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

ABSTRACT 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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Immunogenicity of Nontypeable Haemophilus influenzae Outer Membrane Vesicles and Protective Ability in the Chinchilla Model of Otitis Media

Clinical and Vaccine Immunology ◽

10.1128/cvi.00138-17 ◽

2017 ◽

Vol 24 (10) ◽

Cited By ~ 5

Author(s):

Linda E. Winter ◽

Stephen J. Barenkamp

Keyword(s):

Haemophilus Influenzae ◽

Outer Membrane ◽

Otitis Media ◽

Outer Membrane Proteins ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Nontypeable Haemophilus Influenzae ◽

Protective Ability ◽

Nthi Strain ◽

Specific Antisera

ABSTRACT Outer membrane vesicles (OMVs) produced by Gram-negative bacteria are enriched in several outer membrane components, including major and minor outer membrane proteins and lipooligosaccharide. We assessed the functional activity of nontypeable Haemophilus influenzae (NTHi) OMV-specific antisera and the protective ability of NTHi OMVs as vaccine antigens in the chinchilla otitis media model. OMVs were purified from three HMW1/HMW2-expressing NTHi strains, two of which were also engineered to overexpress Hia proteins. OMV-specific antisera raised in guinea pigs were assessed for their ability to mediate killing of representative NTHi in an opsonophagocytic assay. The three OMV-specific antisera mediated killing of 18 of 65, 24 of 65, and 30 of 65 unrelated HMW1/HMW2-expressing NTHi strains. Overall, they mediated killing of 39 of 65 HMW1/HMW2-expressing strains. The two Hia-expressing OMV-specific antisera mediated killing of 17 of 25 and 14 of 25 unrelated Hia-expressing NTHi strains. Overall, they mediated killing of 20 of 25 Hia-expressing strains. OMVs from prototype NTHi strain 12 were used to immunize chinchillas and the course of middle ear infection was monitored following intrabullar challenge with the homologous strain. All control animals developed culture-positive otitis media, as did two of three HMW1/HMW2-immunized animals. All OMV-immunized animals, with or without supplemental HMW1/HMW2 immunization, were completely protected against otitis media. NTHi OMVs are the first immunogens examined in this model that provided complete protection with sterile immunity after NTHi strain 12 challenge. These data suggest that NTHi OMVs hold significant potential as components of protective NTHi vaccines, possibly in combination with HMW1/HMW2 proteins.

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Antibodies to Haemophilus influenzae type b outer membrane proteins in children with epiglottitis or meningitis and in healthy controls.

Infection and Immunity ◽

10.1128/iai.61.4.1531-1537.1993 ◽

1993 ◽

Vol 61 (4) ◽

pp. 1531-1537 ◽

Cited By ~ 6

Author(s):

P D Johnson ◽

S J MacInnes ◽

G L Gilbert

Keyword(s):

Membrane Proteins ◽

Haemophilus Influenzae ◽

Outer Membrane ◽

Outer Membrane Proteins ◽

Haemophilus Influenzae Type ◽

Haemophilus Influenzae Type B ◽

Healthy Controls ◽

Type B

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Serum antibody response to three non-typeable Haemophilus influenzae outer membrane proteins during acute otitis media and nasopharyngeal colonization in otitis prone and non-otitis prone children

Vaccine ◽

10.1016/j.vaccine.2010.11.055 ◽

2011 ◽

Vol 29 (5) ◽

pp. 1023-1028 ◽

Cited By ~ 45

Author(s):

Ravinder Kaur ◽

Janet R. Casey ◽

Michael E. Pichichero

Keyword(s):

Membrane Proteins ◽

Antibody Response ◽

Haemophilus Influenzae ◽

Outer Membrane ◽

Otitis Media ◽

Outer Membrane Proteins ◽

Serum Antibody ◽

Acute Otitis Media ◽

Nasopharyngeal Colonization ◽

Serum Antibody Response

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10-Valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine (PHiD-CV10) versus 13-valent pneumococcal conjugate vaccine (PCV13) as a booster dose to broaden and strengthen protection from otitis media (PREVIX_BOOST) in Australian Aboriginal children: study protocol for a randomised controlled trial

BMJ Open ◽

10.1136/bmjopen-2019-033511 ◽

2020 ◽

Vol 10 (5) ◽

pp. e033511

Author(s):

Victor M Oguoma ◽

Nicole Wilson ◽

Kim Mulholland ◽

Mathuram Santosham ◽

Paul Torzillo ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Otitis Media ◽

Conjugate Vaccine ◽

Booster Dose ◽

Controlled Trial ◽

Australian Aboriginal ◽

Department Of Health ◽

Randomised Controlled ◽

Antibody Levels ◽

Aboriginal Children

IntroductionStreptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A.Methods and analysesOur randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported.Ethics and disseminationEthics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals.Trial registration numberNCT01735084.

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Evaluation of mixtures of purified Haemophilus influenzae outer membrane proteins in protection against challenge with nontypeable H. influenzae in the chinchilla otitis media model.

Infection and Immunity ◽

10.1128/iai.61.5.1950-1957.1993 ◽

1993 ◽

Vol 61 (5) ◽

pp. 1950-1957 ◽

Cited By ~ 41

Author(s):

B A Green ◽

M E Vazquez ◽

G W Zlotnick ◽

G Quigley-Reape ◽

J D Swarts ◽

...

Keyword(s):

Membrane Proteins ◽

Haemophilus Influenzae ◽

Outer Membrane ◽

Otitis Media ◽

Outer Membrane Proteins

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The immunological role of the outer membrane proteins of non-typableHemophilus influenzae in otitis media with effusion in children

European Archives of Oto-Rhino-Laryngology ◽

10.1007/bf00627639 ◽

1991 ◽

Vol 248 (8) ◽

pp. 483-486 ◽

Cited By ~ 1

Author(s):

Osamu Fujioka

Keyword(s):

Membrane Proteins ◽

Outer Membrane ◽

Otitis Media ◽

Otitis Media With Effusion ◽

Outer Membrane Proteins

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Outer Membrane Protein Composition in Disease Isolates of Haemophilus influenzae : Pathogenic and Epidemiological Implications

Infection and Immunity ◽

10.1128/iai.30.3.709-717.1980 ◽

1980 ◽

Vol 30 (3) ◽

pp. 709-717

Author(s):

Marilyn R. Loeb ◽

David H. Smith

Keyword(s):

Membrane Proteins ◽

Membrane Protein ◽

Haemophilus Influenzae ◽

Outer Membrane ◽

Outer Membrane Protein ◽

Outer Membrane Proteins ◽

Protein Composition ◽

The Other ◽

Major Protein ◽

Single Strain

The outer membrane protein composition of 50 disease isolates of Haemophilus influenzae has been determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. All strains, including 28 strains of serotype b , one strain each of serotypes a, c, d, e , and f , and 17 untypable strains, had an outer membrane protein composition typical of gram-negative bacteria, i.e., these membranes contained two to three dozen proteins with four to six proteins accounting for most of their protein content. Variation in the mobility of these major outer membrane proteins from strain to strain was common but not universal; the observed patterns provided useful data and new insight into the epidemiology of type b disease. The basic findings can be summarized as follows: (i) All 50 strains possessed three proteins (one minor and two major) each having identical mobilities. The other proteins, both major and minor, varied in mobility. (ii) All type b strains possessed a fourth (major) protein of identical mobility. (iii) The 28 type b strains, on the basis of the mobility of the six major outer membrane proteins, could be divided into eight subtypes. Of all the other strains examined, both typable and untypable, only the serotype a strain belonged to one of these subtypes. (iv) The untypable strains showed considerable variation in the mobilities of their major outer membrane proteins. Of these 17 strains, 13 had an additional major outer membrane protein not present in encapsulated strains. (v) The outer membrane protein composition of a single strain remained unchanged after many passages on solid media, but varied with the growth phase. (vi) The outer membrane protein composition of isolates obtained from nine patients during an epidemic of type b meningitis varied, indicating that a single strain was not responsible for the epidemic. At least five different strains were responsible for these nine cases. (vii) Identical outer membrane protein compositions were observed in the following: in a type b strain and a mutant of this strain deficient in capsule production, indicating that the level of capsule synthesis is not obviously related to outer membrane protein composition; in type b strains isolated from different anatomic sites of patients acutely ill with meningitis, indicating that the strain associated with bacteremia is the same as that isolated from the cerebrospinal fluid; in type b strains isolated from siblings who contracted meningitis at about the same time, indicating infection with the same strain; and in type b strains isolated from the initial and repeat infection of a single patient, suggesting that reinfection was due to the same strain.

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