Hib Conjugate Vaccine Research Articles

Molecular size distribution assessment of Haemophilus influenzae vaccine containing lactose by HPAEC-PAD and colorimetric assays

Molecular size distribution of Haemophilus influenzae type b (Hib) conjugate vaccine is an important indicator for its immunogenicity and stability. Molecular size distribution was evaluated by High-Performance Protein Chromatography on Sepharose CL-4B column, and fractions were pooled. The use of high flow rate, incorporation of a calibration standard with the injected buffer and pooling method yielded a superior assay compared to conventional pharmacopeial method. The pools were analyzed for determination of distribution coefficient (KD) of 0.2 and 0.5 using two validated techniques: High Performance Anion Exchange Chromatography with pulsed amperometric detection (HPAEC-PAD) for ribitol determination and an optimized colorimetric assay for phosphorus determination. Linearity was achieved over range of 0.10–10.0 μg/mL and 1.0–8.0 μg/mL with LOD of 0.03 and 0.28 μg/mL for HPAEC and colorimetric assays, respectively. The developed assays were successfully applied in quality control monitoring of Hib conjugate vaccine. The optimized colorimetric method had shortened the analysis time to 25 min compared to 3.5 h for the European pharmacopeial assay by modifying the burning process. HPAEC stability results revealed 40% decrease in MSD after stressed storage conditions. The proposed assays offer a reliable and economic platform for monitoring the quality attributes of Hib for biopharma industry.

Global population structure of Haemophilus influenzae serotype a (Hia) and emergence of invasive Hia disease: capsule switching or capsule replacement?

The population structure of Haemophilus influenzae serotype a (Hia) was examined by interrogation of the H. influenzae MLST website. There were 196 entries of Hia with 55 sequence types (STs) identified (as of 3 September 2020). BURST analysis clustered related STs into four complexes with ST-23, ST-4, ST-21, and ST-62 identified as their ancestral STs. The majority of Hia entries (73.4%) and STs (65.5%) were identified as clonal division I (ST-23 and ST-4 complexes). Only 43 (21.9%) entries and 14 STs (25.5%) were identified as clonal division II (ST-62 and ST-21 complexes). Current data suggest that most invasive Hia belonged to clonal division I and the ST-23 complex, while most clonal division II Hia were respiratory isolates, with the exception of ST-62 which was common among invasive Hia in the US southwest. Comparison of the capsule bexABCD genes from clonal divisions I and II strains showed sequence diversity with variations following the pattern of clonal divisions. Evidence from the literature and the current study suggests that the recent emergence of invasive Hia might be related to capsule replacement subsequent to the implementation of the Hib conjugate vaccine and possibly exacerbated by other conjugate vaccines that may have altered the microbial flora of the human respiratory tract.

Haemophilus influenzae type b (Hib) seroprevalence in France: impact of vaccination schedules

BackgroundHaemophilus influenzae serotype b (Hib) conjugate vaccine was introduced in France in 1992 as a 3 + 1 scheme at 2, 3, and 4 months (primary vaccination) with a booster at the age of 16–18 months. The vaccination was simplified in 2013 to a 2 + 1 scheme at 2 and 4 months (primary immunization) and a booster at the age of 11 months. The coverage was 95.4% in France at 24 months in 2017. During the period 2017–2019 the number of Hib invasive infections increased with several cases of vaccine failure.MethodsThe numbers and proportions of Hib invasive isolates during the period 2017–2019 were compared and vaccine failure cases were explored. A seroprevalence study was performed by measuring anti-polyribosyl-ribitol phosphate (PRP) IgG concentrations by ELISA among children < 5 years of age at the time of sampling covering the periods of the 3 + 1 or 2 + 1 schemes of Hib vaccination. A collection of residual 232 sera was tested (group 3 + 1 n = 130) and (group 2 + 1, n = 102) was used.ResultsAnti-PRP IgG concentrations were significantly higher in toddlers of 2 years (median 2.9 μg/ml) in the 3 + 1 group while these concentrations showed a median of 0.58 μg/ml among children in 2 + 1 group. The proportion of children of 2 years of age who achieved 1 μg/ml threshold (56%) was higher in the 3 + 1 group than that observed in the 2 + 1 group (25%). All the detected cases of vaccine failure received the 2 + 1 scheme and anti-PRP IgG levels were less than 1 μg/ml at the admission. However, these levels increased significantly 1 month after the admission suggesting a secondary immune response to the Hib infection.ConclusionsThe simplification of the vaccination to a 2 + 1 scheme seems to reduce the level of anti PRP IgG. Hib antibodies wane rapidly after the 11 months booster and may not be enough to ensure long term protection. Surveillance of cases and monitoring of titres need to be continued to inform future vaccination policy.

The Impact of Haemophilus Influenzae and Streptococcus Pneumoniae Vaccination in Bacterial Meningitis in a Pediatric Referral Hospital in Mexico

Abstract Objective This study aimed to compare the epidemiology of bacterial meningitis (BM) before and after vaccination, and identify possible risk factors associated with mortality. Methods The medical and microbiologic records of children (1 month–18 years) with a discharge diagnosis of BM in a third level children's hospital in Mexico from 1990 to 2018 were reviewed. The epidemiology, pathogens, and outcomes were compared before and after introducing Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines to the Mexican immunization schedule. Risk factors associated with mortality were determined. Results In the 28-year period, 226 cases with BM were included 55.8% (1990–1999), 27.4% (2000–2008), and 16.8% (2009–2018) (p = 0.0001). The most frequent pathogen was Hib, documented in 39% of cases. There was a reduction in neurological complications after introducing the Hib conjugate vaccine (59 vs. 39%; p = 0.003) and sequelae after the Streptococcus pneumoniae conjugate vaccine (43 vs. 35%; p = 0.05). Independent risk factors associated with mortality were coma (odds ratio [OR]: 15 [2.9–78]), intracerebral bleeding (OR: 3.5 [1.4–12]), and pneumococcal meningitis (OR: 9.4 [2.2–39]). Conclusion Since the introduction of Hib and pneumococcal conjugate vaccines to the national immunization schedule, there was a reduction in BM cases, mainly associated with the Hib vaccine, with the consequent reduction of neurological complications and sequelae.

Racial Disparities in Invasive Haemophilus influenzae Disease-United States, 2008-2017.

Since the introduction of Haemophilus influenzae serotype b (Hib) conjugate vaccines in the United States, invasive H. influenzae disease epidemiology has changed, and racial disparities have not been recently described. Active population- and laboratory-based surveillance for H. influenzae was conducted through Active Bacterial Core surveillance at 10 US sites. Data from 2008-2017 were used to estimate projected nationwide annual incidence, as cases per 100 000. During 2008-2017, Active Bacterial Core surveillance identified 7379 H. influenzae cases. Of 6705 patients (90.9%) with reported race, 76.2% were White, 18.6% were Black, 2.8% were Asian/Pacific Islander, and 2.4% were American Indian or Alaska Native (AI/AN). The nationwide annual incidence was 1.8 cases/100 000. By race, incidence was highest among AI/AN populations (3.1) and lowest among Asian/Pacific Islander populations (0.8). Nontypeable H. influenzae caused the largest incidence within all races (1.3), with no striking disparities identified. Among AI/AN children aged <5 years, incidence of H. influenzae serotype a (Hia) was 16.7 times higher and Hib incidence was 22.4 times higher than among White children. Although Hia incidence was lower among White and Black populations than among AI/AN populations, Hia incidence increased 13.6% annually among White children and 40.4% annually among Black children aged <5 years. While nontypeable H. influenzae causes the largest H. influenzae burden overall, AI/AN populations experience disproportionately high rates of Hia and Hib, with the greatest disparity among AI/AN children aged <5 years. Prevention tools are needed to reduce disparities affecting AI/AN children and address increasing Hia incidence in other communities.

Long Term Impact of Conjugate Vaccines on Haemophilus influenzae Meningitis: Narrative Review.

H. influenzae serotype b (Hib) used to be the commonest cause of bacterial meningitis in young children. The widespread use of Hib conjugate vaccine has profoundly altered the epidemiology of H. influenzae meningitis. This short review reports on the spectrum of H. influenzae meningitis thirty years after Hib conjugate vaccine was first introduced into a National Immunization Program (NIP). Hib meningitis is now uncommon, but meningitis caused by other capsulated serotypes of H. influenzae and non-typeable strains (NTHi) should be considered. H. influenzae serotype a (Hia) has emerged as a significant cause of meningitis in Indigenous children in North America, which may necessitate a Hia conjugate vaccine. Cases of Hie, Hif, and NTHi meningitis are predominantly seen in young children and less common in older age groups. This short review reports on the spectrum of H. influenzae meningitis thirty years after Hib conjugate vaccine was first introduced into a NIP.

#22: Trends in Bacterial Meningitis in a Tertiary-Level Children′s Hospital in Mexico, Following Haemophilus influenzae and Streptococcus pneumoniae Vaccination (1990–2018)

Abstract Background Bacterial meningitis (BM) remains a significant global health problem in pediatric care, with substantial morbidity and mortality. The epidemiology of BM has changed over the last 20 years. The ongoing introduction of conjugate vaccines for the most common meningeal pathogens has reduced the global incidence. However, there is limited epidemiologic and microbiologic data of BM in children before and after the widespread use of these vaccines in Mexico. Methods We conducted a retrospective, observational, analytical study. Pediatric patients (from 1 month to 18 years of age) presenting with BM and hospitalized at the Instituto Nacional de Pediatria in Mexico City, from 1990 to 2018, were included. Meningitis from invasive procedures or complicated head trauma were excluded. BM was classified according to the World Health Organization (WHO) criteria. The cases were analyzed in three periods: period A (1990–1999), period B (2000–2008), and period C (2009–2018). Period A corresponds to the time before the conjugate Haemophilus influenzae type b (Hib vaccine) was introduced in Mexico, while periods B and C correspond to the time after the Hib vaccine was routinely applied. Periods A and B correspond to the period before the pneumococcal conjugate vaccine (PCV7) was administrated in Mexico, while period C is after PCV7 and PCV13 were routinely administrated. The proportion of cases between periods was compared with Chi-square or Fisher exact test; P &amp;lt; 0.05 was considered significant. Binomial logistic regression analysis was used to determine the association between potential risk factors and death due to BM. Results A total of 226 cases with BM were included, 180 (79.6%) confirmed cases, and 46 (20.4%) probable cases. The median age at diagnosis was 10 months. There were 126 (55.8%) cases in Period A, 62 (27.4%) cases in Period B, and 38 (16.8%) cases in Period C, with a statistically significant reduction between periods (P = 0.0001). Hib was the most commonly isolated pathogen, found in 38 (50%) cases. However, its proportion declined significantly after the introduction of the Hib conjugate vaccine (P &amp;lt; 0.0001). S. pneumoniae followed as the second most commonly isolated bacterial pathogen. There was a significant reduction in neurological complications after the Hib conjugate vaccine (P = 0.003) and the S. pneumoniae conjugate vaccine (P = 0. 05) were introduced. Independent risk factors associated with mortality were coma (OR 15, P = 0. 0001), intracerebral bleeding (OR 3.5, P = 0.046), and pneumococcal meningitis (OR 9.4, P = 0. 002). Conclusions BM remains a cause of morbidity and mortality in pediatric patients in this hospital, with a dramatic change in the epidemiology since the introduction of the Hib conjugate vaccine to the national immunization schedule. Routine use of childhood conjugate vaccines against the most frequent etiological agents reduced the number of cases globally, mainly those caused by Hib. Additionally, conjugate vaccines reduced neurological complications and sequelae caused by this disease.

Respiratory Carriage of Haemophilus influenzae Associated with Hib Vaccine in Jordanian Children

Abstract Objective Haemophilus influenzae type b (Hib) is the most virulent serotype that colonizes the upper respiratory tract of children. After introducing Hib conjugate vaccine, Hib has become almost entirely replaced by nontypeable H. influenzae (NTHi) strains. This study investigated the incidence of NTHi, which may cause serious sporadic body infections. Methods A total of 300 nasal and throat swab samples were obtained from children aged 6 to 60 months, who visited outpatient pediatric clinics of Jordan University Hospital and Al-Bashir Hospital, Amman, Jordan. Colonies resembling H. influenzae were tested by conventional laboratory tests including Gram staining and antibiotic susceptibility. The 16S rRNA and bexA (capsulation gene) were amplified from the extracted DNA. Swabs (n = 100) were delivered to the laboratory in transport media. After initial culture, DNA was extracted directly and tested by conventional polymerase chain reaction (PCR) employing actin beta primers for assessing the housekeeping gene, followed by quantitative PCR (qPCR) against Hib-specific primers. Results A total of 31/300 (10.33%) of H. influenzae isolates were recovered by culture and confirmed by PCR for 16S rRNA; 96.77% (30/31) were NTHi, and only one isolate was Hib. This isolate was confirmed by detection region II of the cap locus of Hib gene by qualitative TaqMan real-time qPCR. Antibiotic resistance among NTHi to ampicillin and erythromycin was 50.0 and 20.0%, respectively. Conclusion The conjugated Hib vaccine almost eliminated the occurrence of Hib in the upper respiratory tract of the Jordanian children, while NTHi colonization was found in 10% of them.

Invasive Haemophilus influenzae type b (Hib) disease in children in Italy, after 20 years of routine use of conjugate Hib vaccines

Haemophilus influenzae serotype b (Hib) was the leading cause of bacterial meningitis in children before the implementation of infant immunization with conjugate Hib vaccines. Despite the effectiveness of the vaccine, invasive Hib disease cases (i.e. isolation of Hib from a normally sterile site) are still reported in children.All invasive Hib disease cases in children ≤ 15 years reported through the National Surveillance System of Invasive Bacterial Disease, during 2012–2018 in Italy, were analyzed. Hib PCR-confirmed isolates were subjected to MLST and PFGE analysis. The number of copies of the capb locus, a virulence factor potentially contributing to true vaccine failures (TVFs), was determined by Southern blot analysis. Vaccine effectiveness (VE) was determined using a multiple Poisson regression model.31 cases of invasive Hib disease in children were reported. Fourteen children were vaccinated (TVFs), 14 were unvaccinated and 2 partially vaccinated (vaccination status was unknown for 1 case). The median age of children was 12 months (range 3 months-15 years). A decrease in vaccination coverage was observed in 2014–2016 (source Ministry of Health), and a rise in incidence was documented from 2016 until 2018, especially in children < 5 years. Vaccine effectiveness was estimated to be 83% (95% CI:45–95).24 isolates were available. The predominant ST was ST6 (70.8%). Cluster analysis of ST6 isolates by PFGE identified five variants. Six isolates (25%) contained multiple copies of the capb locus distributed among TVFs (30%) and unvaccinated children (16.7%).Our data show that both failures to vaccinate and TVFs are associated with invasive Hib disease in children in Italy, during the vaccination era. Most cases in children ≤ 2 years were vaccine-preventable, since they occurred in unvaccinated subjects (13/21 cases, 62%). No host predisposing factors for TVF were recognized. TVFs were not significantly associated with either specific genotypes or amplification status of the capb locus.

Comparability studies of hemin from two different origins porcine and bovine in the production of Haemophilus influenzae type b (Hib) polysaccharide

Hemin is one of the critical components of medium required for growth of Haemophilus influenzae type b (Hib) organisms. It is important to have different sources of critical components to ensure continuous supply for commercial production. Regulatory bodies also recommend having multiple sources for critical components. Hemin is produced from animal blood and the main sources are porcine and bovine origin. The approved Hib vaccine of SIIPL used for immunization is produced using hemin obtained from porcine origin. The present work focuses on the comparison of the growth of organisms on a large scale using hemin from bovine or porcine origin. Purified polysaccharide obtained using bovine source is tested with respect to the set WHO specifications as recommended by regulatory bodies and compared with commercial lots of PRP obtained from using hemin of porcine source. Identical product profile and quality attributes were obtained for PRP produced using bovine hemin and the regular commercial product suggests that there is no change in the product. Hemin from bovine source can be used as a replacement for hemin from porcine source in the fermentation medium for country specific requirement of Hib conjugate vaccine as long as it meets the guidelines on TSE/BSE risk.

Lagging Immune Response to Haemophilus influenzae Serotype b (Hib) Conjugate Vaccine after the Primary Vaccination with Hib of Infants in The Netherlands.

In 1993, a Haemophilus influenzae serotype b (Hib) conjugate vaccine was introduced in the Dutch national immunization program, resulting in a sharp decrease in invasive Hib disease. We used a population-based set of serum samples collected in The Netherlands in 2006–2007 (Pienter-II, 5696 sera) to assess the concentration of antibodies to the capsular polysaccharide of Hib, and compared the results with those obtained from a similar set collected in 1995–1996 (Pienter-I, 7837 sera). Post-primary vaccination serum samples from children aged 6–11 months from the Pienter-II study contained approximately 4-fold lower anti-Hib antibody concentrations than samples from children from the Pienter-I study. No such difference was found in post-booster samples from children older than 11 months of age. In Pienter-II, the proportion of children aged 6–11 months with anti-Hib antibody concentrations below the putative protective concentration of 0.15 µg/mL was 30%, which is significantly higher than in the Pienter-I study (12%). Fewer children in the Pienter-II group developed antibodies able to kill Hib in a serum bactericidal assay compared to the Pienter-I children. The cause of the lagged response in Pienter-II children remain uncertain, but lack of natural boosting, interference by the acellular pertussis vaccine, combining vaccines and acceleration of the schedule may have contributed.

Current regional consensus recommendations on infant vaccination of the Latin American pediatric infectious diseases society (SLIPE)

ABSTRACT Introduction The 1st Regional Experts on Infant Vaccination (REIV) meeting generated updated consensus recommendations to improve the control of various major vaccine preventable diseases (VPD) in Latin America. Areas covered Workshops highlighted recent changes in immunization schedules within the region, experience of countries incorporating combined acellular pertussis vaccines schedules and parenteral inactivated polio vaccine (IPV). The need to definitively replace oral polio vaccine (OPV) by IPV, and potential benefits of introducing new combined vaccines, were extensively discussed. Expert opinion REIV strongly advised immediate adoption of either complete IPV schedules for all Latin America or schedules including at least two initial doses of IPV. Use of fractional doses of intradermally administered IPV (fIPV ID) was not recommended due to lower immunogenicity, lack of evidence on long-term protection, and technical difficulty to implement. Routine pertussis vaccination of pregnant women in addition to health workers of neonatology units and any previously unimmunized parent was encouraged. Administration of HBV vaccine to newborns within the first 24 hours of life, and then at 2, 4, and 6 months, and of a booster dose of conjugate Hib vaccine at age 12 through 15 months, was also recommended. Incorporation of combined vaccines (CV) was considered potentially advantageous.

Impact of routine vaccination against Haemophilus influenzae type b in The Gambia: 20 years after its introduction.

BackgroundIn 1997, The Gambia introduced three primary doses of Haemophilus influenzae type b (Hib) conjugate vaccine without a booster in its infant immunisation programme along with establishment of a population-based surveillance on Hib meningitis in the West Coast Region (WCR). This surveillance was stopped in 2002 with reported elimination of Hib disease. This was re-established in 2008 but stopped again in 2010. We aimed to re-establish the surveillance in WCR and to continue surveillance in Basse Health and Demographic Surveillance System (BHDSS) in the east of the country to assess any shifts in the epidemiology of Hib disease in The Gambia.MethodsIn WCR, population-based surveillance for Hib meningitis was re-established in children aged under-10 years from 24 December 2014 to 31 March 2017, using conventional microbiology and Real Time Polymerase Chain Reaction (RT-PCR). In BHDSS, population-based surveillance for Hib disease was conducted in children aged 2-59 months from 12 May 2008 to 31 December 2017 using conventional microbiology only. Hib carriage survey was carried out in pre-school and school children from July 2015 to November 2016.ResultsIn WCR, five Hib meningitis cases were detected using conventional microbiology while another 14 were detected by RT-PCR. Of the 19 cases, two (11%) were too young to be protected by vaccination while seven (37%) were unvaccinated. Using conventional microbiology, the incidence of Hib meningitis per 100 000-child-year (CY) in children aged 1-59 months was 0.7 in 2015 (95% confidence interval (CI) = 0.0-3.7) and 2.7 (95% CI = 0.7-7.0) in 2016. In BHDSS, 25 Hib cases were reported. Nine (36%) were too young to be protected by vaccination and five (20%) were under-vaccinated for age. Disease incidence peaked in 2012-2013 at 15 per 100 000 CY and fell to 5-8 per 100 000 CY over the subsequent four years. The prevalence of Hib carriage was 0.12% in WCR and 0.38% in BHDSS.ConclusionsAfter 20 years of using three primary doses of Hib vaccine without a booster Hib transmission continues in The Gambia, albeit at low rates. Improved coverage and timeliness of vaccination are of high priority for Hib disease in settings like Gambia, and there are currently no clear indications of a need for a booster dose.

Invasive Haemophilus influenzae Type b Disease in the Post Hexavalent Era: Ten Years of Molecular Surveillance in Tuscany.

The epidemiologic characteristics of invasive Haemophilus influenzae type b disease (HIBD) have markedly changed since the introduction of the Haemophilus influenzae type b (Hib) conjugate vaccine worldwide. The immunization schedule against Haemophilus influenzae type b differs in Europe. This is a retrospective observational study which evaluates all the data included in the molecular surveillance register for invasive infectious diseases at the Laboratory of Molecular Diagnosis at Meyer Children's University Hospital from December 2008 to December 2018 with a diagnosis of invasive HIBD in children <5 years of age. We identified 4 cases of HIBD: all the cases presented signs or symptoms of invasive infection and the H. influenzae type b was identified in cerebrospinal fluid, or blood or bronchoalveolar lavage by molecular test. The crude incidence for Hib invasive disease in Tuscany is 0.26/100,000 p-y in children younger than 5 years, significantly different from the incidence rate before the introduction of the Hib vaccination. Vaccination effectiveness can be estimated at 97.9% and the impact of hexavalent (2p+1) vaccine at 99.6%. This work confirms the high impact of the hexavalent vaccine 2p+1 schedule for HIBD in children <5 years, emphasizing the role of molecular test for HIBD diagnosis and surveillance.

Emergence of a clone of invasive fucK-negative serotype e Haemophilus influenzae in British Columbia.

Introduction of the Haemophilus influenzae serotype b (Hib) conjugate vaccine has changed the epidemiology of invasive H. influenzae disease, with most infections now caused by non-typeable (non-encapsulated) and non-Hib encapsulated strains. We describe nine invasive serotype e H. influenzae (Hie) from British Columbia that were determined to have complete deletion of their fucose operon genes. These nine isolates were recovered from blood cultures of three female and six male patients during 2011-2018, with eight recovered in the past 4 years. All nine isolates were biotype IV, with eight showing identical pulsed field gel electrophoresis (PFGE) profiles, whereas the ninth showed 95% similarity. PFGE analysis also showed these fucose operon-negative Hie to be most (94%) similar to the multi-locus sequence type (ST)-18, the most common ST among Hie in British Columbia. These nine fucose operon-negative Hie represented 27.3% of the 33 invasive Hie isolated in British Columbia from 2010 to 2018. Deletion of the fucose operon did not appear to impact the transmission ability of these strains or their ability to cause invasive disease.

Supraglottitis secondary to Haemophilus influenzae serotype f infection: Case report and review of literature

Introduction: Haemophilus influenzae is an important human pathogen capable of causing serious invasive disease. The H. influenzae serotype b (Hib) conjugate vaccine successfully reduced the incidence of invasive Hib disease globally, revealing the significance of other H. influenzae serotypes. The emergence of H. influenzae type f (Hif) invasive disease has been reported worldwide. Case report: We identified a case of supraglottitis secondary to Hif in a 57-year-old female from northwestern Ontario without significant predisposing conditions. We describe the clinical presentation, disease progression, and outcome. The case is discussed in the context of current epidemiology of invasive Hif disease. Conclusion: This report emphasizes the severity of Hif invasive disease and the need for continued surveillance at the international level. We call for the development of health promotion strategies and the consideration of a vaccine against this organism.

856. Invasive Haemophilus influenzae Disease in Children: A Canadian MultiCenter Study on Emerging Serotypes

BackgroundOur objective was to describe the serotype distribution and clinical spectrum of invasive Haemophilus influenza (Hi) disease in children admitted to participating centers within the Paediatric Investigator’s Collaborative Network on Infections in Canada (PICNIC).MethodsAll cases of Hi bacteremia were identified from the PICNIC Database of Gram-negative bacteremia (2013–2017). Disease was defined as complicated if the following occurred: (a) >2 sites were affected, (b) surgical intervention was required, (c) organ failure, (d) ICU admission, (e) seizures, (f) sensory or motor deficits, (g) treatment-related complications, or (h) death.ResultsThere were 98 cases of Hi bacteremia. Male to female ratio was 64:34 and median age was 12 (IQR: 7–48; range 0–216) months. Hi serotypes included: a (N = 31; 32%), b (N = 9; 9%), f (N = 15; 13%), c (N = 1;1%), e (N = 1; 1%), nontypeable (N = 34; 35%) and unknown (N = 7; 7%). Clinical foci included: bacteremia without a focus (N = 19; 19%), meningitis (N = 29; 30%), cellulitis (N = 8; 8%), septic arthritis (N = 6; 6%), pneumonia (n = 33; 34%), epiglottitis (N = 1; 1%), and endovascular infection (n = 3; 3%). Complicated disease occurred in 29 (30%) cases; there was one (1%) death. Where serotyping was available, complication rates were: 42%, 22%, 100%, 0%, 33%, and 21% for Hia, Hib, Hic, Hie, Hif and nontypeable Hi, respectively. Factors associated with complicated disease were: age <5 years (P = 0.009), bacteremia without a focus (P = 0.006) and a CNS focus (P < 0.001). Hia was the leading serotype in meningitis (55%; P = 0.022). Nontypeable Hi was most frequent in pneumonia cases (56%; P = 0.003) and never caused cellulitis (0% vs. 14%; P = 0.023). Neonatal disease (N = 5) was predominantly caused by nontypeable Hi (80%; P = 0.040). Of note, 26 (27%) of our Hi isolates were ampicillin resistant.ConclusionIn the era of efficacious conjugate Hib vaccines, serotype has emerged as the leading cause of typeable Hi disease in Canada and is highly associated with meningitis, especially in young children. Strategies for preventing Hi disease need to target this emerging serotype and efforts should be focused toward developing an effective vaccine for serotype a disease.Disclosures All Authors: No reported Disclosures.

Coverage of Haemophilus influenzae Type b Conjugate Vaccine for Children in Mainland China: Systematic Review and Meta-analysis.

Use of Haemophilus influenzae type b conjugate vaccine is effective in reducing the disease burden, but its coverage in China is unclear. The aim of this meta-analysis is to assess the coverage of Hib conjugate vaccines in children in Mainland China. We systematically searched Pubmed, Web of Science, Medline, CNKI and Wanfang to identify studies assessing the coverage of Hib vaccine in Chinese children. Random-effects models were used to obtain pooled estimates for Hib vaccine coverage and analyzed heterogeneity with meta-regression and subgroup analyses. Thirty-three studies that included 7,227,480 subjects in 12 provinces met our inclusion criteria. The pooled overall coverage of Hib conjugate vaccine was 54.9% [95% confidence interval (CI): 52.9-57.0]. The pooled coverage for the nonlocal population (54.3%; 95% CI: 52.4-56.3) was lower than that for the local residents (62.0%; 95% CI: 58.4-65.6). The region-pooled coverage was higher in the east of China (59.7%; 95% CI: 57.3-62.1) than in the central and west parts of the country (48.5%; 95% CI: 40.6-56.4). Overall, 26.7% (95% CI: 20.1-33.2) had 1 dose only, 14.8% (95% CI: 10.0-19.6%) had 2 doses, 13.5% (95% CI: 9.1-17.8) had 3 doses and 14.3% (95% CI: 9.7-18.9) had 4 doses. We found a low coverage of Hib conjugate vaccine, particularly for the nonlocal children and those living in the central and west parts of China. Including Hib vaccine into the national immunization program is recommended to reduce disparities in vaccination coverage.

Impact of the introduction of the Haemophilus influenzae type b conjugate vaccine in an urban setting in southern India

IntroductionHaemophilus influenzae type b was the leading cause of bacterial meningitis in infants and children below the age of two years prior to the introduction of H. influenzae type b conjugate vaccines. In December 2011, the Indian government introduced H. influenzae b vaccine in the state of Tamilnadu. A prospective surveillance for bacterial meningitis was established at the Institute of Child Health in Chennai to evaluate the etiology of meningitis and impact of the vaccine. Material and MethodsInfants aged one to 23 months who were admitted to the hospital with symptoms of suspected bacterial meningitis were enrolled and lumbar puncture was performed. Cerebrospinal fluid samples were analyzed for white blood cells, protein, and glucose. Bacterial culture and a latex agglutination test for common bacterial pathogens were performed. ResultsBetween January 2009 and March 2014, 4,770 children with suspected bacterial meningitis were enrolled. Prior to the introduction of the vaccine, an average of 11.7 cases of H. influenzae b meningitis and 31.1 cases of probable meningitis with no etiology were identified each year. After introduction, the number of cases were reduced by 79% and 44% respectively. The average H. influenzae b vaccine coverage after introduction was 69% among all children with clinically suspected meningitis. In contrast, the mean number of aseptic meningitis and pneumococcal meningitis cases remained stable throughout the pre and post vaccination period; 28.2 and 4.8 per year, respectively. ConclusionsH. influenzae b conjugate vaccine reduced the number of cases of H. influenzae b meningitis and probable meningitis within the first two years of its introduction. The impact against meningitis was higher than the vaccination rate, indicating indirect effects of the vaccine. India has recently scaled up the use of Hib conjugate vaccine throughout the country which should substantially reduce childhood meningitis rates further in the country.

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.