Vaccines for Nontypeable Haemophilus influenzae: the Future Is Now

Murphy, Timothy F.

doi:10.1128/cvi.00089-15

Cited by 96 publications

(90 citation statements)

References 110 publications

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“…Vaccines composed of polysaccharide capsule conjugated to protein carriers have virtually eliminated infections caused by encapsulated H. influenzae type b, including meningitis and other systemic infections, in regions where the vaccines are widely administered (6,7). However, these conjugate vaccines have no effect on infections caused by NTHi, and in regions with H. influenzae type b vaccination programs, nontypeable strains are now the most common cause of noninvasive H. influenzae infection, so that the development of the vaccine against NTHi is an urgent and challenging task (8)(9)(10).…”

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confidence: 99%

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Chen

Shang

et al. 2016

Clin Vaccine Immunol

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e Nontypeable Haemophilus influenzae (NTHi) is one of the most common etiologies of acute otitis media, rhinosinusitis, and pneumonia. Outer membrane proteins (OMPs) are the main focus in new vaccine development against NTHi, as the H. influenzae type b (Hib) vaccine does not cover noncapsulated NTHi. The OMPs P6 and protein D are the most promising candidate antigens for an NTHi vaccine, and low antibody levels against them in serum may be correlated with infection caused by NTHi. In the current study, we measured the antibody titers against P6, protein D, and their T-and B-cell combined peptide epitopes in healthy individuals of different ages. We found that children <1 month old had the lowest antibody levels against NTHi P6, protein D, and their T-and B-cell combined antigenic epitopes. Antibody titers increased at ages 1 to 6 months, peaked at 7 months to 3 years, and remained high at 4 to 6 years. The antibody titers started to decrease after 6 years and were the lowest in the 21-to 30-year group. The geometric mean titers (GMTs) of T-and B-cell combined antigenic epitopes in P6 and protein D were positively correlated with those of the protein antigens. Among 12 peptides tested, P6-61, P6-123, and protein D-167 epitopes were better recognized than others in human serum. These findings might contribute to the development of an effective serotypeindependent vaccine for H. influenzae. Haemophilus influenzae is one of the normal inhabitants of the human nasopharynx and is responsible for pneumonia, acute otitis media (AOM), and acute rhinosinusitis (1-3). The presence or absence of a polysaccharide capsule segregates this bacterial species into two well-defined groups: one group of encapsulated strains and another group of noncapsulated strains, commonly referred to as nontypeable H. influenzae (NTHi) (3). Common infections caused by NTHi include otitis media in children and lower airway infections of chronic obstructive pulmonary disease in adults (4, 5). Vaccines composed of polysaccharide capsule conjugated to protein carriers have virtually eliminated infections caused by encapsulated H. influenzae type b, including meningitis and other systemic infections, in regions where the vaccines are widely administered (6, 7). However, these conjugate vaccines have no effect on infections caused by NTHi, and in regions with H. influenzae type b vaccination programs, nontypeable strains are now the most common cause of noninvasive H. influenzae infection, so that the development of the vaccine against NTHi is an urgent and challenging task (8-10).Since NTHi organisms are noncapsulated bacteria, the outer membrane proteins (OMPs) are the main targets for vaccine designers. Several research groups have identified conserved surface proteins and tested them as putative vaccines, and the conserved NTHi antigens with demonstrated preclinical protective capacity have been identified, among which P6 and protein D are the most widely studied (11)(12)(13)(14).Experimental data derived from humans and animal models indicate t...

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confidence: 99%

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Chen

Shang

et al. 2016

Clin Vaccine Immunol

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“…Comparative analyses of 25 whole-genome sequences of H. haemolyticus (5) and H. influenzae (20) were performed in an effort to assess whether strains from these two species, which are often confused using classical phenotypic or biochemical methods, can be clearly distinguished at the genomic level. Phylogenetic analysis using individual (16S rRNA) or multiple (MLST) gene loci clearly distinguishes H. haemolyticus and H. influenzae evolutionary lineages (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…NT H. influenzae has emerged as the major cause of invasive H. influenzae disease since the implementation of H. influenzae serotype b (H. influenzae b) vaccine (4). NT H. influenzae infections such as childhood otitis media and respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD) result in an enormous social and economic burden to societies (5). H. haemolyticus was recently reported to cause invasive disease (1).…”

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confidence: 99%

Comparative Genomic Analysis of Haemophilus haemolyticus and Nontypeable Haemophilus influenzae and a New Testing Scheme for Their Discrimination

Rishishwar

Sivadas

et al. 2016

J Clin Microbiol

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g Haemophilus haemolyticus has been recently discovered to have the potential to cause invasive disease. It is closely related to nontypeable Haemophilus influenzae (NT H. influenzae). NT H. influenzae and H. haemolyticus are often misidentified because none of the existing tests targeting the known phenotypes of H. haemolyticus are able to specifically identify H. haemolyticus. Through comparative genomic analysis of H. haemolyticus and NT H. influenzae, we identified genes unique to H. haemolyticus that can be used as targets for the identification of H. haemolyticus. A real-time PCR targeting purT (encoding phosphoribosylglycinamide formyltransferase 2 in the purine synthesis pathway) was developed and evaluated. The lower limit of detection was 40 genomes/PCR; the sensitivity and specificity in detecting H. haemolyticus were 98.9% and 97%, respectively. To improve the discrimination of H. haemolyticus and NT H. influenzae, a testing scheme combining two targets (H. haemolyticus purT and H. influenzae hpd, encoding protein D lipoprotein) was also evaluated and showed 96.7% sensitivity and 98.2% specificity for the identification of H. haemolyticus and 92.8% sensitivity and 100% specificity for the identification of H. influenzae, respectively. The dual-target testing scheme can be used for the diagnosis and surveillance of infection and disease caused by H. haemolyticus and NT H. influenzae. Haemophilus haemolyticus is a human commensal that colonizes the respiratory tract. It shares high similarities in morphology, biochemistry, and genetics with nontypeable Haemophilus influenzae (NT H. influenzae) (1-3). NT H. influenzae has emerged as the major cause of invasive H. influenzae disease since the implementation of H. influenzae serotype b (H. influenzae b) vaccine (4). NT H. influenzae infections such as childhood otitis media and respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD) result in an enormous social and economic burden to societies (5). H. haemolyticus was recently reported to cause invasive disease (1). These cases were previously misidentified as NT H. influenzae due to the lack of proper identification methods to discriminate between the two species (6). Reevaluation of NT H. influenzae cases from previous years revealed that about 2% (7/374) of the NT H. influenzae invasive cases reported from Active Bacterial Core surveillance (ABCs) were in fact caused by H. haemolyticus (1).Misidentification of H. haemolyticus as NT H. influenzae has been repeatedly reported by multiple research groups, with up to 40% of isolates being misidentified as NT H. influenzae using classical phenotypic methods in clinical microbiology laboratories (1, 7-11). The misidentification of H. haemolyticus has a potential impact on accurate assessment of the prevalence of antibioticresistant NT H. influenzae (12). Therefore, a rapid and accurate method is needed to distinguish H. haemolyticus from NT H. influenzae and to better understand the epidemiology of H. haemolyticus infections....

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“…A number of lower-molecular-weight bacterial surface proteins, including protein D, P2, P5, and P6, among others, remain under active investigation as potential vaccine candidates (48), and several of these proteins have been demonstrated to be naturally immunogenic in the course of NTHi colonization or disease (13,25). In the WC-RIP studies described here, we noted occasional antibody activity against lower-molecular-weight proteins, one of which was likely the P2 protein, based upon the apparent molecular weight of the precipitated bands (Fig.…”

Section: Discussionmentioning

confidence: 99%

Naturally Acquired HMW1- and HMW2-Specific Serum Antibodies in Adults and Children Mediate Opsonophagocytic Killing of Nontypeable Haemophilus influenzae

Winter

Barenkamp

2016

Clin Vaccine Immunol

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The HMW1 and HMW2 proteins are highly immunogenic adhesins expressed by approximately 75% of nontypeable Haemophilus influenzae (NTHi) strains, and HMW1-and HMW2-specific antibodies can mediate opsonophagocytic killing of NTHi. In this study, we assessed the ability of HMW1-and HMW2-specific antibodies in sera from healthy adults and convalescent-phase sera from children with NTHi otitis media to mediate killing of homologous and heterologous NTHi. The serum samples were examined pre-and postadsorption on HMW1 and HMW2 affinity columns, and affinity-purified antibodies were assessed for ability to mediate killing of homologous and heterologous strains. Adult serum samples mediated the killing of six prototype NTHi strains at titers of <1:10 to 1:1,280. HMW1-and HMW2-adsorbed sera demonstrated unchanged to 8-fold decreased opsonophagocytic titers against the homologous strains. Each affinity-purified antibody preparation mediated the killing of the respective homologous strain at titers of <1:10 to 1:320 and of the five heterologous strains at titers of <1:10 to 1:320, with most preparations killing most heterologous strains to some degree. None of the acute-phase serum samples from children mediated killing, but each convalescent-phase serum sample mediated killing of the infecting strain at titers of 1:40 to 1:640. HMW1-and HMW2-adsorbed convalescent-phase serum samples demonstrated >4-fold decreases in titer. Three of four affinitypurified antibody preparations mediated killing of the infecting strain at titers of 1:20 to 1:320, but no killing of representative heterologous strains was observed. HMW1-and HMW2-specific antibodies capable of mediating opsonophagocytic killing are present in the serum from normal adults and develop in convalescent-phase sera of children with NTHi otitis media. Continued investigation of the HMW1 and HMW2 proteins as potential vaccine candidates for the prevention of NTHi disease is warranted. Nontypeable Haemophilus influenzae (NTHi) comprises small Gram-negative bacteria that colonize the upper respiratory tract of humans beginning at a very early age (1). Although these organisms are normally commensals, when host defenses are compromised by underlying medical conditions, such as malnutrition, immunodeficiency, chronic lung disease, or acute viral infection, disease caused by NTHi may develop (2, 3). Among children in the developed world, NTHi is currently responsible for an estimated 40 to 50% of the cases of acute otitis media and an even higher percentage of cases of chronic and recurrent disease (4, 5). Among adults, particularly among patients with chronic obstructive pulmonary disease, NTHi is a major cause of illness, particularly during the acute exacerbations that often characterize this disease (6). A vaccine capable of preventing disease caused by these organisms would offer substantial benefit to adult and pediatric populations alike.NTHi vaccine development efforts are ongoing in a number of laboratories. Published studies have suggested that NTHi outer membrane pr...

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Vaccines for Nontypeable Haemophilus influenzae: the Future Is Now

Abstract: Infections due to nontypeable

Cited by 96 publications

References 110 publications

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Comparative Genomic Analysis of Haemophilus haemolyticus and Nontypeable Haemophilus influenzae and a New Testing Scheme for Their Discrimination

Naturally Acquired HMW1- and HMW2-Specific Serum Antibodies in Adults and Children Mediate Opsonophagocytic Killing of Nontypeable Haemophilus influenzae

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