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10-Valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine (PHiD-CV10) versus 13-valent pneumococcal conjugate vaccine (PCV13) as a booster dose to broaden and strengthen protection from otitis media (PREVIX_BOOST) in Australian Aboriginal children: study protocol for a randomised controlled trial
  1. Victor M Oguoma1,
  2. Nicole Wilson1,
  3. Kim Mulholland2,
  4. Mathuram Santosham3,
  5. Paul Torzillo4,
  6. Peter McIntyre5,
  7. Heidi Smith-Vaughan1,
  8. Anne Balloch6,
  9. Mark Chatfield7,
  10. Deborah Lehmann8,
  11. Michael J Binks1,
  12. Anne Chang1,
  13. Jonathan Carapetis9,
  14. Vicki Krause10,
  15. Ross Andrews1,
  16. Tom Snelling11,12,
  17. Paul Licciardi13,14,
  18. Peter Morris1,
  19. Amanda Jane Leach1
  1. 1Child Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
  2. 2Infection and Immunity: Pneumococcal Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
  3. 3Center American Indian Health, John Hopkins School of Public Health, Baltimore, Maryland, USA
  4. 4Respiratory Medicine, Prince Alfred Hospital, Sydney, New South Wales, Australia
  5. 5Director, National Centre for Immunisation Research and Surveillance, Sydney, New South Wales, Australia
  6. 6Pneumococcal Immunology, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
  7. 7Cerebral Palsy and Rehabilitation Research Centre, University of Queensland, Brisbane, Queensland, Australia
  8. 8Division of Population Sciences, Telethon Institute for Child Health Research, West Perth, Western Australia, Australia
  9. 9Director, Telethon Kids Institute, Perth, Western Australia, Australia
  10. 10Centre for Disease Control, Department of Health, Darwin, Northern Territory, Australia
  11. 11Infectious Disease Implementation Research Team, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
  12. 12Wesfarmers Centre of Vaccines & Infectious Diseases, Telethon Kids Institute, West Perth, Western Australia, Australia
  13. 13Infections and Immunity: Pneumococcal Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
  14. 14Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Professor Amanda Jane Leach; amanda.leach{at}menzies.edu.au

Abstract

Introduction Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A.

Methods and analyses Our randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported.

Ethics and dissemination Ethics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals.

Trial registration number NCT01735084.

  • otitis media
  • nasopharyngeal carriage
  • PHiD-CV10
  • PCV13
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Footnotes

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  • Collaborators PREVIX research managers and research nurses (33): Nicole Wilson, Beth Arrowsmith, Tracy Grierson, Carolyn Gage-Pearson (admin), Nicole Weinert, Natalie Bert, Zeina Hayes, Melanie Schwarz, Julie Wheeler, Bronwyn Nankervis, Laura Bell, Jessica Young, Kelly Whykes, Sabine Sprenger, Melisa Downie, Valerie Coomber, Kate Ranford, Rachel Sharp, Elissa Rowe, Jodie Howes, Chantelle Dowling, Claire Haynes, Christine Byrne, Niki Emmett, Sarah Carlisle, Fiona Hildebrand, Kate Dohle, Cathy O’Driscoll, Peta Hamilton, Jesse Abbott. Statisticians: Mark Chatfield, Victor Oguoma. PREVIX audiologists : Dino Hodge, Jennifer Jenson, Janine Pisula, Jana Fogarty, Annette Kaspar. PREVIX laboratory team (16): Jemima Beissbarth, Vanya Hampton, Nerida Liddle, Christopher Wevill, Yuki Ruzsicska, Donna Woltring, Rebeccca Cass, Cain Hendy, Shennelle Waters, Shae Tozer, Erin Gargan, Nicole Smitran, Amy Llewellyn, Katrina Lawrence, Jessie Spargo, Kim Hare. Community Researchers: Jeanette Warnir and Georgina Parmbuk (Wadeye), Amanda Turner (Alice Springs), Kaylene Puruntatameri (Wurrumiyanga) Clinic managers and midwives: Tracy Porter & Sharon Overend, Kris O’Connell & Sophie Eakins, Kim Henschke & Maree Daniel, Evelyn Semmens & Amy Richie. M Audiology student: Belinda Inglis UniMelb Medical Degree Research Program students: Joanna Sen, Jarod Pak, Nashwa Saad CDU MPH student: Leigh Moore Expert advisory group: Allen Cheng, Chris Blyth, Kathy Currie, Michael Binks.

  • Contributors VMO drafted the manuscript, assisted with statistical analysis plan, revised the manuscript and approved the final version of the manuscript. NW drafted the manuscript, was the Clinical Trial Manager for 5 years and approved the final version of the manuscript. KM and PJT advised on study design, assisted with funding application, participated in investigator meetings, advised on risk management and read the final version of the manuscript. MS advised on study design, assisted with funding application, participated in investigator meetings, advised on risk management, reviewed and approved the final version of the manuscript. PMcI advised on study design, assisted with funding application, participated in investigator meetings, advised on risk management and approved the final version of the manuscript. HS-V advised on study design, assisted with funding application, participated in investigator meetings, advised on laboratory protocols, particularly microbiology, reviewed and approved the final version of the manuscript. AB advised on study design, assisted with funding application, participated in investigator meetings and advised on laboratory protocols, particularly immunogenicity, but was not available to read the final version of the manuscript. MDC advised on study design, assisted with funding application, participated in investigator meetings, assisted with statistical analysis plan, reviewed and approved the final version of the manuscript. DL, MJB and ABC advised on study design, assisted with funding application, reviewed and approved the final version of the manuscript. JC advised on study design, assisted with funding application, reviewed and approved the final version of the manuscript. VK advised on study design, assisted with funding application, advised on immunisation policy implications and approved the final version of the manuscript. RMA and TS advised on study design, assisted with funding application, reviewed and approved the final version of the manuscript. PL advised on study design, assisted with funding application, reviewed and approved the final version of the manuscript. PSM advised on study design, assisted with funding application, participated in investigator meetings, advised on risk management and provided day-to-day supervision of clinical training, reviewed and approved the final version of the manuscript. AJL (principal investigator, PI) conceived the study, led funding applications, obtained HREC approval and other regulatory approvals, undertook consultations, reporting and has overseen day-to-day management and implementation of the trial, and reviewed and approved the final version of the manuscript.

  • Funding The PREVIX_BOOST and VOICES trials are funded by the Australian National Health and Medical Research Council, NHMRC (Project Grants GNT1046999 and GNT1120353). GlaxoSmithKline (GSK) supported costs associated with travel to remote settings. The trial sponsor is the Menzies School of Health Research, PO Box 41096, Casuarina, 0811, Northern Territory, Australia.

  • Competing interests In the last 5 years, AJL and PM have served on an OM Advisory Board for GSK and have received GSK support for the clinical outreach training program. KM has served on Advisory Boards for GSK who provided in kind support for the Vietnam Pneumococcal trial, of which he is the PI. His group is involved in a collaborative research project with Pfizer on adult pneumonia in Mongolia, and they have received a small grant to support research capacity building in the paediatric hospitals in Ho Chi Minh City, Vietnam. MS has served on the Advisory Board of GSK and Pfizer. He is also co-investigator on projects funded by GSK and Pfizer. ABC serves on an independent data safety monitoring board for two unlicensed GSK vaccines studies currently under evaluation. DL has received support from Pfizer Australia to attend conferences and is an investigator on an investigator-initiated research grant that was funded by Pfizer Australia.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No individual patient data will be available.

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