Antibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency

Hawdon, Nicole; Biman, Birubi; McCready, William; Brigden, Malcolm L.; Malik, Sanjeev; Vergidis, D.; Kisselgoff, O.; Ulanova, Marina

doi:10.1016/j.vaccine.2011.12.113

Cited by 11 publications

(8 citation statements)

References 21 publications

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“…IgG1 is the most abundant human IgG isotype[23] and is thought to be largely involved in recognising protein antigens. As a non-encapsulated bacterium, NTHi immune correlates of protection from infection are likely to include IgG1 against Protein D, Protein F and outer membrane proteins, such as omp6, all previously demonstrated to be potential NTHi vaccine candidates[24–26]. Deficiencies in airway IgG1 may therefore predispose to infection of the COPD lung by this bacterium.…”

Section: Discussionmentioning

confidence: 99%

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

et al. 2016

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Non-typeable Haemophilus influenzae (NTHi) is a key pathogen in COPD, being associated with airway inflammation and risk of exacerbation. Why some patients are susceptible to colonisation is not understood. We hypothesised that this susceptibility may be due to a deficiency in mucosal humoral immunity. The aim of our study (NCT01701869) was to quantify the amount and specificity of antibodies against NTHi in the lungs and the associated risk of infection and inflammation in health and COPD. Phlebotomy, sputum induction and bronchoscopy were performed on 24 mild-to-moderate COPD patients and 8 age and smoking-matched controls. BAL (Bronchoalveolar lavage) total IgG1, IgG2, IgG3, IgM and IgA concentrations were significantly increased in COPD patients compared to controls. NTHi was detected in the lungs of 7 of the COPD patients (NTHi+ve—29%) and these patients had a higher median number of previous exacerbations than NTHi-ve patients as well as evidence of increased systemic inflammation. When comparing NTHi+ve versus NTHi-ve patients we observed a decrease in the amount of both total IgG1 (p = 0.0068) and NTHi-specific IgG1 (p = 0.0433) in the BAL of NTHi+ve patients, but no differences in total IgA or IgM. We observed no evidence of decreased IgG1 in the serum of NTHi+ve patients, suggesting this phenomenon is restricted to the airway. Furthermore, the NTHi+ve patients had significantly greater levels of IL-1β (p = 0.0003), in BAL than NTHi-ve COPD patients.This study indicates that the presence of NTHi is associated with reduced levels and function of IgG1 in the airway of NTHi-colonised COPD patients. This decrease in total and NTHI-specific IgG1 was associated with greater systemic and airway inflammation and a history of more frequent exacerbations and may explain the susceptibility of some COPD patients to the impacts of NTHi.

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Section: Discussionmentioning

confidence: 99%

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

et al. 2016

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“…Previous studies by our group did not identify aberrant immune responses to NTHi proteins in young non-Aboriginal children with rAOM (14); however, others demonstrated that otitis-prone children have poor responses to NTHi proteins following AOM (23, 25). NTHi-specific antibody deficiencies have also been described for adults with chronic obstructive pulmonary disease (COPD), diabetes mellitus, and chronic renal failure, who experience high rates of NTHi infection, compared to age-matched healthy controls (45). Antibody deficiency was particularly evident in adults with COPD, with 63% of patients having no detectable anti-PD serum IgG (45).…”

Section: Discussionmentioning

confidence: 99%

“…NTHi-specific antibody deficiencies have also been described for adults with chronic obstructive pulmonary disease (COPD), diabetes mellitus, and chronic renal failure, who experience high rates of NTHi infection, compared to age-matched healthy controls (45). Antibody deficiency was particularly evident in adults with COPD, with 63% of patients having no detectable anti-PD serum IgG (45). These data suggest that populations at high risk of NTHi infection have impaired responses to NTHi antigens, particularly PD.…”

Section: Discussionmentioning

confidence: 99%

Australian Aboriginal Children with Otitis Media Have Reduced Antibody Titers to Specific Nontypeable Haemophilus influenzae Vaccine Antigens

Thornton

Kirkham

Corscadden

et al. 2017

Clin Vaccine Immunol

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Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bacteria in these high-risk populations are lacking. Nontypeable Haemophilus influenzae (NTHi) is the predominant otopathogen in Australia. No vaccines are currently licensed to target NTHi; however, protein D (PD) from NTHi is included as a carrier protein in the 10-valent pneumococcal polysaccharide conjugate vaccine (PHiD10-CV), and other promising protein vaccine candidates exist, including outer membrane protein 4 (P4) and protein 6 (P6). We measured the levels of serum and salivary IgA and IgG against PD, P4, and P6 in Aboriginal and non-Aboriginal children with chronic OM who were undergoing surgery and compared the levels with those in healthy non-Aboriginal children (controls). We found that Aboriginal cases had lower serum IgG titers to all NTHi proteins assessed, particularly PD. In contrast, serum IgA and salivary IgA and IgG titers to each of these 3 proteins were equivalent to or higher than those in both non-Aboriginal cases and healthy controls. While serum antibody levels increased with age in healthy controls, no changes in titers were observed with age in non-Aboriginal cases, and a trend toward decreasing titers with age was observed in Aboriginal cases. This suggests that decreased serum IgG responses to NTHi outer membrane proteins may contribute to the development of chronic and severe OM in Australian Aboriginal children and other indigenous populations. These data are important for understanding the potential benefits of PHiD10-CV implementation and the development of NTHi protein-based vaccines for indigenous populations.

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“…While the bacterial pathogens invading the middle ear cavities and the lower respiratory tracts of these patients are similar, the bacterial clearance mechanisms and immunity induced following a parenterally administered vaccine may differ between the two anatomical sites. In addition, a recent small study identified significantly reduced natural antibody levels to PD in adult patients with COPD (without exacerbation at time of specimen collection) and secondary immunodeficiency disorders compared to healthy controls, and that natural antibody levels declined with age [56]. Suboptimal circulating functional T-helper memory and reduced IgG responses to S. pneumoniae or H. influenzae have also been identified in otitis-prone children [49].…”

Section: Discussionmentioning

confidence: 99%

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: protocol for a randomised controlled trial

O'Grady

Grimwood

Cripps

et al. 2013

Trials

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BackgroundRecurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children.MethodsA multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW135) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and ≥6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged ≥6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine- related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged ≥6 years; and vaccine safety.DiscussionAs H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.Trial registrationAustralia and New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12612000034831.

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Antibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency

Cited by 11 publications

References 21 publications

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

Australian Aboriginal Children with Otitis Media Have Reduced Antibody Titers to Specific Nontypeable Haemophilus influenzae Vaccine Antigens

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: protocol for a randomised controlled trial

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