Invasive Hib Disease Research Articles

Oropharyngeal Colonization of Haemophilus influenzae Type b and Serologic Response After Administration of Third Dose of Pentavalent Vaccine to 12-Month-Old Children in Karaj, Iran, 2016

Background: The administration of Haemophilus influenzae type b (Hib) conjugate vaccine led to a decrease of over 90% in the prevalence of severe Hib diseases in the countries with universal coverage vaccine. After addition of Hib vaccine to the national vaccination program and since no study has yet investigated this subject. Objectives: The current study aimed at investigating the serologic response and assessing oropharyngeal colonization with Hib after the last dose of vaccine. Methods: A total of 500 blood and oropharyngeal samples were collected from one-year-old children referred to Karaj health care centers, Iran. Demographic information and risk factors of the children were collected. Oropharyngeal and blood samples were transferred to the laboratory to determine antibody titer by the enzyme-linked immunosorbent assay (ELISA) technique, culture testing, and polymerase chain reaction (PCR). Results: In the current study, 11.8% of children (95% confidence interval (CI): 8.97 - 14.63) had an anti-Hib IgG titer of ≥ 5 µg/mL. Geometric mean titer (GMT) of vaccine antibody was 6.92 µg/mL (95% CI: 6.76 - 7.08); 9% of oropharyngeal culture results were positive for H. influaenzae (non-type b) and 8.2% were confirmed by PCR. Prevalence of oropheryngeal Hib colonization was 0.02%. There was no significant correlation between the titer of H. influaenzae antibody and positive culture of H. influaenzae and the other studied variables (P > 0.05). Conclusions: In Iran, similar to most countries, pentavalent vaccine in national vaccination program decreased the prevalence of Hib colonization. Prevalence of Hib colonization is an important factor in invasive diseases incidence. It is suggested that further studies asses the prevalence of invasive Hib diseases after national vaccination.

Increasing trend in invasive non-typeable Haemophilus influenzae disease and molecular characterization of the isolates, Italy, 2012–2016

Routine immunization of infants with conjugate vaccines against Haemophilus influenzae type b (Hib) has greatly reduced the incidence of invasive Hib disease; however changes in the epidemiology of H. influenzae disease have occurred. We describe the epidemiology of invasive H. influenzae disease and the characterization of isolates collected in Italy between 2012 and 2016.Trends in the overall incidence of invasive H. influenzae disease were calculated. Isolates were characterized by PCR capsular genotyping, antimicrobial susceptibility testing, ampicillin resistance-associated gene sequencing and MLST. Trends in incidence by serotype and serotype-specific distribution were estimated using multiple imputation of missing data.The overall incidence of invasive H. influenzae disease increased 22.5% yearly (from 0.11/100,000 in 2012 to 0.24/100,000 in 2016). Most cases (82.0%) were due to non-typeable H. influenzae (NTHi). An increasing trend in NTHi disease burden was estimated; the highest rise was among infants <12 months (40.8% annual increase). Invasive Hib disease showed a fluctuating trend with a clear increase in 2016, while we found an increasing trend for disease due to non-Hib capsulated serotypes in the elderly (32.9% annual increase). Ampicillin resistance mediated by either β-lactamase or altered penicillin-binding proteins 3 (PBP3) increased. In spite of genetic diversity of NTHi, sequence types (STs) associated with ampicillin resistance status were identified (ST103/ST106 linked to β-lactamase production and ST14 linked to a specific PBP3 substitution pattern). The increasing trend in invasive NTHi disease in infants is of concern underlying the need for the development of a future vaccine against NTHi.

Antibodies prevalence against Haemophilus influenzae type b in Jeddah population, Saudi Arabia. I. Total antibodies.

In this national comprehensive seroprevalence study, indirect ELISA test was used to evaluate Haemophilus influenzae type b (Hib) anti-polyribosyl-ribitol phosphate (PRP) total antibodies (IgM, IgG, IgA) in 1,003 sera samples from routine medical check-up of healthy individuals attending the local medical facility in Jeddah, Saudi Arabia in the period from February 2014 to January 2016. Serum anti-CPS antibodies confer immunity against invasive Hib disease. An anti-CPS concentration of ⩾0.15 μg/mL is believed to be a serological indication for short-term immunity protection against invasive Hib disease, while a concentration of ⩾ 1.0 μg/mL is believed to be long-term protective. Results showed higher level of anti-Hib IgG (2.41 μg/ml average geometric mean concentration (GMC) regardless of age and gender, followed by levels of IgM (0.91 μg/ml) and IgA (0.34 μg/ml), reflecting the community immunity against Hib. Low anti-Hib level (< 0.15 μg/ml of anti-PRP IgG) in elderly people (males aged 57-91 years and females aged 35-64 years) may indicate a need for a booster dose of Hib vaccine to elderly people in the community. The IgG prevalence over IgM, and IgM prevalence over IgA indicate the major role of IgG over IgM and IgA in keeping immunity in the track against Hib. Low level of IgM and IgA comparing to IgG may indicate the absence of Hib acute infections in the population.

A nationwide population-based surveillance of invasive Haemophilus influenzae diseases in children after the introduction of the Haemophilus influenzae type b vaccine in Japan

BackgroundHaemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. MethodsTo evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008–2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. ResultsDuring the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013–2017 decreased by 93% (IRR: 0.07, 95%CI 0.05–0.10, p < 0.001) compared with those occurring during 2008–2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. ConclusionsAfter the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types.

Immune responses to vaccine-preventable diseases among toddlers and preschool children after primary immunization and first booster in Northwestern Algiers, Algeria

ObjectivesTo determine immune responses to selected vaccine-preventable communicable diseases: pertussis, diphtheria and Haemophilus influenzae type b (Hib11Hib: Haemophilus influenzae type b.) in Algerian toddlers and preschool children after primary vaccination and first booster, recruited from three local healthcare facilities in Northwestern Algiers. MethodsThe information of demographic characteristics and vaccination status were collected for each subject by questionnaire. Specific antibody levels and Hib antibody avidity were determined using commercial ELISA kits. ResultsA total of eighty-one subjects aged between 19 and 55 months were studied. Almost all subjects were fully protected against diphtheria (76/81; 93.83%; 95% CI22CI: confidence intervals.: 86.35–97.33) and invasive Hib disease (29/30; 96.67%; 95% CI: 83.33–99.41), while only 20/78 (25.64%; 95% CI: 17.26–36.31) had anti-PT33PT: pertussis toxin. (pertussis toxin) antibody levels above 25 IU/ml. A significant decrease of anti-PT antibody levels was observed until the age of 36 months (p = 0.02). GMTs44GMT: geometric mean titer. (geometric mean titers) of anti-PT antibodies were low, but remain significantly higher in children ≤36 months of age (p = 0.02). Both GMT and rates of ≥0.15 μg/ml, ≥1 μg/ml, and ≥5 μg/ml titers were significantly higher in Hib-vaccinated subjects (p < 0.01). Relative Hib-avidity index (≥50%) and GMAI55GMAI: geometric mean avidity index. (geometric mean avidity index) were high in both Hib-vaccinated and -unvaccinated groups. ConclusionsAs shown in the present study, young children were fully protected against diphtheria and Hib, but showed low immunity to pertussis. Further sero-epidemiological studies including a large number of subjects with a wider range of age are needed to explore the immunity level in older children, adolescents and adults.

RNA gene profile variation in peripheral blood mononuclear cells from rhesus macaques immunized with Hib conjugate vaccine, Hib capsular polysaccharide and TT carrier protein

BackgroundThe Haemophilus influenzae type b (Hib) conjugate vaccine has been widely used in children to prevent invasive Hib disease because of its strong immunogenicity and antibody response induction relative to the capsular polysaccharide (CPS) antigen. The data from vaccine studies suggest that the conjugate vaccine contains carrier proteins that enhance and/or regulate the antigen’s immunogenicity, but the mechanism of this enhancement remains unclear.MethodsTo explore the immunological role of the conjugate vaccine, we compared the immune responses and gene profiles of rhesus macaques after immunization with CPS, carrier protein tetanus toxoid (TT) or conjugate vaccine.ResultsA distinct immune response was induced by the Hib conjugate vaccine but not by CPS or carrier protein TT. The genes that were dynamically regulated in conjunction with the macaque immune responses to the conjugate vaccine were investigated.ConclusionsWe propose that these genes are involved in the induction of specific immunity that is characterized by the appearance and maintenance of antibodies against Hib.

Haemophilus influenzae type b (Hib) seroprevalence and current epidemiology in England and Wales

IntroductionThe implementation of the Hib conjugate vaccine in the United Kingdom in 1992 resulted in a rapid decline in invasive Hib disease across all age groups. However, a resurgence in 2000–2002 prompted the introduction of additional control measures, including a routine 12-month booster in 2006. Here we describe results from a national serosurvey in children eligible for the 12-month booster and recent Haemophilus influenzae epidemiology in England and Wales. MethodsA national serosurvey was performed to determine the prevalence of anti-polyribosyl-phosphate (anti-PRP) IgG antibodies in 1000 residual samples from children up to 8 years of age in 2013–2014. Data were compared to previous national serosurveys performed by the same laboratory. Current epidemiology of invasive H. influenzae disease in England and Wales is also reported. ResultsMedian anti-PRP IgG concentrations were highest among 1 year olds at 4.4 µg/mL (IQR, 1.3–14.9; n = 99) and then declined rapidly but remained ≥1.0 µg/mL across the age-groups in the cohort eligible for the 12-month booster. Overall, 89% of children (719/817) had anti-PRP concentrations ≥0.15 µg/mL, the putative threshold for short-term protection against invasive Hib disease. During 2012–2016, annual Hib disease incidence remained below one case per million population, responsible for only 67 of 3523 laboratory-confirmed H. influenzae cases, including one case of Hib meningitis during the 5-year period. There were only two deaths within 30 days over the five-year period (case fatality rate, 3.0%). ConclusionsHib control in England and Wales is currently the best achieved since the vaccine was introduced more than two decades ago. However, Hib antibodies wane rapidly after the 12 months booster. Although most children remain protected against disease, antibody levels may not be high enough to prevent carriage among toddlers. Ongoing monitoring is essential to inform future vaccination policy.

Differences by sex in IgG levels following infant and childhood vaccinations: An individual participant data meta-analysis of vaccination studies

BackgroundIf immune responses to vaccination differ between males and females, sex-specific vaccination schedules may be indicated. We systematically reanalysed childhood vaccination studies conducted in The Netherlands for sex-differences in IgG-responses. To assess the impact of potential sex-differences in IgG-responses, we explored sex-differences in vaccine failure/effectiveness and reactogenicity. MethodsSix studies with IgG-measurements for 1577 children following infant pneumococcal (PCV7/PCV10/PCV13) and/or DTaP-IPV-Hib(-HepB) vaccinations, or the pre-school DTaP-IPV booster were included. We performed one-stage individual participant data meta-analyses per time-point of the effect of sex on IgG levels against pneumococcal serotypes, diphtheria toxoid, tetanus toxoid, pertussis Ptx/FHA/Prn and Hib-PRP using linear mixed models. Using existing study data, we compared reactogenicity after PCV7/PCV10 and DTaP-IPV-Hib(-HepB) vaccination in girls and boys. Vaccine failure/effectiveness was compared between girls and boys for invasive pneumococcal disease (IPD), invasive Hib disease and pertussis using notification data. ResultsFor pneumococcal vaccination, the geometric mean concentration ratio of IgG levels in girls versus boys pooled across serotypes was 1.15 (95%CI 0.91–1.45) 1 month following the primary series, 1.16 (1.02–1.32) at age 8 months, 1.12 (1.02–1.23) pre-booster (age 11 months) and 0.99 (0.89–1.10) post-booster (age 12 months). Diphtheria toxoid, tetanus toxoid, pertussis Ptx/FHA/Prn and Hib-PRP IgG levels did not differ between girls and boys, except for Hib post-booster (1.24; 95%CI 1.01–1.52) and tetanus before pre-school booster (0.71; 0.53–0.95). We found no difference between boys and girls in reactogenicity at age 4 or 11 months or in vaccine failure/effectiveness for IPD, invasive Hib disease or pertussis. ConclusionFor most vaccine antigens investigated, there were no consistent differences in vaccine-induced IgG levels. Vaccine-induced pneumococcal IgG levels were slightly higher in girls, but only between the primary series and the 11-month booster. These results, along with similar reactogenicity and vaccine failure/effectiveness, support the uniform infant vaccination schedule in the Dutch national immunisation programme.

The changing epidemiology of invasive Haemophilus influenzae disease: Emergence and global presence of serotype a strains that may require a new vaccine for control

BackgroundMore than two decades after the implementation of the Hib conjugate vaccine in North America, Haemophilus influenzae serotype a (Hia) has emerged as a significant cause of invasive disease in Indigenous communities. However, little is known about the global presence of this pathogen. MethodsWe interrogated the H. influenzae Multi-Locus Sequence Typing (MLST) website (https://pubmlst.org/hinfluenzae/) by selecting for serotype a records. We also updated our previous literature review on this subject matter. ResultsHia has been reported from at least 35 countries on six major continents. However, most Hia diseases were associated with Indigenous communities. Clonal analysis identified two clonal populations with one typified as ST-23 responsible for most invasive disease in North America and being the predominant clone described on the H. influenzae MLST website. Incidence of invasive Hia disease in Indigenous communities in North America are similar to the rates of Hib disease reported prior to the Hib conjugate vaccine era. Hia causes severe clinical diseases, such as meningitis, septicaemia, pneumonia, and septic arthritis with case-fatality rates between 5.6% and 33% depending on the age of the patient and the genetic makeup of the Hia strain. ConclusionAlthough invasive Hia disease can be found globally, the current epidemiological data suggest that this infection predominantly affects Indigenous communities in North America. The clinical disease of Hia and the clonal nature of the bacteria resemble that of Hib. The high incidence of invasive Hia disease in Indigenous communities, along with potential fatality and severe sequelae causing long-term disability in survivors, may support the development of a new Hia conjugate vaccine for protection against this infection similar in design to the one introduced in the 1990s to control invasive Hib disease.

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study

BackgroundBroad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. MethodsWe compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria–tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the “long-term seroprotection rate”, defined as the group proportion with anti-PRP antibody titers ⩾1.0μg/mL, after the primary series. ResultsLong-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group – PRP-T group) was 3.7% (95% confidence interval: 0.099–7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the “short-term seroprotection rate” (anti-PRP antibody titer ⩾0.15μg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. ConclusionThe immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns.Clinical trial registry: Registered on ClinicalTrials.gov: NCT01379846

Haemophilus influenzae Type b (Hib) Invasive Disease in Amish Children, Missouri 2014

Haemophilus influenzae Type b (Hib) Invasive Disease in Amish Children, Missouri 2014

Long-term trends in invasive Haemophilus influenzae type B disease among indigenous Australian children following use of PRP-OMP and PRP-T vaccines.

Among indigenous populations with high incidence and early onset of invasive Haemophilus influenzae type b (Hib) disease, PRP-OMP vaccines are used in the United States and PRP-T vaccines in Canada. In Australia, PRP-OMP vaccines were exclusively used in indigenous children from 1993 until they were replaced by PRP-T between late 2005 and 2009. Analytic descriptive study of 20 years of enhanced surveillance data (1993-2013) for invasive Hib disease in Australian children <10 years of age was conducted. Of 579 Hib cases under 10 years of age reported from vaccine introduction in 1993 to 2013, 78 (13%) were in indigenous children, 47 (60%) of whom lived in regions with high prevaccine incidence. In this population, incidence per 100,000 declined from 18.1 (95% confidence interval [CI]: 10.4, 29.4) in the early PRP-OMP period (1993-1996) to 6.2 (95% CI: 4.0, 9.2) and 4.7 (95% CI: 1.7, 10.3) in the later PRP-OMP (1996-2009) and PRP-T periods (2009-2013), respectively. The indigenous:nonindigenous incidence rate ratio increased to 43 (95% CI: 16, 145) and 58 (95% CI: 7, 2660) in the later PRP-OMP and PRP-T periods, respectively, more than 10-fold higher than in lesser-incidence Australian regions. We found no change in Hib incidence among indigenous Australian children living in high-incidence regions in the first 4 years following a change to PRP-T-containing combination vaccines. This may be of relevance to North American indigenous populations characterized by suboptimal living conditions and young age of onset for whom PRP-OMP continues to be recommended, such as Alaska Natives.

Trends in the epidemiology of invasive Haemophilus influenzae disease in Queensland, Australia from 2000 to 2013: what is the impact of an increase in invasive non-typable H. influenzae (NTHi)?

Following the introduction of vaccination against Haemophilus influenzae type b (Hib), cases of invasive encapsulated Hib disease have decreased markedly. This study aimed to examine subsequent epidemiological trends in invasive H. influenzae disease in Queensland, Australia and in particular, assess the clinical impact and public health implications of invasive non-typable H. influenzae (NTHi) strains. A multicentre retrospective study was conducted from July 2000 to June 2013. Databases of major laboratories in Queensland including Queensland Forensic and Scientific Services (jurisdictional referral laboratory for isolate typing) were examined to identify cases. Demographic, infection site, Indigenous status, serotype, and mortality data were collected. In total, 737 invasive isolates were identified, of which 586 (79·5%) were serotyped. Hib, NTHi and encapsulated non-b strains, respectively, constituted 12·1%, 69·1% and 18·8% of isolates. The predominant encapsulated non-b strains were f (45·5%) and a (27·3%) serotypes. Of isolates causing meningitis, 48·9% were NTHi, 14·9% Hib, 14·9% Hie, 10·6% Hif, 6·4% Hia and 4·3% were untyped. During the study period, there was an increase in the incidence of invasive NTHi disease (P = 0·007) with seasonal peaks in winter and spring (P 0·001) and Hib (P = 0·039) than non-Indigenous patients. In Queensland, invasive H. influenzae disease is now predominantly encountered in adults and most commonly caused by NTHi strains with demonstrated pathogenicity extending to otherwise young or immunocompetent individuals. Routine public health notification of these strains is recommended and recent available immunization options should be considered.

Pneumococcal conjugate vaccine and changing epidemiology of childhood bacterial meningitis

This resulted fromimmunization of young children, which not only conferreddirect protection against invasive Hib disease among immu-nized children, but also indirect protection of unvaccinatedindividuals, due to the interruption of transmission of thebacterium within communities through targeted vaccinationof young children.

Two or three primary dose regime for Haemophilus influenzae type b conjugate vaccine: meta-analysis of randomized controlled trials.

Haemophilus influenzae type b (Hib) is an important cause of meningitis and pneumonia in children. Despite the availability of Hib conjugate vaccine, many countries are still to implement it in their immunization schedule. Before introducing the vaccine in routine immunization programs, it is important to know not only the cumulative efficacy but also the efficacy of each vaccine dose. The primary objective of this review is to find whether two primary dose schedule of Hib vaccine is equally efficacious as the standard three primary dose schedule. A highly sensitive online search was run using the terms 'Haemophilus Vaccines' or 'Haemophilus influenzae type b' and 'conjugate vaccine', and Medline (Ovid), PubMed, Embase, CENTRAL and Scopus were explored for prospective randomized controlled studies. Data were extracted in a predesigned proforma and analyzed using RevMan software. Nine randomized studies were included in the analysis. Pooled vaccine efficacy using a fixed effects model against confirmed invasive Hib disease following the 3, 2 and 1 primary dose schedule were 82% [95% confidence interval (CI) 73-87], 79% (95% CI 54-90) and 65% (95% CI 23-84), respectively, and the overall efficacy was 80% (95% CI 72-85). To conclude, we found that Hib conjugate vaccine is highly efficacious and that the two dose regime is as good as the three dose regime. [The protocol was registered with PROSPERO (CRD42013004490)].

Hospital-based Sentinel Surveillance of Haemophilus Influenzae Type B among Children in Burkina Faso, 2004-2012: Impact of Vaccine Introduction

Background: Haemophilus influenzae type b (Hib) is a leading cause of childhood bacterial meningitis in Africa. This study assessed the impact of Hib conjugate vaccine introduced in 2006 into the Expanded Program on Immunization (EPI) in Burkina Faso. Methods: From 2004-2012, we conducted hospital-based surveillance for invasive Hib disease among children <5 years of age with suspected bacterial meningitis. All cerebrospinal fluid (CSF) samples were tested using culture methods and/or PCR. Incidences calculated using population denominators were compared between pre-vaccine (2004-2005) and post- vaccine (2007-2012) periods. Results: 3928 cases of suspected meningitis were identified from the pediatric service, 231(5.9%) of whom had a bacterial pathogen confirmed. Hib was found in 80 (34.6%) of confirmed cases, followed by Streptococcus pneumoniae in 76 (32.90%) and Neisseria meningitidis in 54 (23.38%). The average annual incidence (per 1,00,000 children) of Hib meningitis was 4.11; the annual incidence of Hib meningitis declined by 94.13% from 16 per 1,00,000 in pre-vaccine (2004-2005) to 0.94 per 100 000 in post-vaccine (2007-2012) periods. None of the 80 Hib confirmed cases was immunized and no death was notified after the introduction of the vaccine. Conclusion: Admissions for Hib meningitis in the department of pediatrics at University Hospital, CHU-Yalgado Ouedraogo have practically disappeared two years after the introduction of the Hib vaccine into Burkina Faso’s Expanded Program on Immunization.

A case of acute epiglottitis caused by Haemophilus influenzae type a in an adult

Introduction: Prior to the introduction of a paediatric conjugate vaccine in the early 1990s, Haemophilus influenzae serotype b (Hib) was a major cause of childhood meningitis and pneumonia. Since becoming part of national immunization programmes, the Hib conjugate vaccine has been very successful in preventing invasive Hib disease worldwide. However, in the post‐Hib vaccine era, the emergence of invasive disease caused by non‐type b H. influenzae has been reported from several countries. Previous studies by our group found an increased incidence of invasive disease caused by H. influenzae serotype a in Northwestern Ontario, Canada, during 2002–2011. Most of the cases of invasive H. influenzae type a disease occurred in young children. Case presentation: Our continued surveillance identified a case of epiglottitis caused by H. influenzae type a in a 65‐year old woman. This life‐threatening condition was historically associated with invasive Hib disease in young children but had not previously been reported in association with H. influenzae type a. We describe the clinical presentation of this case as well as characteristics of the H. influenzae type a isolate. Conclusion: Our findings stress the importance of continued surveillance of H. influenzae in the post Hib‐vaccine era, and point to the significance of H. influenzae type a as a cause of severe invasive disease in countries with a universal paediatric anti‐Hib immunization programme.

Near disappearance of childhood invasive Haemophilus influenzae type b disease in Singapore

BackgroundHaemophilus influenzae type b (Hib) conjugate vaccines have significantly limited Hib's disease impact in every country where it was introduced. We previously estimated invasive Hib disease incidence in Singapore at ∼4.4 per 100,000 children <5 years (from 1994 to 2003, period 1), but the vaccine was not included in the national childhood immunization schedule until May 2013 (although it was available privately). The current study aims to describe changes in Hib disease incidence and vaccine coverage prior to the introduction of the vaccine. MethodologyWe retrospectively reviewed all invasive Hib cases from January 2004 to December 2012 (period 2) and estimated population-based incidence rates. Vaccine coverage was estimated from vaccine sales for 1994–2003, and from National Immunisation Registry for 2004–2010. ResultsThere were 8 cases of invasive Hib disease in period 2, of whom 5 were <5 years. Invasive Hib incidence for period 2 was 0.57 per 100,000 children <5 years, representing an 86.4% reduction compared to period 1 (rate ratio 0.14, 95% confidence interval 0.06–0.26). However, for the later part of period 2 (2008–2012), incidence was 0.2 per 100,000 children <5 years; this represented a 95% reduction from period 1 (rate ratio 0.05, 95% confidence interval 0.01–0.18). Between periods 1 and 2, national Hib vaccine coverage rose from 22% to >80%, with >99% of children receiving combination Hib-containing vaccines. ConclusionsChildhood invasive Hib disease has nearly disappeared from Singapore, despite the absence of universal mass vaccination. We believe this is likely due to excellent uptake of combination vaccines.

Evaluation and validation of a serum bactericidal antibody assay for Haemophilus influenzae type b and the threshold of protection

Prior to routine immunisation, Haemophilus influenzae serotype b (Hib) was a major cause of serious bacterial infections, particularly in young children. In the United Kingdom, introduction of the Hib conjugate vaccine into the national childhood immunisation schedule has led to a sustained decline in invasive Hib disease across all age-groups. Evaluation of the immune response to Hib conjugate vaccines involves measurement of serum IgG antibodies against the capsular polyribosyl-ribitol-phosphate (PRP) polysaccharide by enzyme-linked immunosorbent assay (ELISA), with accepted short-term and long-term protective thresholds of ≥0.15μg/mL and ≥1.0μg/mL, respectively. These levels were derived by passive immunisation or immunisation with pure polysaccharide, and their relevance for protection following immunisation with conjugate vaccines remains unclear. This study aimed to modify and optimise a serum bactericidal antibody (SBA) assay to evaluate the functional activity of Hib antibodies generated following Hib conjugate vaccination. Validation of the Hib SBA assay was deemed acceptable for all assay parameters tested. A strong correlation between anti-PRP IgG concentrations and SBA titres was observed in vaccinated adults (r=0.81), as well as infants after primary immunisation at 2, 3, and 4 months (r=0.635) and after the 12-month booster (r=0.746). The assay identified some children with high anti-PRP IgG but low SBA activity and vice versa. The predictive protective SBA titre corresponding to a post-booster anti-PRP IgG of 1.0μg/mL was 8. Thus, the optimised Hib SBA assay was specific and reproducible and correlated with anti-PRP IgG. Such assays may have a role in evaluating immune responses to conjugate vaccines in addition to measuring capsular antibodies.

A review of invasive Haemophilus influenzae disease in the Indigenous populations of North America.

Historically, the highest incidence rates of invasive Haemophilus influenzae disease in the world were found in North American and Australian Indigenous children. Although immunization against H. influenzae type b (Hib) led to a marked decrease in invasive Hib disease in countries where it was implemented, this disease has not been eliminated and its rates in Indigenous communities remain higher than in the general North American population. In this literature review, we examined the epidemiology of invasive H. influenzae disease in the pre-Hib vaccine era, effect of carriage on disease epidemiology, immune response to H. influenzae infection and Hib vaccination in Indigenous and Caucasian children, and the changing epidemiology after Hib conjugate vaccine has been in use for more than two decades in North America. We also explored reasons behind the continued high rates of invasive H. influenzae disease in Indigenous populations in North America. H. influenzae type a (Hia) has emerged as a significant cause of severe disease in North American Indigenous communities. More research is needed to define the genotypic diversity of Hia and the disease burden that it causes in order to determine if a Hia vaccine is required to protect the vulnerable populations.