Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life

Martinovich, Kelly M.; Rahman, Tasmina; Gier, Camilla de; Seppanen, Elke; Orami, Tilda; Granland, Caitlyn; Francis, Jacinta; Yoannes, Mition; Corscadden, Karli J.; Ford, Rebecca; Jacoby, Peter; Biggelaar, Anita H. J. van den; Cripps, Allan W.; Lehmann, Deborah; Richmond, Peter; Pomat, William; Kirkham, Lea‐Ann S.; Thornton, Ruth B.

doi:10.3389/fimmu.2021.725244

Cited by 5 publications

(8 citation statements)

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“…We wish to identify if immunisation increases maternal and cord blood IgG antibodies to vaccine-type pneumococcal serotypes and to H. influenzae PD. This is significant as a recent study from Papua New Guinea suggested that antibodies to NTHi outer membrane proteins may not be transferred from mothers to their infants ( 72 ). We will also determine innate and systemic immune responses to pneumococci and H. influenzae in both mothers and their infants.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…As expected, >80% cross-reactivity was demonstrated between rsPilA and ChimV4, with little cross-reactivity observed with/between other antigens (<10%). All antigens were conjugated to fluorescent carboxylated microspheres for measurement of serum IgG-specific titres ( Martinovich et al., 2021 ). Briefly, samples were diluted 1:200 in serum diluent (phosphate buffer saline, 2% bovine serum and 0.05% tween20).…”

Section: Methodsmentioning

confidence: 99%

Australian Aboriginal Otitis-Prone Children Produce High-Quality Serum IgG to Putative Nontypeable Haemophilus influenzae Vaccine Antigens at Lower Titres Compared to Non-Aboriginal Children

Clark

Seppanen

Kirkham

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundNontypeable Haemophilus influenzae (NTHi) is the most common bacterial otopathogen associated with otitis media (OM). NTHi persists in biofilms within the middle ears of children with chronic and recurrent OM. Australian Aboriginal children suffer exceptionally high rates of chronic and recurrent OM compared to non-Aboriginal children. NTHi protein vaccines comprised of antigens associated with both adhesion and persistence in a biofilm are under development and could be beneficial for children with chronic and recurrent OM. Understanding the ontogeny of natural antibody development to these antigens provides insight into the value of vaccinating with particular antigens.MethodsAn in-house multiplex fluorescent bead immunoassay was used to measure serum IgG titres and avidity for three putative vaccine antigens: recombinant soluble PilA (rsPilA), ChimV4, and outer membrane protein 26 (OMP26) in sera from Australian Aboriginal otitis-prone children (n=77), non-Aboriginal otitis-prone children (n=70) and non-otitis-prone children (n=36). Serum IgG titres were adjusted for age, and geometric mean concentrations (GMCs) were compared between groups using a univariate analysis model. Antibody avidity was calculated as a relative avidity index and compared between groups using ANOVA.ResultsAustralian Aboriginal otitis-prone children had lower serum IgG titres to rsPilA and ChimV4 than non-Aboriginal otitis-prone children (p<0.001), and non-otitis-prone children (p<0.020). No differences were observed between serum IgG titres from non-Aboriginal otitis-prone children and non-otitis-prone children. There were also no differences in the proportion of high avidity IgG specific for these antigens between these groups. Serum IgG titres to OMP26 were similar between all groups (p>0.670) although otitis-prone children had a higher proportion of high avidity antibodies to this antigen.ConclusionsAustralian Aboriginal otitis-prone children had lower serum IgG titres to 2/3 major NTHi vaccine candidate antigens, suggesting these children are unable to develop persistent IgG responses due to repeated NTHi exposure. These reduced IgG titres may relate to earlier and more frequent exposure to diverse NTHi strains in Aboriginal children through carriage or infection. These data suggest that Aboriginal children may benefit from immunisation with vaccines containing these antigens to increase titres of protective antibodies.

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“…Pure, stable and endotoxin free recombinant PD was produced by the Protein Expression Facility (The University of Queensland) according to optimised protocols and adapted from methods used previously ( 33 ). H. influenzae antigens OMP26, rsPilA and ChimV4 were prepared as described previously ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

“…Sera were assessed for specific IgG antibodies against S. pneumoniae antigens PspA1, PspA2, CbpA, Ply, and H. influenzae antigens PD, OMP26, rsPilA and ChimV4 using multiplex bead-based immunoassays that have been described previously ( 21 ). The final assays consisted of a 5-plex immunoassay containing PspA1, PD, ScpA ( Streptococcus pyogenes antigen, data not shown here), OMP26 and rsPilA, and a 4-plex immunoassay containing PspA2, CbpA, Ply and ChimV4.…”

Section: Methodsmentioning

confidence: 99%

“…Measuring the concentrations of circulating antibodies against putative vaccine candidate antigens following natural pathogen exposure provides a valuable indication of the antigen immunogenicity and in terms of maternal vaccines, the transplacental antigen-specific antibody transfer efficiency. We previously observed the natural waning of sera IgG to S. pneumoniae , but not H. influenzae , protein antigens between birth and 9 months of age among Papua New Guinean (PNG) infants ( 21 ). However, it was unclear due to lack of appropriately matched samples whether the lack of observed waning simply related to low baseline levels due to either (i) low maternal levels or (ii) poor transplacental transfer.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of maternal transfer of antigen-specific antibodies in serum and breast milk to infants at high-risk of S. pneumoniae and H. influenzae disease

et al. 2022

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IntroductionChildren in low-mid income countries, and First Nations children in high-income countries, experience disproportionately high rates of Streptococcus pneumoniae and Haemophilus influenzae infections and diseases including pneumonia and otitis media. We previously observed that infants from Papua New Guinea had no evidence of waning maternal immunity for H. influenzae-specific antibodies. In this study, we assessed S. pneumoniae and H. influenzae antibody titres in Australian First Nation mothers and infants to determine antigen-specific antibody ontogenies and whether H. influenzae antibody titres in infants were due to low maternal antibody titres or lack of placental transfer.MethodsBreast milk, infant nasopharyngeal swabs and ear assessment data were collected 1-, 2-, 7-months post-birth as well as maternal, cord and 7-month-old infant sera, from 85 Australian Aboriginal and Torres Strait Islander mother-infant pairs. Serum IgG and breast milk IgG and IgA antibody titres to S. pneumoniae antigens (PspA1, PspA2, CbpA, Ply) and H. influenzae antigens (PD, ChimV4, OMP26, rsPilA) were measured.ResultsIgG titres in maternal and cord sera were similar for all antigens, except Ply (higher in cord; p=0.004). Sera IgG titres at 7-months of age were lower than cord sera IgG titres for all S. pneumoniae antigens (p<0.001). Infant sera IgG titres were higher than cord sera for H. influenzae PD (p=0.029), similar for OMP26 (p=0.817) and rsPilA (p=0.290), and lower for ChimV4 (p=0.004). Breast milk titres were similar for all antigens at 1, 2 and 7-months except OMP26 IgA (lower at 7-months than 1-month; p=0.035), PspA2 IgG (p=0.012) and Ply IgG that increased by 7-months (p=0.032). One third of infants carried nontypeable Haemophilus influenzae (NTHi), 45% carried S. pneumoniae and 52% had otitis media (OM) observed at least once over the 7-months. 73% of infants who carried either S. pneumoniae or NTHi, also had otitis media observed.ConclusionsSimilarities between maternal and cord IgG titres, and absence of waning, support a lack of maternal H. influenzae IgG antibodies available for cross-placental transfer. Increased maternal anti-PD IgG could offer some protection from early carriage with NTHi, and maternal immunisation strategies should be considered for passive-active immunisation of infants to protect against S. pneumoniae and H. influenzae diseases.Trial registrationClinicalTrials.gov NCT00714064 and NCT00310349.

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Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life

Cited by 5 publications

References 51 publications

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

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

Australian Aboriginal Otitis-Prone Children Produce High-Quality Serum IgG to Putative Nontypeable Haemophilus influenzae Vaccine Antigens at Lower Titres Compared to Non-Aboriginal Children

Evidence of maternal transfer of antigen-specific antibodies in serum and breast milk to infants at high-risk of S. pneumoniae and H. influenzae disease

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