The burden of nonencapsulated Haemophilus influenzae in children and potential for prevention

St. George's University of London, Cranmer Terrace, London, UK.
Current Opinion in Infectious Diseases (Impact Factor: 5.01). 06/2012; 25(3):266-72. DOI: 10.1097/QCO.0b013e32835310a4
Source: PubMed


In countries with established Haemophilus influenzae serotype b (Hib) immunization programmes, nonencapsulated H. influenzae (ncHi) is responsible for most invasive H. influenzae infections across all age groups and is associated with higher case fatality. A pneumococcal conjugate vaccine has recently been licensed, which may potentially also protect against invasive H. influenzae infections.
Invasive ncHi disease is uncommon in childhood but has a much higher incidence in the first month of life. Most neonates with invasive ncHi infections are born prematurely and develop septicaemia in the first 48 h of life which can be fatal. After this period, invasive ncHi incidence falls rapidly and remains low throughout childhood. Most infants and children who develop invasive ncHi disease have significant underlying comorbidities, particularly neurological disease, malignancy and other conditions requiring immunosuppressive therapy. Although characteristically associated with respiratory tract infections, at least a quarter of invasive ncHi infections present with meningitis.
A vaccine against ncHi could have an important preventive role in children with comorbidities. Future studies should focus on assessing specific risk factors for neonatal and childhood ncHi disease and long-term outcomes of children with invasive ncHi meningitis.

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    • "Occasionally, NTHi can cause serious invasive infections, including septicaemia and meningitis, particularly in individuals with underlying co-morbidities, and is associated with significant case-fatality [3] [4]. However, the main burden of disease with NTHi is pneumonia [5] and although data on the aetiology of non-bacteraemic pneumonia are limited, numerous studies have identified NTHi in lung aspirates and sputum of patients with pneumonia [6] [7]. "
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    ABSTRACT: A recently-licensed 10-valent pneumococcal conjugate vaccine (PHiD-CV; Synflorix, GSK) uses Protein D from Haemophilus influenzae as a carrier protein. PHiD-CV therefore has the potential to provide additional protection against nontypeable H. influenzae (NTHi). NTHi frequently causes respiratory tract infections and is associated with significant morbidity and mortality worldwide and there is currently no vaccine. We developed mouse models of NTHi infection and influenza/NTHi superinfection. Mice were immunized with PHiD-CV, heat-killed NTHi, or a 13-valent pneumococcal conjugate vaccine that did not contain Protein D (PCV13; Prevenar, Pfizer) and then infected intranasally with NTHi. Infection with NTHi resulted in weight loss, inflammation and airway neutrophilia. In a superinfection model, prior infection with pandemic H1N1 influenza virus (strain A/England/195/2009) augmented NTHi infection severity, even with a lower bacterial challenge dose. Immunization with PHiD-CV produced high levels of antibodies that were specific against Protein D, but not heat-killed NTHi. Immunization with PHiD-CV led to a slight reduction in bacterial load, but no change in disease outcome. PHiD-CV induced high levels of Protein D-specific antibodies, but did not augment pulmonary clearance of NTHi. We found no evidence to suggest that PHiD-CV will offer added benefit by preventing NTHi lung infection. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jul 2015 · Vaccine
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    • "Among the vaccine candidates, pneumococcal surface protein A (PspA), pneumococcal histidine triad proteins-PhtD and PhtE, a choline binding protein-PcpA, a murein hydrolase (-LytB) and a non-toxic pneumolysin derivative PlyD1, have emerged as most likely to proceed to clinical trials in humans [7] [8] [9] [10] [11]. Besides that, at this time there is no licensed vaccine to prevent NTHi infections such as acute otitis media, sinusitis, bronchopneumonia and acute exacerbations of chronic bronchitis [12]. Protein D has been used as a carrier in a conjugate Spn polysaccharide vaccine, shown to be immunogenic in young children and to possibly have efficacy in reducing acute otitis media caused by NTHi [13], but it is yet awaiting approval from regulatory authorities as an NTHi vaccine. "
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    ABSTRACT: We characterized cytokine profiles of CD4(+) T-helper (h) cells in adults and young children to ascertain if responses occur to next-generation candidate vaccine antigens PspA, PcpA, PhtD, PhtE, Ply, LytB of Streptococcus pneumonia (Spn) and protein D and OMP26 of non-typeable Haemophilus influenzae (NTHi). Adults had vaccine antigen-specific Th1 and Th2 cells responsive to all antigens evaluated whereas young children had significant numbers of vaccine antigen-specific CD4(+) T cells producing IL-2, (p=0.004). Vaccine antigen-specific CD4(+) T-cell populations in adults were largely of effector (TEM) and/or central memory (TCM) phenotypes as defined by CD45RA(-)CCR7(+) or CD45RA(-)CCR7(-) respectively; however among young children antigen-specific IL-2 producing CD4(+) T cells demonstrated CD45RA(+) expression (non-memory cells). We conclude that adults have circulating memory CD4(+) T cells (CD45RA(-)) that can be stimulated by all the tested Spn and NTHi protein vaccine candidate antigens, whereas young children have a more limited response.
    Full-text · Article · Apr 2013 · Vaccine
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    ABSTRACT: Background: Pneumococcus, meningococcus, and Haemophilus influenzae cause a similar spectrum of infections in the ear, lung, blood, and brain. They share cross-reactive antigens that bind to the laminin receptor of the blood-brain barrier as a molecular basis for neurotropism, and this step in pathogenesis was addressed in vaccine design. Methods: Biologically active peptides derived from choline-binding protein A (CbpA) of pneumococcus were identified and then genetically fused to L460D pneumolysoid. The fusion construct was tested for vaccine efficacy in mouse models of nasopharyngeal carriage, otitis media, pneumonia, sepsis, and meningitis. Results: The CbpA peptide-L460D pneumolysoid fusion protein was more broadly immunogenic than pneumolysoid alone, and antibodies were active in vitro against Streptococcus pneumoniae, Neisseria meningitidis, and H. influenzae. Passive and active immunization protected mice from pneumococcal carriage, otitis media, pneumonia, bacteremia, meningitis, and meningococcal sepsis. Conclusions: The CbpA peptide-L460D pneumolysoid fusion protein was broadly protective against pneumococcal infection, with the potential for additional protection against other meningeal pathogens.
    Full-text · Article · Sep 2013 · The Journal of Infectious Diseases
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