneumococcal serotypes to antibiotics like penicillins (penicillin,
amoxicillin), and macrolides/lincosamides (erythromycin, clindamycin)

Observational, cross-sectional surveillance study

The burden and risk of a transnasal nasopharyngeal swab and two saliva samples
from the children and parents of 24-month-old children with an additional
collection of a transoral nasopharyngeal swab from the parents is minimal. The
nose swab may cause a minor self-limiting nose bleeding (less than 1:3000 from
own experience). No risk or burden is involved in the saliva sample collection
using a sponge in the mouth. The burden and risk of the voluntary blood sample
(10 ml in children and 24 ml in adults) is minimal; the voluntary blood
collection is harmless but may be slightly painful and can cause a bruise at
the injection site. Overall, the home visit will take 45 minutes. The children
and parents themselves have no benefit in participating in this study. Children
between 12 and 60 months have the highest pneumococcal carriage rates and are
the key transmittors of pneumococci in the population, e.g. to their parents.
The 11-month old children of the OKIDOKI-3 study are followed longitudinally as
they form most of the 46-month-old group of the OKIDOKI-4 study. To monitor the
Dutch pneumococcal vaccination program, children that participate in the NIP
are the only possible study subjects.