Effect of Two Versus Three Pneumococcal Conjugate Vaccinations

Study Overview
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Brief Summary
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Two( 2) or three (3) instead of four vaccinations before the age of 6 months with pneumococcal conjugate vaccine are presumed to protect children against invasive pneumococcal disease like meningitis, at least on the short term till 18-24 months of age. The current hypothesis in this study is 2 or 3 vaccinations will protect against IPD but will not alter pneumococcal nasopharyngeal carriage in infants, and consequently not change pneumococcal transmission and induce no herd-immunity. Furthermore, antibody development and memory may benefit from carriage of vaccine type S. pneumoniae

Detailed Description
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Two(2 and 4 months) and three vaccinations (2,4 and 11 months) with 7-valent pneumococcal conjugate vaccine Prevnar in infants are presumed to provide about 90% protection against invasive pneumococcal disease (IPD) for vaccine type pneumococci, at least until 18-24 months of age. Licensure of the vaccine however is based on studies with 3 vaccinations before 6 months and a booster vaccination half a year later (3+1 scheme). Cost-effectiveness in national infant vaccination programs (NIPs)is much improved by high herd-immunity effects,as observed in the USA after licensure of Prevnar in 2000, both for IPD and AOM. However, overall pneumococcal carriage reduction (and nasopharyngeal replacement) has not been assessed in studies with reduced doses. With reduced carriage reduction, effects on respiratory tract infections and herd immunity may be significantly less. The primary aim of the current study is to compare effect of 2-doses (at ages 2 and 4 months) with a 3-doses scheme(2+1, at 2, 4 and 11 months) on nasopharyngeal pneumococcal carriage and replacement and family transmission(sibs and caregivers), in order to allow modelling for herd-immunity. The secondary aim is to determine the effect of a reduced doses scheme on serum antipneumococcal antibody levels at the age of 12 and 24 months. A third aim is to determine antipneumococcal antibody levels and memory B-cell development after booster vaccination at 24 months of age, after 2 or 2+1 doses and compare these with a first vaccination at 24 months of age. Opportunities are the determination of nasopharyngeal colonizing pneumococci in unvaccinated infants in the Netherlands before implementation of Prevnar in the NIP, evaluation of replacing pneumococci in the nasopharynx after vaccinations and analysis of effects on other colonizing bacteria like H.influenzae, M. catarrhalis and S.aureus. Furthermore, the relation between colonizing pneumococci and serotypes causing IPD in the Netherlands can be evaluated. Methods : 1000 infants and families will be included in a randomized,controlled study with 3 interventions groups Prevnar at 2 and 4 months Prevnar at 2, 4 and 11 months Prevnar at 24 months (controls) The children will be followed until 2 years of age with nasopharyngeal swabs for bacterial culture before the first vaccination, at 6, 12, 18 and 24 months of age. One sibling and one parent/caregiver will be swabbed when the infant is 12 and 24 months. Blood for antibody determination will be obtained from 80 children of groups 1 and 2, and from 30 children in the control group. Questionnaires on health and respiratory infections and antibiotic prescription for RTI will be obtained. At 24 months of age, all children of groups 1 and 2 will be offered a booster vaccination. Antibody levels will be measured before and 4 weeks after this vaccination at 2 years of age in a subset of 80 children per group and compared with 80 children who received a first vaccination at 24 months of age.

Official Title
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Effect of 2 Versus 3 Pneumococcal Conjugate Vaccinations Prevnar on Nasopharyngeal Carriage, Transmission and Herd-immunity;a Randomized, Controlled Study

Conditions
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Streptococcus Pneumoniae Infection

Intervention / Treatment
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* Biological: PCV7
* Biological: PCV7


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newborn infants eligible for participation in the national infant vaccination program in the Netherlands Exclusion Criteria: exclusion from the national vaccination program because of the presence of a medical condition requiring treatment that can interfere with the effect of vaccinations known or suspected allergy to components of the pneumococcal conjugate vaccine known or suspected immunodeficiency disease previous treatment with plasma or immunoglobulins previous vaccinations other than hepatitis B vaccinations coagulation disorders

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 3 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2-dose<br>PCV7 at age 2 and 4 months | Biological: PCV7<br>* PCV7 at age 2 and 4 months<br>* Other names: Prevenar;|
| Experimental: 2+1-dose<br>PCV7 at age 2, 4 and 11 months | Biological: PCV7<br>* PCV7 at age 2, 4 and 11 months<br>* Other names: Prevenar;|
| No Intervention: Control<br>Control group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasopharyngeal bacterial (pneumococcal) colonization at 6 weeks, 6, 12, 18 and 24 months in infants and at 12 and 24 months of family members |  | duration of study, 23 months per subject | 
| transmission to family members( sib, caregiver) |  | at infants age of 12 and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| anti-pneumococcal antibody levels at 12 and 24 months of age |  | 23 months | 
| antibody levels and B-memory cells after vaccination at 24 months |  | 23 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pneumococcal conjugate vaccination, nasopharyngeal carriage, herd immunity, antipneumococcal antibodies, respiratory tract infections, National infant vaccination program