Interchangeability, immunogenicity and safety of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (Synflorix) and 13-valent-PCV (Prevenar13) schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial
Amanda Jane Leach,
Edward Kim Mulholland,
Mathuram Santosham,
Paul John Torzillo,
Peter McIntyre,
Heidi Smith-Vaughan,
Nicole Wilson,
Beth Arrowsmith,
Jemima Beissbarth,
Mark D. Chatfield,
Victor M. Oguoma,
Paul Licciardi,
Sue Skull,
Ross Andrews,
Jonathan Carapetis,
Joseph McDonnell,
Vicki Krause,
Peter Stanley Morris
Affiliations
Amanda Jane Leach
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia; Corresponding author at: Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Northern Territory, Australia.
Edward Kim Mulholland
Murdoch Children’s Research Institute, Department of Paediatrics, University of Melbourne, Australia; London School of Hygiene and Tropical Medicine, UK
Mathuram Santosham
Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
Paul John Torzillo
Prince Alfred Hospital, Sydney, Australia; University of Sydney, Sydney, Australia
Peter McIntyre
National Centre for Immunization Research and Surveillance, Sydney, Australia
Heidi Smith-Vaughan
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia
Nicole Wilson
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia
Beth Arrowsmith
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia
Jemima Beissbarth
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia
Mark D. Chatfield
Centre for Health Services Research, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia; Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia
Victor M. Oguoma
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia; Health Research Institute, University of Canberra, Canberra, Australia
Paul Licciardi
Murdoch Children’s Research Institute, Dept of Paediatrics, University of Melbourne, Melbourne, Australia
Sue Skull
Dept of Child Health Research, Perth Children’s Hospital, University of Western Australia, Perth, Australia
Ross Andrews
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia; Australian National University, Canberra, Australia
Jonathan Carapetis
Telethon Kids Institute, University of Western Australia, Australia; Perth Children’s Hospital, Perth, Australia
Centre for Disease Control, Northern Territory Department of Health, Darwin, Australia
Peter Stanley Morris
Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia; Charles Darwin University, Northern Territory, Australia; Department of Paediatrics, Royal Darwin Hospital, Darwin Northern Territory, Australia
Background: Aboriginal children living in remote communities are at high risk of early and persistent otitis media. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are primary pathogens. Vaccines with potential to prevent early OM have not been evaluated in this population. We compared immunogenicity (ELISA and opsonophagocytic activity) of a combination of Synflorix™ (PHiD-CV10, 10 serotypes and protein D of NTHi) and Prevenar13™ (PCV13, 10 serotypes plus 3, 6A, and 19A), with recommended schedules. Methods: This open-label superiority trial randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to PCV13 (P) at 2–4-6 months (_PPP), PHiD-CV10 (S) at 2–4-6 months (_SSS), or PHiD-CV10 at 1–2–4 plus PCV13 at −6 months (SSSP). Primary outcomes (blinded) were immunogenicity against PCV13-only serotypes 3, 6A, 19A, and PHiD-CV10-only protein D at 7 months. Secondary outcomes include immunogenicity against all serotypes at 2, 4 and 7 months. Findings: Between 2011 and 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). An intention to treat approach including all available data was used. The SSSP group had superior immunogenicity against serotypes 3, 6A, and 19A compared to _SSS (OPA GMT ratios 8.1 to 59.5, p < 0.001), and against protein D compared to _PPP (GMC ratio 11.9 (95%CI 9.7 to 14.6)). Immune responses to protein D and 3, 6A, and 19A in SSSP were not significantly lower (i.e. no harm) than either _SSS or _PPP. For ten common serotypes responses at 2, 4 and 7 months were superior for SSSP (following 1-, 2-, and 4- doses) than _SSS and _PPP (following 0-, 1-, and 3- doses). At 4 months, _SSS was superior to _PPP. Reactogenicity and hospitalisations were rare and unrelated to the intervention. Interpretation: From two months, the 1–2–4–6-month combined schedule (SSSP) was safe and significantly more immunogenic than 2–4–6-month schedules. The earlier responses may be beneficial in high-risk populations.
