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

A 2008 analysis of the global burden of acute and chronic suppurative otitis media (AOM and CSOM) estimated an overall CSOM incidence rate of 4.76 per thousand people, 22.6% cases in under five-year-old children. In the first year of life, the lowest CSOM incidence rate was 1.59 per thousand in High Income Asia Pacific, the highest was in Oceania (36 per thousand) [1]. Australian Aboriginal and non-Aboriginal data were included in Oceania, combined and weighted by population size. The original national study of otitis media diagnoses in Australian primary healthcare settings reported that Aboriginal and Torres Strait Islander children were significantly more likely to have severe OM, particularly “discharging ears” which was 40-fold higher [2]. In remote Northern Territory (NT) communities, longitudinal birth cohort studies conducted in the pre- and post- 7-valent pneumococcal conjugate vaccine (PCV7) eras and including a maternal pneumococcal polysaccharide vaccination trial all found early nasopharyngeal colonisation and concomitant onset of otitis media (OM) within weeks of birth [3‐5]. OM generally persisted throughout the first year of life, including 12% having chronic suppurative otitis media (CSOM) at 12 months of age, and less than 10% having bilaterally normal middle ears [4]. A West Australian study conducted in the early years of the PCV7 era also found that prevalence of OM and hearing loss were around 40% during first year of life [6]. Recent analyses using data-linkage has provided evidence that Aboriginal children with a history of hearing loss on entering school are at increased risk of vulnerability on entering school, [7] poor school attendance [8] and performance, [9] and substantiated child maltreatment [10].

During surveillance studies in the NT, culture of ear discharge from 83 cases of acute otitis media with perforation (AOMwiP) or CSOM in PCV7-vaccinees detected non-typeable Haemophilus influenzae (NTHi) in 58% cases and PCV7-type pneumococci in 5%, compared to 55 and 17%, respectively in non-PCV historic controls [11].

Few early-intervention trials for prevention or treatment of OM have been conducted in this population. One randomised controlled trial reported that long term antibiotics compared to placebo increase the resolution of OME and prevented progression to tympanic membrane perforation (TMP), with no increase in bacterial resistance [12]. Whilst effective, long term adherence is difficult and prevention strategies are the preferred approach.

At commencement of this trial, clinical trials of the effect of PCV7 on all-cause AOM found 6% relative risk reduction (RRR) in low-risk infants, and a lack of effect in a small RCT in high-risk infants [13]. The RRR was around 20% for pneumococcal AOM and 10% for recurrent AOM. The effect of a pre-cursor to PHiD-CV10, PD-11Pn, on all-cause AOM was 34% in healthy infants [14]. In the Northern Territory the childhood vaccination schedule transitioned through three PCVs over the period 7-valent PCV7 (2001 to 2009), ten-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine, PHiD-CV10 (2009 to 2011), and 13-valent PCV13 (from 2011) (see Table 1 and below for PCV13 and PHiD-CV10 formulations). Cross sectional surveys conducted prior to and during this current trial identified significant but modest reductions in the prevalence of severe OM and a significant reduction in NTHi-culture-positive middle ear discharge in PHiD-CV10 vaccinees compared to the PCV7 vaccinees [15‐18]. The Cochrane review of PCVs in the prevention of all-cause acute otitis media was updated during the course of this RCT. RCTs of new PCVs including PHiD-CV10 were underway (including this RCT) and therefore not able to be included [14]. Our RCT was the only study proposing to evaluate a combination of PCVs within the primary series.

Details of the trial protocol have been published [20]. Brief summaries are provided.

Five communities commenced between September 2011 and August 2014. Of 1018 pregnancy notifications, 593 were excluded, 425 infants were randomised to _PPP (143), _SSS (141) or SSSP (141). 396 (93%) infants were randomised within the study window of 28 to 38 days of age (Fig. 1). Final randomisation of 425 infants occurred on 21st September 2017. Overall, infant birth characteristics were similar between groups (Table 3). Ear assessments were achieved in at least 90% infants across vaccine groups and time points (Fig. 1). Exclusion of protocol deviations or violations made no difference to our findings.

Despite indications of potential early and broadened immune protection from vaccine type pneumococci and NTHi, [19] our clinical findings clearly demonstrate a failure of this strategy to prevent early onset of OM in this population. We found no statistically significant differences in any OM diagnosis between vaccine groups at any age. Our study shows that PCVs do not directly or via herd effects, prevent early onset of all-cause OM during or one month after completing primary course schedules. Although tympanocentesis is not performed in Australia, nasopharyngeal carriage studies and culture of middle ear discharge during spontaneous perforation provide a close proxy for middle ear microbiology and confirm non-vaccine type pneumococci and NTHi as dominant pathogens in OM [11, 18]. We will report nasopharyngeal carriage outcomes at all timepoints for infants in this trial. In surveillance studies across the NT remote communities in 2013 (during this trial) we found that pneumococcal nasopharyngeal carriage in PCV13-vaccinated one-year old children was 77%, and the dominant serotypes were 16F (23%) and 15A (10%), followed by 23F, 11A, 35B, and 19F (each ~ 6%). Carriage of NTHi was 63% [18]. Respiratory viral infections may also contribute, although our previous work has shown only adenovirus is independently associated with AOM (~ 13% cases), whereas other viruses exacerbate bacterial OM through co-infection which increases bacterial load and risk of AOM [23].

In this high-risk population, and for infants at high-risk in other populations [24], prevention of early onset OM is critical as early onset is invariably followed by persistent and increasingly severe and intractable infections. Few vaccine studies have reported early otitis media outcomes, within the primary schedule. A 2016 systematic review of nasopharyngeal carriage following each primary dose of PCV7 or PHiD-CV10 found no significant difference between vaccinees and controls at 4 or 6 months, whereas at 7 months vaccinees had lower carriage of vaccine types, higher carriage of non-vaccine types [25]. No differences in overall pneumococcal or NTHi carriage were found at any timepoint. The latest update of the Cochrane review of pneumococcal vaccines for prevention of all-cause or pneumococcal AOM was to 29 March 2019 [14]. The review evaluated outcomes of early infancy schedules and administration in older children. The included studies had a minimum follow-up duration of 6 months and therefore likely measured outcomes after the booster dose. The effect of PHiD-CV10 varied from 6 to 15% RRR in healthy infants (non-significant) and there was no RCT evaluating otitis media outcomes of PCV13. The authors noted that in the absence of RCTs, data from population studies show further reductions in OM hospitalisations following PCV13 licensure, compared to PCV7 era [26]. The review also found that PCVs did not reduce all-cause AOM when administered in high risk infants, after early infancy, or in older children with a history of respiratory illness or frequent AOM. There was limited evidence that administration of PCVs in early infancy may reduce the risk of recurrent AOM. The authors suggested that the mechanism for this may be that PCVs prevent early vaccine-type AOM and thereby disrupt the progression and chronicity of subsequent all-cause AOM (non-vaccine serotype-AOM and NTHi-AOM) [27, 28]. Our study does not support this hypothesis. Although nasopharyngeal carriage of PCV13 serotypes has declined, we have seen replacement by non-PCV13 serotypes, and ongoing NTHi carriage.

The importance of preventing NTHi and non-PCV13-type early, persistent and severe OM in this populations is highlighted by our work. Our analysis of transitions in OM status during the first 6 months of life found less than 10% infants with OM had returned to normal healthy ears at subsequent visits. Where a diagnosis of bilaterally normal ears was made, this was transient, indicating the importance of regular and opportunistic ear assessments throughout the first months and years of life for these children. The National Guide for prevention of hearing loss in Aboriginal and Torres Strait Islander populations recommends timely vaccinations, surveillance, exclusive breast feeding, avoidance of smoke exposure, surgical interventions to reduce hearing impairment, chemoprophylaxis for high-risk children, and assessment of household overcrowding [29]. Many of these strategies prevent other infections and are broadly recommended. However, evidence for prevention of OM is weak or lacking, and where reported, effect size is generally small [21]. Our univariate and multivariable analyses of risk factors did not show statistically significant associations between OM and the classical risk factors, possibly due to high rates of OM with or without risk factor exposures. All infants in our study received appropriate management plans for their OM detected by research nurses at the time of vaccination, and according to otitis media guidelines for Aboriginal and Torres Strait Islander children, including education and guidance about detecting and managing ear and hearing problems, primary health care and specialist service referrals [21]. Very few infants received follow-up from their primary care providers, nor specialist services. The failure of these combined efforts to prevent and treat OM in these infants warrants a much greater local investment.

A limitation of our study was low sample size and limited ability to detect small but potentially important clinical differences between vaccines and schedules.

Our study confirms that a multi-modal approach to otitis media prevention, detection, treatment, and support for hearing impaired children and their families will be required to tackle this crisis. Ongoing vaccine development to broaden pneumococcal serotype coverage and to elicit protective immune responses to NTHi is needed globally. New generation vaccines and schedules must be evaluated in high-risk populations. In Australia, strategies that address the social determinants of otitis media in Aboriginal and Torres Strait Islander children, particularly housing and access to quality health care can also contribute to elimination of childhood hearing impairment and social disadvantage. These too must be evaluated to ensure they are adequate, and that significant change is achieved.