Otitis media outcomes of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine and 13-valent pneumococcal conjugate vaccine 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, Peter Stanley Morris, 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, Peter Stanley Morris

Abstract

Background: Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months.

Methods: In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2-4-6 months (_PPP), Synflorix™ (S) at 2-4-6 months (_SSS), or Synflorix™ at 1-2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM).

Results: Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM.

Conclusions: Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life.

Trial registration: ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.gov NCT01174849 registered 04/08/2010.

Keywords: 3-arm randomised controlled trial; Aboriginal; Combination schedule; Head-to-head; Infant; Otitis media; PCV13; PHiD-CV10; Pneumococcal conjugate vaccines.

Conflict of interest statement

Between 2010 and 2012, AJL received research funds Pfizer (manufacturers of Prevenar13™). In 2013, AJL received financial support from GSK and Pfizer to attend conferences. In 2018 AJL served on an advisory board for GSK. KM has served on an advisory board for GSK. GSK provided in-kind support for the Vietnam Pneumococcal trial, of which KM is the PI. MS served on the scientific advisory boards of Pfizer and GSK. MS also received research grants from Pfizer and GSK. PT and PMcI have no financial or other competing interests.

Figures

Fig. 1
Fig. 1
PARTICIPANT FLOW
Fig. 2
Fig. 2
Prevalence (%, 95 confidence interval) of any otitis media, by age and vaccine group
Fig. 3
Fig. 3
Proportion of infants (%) with a worst ear diagnosis* of each form of otitis media, by vaccine group and age (months)**
Fig. 4
Fig. 4
Cumulative proportion of infants with any OM, any bilateral OM, any suppurative OM# or any tympanic membrane perforation##, by age and vaccine group

References

    1. Monasta L, Ronfani L, Marchetti F, Montico M, Vecchi Brumatti L, Bavcar A, Grasso D, Barbiero C, Tamburlini G. Burden of disease caused by otitis media: systematic review and global estimates. PLoS One. 2012;7(4):e36226. doi: 10.1371/journal.pone.0036226.
    1. Gunasekera H, Knox S, Morris P, Britt H, McIntyre P, Craig JC. The spectrum and management of otitis media in Australian indigenous and non-indigenous children: a national study. PediatrInfectDisJ. 2007;26(8):689–692.
    1. Leach AJ, Boswell JB, Asche V, Nienhuys TG, Mathews JD. Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in Australian Aboriginal infants. PediatrInfect Dis J. 1994;13(11):983–989. doi: 10.1097/00006454-199411000-00009.
    1. Mackenzie GA, Carapetis JR, Leach AJ, Morris PS. Pneumococcal vaccination and otitis media in Australian Aboriginal infants: comparison of two birth cohorts before and after introduction of vaccination. BMCPediatr. 2009;9:14.
    1. Binks MJ, Moberley SA, Balloch A, Leach AJ, Nelson S, Hare KM, Wilson C, Morris PS, Nelson J, Chatfield MD et al: PneuMum: impact from a randomised controlled trial of maternal 23-valent pneumococcal polysaccharide vaccination on middle ear disease amongst indigenous infants, Northern Territory, Australia. Vaccine 2015.
    1. Lehmann D, Weeks S, Jacoby P, Elsbury D, Finucane J, Stokes A, Monck R, Coates H. Absent otoacoustic emissions predict otitis media in young Aboriginal children: a birth cohort study in Aboriginal and non-Aboriginal children in an arid zone of Western Australia. BMCPediatr. 2008;8:32.
    1. Su JY, Guthridge S, He VY, Howard D, Leach AJ. Impact of hearing impairment on early childhood development in Australian Aboriginal children: a data linkage study. J Paediatr Child Health. 2020.
    1. Su JY, He VY, Guthridge S, Howard D, Leach A, Silburn S. The impact of hearing impairment on Aboriginal children's school attendance in remote Northern Territory: a data linkage study. Aust N Z J Public Health. 2019;43(6):544–550. doi: 10.1111/1753-6405.12948.
    1. Su JY, Guthridge S, He VY, Howard D, Leach AJ. The impact of hearing impairment on early academic achievement in Aboriginal children living in remote Australia: a data linkage study. BMC Public Health. 2020;20(1):1521. doi: 10.1186/s12889-020-09620-6.
    1. He VY, Guthridge S, Su J-Y, Howard D, Stothers K, Leach A: The link between hearing impairment and child maltreatment among Aboriginal children in the Northern Territory of Australia: is there an opportunity for a public health approach in child protection? BMC Public Health 2020, 20(1).
    1. Leach A, MacKenzie G, Hare K, Stubbs E, Beissbarth J, Kennedy M, Wilson C, Mellon G, Wigger C, Tippakalipa P. Microbiology of acute otitis media with perforation (AOMwiP) in Aboriginal children living in remote communities—monitoring the impact of 7-valent pneumococcal conjugate vaccine (7vPCV) Int Congr Ser. 2006;1289:89–92. doi: 10.1016/j.ics.2005.11.078.
    1. Leach AJ, Morris PS, Mathews JD. Compared to placebo, long-term antibiotics resolve otitis media with effusion (OME) and prevent acute otitis media with perforation (AOMwiP) in a high-risk population: a randomized controlled trial. BMCPediatr. 2008;8:23.
    1. O'Brien KL, David AB, Chandran A, Moulton LH, Reid R, Weatherholtz R, Santosham M. Randomized, controlled trial efficacy of pneumococcal conjugate vaccine against otitis media among Navajo and White Mountain apache infants. Pediatr Infect Dis J. 2008;27(1):71–73. doi: 10.1097/INF.0b013e318159228f.
    1. Fortanier AC, Venekamp RP, Boonacker CW, Hak E, Schilder AG, Sanders EA, Damoiseaux RA. Pneumococcal conjugate vaccines for preventing acute otitis media in children. The Cochrane database of systematic reviews. 2019;5:CD001480.
    1. Leach AJ, Wigger C, Andrews R, Chatfield M, Smith-Vaughan H, Morris PS. Otitis media in children vaccinated during consecutive 7-valent or 10-valent pneumococcal conjugate vaccination schedules. BMC Pediatr. 2014;14(1):200–211. doi: 10.1186/1471-2431-14-200.
    1. Morris PS, Leach AJ, Silberberg P, Mellon G, Wilson C, Hamilton E, Beissbarth J. Otitis media in young Aboriginal children from remote communities in northern and Central Australia: a cross-sectional survey. BMCPediatr. 2005;5:27–37.
    1. Leach AJ, Wigger C, Hare K, Hampton V, Beissbarth J, Andrews R, Chatfield M, Smith-Vaughan H, Morris PS. Reduced middle ear infection with non-typeable Haemophilus influenzae, but not Streptococcus pneumoniae, after transition to 10-valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine. BMC Pediatr. 2015;15(1):162–175. doi: 10.1186/s12887-015-0483-8.
    1. Leach AJ, Wigger C, Beissbarth J, Woltring D, Andrews R, Chatfield MD, Smith-Vaughan H, Morris PS. General health, otitis media, nasopharyngeal carriage and middle ear microbiology in Northern Territory Aboriginal children vaccinated during consecutive periods of 10-valent or 13-valent pneumococcal conjugate vaccines. Int J Pediatr Otorhinolaryngol. 2016;86:224–232. doi: 10.1016/j.ijporl.2016.05.011.
    1. Leach AJ, Mulholland EK, Santosham M, Torzillo P, McIntyre P, Smith-Vaughan H, Wilson N, Arrowsmith B, Chatfield M, Oguoma V et al: 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. Vaccine:X 2021, 10.1016/j.jvacx.2021.100086.
    1. Leach AJ, Mulholland EK, Santosham M, Torzillo PJ, Brown NJ, McIntyre P, Smith-Vaughan H, Skull S, Balloch A, Andrews R, et al. Pneumococcal conjugate vaccines PREVenar13 and SynflorIX in sequence or alone in high-risk indigenous infants (PREV-IX_COMBO): protocol of a randomised controlled trial. BMJ Open. 2015;5(1):e007247–e007257. doi: 10.1136/bmjopen-2014-007247.
    1. Leach AJ, Morris P, Coates HLC, al. e. Otitis media guidelines for Australian Aboriginal and Torres Strait Islander children: summary of recommendations. Med J Aust; 2021. [in press].
    1. Statacorp: Stata Statistical Software: Release 15. College Station, Texas:. Stata Corporation 2017.
    1. Binks MJ, Cheng AC, Smith-Vaughan H, Sloots T, Nissen M, Whiley D, McDonnell J, Leach AJ. Viral-bacterial co-infection in Australian indigenous children with acute otitis media. BMC Infect Dis. 2011;11:161. doi: 10.1186/1471-2334-11-161.
    1. Leach AJ, Homøe P, Chidziva C, Gunasekera H, Kong K, Bhutta MF, Jensen R, Tamir SO, Das SK, Morris P. Panel 6: otitis media and associated hearing loss among disadvantaged populations and low to middle-income countries. Int J Pediatr Otorhinolaryngol. 2020.
    1. Nicholls TR, Leach AJ, Morris PS. The short-term impact of each primary dose of pneumococcal conjugate vaccine on nasopharyngeal carriage: systematic review and meta-analyses of randomised controlled trials. Vaccine. 2016;34(6):703–713. doi: 10.1016/j.vaccine.2015.12.048.
    1. Marom T, Tan A, Wilkinson GS, Pierson KS, Freeman JL, Chonmaitree T. Trends in otitis media-related health care use in the United States, 2001-2011. JAMA Pediatr. 2014;168(1):68–75. doi: 10.1001/jamapediatrics.2013.3924.
    1. Ben-Shimol S, Givon-Lavi N, Leibovitz E, Raiz S, Greenberg D, Dagan R. Near-elimination of otitis media caused by 13-valent pneumococcal conjugate vaccine (PCV) serotypes in southern Israel shortly after sequential introduction of 7-valent/13-valent PCV. Clin Infect Dis. 2014;59(12):1724–1732. doi: 10.1093/cid/ciu683.
    1. Dagan R, Pelton S, Bakaletz L, Cohen R. Prevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease. Lancet Infect Dis. 2016;16(4):480–492. doi: 10.1016/S1473-3099(15)00549-6.
    1. Practitioners. NACCHOaTRACoG: National guide to a preventive health assessment for Aboriginal and Torres Strait Islander people, 3rd edn. East Melbourne, Vic; 2018.

Source: PubMed

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