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

Abstract

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.

Overcoming barriers: a review on innovations in drug delivery to the middle and inner ear

“…Idiopathic SSNHL does spontaneously resolve in 45%-65% of patients, however controversy remains on potential etiologies and best course of treatment (Conlin and Parnes, 2007;Kuhn et al, 2011). such as Amoxicillin, but vaccination against common middle ear pathogens such as S. pneunomiae and H. influenzae has become standard practice in some countries (Martinovich et al, 2021;Clark et al, 2022;Izurieta et al, 2022). The treatment of CSOM remains a clinical challenge and often requires the combination of oral antibiotics, eardrops, and surgery due to the presence of antibiotic-resistant bacteria and bacterial biofilm (Mittal et al, 2018;Leach et al, 2021).…”

Biofilms and intracellular infection in otitis media

“…[29][30][31] Assessing natural responses in children to these highly conserved, but clinically relevant proteins, we saw that otitis-prone children, and in particular Australian Aboriginal otitis-prone children, had reduced antibody responses when compared to non-otitisprone children. 28,32 Together these data highlight the need to better understand the differences in protein expression and develop appropriate disease models to identify suitable vaccine candidates to both prevent and resolve chronic diseases such as OM. These future strategies also need to take into account the polymicrobial nature of this disease.…”

Epidemic Trends and Biofilm Formation Mechanisms of Haemophilus influenzae: Insights into Clinical Implications and Prevention Strategies

“… 132 Australian Aboriginal otitis-prone children had lower serum IgG titres to major NTHi vaccine candidate antigens (rsPilA, ChimV4 and outer membrane protein 26), suggesting that Aboriginal children may benefit from immunisation with vaccines containing these antigens to increase titres of protective antibodies. 133 There are also other NTHi surface dominant antigens that can be used as candidate vaccine molecules. However, unlike capsular type H. influenzae , NTHi lacks a single surface antigen and may require a multi component binding targeted vaccine.…”