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^{1

2}, Edward Kim Mulholland^{3

4}, Mathuram Santosham⁵, Paul John Torzillo^{6

7}, Peter McIntyre⁸, Heidi Smith-Vaughan^{1

2}, Nicole Wilson^{1

2}, Beth Arrowsmith^{1

2}, Jemima Beissbarth^{1

2}, Mark D Chatfield^{9

1

2}, Victor M Oguoma^{1

2

10}, Paul Licciardi¹¹, Sue Skull¹², Ross Andrews^{1

2

13}, Jonathan Carapetis^{14

15}, Joseph McDonnell¹⁶, Vicki Krause¹⁷, Peter Stanley Morris^{1

2

18}

Affiliations

¹ Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia.
² Charles Darwin University, Northern Territory, Australia.
³ Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Australia.
⁴ London School of Hygiene and Tropical Medicine, UK.
⁵ Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
⁶ Prince Alfred Hospital, Sydney, Australia.
⁷ University of Sydney, Sydney, Australia.
⁸ National Centre for Immunization Research and Surveillance, Sydney, Australia.
⁹ Centre for Health Services Research, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
¹⁰ Health Research Institute, University of Canberra, Canberra, Australia.
¹¹ Murdoch Children's Research Institute, Dept of Paediatrics, University of Melbourne, Melbourne, Australia.
¹² Dept of Child Health Research, Perth Children's Hospital, University of Western Australia, Perth, Australia.
¹³ Australian National University, Canberra, Australia.
¹⁴ Telethon Kids Institute, University of Western Australia, Australia.
¹⁵ Perth Children's Hospital, Perth, Australia.
¹⁶ Consultant Statistician, 3291TR Strijen, Netherlands.
¹⁷ Centre for Disease Control, Northern Territory Department of Health, Darwin, Australia.
¹⁸ Department of Paediatrics, Royal Darwin Hospital, Darwin Northern Territory, Australia.

PMID: 33681756
PMCID: PMC7930582
DOI: 10.1016/j.jvacx.2021.100086

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 et al. Vaccine X. 2021.

. 2021 Feb 15:7:100086.

doi: 10.1016/j.jvacx.2021.100086. eCollection 2021 Apr.

Authors

Affiliations

¹ Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia.
² Charles Darwin University, Northern Territory, Australia.
³ Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Australia.
⁴ London School of Hygiene and Tropical Medicine, UK.
⁵ Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
⁶ Prince Alfred Hospital, Sydney, Australia.
⁷ University of Sydney, Sydney, Australia.
⁸ National Centre for Immunization Research and Surveillance, Sydney, Australia.
⁹ Centre for Health Services Research, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
¹⁰ Health Research Institute, University of Canberra, Canberra, Australia.
¹¹ Murdoch Children's Research Institute, Dept of Paediatrics, University of Melbourne, Melbourne, Australia.
¹² Dept of Child Health Research, Perth Children's Hospital, University of Western Australia, Perth, Australia.
¹³ Australian National University, Canberra, Australia.
¹⁴ Telethon Kids Institute, University of Western Australia, Australia.
¹⁵ Perth Children's Hospital, Perth, Australia.
¹⁶ Consultant Statistician, 3291TR Strijen, Netherlands.
¹⁷ Centre for Disease Control, Northern Territory Department of Health, Darwin, Australia.
¹⁸ Department of Paediatrics, Royal Darwin Hospital, Darwin Northern Territory, Australia.

PMID: 33681756
PMCID: PMC7930582
DOI: 10.1016/j.jvacx.2021.100086

Abstract

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.

Keywords: Aboriginal and Torres Strait Islander; Mixed schedule primary course vaccination; Non-typeable Haemophilus influenzae protein D; Pneumococcal conjugate vaccines; Randomised controlled trial.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
Trial profile. * This Figure shows number of sera with adequate volumes for testing serotypes 3, 6A, and 19A. See Tables for numbers of sera with adequate volumes for Protein D, ten additional serotypes, and OPA.

**Fig. 2**
Vaccine group comparisons of IgG GMCs, µg/mL (95%CI) against serotypes 3, 6A, 19A, and ten common serotypes at 2, 4, and 7 months of age. P = PCV13 or Prevenar13; S = PHiD-CV10 or Synflorix. GMC geometric mean concentration. 95%CI, 95% confidence interval. Seroprotection threshold of 0·35 µg/mL and putative threshold of 1·0 µg/mL for pneumococcal serotypes, are indicated by red dashed lines. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

**Fig. 3**
Vaccine group comparisons of the proportion of infants (%, 95%CI) with IgG ≥ 0·35 µg/mL against serotypes 3, 6A, and 19A, and ten common serotypes, at 2, 4, and 7 months of age. P = PCV13 or Prevenar13; S = PHiD-CV10 or Synflorix. GMC geometric mean concentration. 95%CI, 95% confidence interval.

**Fig. 4**
Vaccine group comparisons of OPA GMTs (95%CI) against serotypes 3, 6A, and 19A, and ten common serotypes, at 7 months of age. P = PCV13 or Prevenar13; S = PHiD-CV10 or Synflorix. OPA opsonophagocytic activity. GMT geometric mean titre. 95%CI, 95% confidence interval. Seroprotection threshold GMT of 8 indicated by red dashed lines. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

See this image and copyright information in PMC

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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