Study Protocol for Preventing Early-Onset Pneumonia in Young Children Through Maternal Immunisation: A Multi-Centre Randomised Controlled Trial (PneuMatters)

Abstract

Background: Preventing and/or reducing acute lower respiratory infections (ALRIs) in young children will lead to substantial short and long-term clinical benefits. While immunisation with pneumococcal conjugate vaccines (PCV) reduces paediatric ALRIs, its efficacy for reducing infant ALRIs following maternal immunisation has not been studied. Compared to other PCVs, the 10-valent pneumococcal-Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) is unique as it includes target antigens from two common lower airway pathogens, pneumococcal capsular polysaccharides and protein D, which is a conserved H. influenzae outer membrane lipoprotein.Aims: The primary aim of this randomised controlled trial (RCT) is to determine whether vaccinating pregnant women with PHiD-CV (compared to controls) reduces ALRIs in their infants' first year of life. Our secondary aims are to evaluate the impact of maternal PHiD-CV vaccination on different ALRI definitions and, in a subgroup, the infants' nasopharyngeal carriage of pneumococci and H. influenzae, and their immune responses to pneumococcal vaccine type serotypes and protein D.Methods: We are undertaking a parallel, multicentre, superiority RCT (1:1 allocation) at four sites across two countries (Australia, Malaysia). Healthy pregnant Australian First Nation or Malaysian women aged 17–40 years with singleton pregnancies between 27+6 and 34+6 weeks gestation are randomly assigned to receive either a single dose of PHiD-CV or usual care. Treatment allocation is concealed. Study outcome assessors are blinded to treatment arms. Our primary outcome is the rate of medically attended ALRIs by 12-months of age. Blood and nasopharyngeal swabs are collected from infants at birth, and at ages 6- and 12-months (in a subset). Our planned sample size (n = 292) provides 88% power (includes 10% anticipated loss to follow-up).Discussion: Results from this RCT potentially leads to prevention of early and recurrent ALRIs and thus preservation of lung health during the infant's vulnerable period when lung growth is maximum. The multicentre nature of our study increases the generalisability of its future findings and is complemented by assessing the microbiological and immunological outcomes in a subset of infants.Clinical Trial Registration:https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374381, identifier: ACTRN12618000150246.

Randomised controlled trial of perinatal vitamin D supplementation to prevent early-onset acute respiratory infections among Australian First Nations children: the ‘D-Kids’ study protocol

“…The primary outcome is the incidence of ARI episodes receiving medical attention in the first 12 months of the infant’s life. ARI episodes are identified via electronic medical records using established methods 33–35. Our ARI case definition encompasses any episode of hospital or primary healthcare documented in the medical records as either an acute lower respiratory infection, acute upper respiratory infection or OM.…”

“…Protocol adherence (deviations/violations) are continuously monitored and documented by study staff. Established methods are used to document episodes of respiratory infection from medical records 33–35. Collection and processing times, and quality measures are recorded for all biological samples.…”

“…Established methods are being used for the collection and processing of blood, breast milk, nasal, stool and saliva samples 4 34 35 42 51. Briefly, whole cord blood is collected via venepuncture: (1) into three (10 mL) heparinised tubes containing an equal volume of RMPI (Sigma-Aldrich) cell culture media; (2) into heparinised paediatric blood tubes (<1 mL) and (3) onto Guthrie cards (~80 µL).…”

“…Established methods are used to document episodes of respiratory infection from medical records. [33][34][35] Collection and processing times, and quality measures are recorded for all biological samples. A GCP compliant protocol is employed if corrections are made to paper-based records.…”

“…ARI episodes are identified via electronic medical records using established methods. [33][34][35] Our ARI case definition encompasses any episode of hospital or primary healthcare documented in the medical records as either an acute lower respiratory infection, acute upper respiratory infection or OM. Associated signs, symptoms and observations are comprehensively documented for each ARI episode.…”