TY - JOUR
T1 - 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
T2 - PREVIX_COMBO, a 3-arm randomised controlled trial
AU - Leach, Amanda Jane
AU - Mulholland, Edward Kim
AU - Santosham, Mathuram
AU - Torzillo, Paul John
AU - McIntyre, Peter
AU - Smith-Vaughan, Heidi
AU - Wilson, Nicole
AU - Arrowsmith, Beth
AU - Beissbarth, Jemima
AU - Chatfield, Mark D.
AU - Oguoma, Victor M.
AU - Licciardi, Paul
AU - Skull, Sue
AU - Andrews, Ross
AU - Carapetis, Jonathan
AU - McDonnell, Joseph
AU - Krause, Vicki
AU - Morris, Peter Stanley
N1 - Funding Information:
The PREVIX_COMBO trial is funded by the Australian National Health and Medical Research Council, NHMRC (GNT605810). AJL was supported by a NHMRC Senior Research Fellowship (GNT1020561). PVL was supported by a NHMRC Career Development Fellowship (GNT1146198). Opsonophagocytic Activity (OPA) assays were funded by Financial Markets for Children (Grant number 2012-057). The trial sponsor is the Menzies School of Health Research, PO Box 41096, Casuarina, 0811, Northern Territory, Australia. GlaxoSmithKline provided reagents necessary for the protein D immunogenicity assays. Protocol deviations and protocol violations can be provided on written request.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/4
Y1 - 2021/4
N2 - 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(1 4 1). 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.
AB - 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(1 4 1). 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.
KW - Aboriginal and Torres Strait Islander
KW - Mixed schedule primary course vaccination
KW - Non-typeable Haemophilus influenzae protein D
KW - Pneumococcal conjugate vaccines
KW - Randomised controlled trial
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U2 - 10.1016/j.jvacx.2021.100086
DO - 10.1016/j.jvacx.2021.100086
M3 - Article
C2 - 33681756
AN - SCOPUS:85101682820
SN - 2590-1362
VL - 7
JO - Vaccine: X
JF - Vaccine: X
M1 - 100086
ER -