Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial

Hanna Rinta-Kokko, Arto A Palmu, Esa Ruokokoski, Heta Nieminen, Marta Moreira, Lode Schuerman, Dorota Borys, Jukka Jokinen, Hanna Rinta-Kokko, Arto A Palmu, Esa Ruokokoski, Heta Nieminen, Marta Moreira, Lode Schuerman, Dorota Borys, Jukka Jokinen

Abstract

Background: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes.

Methods: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010.

Results: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years.

Conclusions: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

Conflict of interest statement

The Finnish Institute for Health and Welfare (THL) received funding for the conduct of the FinIP study from the GSK group of companies. AAP, HN, ER, and JJ are employees of THL. HR-K was an employee of THL at the time of study conduct. DB and LS are employees of the GSK group of companies; MM was an employee of the GSK group of companies. MM, DB and LS have shares in the GSK group of companies. We note that several authors have an affiliation to the commercial funder of this research study: GlaxoSmithKline Biologicals SA. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Trial profile of 78 clusters.
Fig 1. Trial profile of 78 clusters.
The 3+1 and 2+1 clusters differed only for the infant schedules. Catch-up schedules were identical for the 3+1 and 2+1 clusters and were always combined for the analyses. For the indirect effect analysis, 72 clusters were included. * = Includes one subject withdrawn from the register follow-up during the blinded follow-up period. The figure has been presented previously [23].
Fig 2. Incidence of IPD by age…
Fig 2. Incidence of IPD by age group (in years) in PHiD-CV10 and control clusters, average over years 2010―2015.
(A) Incidence of all IPD. (B) Incidence of vaccine-type IPD.
Fig 3. Rates of clinically suspected IPD…
Fig 3. Rates of clinically suspected IPD by age group (in years) in PHiD-CV10 and control clusters, average over years 2010―2015.
(A) Incidence of hospital-diagnosed non-laboratory-confirmed IPD or unspecified sepsis. (B) Incidence of hospital-diagnosed non-laboratory-confirmed IPD.
Fig 4. Incidence of pneumonia by age…
Fig 4. Incidence of pneumonia by age group (in years) in PHiD-CV10 and control clusters, average over years 2010―2015.
(A) Incidence of hospital-diagnosed pneumonia. (B) Incidence of hospital-diagnosed empyema.
Fig 5. Incidence of tympanostomy tube placements…
Fig 5. Incidence of tympanostomy tube placements by age year in PHiD-CV10 and control clusters, average over years 2010―2015.
Fig 6. Incidence of outpatient antimicrobial prescriptions…
Fig 6. Incidence of outpatient antimicrobial prescriptions by age year in PHiD-CV10 and control clusters, average over years 2010―2015.

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