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The aims of this study were to estimate the cost-effectiveness of the Haemophilus influenzae type b (Hib) vaccine for the prevention of childhood pneumonia, meningitis and other vaccine-preventable diseases in mainland China from a societal perspective and to provide information about the addition of the Hib vaccine to Chinese immunization programs.A decision tree and the Markov model were used to estimate the costs and effectiveness of the Hib vaccine versus no Hib vaccine for a birth cohort of 100,000 children in 2016. The disease burden was estimated from the literature, statistical yearbooks and field surveys. Vaccine costs were calculated from government reports and the United Nations International Children's Emergency Fund (UNICEF) website. The WHO cost-effectiveness thresholds were used to evaluate the Hib vaccine intervention. A one-way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the parameter uncertainties.Within the hypothetical cohort, under a vaccination coverage of 90%, the Hib vaccine could reduce 91.4% of Hib pneumonia and 88.3% of Hib meningitis; the Hib vaccine could also prevent 25 deaths, 24 meningitis sequelae cases and 9 hearing loss cases caused by Hib infection. From a societal perspective, the incremental cost-effectiveness ratio (ICER) of the Hib vaccine compared with no vaccination was US$ 13,640.1 at the market price, which was less than 3 times the GDP per capita of China in 2016. The ICER of the Hib vaccine was US$ -59,122.9 at the UNICEF price, indicating a cost savings. The largest portion of the uncertainty in the result was caused by the annual incidence of all-cause pneumonia, proportion of pneumonia caused by Hi, vaccine costs per dose, annual incidence of Hib meningitis and costs per episode of meningitis. The models were robust considering parameter uncertainties.The Hib vaccine is a cost-effective intervention among children in mainland China. The cost of Hib vaccine should be reduced, and it should be introduced into Chinese immunization programs.

This study aims to examine the association between the Haemophilus influenza type B (Hib) vaccination and child anthropometric outcomes in India. The study used prospective cohort data from the Young Lives Study (YLS) conducted in Andhra Pradesh, India. The participants were 1,824 children (aged 54–76 months). Stunting and underweight were used to measure the child anthropometric outcomes. The study used the multivariate logistic regression model to examine the association between Hib vaccination and childhood stunting and underweight. The result shows that stunting was lower among children who were vaccinated against Hib as compared to those who were not vaccinated (30.8% versus 39.5%). Similarly, the prevalence of underweight was also lower among the vaccinated children than the non-vaccinated ones (39.1% versus 48.0%). The results of the multivariate logistic regression analysis also suggest that children vaccinated against Hib were significantly less likely to be stunted (AOR: 0.76, 95% CI: 0.61–0.95) and underweight (AOR: 0.79, 95% CI: 0.64–0.98) than children who were not vaccinated against Hib, after controlling potentially confounding variables. The study concludes that vaccination against Hib, in addition to being a major intervention for reducing childhood infectious diseases and mortality, may be considered as a potential tool for reducing the burden of undernutrition in India. Therefore, the inclusion of the Hib vaccine into the Universal Immunization Programme will be helpful in reducing the burden of child malnutrition in India.

The World Health Organization (WHO) recommends the use of Haemophilus influenzae type b (Hib) conjugate vaccines, but China and Thailand have not used Hib vaccination in their national immunization programs. This systematic review aimed to update published economic evaluations of Hib vaccinations and to determine factors that potentially affected their cost-effectiveness.Searches were performed from the inception until December 2015 using 13 databases: CAB direct; CEA registry; EconLit; EMBASE; E-library; NHSEED; PAHO; POPLINE; PubMed; Redalyc project; RePEc; SciELO; and WHOLIS. Reference lists of relevant studies and grey literature were also searched. Full economic evaluations of Hib vaccination with results of costs and outcomes were included. The WHO checklist was used to evaluate the quality of the included studies. Data from eligible studies were extracted using a standardized data collection form.Out of 830 articles, 27 were included. Almost half of the studies (12/27) were conducted in high-income countries. Twelve studies (12/27) investigated the Hib vaccine as an addition to the existing vaccination program. Most studies (17/27) examined a 3-dose schedule of Hib vaccine. Nineteen studies (19/27) reported the model used, where all were decision tree models. Most of the studies (23/27) demonstrated an economic value of Hib vaccination programs, key influential parameters being incidence rates of Hib disease and vaccine price.Hib vaccination programs are mostly found to be cost-effective across geographic regions and country income levels, and Hib vaccination is recommended for inclusion into all national immunization programs. The findings are expected to support policy-makers for making decisions on allocating limited resources of the Hib vaccination program effectively.

We evaluated 24 children with invasive Haemophilus influenzae infections between 2006 and 2015 in Kamikawa subprefecture of Hokkaido, Japan. The most frequent disease was pneumonia in 12 cases (50.0%), followed by meningitis in 7 (29.2%) and bacteremia in 5 (20.8%). Patients ranged in age from 3 months to 12 years of age. Seventeen (70.8%) of the total were less than 2 years old. The incidence rate of H. influenzae infection varied from 15.1 to 36.3 per 100,000 population in the Kamikawa area during the period from 2006 through 2011. The corresponding rate decreased to 10.4 per 100,000 population in 2012, and there were no cases after 2013. Meningitis occurred in 1–2 patients annually from 2006 to 2011, showing an incidence rate of 4–10 per 100,000 population per year, while no cases were reported during or after 2012. No patients with invasive H. influenzae infection died, but sequelae were seen at discharge in 1 patient with meningitis, that had hydrocephalus and developmental delay. In Japan, introduction of the H. influenzae type b (Hib) vaccine was in November 2008. Initially, this vaccination was voluntary, resulting in a low vaccination rate. According to the national policy, and the self-pay burden for vaccination was decreased in December 2010, and the vaccination rate increased markedly to over 90%. This report provides a meaningful demonstration that introduction of the Hib vaccine markedly reduced invasive H. influenzae infections, exerting a beneficial effect in Japan, as it has in the world.

Vaxelis® (DTaP5-HB-IPV-Hib vaccine) is a fully liquid, ready-to-use, hexavalent vaccine containing diphtheria toxoid, tetanus toxoid, five acellular pertussis antigens, hepatitis B surface antigen, inactivated poliovirus and the Haemophilus influenzae type b capsular polysaccharide polyribosylribitol phosphate conjugated to the outer membrane protein complex of Neisseria meningitidis. In pivotal clinical studies in infants and toddlers, Vaxelis® was highly immunogenic for all its component toxoids/antigens when administered by three different schedules. In general, primary endpoints of seroprotection or vaccine response rates with Vaxelis® met the predefined acceptability criteria and were noninferior to those with comparator vaccines (Infanrix® hexa or Pentacel® + Recombivax HB®). Vaxelis® can be coadministered with a number of common childhood vaccines. In clinical studies, Vaxelis® was generally well tolerated with a tolerability profile similar to that of the comparator vaccines. Available clinical data indicate that Vaxelis® is a new hexavalent vaccine option for immunization against several serious childhood infectious diseases.

Prophylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine.Subjects received prophylactic paracetamol or ibuprofen at 0, 6-8, and 12-16 h after vaccination, or 6-8 and 12-16 h after vaccination at 2, 3, 4, and 12months of age. At 5 and 13months, immune responses were evaluated versus responses in controls who received no prophylaxis.After the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose.Prophylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration. ClinicalTrials.gov identifier: NCT01392378https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378rank=1.

By September 2013, war between Sudan and South Sudan resulted in >70,000 Sudanese refugees and high pneumonia incidence among the 20,000 refugees in Yida camp, South Sudan. Using Médecins Sans Frontières (MSF)-provided data and modifying our decision-tree models, we estimated if administering Haemophilus influenzae type b (Hib)-containing (pentavalent vaccine, also with diphtheria pertussis and tetanus [DPT] and hepatitis B) and pneumococcal conjugate (PCV) vaccines were cost-effective against hospitalized pneumonia. Among children

A major cause of morbidity and mortality in patients with cancer is infection. Since the introduction of the Haemophilus influenzae type b (Hib) vaccine in the United States in the 1990s, invasive H influenzae infection has become less common. We report on 5 patients with cancer and invasive H influenzae infection. A literature review was also performed of the dominant Haemophilus subtype and the clinical features associated with the infection and concomitant cancer. Of the 17 cases found in the literature, had hematological malignancies and 1 case each had thymoma, schwannoma, teratoma, and pancreatic, Merkel cell, pharyngeal, laryngeal, and rectal carcinomas. Two cases occurred with AIDS and Kaposi sarcoma. Pneumonia with bacteremia was seen in 8 cases, whereas pleuritis, neck cellulitis, septic arthritis, meningitis, and mediastinitis were diagnosed in the others. No focus of infection was identified in 2 cases. Nontypable H influenzae (NTHi) occurred in 4 cases, and Hib was isolated in 2 cases; serotyping was not reported in the others. Leukocytosis occurred in 7 cases and lymphopenia in 3; no cases presented with neutropenia. Four isolates were positive for beta-lactamase. Susceptibility data were unavailable in 5 case patients. Among serotyped cases, 67% were of the NTHi strain - a finding consistent with the change in the epidemiology of H influenzae since the introduction of the Hib vaccine.

Vaxelis® is a fully liquid, ready-to-use, hexavalent vaccine approved in the EU for primary and booster vaccination in infants and toddlers from the age of 6 weeks against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b (Hib). It contains diphtheria and tetanus toxoids, five acellular pertussis antigens, recombinant hepatitis B virus surface antigen produced in the yeast, Saccharomyces cerevisiae, inactivated poliovirus, and the Hib polysaccharide (polyribosylribitol phosphate) conjugated to the outer membrane protein complex of Neisseria meningitidis. In pivotal clinical studies, Vaxelis® was highly immunogenic for all its component toxoids/antigens when administered by three different schedules. Primary endpoints of seroprotection or vaccine response rates with Vaxelis® met the predefined acceptability criteria and were noninferior to those with comparator vaccines (Infanrix® hexa or Pentacel® plus Recombivax HB®). Limited data indicate that immune responses to Vaxelis® in preterm infants were generally similar to those seen in the overall population. Vaxelis® can be coadministered with a number of common childhood vaccines. In clinical studies, Vaxelis® was generally well tolerated with a tolerability profile similar to that of the comparator vaccines. Available clinical data indicate that Vaxelis® is a new hexavalent vaccine option for immunization against several serious childhood infectious diseases.

Background Globally, the use of single DTaP-IPV/Hib vaccines that combine DTaP-IPV and Hib is widespread, but in Japan vaccination is usually concomitant at separate sites. The immunogenicity and safety of a primary vaccination series and booster of a combined pentavalent DTaP-IPV/Hib vaccine were evaluated and compared to separate administration of DTaP-IPV and Hib in Japanese infants. Methods Healthy Japanese infants were administered DTaP-IPV/Hib (Group A: N = 207) or DTaP-IPV + Hib (Group B: N = 207) by the subcutaneous (SC) or DTaP-IPV/Hib by the intramuscular (IM) route (Group C: N = 10). All subjects received a 3-dose primary vaccination series and a booster. Non-inferiority (Group A versus Group B) was tested post-primary series and subsequent post hoc analyses were performed for anti-Hib. Safety was assessed by parental reports. Results Non-inferiority for SC administration of Group A versus Group B for the primary series was demonstrated for antibody responses to all antigens except Hib using the threshold of 1.0 μg/mL. Post hoc analyses for anti-Hib demonstrated non-inferiority for the primary series response using 0.15 μg/mL, and for pre-booster antibody persistence and the booster response using 0.15 μg/mL and 1.0 μg/mL. The immune response was similar for each antigen following SC or IM administration. There were no safety concerns in any group, and a lower incidence of injection sites for the IM route was observed as expected. Conclusions These data show the good immunogenicity and safety profile of the DTaP-IPV/Hib vaccine as a 3-dose infant primary series followed by a booster in the second year of life in Japan.

Hexyon® is a fully-liquid, ready-to-use, hexavalent vaccine approved in the EU since 2013 for primary and booster vaccination in infants and toddlers from age 6 weeks against diphtheria, tetanus, pertussis, hepatitis B (HB), poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b (Hib). While the source of HB antigen in Hexyon® is different from other vaccines, the rest of its valences have been extensively used in other approved vaccines. Hexyon® is highly immunogenic for all its component toxoids/antigens when used as primary and booster vaccine in infants and toddlers, irrespective of vaccination schedule. It provides durable protection against hepatitis B. Hexyon® can be used for a mixed primary series of hexavalent-pentavalent-hexavalent vaccines or as a booster in infants primed with Infanrix hexa™ or pentavalent (whole-cell or acellular pertussis) vaccines. Coadministration of Hexyon® with other common childhood vaccines did not affect immune response to any vaccines. Hexyon® has a good reactogenicity/safety profile. The immunogenicity and safety profile of Hexyon® was similar to that of several approved vaccines, including Infanrix hexa™. However, Hexyon® offers the convenience of full-liquid, ready-to-use formulation, which may minimize vaccination errors and preparation time. Thus, Hexyon® is a convenient, useful option for vaccination against childhood diseases caused by six major pathogens.

Introduction: In Asia Pacific, most countries recommend a monovalent hepatitis B virus (HBV) vaccine dose at birth followed by primary vaccination series including three or four doses of combination vaccines against diphtheria, tetanus, and pertussis, with or without Haemophilus influenzae type b (Hib), HBV or poliomyelitis antigens. If hexavalent conjugate vaccines against diphtheria-tetanus-acellular pertussis-HBV-inactivated poliovirus-Hib (DTPa-HBV-IPV/Hib) replace the vaccines included in the primary vaccination series, co-administration of lower-valent vaccines would be avoided but infants would receive ≥4 doses of HBV-containing vaccines before the age of 2 years. Areas covered: We searched for clinical trials conducted in the South-East Asia and Western Pacific Regions (World Health Organization geographic definition), investigating vaccination regimens with >3 doses of HBV-containing vaccines in infants, including a monovalent HBV vaccine birth dose and ≥1 dose of GSK's hexavalent DTPa-HBV-IPV/Hib vaccine. Expert opinion: The six clinical trials included in this review showed that infants who received the monovalent HBV vaccine at birth and three or four doses of DTPa-HBV-IPV/Hib vaccine achieved protective immunogenic titers with a clinically acceptable safety profile. Our results support the integration of hexavalent DTPa-HBV-IPV/Hib vaccine within existing national recommendations in the Asia Pacific region to reduce the number of injections during infancy.

Haemophilus influenzae is a gram-negative coccobacillus that colonizes the nasopharyngeal surface and upper respiratory tract of healthy individuals and includes six encapsulated serotypes as well as non-encapsulated, non-typeable strains. Since the widespread use of the Haemophilus influenzae type b (Hib) conjugate vaccine implemented in 1990, the majority of invasive illness now seen in the United States is secondary to capsular serotypes other than type b and non-typeable strains with the largest burden of disease affecting the extremes of age-infants and the elderly. We report a case of acute Haemophilus influenzae type f meningitis in a 12-month-old female who was previously healthy and had been fully immunized. She demonstrated clinical improvement on ceftriaxone, but persistent fever and ear-tugging resulted in obtaining an MRI that displayed bilateral subdural empyemas requiring burr-hole craniotomy, central venous thrombosis requiring anticoagulation, and bilateral sensorineural hearing loss requiring cochlear implants. Immunological studies confirmed immunocompetency and appropriate response to her previous Hib vaccination, suggesting a significant impact of bacterial virulence. These complications, with the exception of sensorineural hearing loss, have not been reported in the literature for Haemophilus influenzae type f and should be considered in the care of these patients despite clinical appearance given the severity of complications and potential for acute decompensation. Despite the success of vaccination in reducing invasive disease, cases of H. influenzae meningitis continue to occur via less common encapsulated serotypes with unknown complications, making the management and treatment of these infections more difficult for practitioners.

Introduction and Aims: Haemophilus influenzae is a frequent colonizer of the upper airways that can easily spread through respiratory tract leading to invasive infections in both children and adults. H. influenzae serotype b (Hib) has been prevented by vaccination, in Portugal, since 2000, but the emergence of non-typeable isolates (NTHi), as well as non-b serotypes responsible for invasive disease have been documented.1,2 We aim to characterize H. influenzae invasive isolates recovered in Portugal, during the last two years and compare results from previous studies. 1,2 Materials and Methods: As part of a laboratory-based surveillance system, 108 invasive H. influenzae were received at the National Reference Laboratory for Haemophilus influenzae for characterization. Capsular status was identified by PCR with primers and conditions described in the literature.3 Antibiotic susceptibility was determined by microdilution, according to EUCAST guidelines. 4 β-lactamase production was assessed with nitrocefin. Genetic relatedness among the isolates was examined by MLST as previously described.5 Sequences were analysed and submitted to the MLST website (https://pubmlst.org/hinfluenzae/) for assignment of the sequence type (ST). goeBURST analysis was performed using the PHYLOViZ platform.6 Results: Among 108 H. influenzae isolates, 90% were from blood, and 66% were from adults. Serotyping revealed that 74% were NTHi (80/108) and 26% (28/108) were capsulated isolates. Among capsulated isolates, 10.7% were Hia, 60.7% Hib, 10.7% Hie and 7.1% Hif. Most of the isolates were susceptible to the antibiotics studied, with the exception of 12.9% (14/108) ampicillin resistant by β-lactamase producing and 9.6% (9/94) that correlates with BLNAR phenotype (MIC≥1 to ampicillin and co-amoxiclave). MLST profiles revealed, as expected, high genetic variability (74.1%), with 23 different STs among 31 NTHi isolates tested. In opposition, encapsulated isolates were clonal with all Hia assigned to CC23, Hib assigned to CC6, (ST6 and ST1231), Hie to CC18, and Hif to CC124. Conclusion: After vaccine implementation and the great decline observed in Hib invasive disease (from 81% in 1989-2001 to 13% in 2002-2010),1,2 we are now concerned about Hib isolates (16%) that still in circulation in our country, affecting mostly children (88%), and accounting for 47% of vaccine failures. In addition, Hia increased, from 2% in the last period of five years (2012-2016) to 3% in this two years period (2017-2018), with all isolates from infants, up to two years old. It is important to continue the surveillance of H. influenzae invasive disease to monitor the true magnitude of these problems and develop public health prevention strategies. info:eu-repo/semantics/publishedVersion

DTaP5-HB-IPV-Hib is a fully liquid, hexavalent vaccine containing a 5-antigen pertussis component, approved since 2016 in Europe [Vaxelis; DTaP5-HB-IPV-Hib vaccine: Diphtheria, tetanus, pertussis (5 acellular components: pertussis toxoid [PT], filamentous haemagglutinin [FHA], pertactin (PRN), and fimbriae Types 2 and 3 [FIM]), hepatitis B (recombinant DNA: rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b conjugate vaccine (adsorbed); MCM Vaccine B.V., The Netherlands] for primary and booster vaccination in infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b. The comparator vaccine (control) was INFANRIX hexa (GlaxoSmithKline Biologics S.A., Rixensart, Belgium) (DTaP3-IPV-HepB/Hib) in European studies and PENTACEL (DTaP5-IPV/Hib) (Sanofi Pasteur, Swiftwater, PA) in US studies.Data from 6 studies were integrated and analyzed to provide a comprehensive safety profile. Numbers and proportions of subjects with adverse events (AEs) were summarized by treatment group. Group differences in proportion of AEs were calculated.Among the DTaP5-HB-IPV-Hib (N = 5223) and 2295 control (N = 2295) groups, solicited injection-site and systemic AEs were very common. Serious AEs were reported by 3.9% of DTaP5-HB-IPV-Hib and 3.7% of control subjects. Vaccine-related serious AEs occurred infrequently, 0.2% for both groups. Most AEs were mild-to-moderate and did not lead to subject withdrawal. Group differences for solicited systemic AEs were small (3%) and not statistically significant, except for pyrexia (estimated difference 9.4% [95% CI: 6.7%-12%]). The difference was driven by the 2 US studies where the PENTACEL control group had a lower fever rate. Among European studies, there was no significant difference in rates of pyrexia between DTaP5-HB-IPV-Hib and INFANRIX hexa.The safety of DTaP5-HB-IPV-Hib is consistent with the safety profile of its components and similar to comparator vaccines, including INFANRIX hexa. The vaccine provides a new, fully liquid and convenient hexavalent vaccination option for use with various vaccination schedules in Europe.

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.

Since the global Expanded Program on Immunization (EPI) was launched in 1974, vaccination against six diseases (tuberculosis, polio, diphtheria, tetanus, pertussis, and measles) has prevented millions of deaths and disabilities (1). Significant advances have been made in the development and introduction of vaccines, and licensed vaccines are now available to prevent 25 diseases (2,3). Historically, new vaccines only became available in low-income and middle-income countries decades after being introduced in high-income countries. However, with the support of global partners, including the World Health Organization (WHO) and the United Nations Children's Fund, which assist with vaccine prequalification and procurement, as well as Gavi, the Vaccine Alliance (Gavi) (4), which provides funding and shapes vaccine markets through forecasting and assurances of demand in low-income countries in exchange for lower vaccine prices, vaccines are now introduced more rapidly. Based on data compiled in the WHO Immunization Vaccines and Biologicals Database* (5), this report describes the current status of introduction of Haemophilus influenzae type b (Hib), hepatitis B, pneumococcal conjugate, rotavirus, human papillomavirus, and rubella vaccines, and the second dose of measles vaccine. As of September 2016, a total of 191 (99%) of 194 WHO member countries had introduced Hib vaccine, 190 (98%) had introduced hepatitis B vaccine, 132 (68%) had introduced pneumococcal conjugate vaccine (PCV), and 86 (44%) had introduced rotavirus vaccine into infant vaccination schedules. Human papillomavirus vaccine (HPV) had been introduced in 67 (35%) countries, primarily targeted for routine use in adolescent girls. A second dose of measles-containing vaccine (MCV2) had been introduced in 161 (83%) countries, and rubella vaccine had been introduced in 149 (77%). These efforts support the commitment outlined in the Global Vaccine Action Plan (GVAP), 2011-2020 (2), endorsed by the World Health Assembly in 2012, to extend the full benefits of immunization to all persons.

Multivalent combination vaccines have reduced the number of injections and therefore improved vaccine acceptance, timeliness of administration and global coverage. The hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b (DTPa-HBV-IPV/Hib; Infanrix hexa™) vaccine, administered according to various schedules, is widely used for the primary vaccination of infants worldwide. In the current publication, we are presenting the immunogenicity and safety of 3 doses of DTPa-HBV-IPV/Hib vaccine when administered to Indian infants. 224 healthy infants (mean age 6.8 weeks) were vaccinated at 6–10–14 weeks (W) of age (n = 112) or 2–4–6 months (M) of age (n = 112). One month after the third vaccine dose, the seroprotection/seropositivity status against diphtheria, pertussis, tetanus, polio, hepatitis B and Hib antigens ranged from 98.6% to 100% in both groups. The vaccine response rate to the pertussis antigens ranged from 97% to 100%. Pain (6–10–14W group: 25.2%; 2–4–6M group: 13.4%) and fever (15.3% and; 15.2%, respectively) were the most frequently reported solicited local and general symptoms. Unsolicited adverse events were reported for 35.7% (6–10–14W group) and 22.3% (2–4–6M group) of subjects. No vaccine related serious adverse events were reported. In conclusion, the hexavalent DTPa-HBV-IPV/Hib vaccine was immunogenic and well tolerated, irrespective of the dosing schedule.

Objective: This study was performed to investigate changes in bacteremia in children at Juntendo University Urayasu Hospital. Materials: A total of 10,487 blood culture specimens were examined from 3,916 children who were admitted to the Department of Pediatrics, Juntendo University Urayasu Hospital and underwent blood cultures from January 2006 to December 2014. Methods: Results for blood culture-positive children were compared before and after introduction of Haemophilus influenzae type b (Hib) vaccine (December 2008) and Streptococcus pneumoniae vaccine (February 2010), based on a retrospective analysis of a bacterial laboratory database. Results: A total of 94 patients had significant bacteria isolated from blood culture, giving a detection rate of 2.4%. Based on annual changes in the number of blood culture-positive patients aged 1 month or older, the number of Streptococcus pneumoniae-positive patients significantly decreased after 2010 and the number of Hib-positive patients reached a peak in 2008 and subsequently decreased. The major cause of fever without source in patients aged 1 month or older was Streptococcus pneumoniae until 2010, but subsequently changed to other bacteria that were unrelated to the vaccines. Conclusions: Introduction of Hib vaccine and Streptococcus pneumoniae vaccine significantly decreased both the number of cases of bacteremia in children and the incidence of invasive infections caused by Hib and Streptococcus pneumoniae. However, serotype replacement should be noted as a growing concern.

Background: The technically complex pneumococcal conjugate vaccine (PCV) is arguably one of the most important and widely studied vaccines since the Hib vaccine. Given the complexity of its design, the cost of administering the PCV is tremendous. While we cannot make adjustments to the vaccine itself post licensure, we can manipulate the dosing schedule. And yet little work has been done to understand the differences in immune responses across different dosing schedules. Methods: Accordingly, we conducted a review of three recently published randomized control trials that compared immune responses across commonly used vaccine schedules in both high- and low-income countries. Results: Each of these studies assessed how changes to the number of doses, spacing between doses and the use/timing of a booster dose affected ELISA geometric mean concentrations post-primary and post-booster dose. If the goal is to administer vaccinations in the most immunologically efficient manner as possible, evidence from these studies would suggest that several commonly used vaccine schedules are missing the mark. Conclusions: In order to deliver the most “bang for its buck”, PCV dosing schedules should not only leverage convenience but also immunological data. Without the reexamination of PCV schedules the status quo will remain inefficient, ineffective and needlessly expensive, threatening the sustainability of its implementation long-term.

Background: We aimed to describe the episodes and trends of admissions for community-acquired Respiratory Infections (RI) over a 12-year period and to assess the impact of Haemophilus influenza type b (Hib) vaccine on RI admissions in children aged up to 3 years. Methods: We conducted a twelve-year retrospective observational study on all community-acquired RI admitted to Fattouma Bourguiba Hospital in Monastir Governorate (Tunisia) from 1 January 2002 to 31 December 2013. RI cases were selected from the Regional Registry of Hospital Morbidity. Data were coded according to ICD-10. To assess the impact of the Hib vaccine, three cohorts were defined based on vaccine status (unvaccinated cohort, first vaccinated cohort (VC) by monovalent form and second VC by pentavalent combination). Results: Admissions for RI represented 17.6% (CI95%: 17.3–18.1) of all communicable diseases hospitalizations (n = 6 061/34 289). The crude incidence rates (CIR) per 100,000 inh were 24.2 for upper RI (URI) and 77.5 and for Lower RI (LRI) (p < 0.0001). Pneumonias represented 53.9% of LRI. Sex-ratio (male/female) was 1.12 for URI and 1.64 for LRI (p < 0.0001). At admission, the median age was 22 years (IQR: 3–52). Admission for Pneumonia increased significantly during study period (slope ‘b’ = 5.16; p < 0.0001) especially in children up to 5 years old (slope ‘b’ = 5.53) and in elderly (slope ‘b’ = 2.13). Among children up to 3 years old, the CIRs per 100,000 for Hib pneumonia admission were 11.6 in Non-Vaccinated Cohort (NVC), 10.6 in Vaccinated Cohort (VC) by protocol 1 (Hib Vaccine monovalent) and 0.80 in VC by protocol 2 (pentavalent vaccine combination).The relative risk reduction was 99% for protocol 2 (p < 0.001). Conclusion: Admissions for RI in a tertiary level hospital were common with an increasing trend. The Hib immunization program, in particular the pentavalent combination, has had a positive impact on the reduction of related acute diseases.

Haemophilus influenzae, originally named Pfeiffer’s bacillus after its discoverer Richard Pfeiffer in 1892, was a major risk for global health at the beginning of the 20th century, causing childhood pneumonia and invasive disease as well as otitis media and other upper respiratory tract infections. The implementation of the Hib vaccine, targeting the major capsule type of H. influenzae, almost eradicated the disease in countries that adapted the vaccination scheme. However, a rising number of infections are caused by non-typeable H. influenzae (NTHi), which has no capsule and against which the vaccine therefore provides no protection, as well as other serotypes equally not recognised by the vaccine. The first line of treatment is ampicillin, but there is a steady rise in ampicillin resistance. This is both through acquired as well as intrinsic mechanisms, and is cause for serious concern and the need for more surveillance. There are also increasing reports of new modifications of the intrinsic ampicillin-resistance mechanism leading to resistance against cephalosporins and carbapenems, the last line of well-tolerated drugs, and ampicillin-resistant H. influenzae was included in the recently released priority list of antibiotic-resistant bacteria by the WHO. This review provides an overview of ampicillin resistance prevalence and mechanisms in the context of our current knowledge about population dynamics of H. influenzae.

Background. H. influenzaeremains an organism of a major public health challenge worldwide despite the availability of the Hib vaccine, particularly among children under 5 years. Information on the current carriage status and antibiotic susceptibility is key on proper health-care provision. Therefore, we conducted a study to determineH. influenzaecarriage rate and antibiotic susceptibility testing of the isolates among the children.Methods. This was a cross-sectional study conducted between January and May 2018, among clinically healthy children under five years attending Maternal and Child Health (MCH) Clinic in Mbarara Regional Referral Hospital (MRRH). We carried out standard microbiology methods to culture, isolate, and identifyH. influenzae, and then, we tested for their susceptibility to commonly used antibiotics following the CLSI standards.Results. Of the 248 participants included in the study, 116 (46.77%) were females and 132 (53.23%) males and 78 (31.45%) were below the age of 3 months. Fifty one of the study participants hadH. influenzaein their nasopharynx, which represents 20.56% carriage (95% CI 15.49 to 25.63). There was a general high susceptibility of the isolates to the antimicrobial agents commonly used. There was 100% susceptibility to ciprofloxacin and imipenem antibiotic agents, though 6 (11.76%) and 4 (7.84%) of the isolates showed resistance to chloramphenicol and ampicillin, respectively.Conclusion. The high burden presented byH. influenzaeand the resultant impact on child health require much attention to prevention of infections associated with the organism. A well-funded molecular study focusing on typing the isolates would determine the impact of the vaccine, given the carriage rates are still high.

Disease surveillance can be used as an opportunity to determine priorities for research and the development of new therapeutics. This is evident in the work underway to develop a new vaccine to combat a serious invasive childhood disease: Haemophilus influenzae serotype a (Hia). Following the introduction of Hib vaccine into the routine childhood immunization schedule in Canada in the early 1990's, the Public Health Agency of Canada (PHAC) began to document the dropping rates of H influenzae serotype b (Hib) infection. However, invasive H. influenzae diseases due to non-Hib strains began to increase and in 2007, surveillance for invasive H. influenzae disease due to all serotypes as well as non-typeable strains was initiated. Current data suggests Hia is a cause of serious invasive disease, particularly in Aboriginal populations. Similar to Hib, Hia causes severe illnesses such as meningitis, sepsis and bacteremic pneumonia in young children under the age of five. Given the emerging threat due to Hia in Aboriginal populations in Canada, PHAC formed a partnership with the National Research Council of Canada (NRC) to investigate the potential of creating a capsular polysaccharide vaccine against Hia. At the present time, candidate vaccine seed strains have been identified and PHAC and the NRC are working with the Northern Ontario School of Medicine, the US Centers for Disease Control and Prevention and others. The goal of this research is to identify and prepare a candidate vaccine against Hia while increasing the understanding of how such a vaccine would improve the health of a vulnerable population.

BACKGROUND Haemophilus influenzae type b (Hib) bacterium causes severe illness in infants and children, but has largely been eliminated by introducing a universal Hib conjugate vaccine. While effects of certain vaccinations on atopic disease have been studied, little is known about the relationship between Hib vaccination and diseases of altered immunoglobulin E (IgE) regulation (asthma or atopy). As such, it is necessary to provide more evidence concerning Hib vaccination as a possible risk factor for atopic disease. METHODS Total serum IgE and IgE-and IgG-anti-Hib antibody responses were studied in Hib vaccinated asthmatic (N.=14) and non-asthmatic children (N=26) (VaccZyme™ Human Anti Hib Enzyme Immunoassay Kit). Data are reported as mean optical density (OD) values. RESULTS We found that: 1) total serum IgE levels were higher in asthmatic compared with non-asthmatic subjects (389±125 vs. 125±129, P

Objective: In China, Hib vaccine is a private-sector vaccine that is an option for parents to select to give to their children; it must be paid for out-of-pocket because it is not included in the government's Expanded Program on Immunization (EPI). We evaluated utilization patterns of Hib vaccine to provide evidence in support of development of a national Hib vaccination strategy. Methods: We obtained lists of children from immunization information systems (IIS) of counties or districts in 8 provinces of China. Using these lists, we selected 10 children at random from each birth cohort from 2008 through 2012. We obtained Hib vaccination dates from official vaccination certificates. The target sample size was 1,000 children. Results: We were able to obtain records for 978 subjects of the selected subjects; of these, 44.79% had received at least 1 dose of Hib vaccine, and 15.54%, 5.83%, 12.27%, and 11.15% had received one, two, three, and four doses, respectively. Per capita GDP was positively correlated with receipt of at least one dose of Hib vaccine. Among the 438 subjects who received Hib vaccine, 27% received 1 dose after 12 months of age; 15%, 7%, and 23% received one of three other patterns of Hib vaccination recommended by the World Health Organization (WHO) [a 3-dose primary series; 2 primary series doses and 1 booster; or 3 primary series doses and 1 booster]. The other 28% of subjects received patterns of Hib vaccination not recommended by WHO. Considering protection from Hib disease as receipt of a WHO-recommended Hib vaccine schedule, 29% of subjects could be considered protected after 12 months of age, 52% could be considered protected during infancy and beyond, and 19% could be considered to not have been protected adequately, despite being vaccinated. Conclusions: Coverage with Hib vaccine was low. There were significant differences between WHO recommendations and actual patterns of use of Hib vaccine, with half of vaccine recipients receiving no protection during infancy and one fifth receiving non-protective Hib vaccination patterns. Inclusion of Hib vaccine into China's EPI system, which provides vaccine at no charge to parents and makes specific vaccination schedule standards, has potential to make more effective use of Hib vaccine.

All infants without contraindications should receive the conjugate Hib vaccine series; either as 3 doses of PRP-OMP (trade name: PedvaxHIB®), or as 4 doses of PRP-T (trade names: ActHIB®, Hiberix®; also included in the DTaP-Hib-IPV combination vaccine Pentacel®). Doses of Hib vaccine should be given at least 4 weeks apart, with the first dose administered at a minimum of 6 weeks of age. Doses are generally recommended to be given at 2 and 4 months of age, and for the PRP-T vaccines, 6 months of age as well. A booster dose should then be given a minimum of 8 weeks after the previous dose, generally between 12-15 months of age. Although Hib vaccine is generally not recommended for those over 59 months of age, there are exceptions for certain persons at increased risk; for example, previously unimmunized asplenic patients should receive one dose of Hib vaccine, and recipients of a hematopoietic cell transplant should be given the full three-dose series beginning 6-12 months after the transplant regardless of their vaccination history.

The aim of the present study was to assess the prevalence of Haemophilus influenzae type b (Hib) nasopharyngeal (NP) colonisation among healthy children where Hib vaccination using a 3p+0 dosing schedule has been routinely administered for 10 years with sustained coverage (> 90%). NP swabs were collected from 2,558 children who had received the Hib vaccine, of whom 1,379 were 12-< 24 months (m) old and 1,179 were 48-< 60 m old. Hi strains were identified by molecular methods. Hi carriage prevalence was 45.1% (1,153/2,558) and the prevalence in the 12-< 24 m and 48-< 60 m age groups were 37.5% (517/1,379) and 53.9% (636/1,179), respectively. Hib was identified in 0.6% (16/2,558) of all children in the study, being 0.8% (11/1,379) and 0.4% (5/1,179) among the 12-< 24 m and 48-< 60 m age groups, respectively. The nonencapsulate Hi colonisation was 43% (n = 1,099) and was significantly more frequent at 48-< 60 m of age (51.6%, n = 608) compared with that at 12-< 24 m of age (35.6%, n = 491). The overall resistance rates to ampicillin and chloramphenicol were 16.5% and 3.7%, respectively; the co-resistance was detected in 2.6%. Our findings showed that the Hib carrier rate in healthy children under five years was very low after 10 years of the introduction of the Hib vaccine.

With GAVI support, Vietnam introduced Haemophilus influenzae type b (Hib) vaccine in 2010 without evidence on cost-effectiveness. We aimed to analyze the cost-effectiveness of Hib vaccine from societal and governmental perspectives.We constructed a decision-tree cohort model to estimate the costs and effectiveness of Hib vaccine versus no Hib vaccine for the 2011 birth cohort. The disease burden was estimated from local epidemiologic data and literature. Vaccine delivery costs were calculated from governmental reports and 2013 vaccine prices. A prospective cost-of-illness study was conducted to estimate treatment costs. The human capital approach was employed to estimate productivity loss. The incremental costs of Hib vaccine were divided by cases, deaths, and disability-adjusted life years (DALY) averted. We used the WHO recommended cost-effectiveness thresholds of an intervention being highly cost-effective if incremental costs per DALY were below GDP per capita.From the societal perspective, incremental costs per discounted case, death and DALY averted were US$ 6252, US$ 26,476 and US$ 1231, respectively; the break-even vaccine price was US$ 0.69/dose. From the governmental perspective, the results were US$ 6954, US$ 29,449, and US$ 1373, respectively; the break-even vaccine price was US$ 0.48/dose. Vietnam's GDP per capita was US$ 1911 in 2013. In deterministic sensitivity analysis, morbidity and mortality parameters were among the most influential factors. In probabilistic sensitivity analysis, Hib vaccine had an 84% and 78% probability to be highly cost-effective from the societal and governmental perspectives, respectively.Hib vaccine was highly cost-effective from both societal and governmental perspectives. However, with GAVI support ending in 2016, the government will face a six-fold increase in its vaccine budget at the 2013 vaccine price. The variability of vaccine market prices adds an element of uncertainty. Increased government commitment and improved resource allocation decision making will be necessary to retain Hib vaccine.

BackgroundPneumonia is a leading cause of death among children less than five years old during humanitarian emergencies. Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae are the leading causes of bacterial pneumonia. Vaccines for both of these pathogens are available to prevent pneumonia.ProblemThis study describes an economic analysis from a publicly funded health care system perspective performed on a birth cohort in Somalia, a country that has experienced a protracted humanitarian emergency.MethodsAn impact and cost-effectiveness analysis was performed comparing: no vaccine, Hib vaccine only, pneumococcal conjugate vaccine 10 (PCV10) only, and both together administered through supplemental immunization activities (SIAs). The main summary measure was the incremental cost per disability-adjusted life-years (DALYs) averted. One-way sensitivity analysis was conducted for uncertainty in parameter values.ResultsEach SIA would avert a substantial number of cases and deaths. Compared with no vaccine, the DALYs averted by two SIAs for two doses of Hib vaccine was US $202.93 (lower and upper limits: $121.80-$623.52), two doses of PCV10 was US $161.51 ($107.24-$227.21), and two doses of both vaccines was US $152.42 ($101.20-$214.42). Variables that influenced the cost-effectiveness for each strategy most substantially were vaccine effectiveness, case fatality rates (CFRs), and disease burden.ConclusionsThe World Health Organization (WHO) defines a cost-effective intervention as costing one to three times the per capita gross domestic product (GDP; in 2011, for Somalia=US $112). Based on the presented model, Hib vaccine alone, PCV10 alone, or Hib vaccine and PCV10 given together in SIAs are cost-effective interventions in Somalia. The WHO/Strategic Advisory Group of Experts decision-making factors for vaccine deployment appear to have all been met: the disease burden is large, the vaccine-related risk is low, prevention in this setting is more feasible than treatment, the vaccine duration probably is sufficient for the vulnerable period of the child’s life, cost is reasonable, and herd immunity is possible.GarganoLM, HajjehR, CooksonST. Pneumonia prevention during a humanitarian emergency: cost-effectiveness of Haemophilus influenzae type b conjugate vaccine and pneumococcal conjugate vaccine in Somalia. Prehosp Disaster Med. 2015;30(4):110.

Worldwide bacterial meningitis accounts for more than one million cases and 135,000 deaths annually. Profound, lasting neurological complications occur in 9-25% of cases. This review confirms the greatest risk from bacterial meningitis is in early life in Malaysia. Much of the disease burden can be avoided by immunization, particularly against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Despite inclusion of the Hib vaccine in the National Immunisation Programme and the licensure of pneumococcal vaccines, these two species are the main contributors to bacterial meningitis in Malaysia, with Neisseria meningitidis and Mycobacterium tuberculosis, causing a smaller proportion of disease. The high Hib prevalence may partly be due to dated, small-scale studies limiting the understanding of the current epidemiological situation. This highlights the need for larger, better quality surveillance from Malaysia to evaluate the success of Hib immunization and to help guide immunization policy for vaccines against S. pneumoniae and N. meningitidis.

Background A compact pre-filled auto-disable injection (cPAD) presentation is being developed for the fully liquid pentavalent DTP-HepB-Hib vaccine. A cost analysis (CA) to compare this presentation with the presently used single-dose vial (SDV) and multi-dose vial (MDV) was conducted in Cambodia, Ghana, and Peru. Methodology The CA included the development of an excel-based costing model and considered the costs of vaccine, safe injection equipment, procurement, storage, transport and distribution, vaccine administration by health staff, medical waste management, start-up activities, as well as coverage, birth cohort, vaccine, and safe injection equipment wastage rates. The outcome was the change in cost per pentavalent fully immunized child (PFIC) for a switch to cPAD. Field visits to health facilities, and interviews with key informants from immunization services and regulatory authorities, were conducted to collect data and to test the costing model in country context. Cost data were also obtained from manufacturers, published price lists, and author estimates. A sensitivity analysis (SA) was conducted to explore possible variations in values of data collected. Results Based on vaccine price trends estimated for 2016, cPAD is less costly in Ghana [incremental cost per PFIC: $US−0.59 (−6.46 %)] than the current presentation (ten-dose MDV) and in Peru (SDV): $US−0.89 (−7.14 %). In Cambodia, cPAD is more costly than SDV: $US+0.33 (+3.90 %). Discussion and Conclusion The most significant cost item per PFIC is the vaccine (reflecting wastage rates) in all presentations. The dominance of the vaccine price per dose and, to a lesser extent, the wastage rates in the incremental cost per PFIC show potential to simplify future analyses. Other relevant considerations at country level for a change of presentation include the potential for improved safety with cPAD, planned introduction of other vaccines, environmental and safety issues, and financial sustainability. Electronic supplementary material The online version of this article (doi:10.1007/s40801-015-0010-0) contains supplementary material, which is available to authorized users.

We analyzed non-serotype b encapsulated Haemophilus influenzae (non-b Hi) isolated from pediatric patients at Chiba Children's Hospital during 2000-2012. Among 3,532 clinical isolates of H. influenzae, there were 57 (1.6%) strains of non-b Hi, 152 (4.3%) of serotype b H. influenzae (Hib), and 3,323 (94.1%) of non-typeable H. influenzae (NTHi). Fifty-seven strains of non-b Hi were serotyped useing the slide agglutination test and PCR. Twenty-nine strains were identified as type e (Hie) and 28 as type f (Hif), and the results according to the slide agglutination test and PCR were completely identical. Whereas 52 of 57 strains (91.2%) were isolated from respiratory specimen, only one Hif strain (1.8%) was isolated from a sterile site. There were 47 (82.4%) β-lactamase-non-producing ampicillin (ABPC)-sensitive strains (BLNAS), 5 (8.8%) β-lactamase-producing strains (BLP), and only 1 (1.8%) β-lactamase-non-producing ABPC-resistant strain (BLNAR). Thus the frequency of non-b Hi was lower than that of Hib. The source of non-b Hi was similar to that of NTHi, which was mainly isolated from respiratory specimen. Antimicrobial resistant pattern of non-b Hi was different from that of Hib in which the frequency of BLP was relatively high, and NTHi in which that of BLNAR was high. An increase of invasive H. influenzae infections caused by NTHi, Hie, and Hif was reported in the countries where Hib vaccine had been widely used. Because it is assumed that invasive non-Hib infection will be predominant in the near future in Japan, serotyping of invasive strains is crucial. Continuous monitoring of distribution of non-b Hi in the clinical isolates of H. influenzae is also important.

Haemophilus influenzae type b (Hib) can cause severe invasive diseases which are, however, preventable by vaccination. To increase access to Hib vaccine, GAVI – the Vaccine Alliance – has provided financial support for 73 lower income countries worldwide. At the same time, GAVI has been implementing its co-financing policy, requiring recipient countries to pay a portion of vaccine costs and to increase this amount over time. Starting in 2016, 5 countries will stop receiving GAVI funding and procure the vaccine themselves. Although the graduating countries have access to the UNICEF/GAVI tendered vaccine price for 5 more years, the uncertainty in market vaccine price may hamper the post-GAVI program sustainability. A possible increase in vaccine price would cause a significant burden on governmental budgets, discouraging countries to continue the program. As a special tool, economic evaluation (EE) can assist decision makers by identifying the maximum affordable vaccine price for countries to pay. Given that only 6 GAVI-eligible countries have such analyses published, more EEs are necessary to strengthen countries' commitment during this transition period. The information will also be useful for manufacturers to determine their pricing policy.

Meningitis caused by Haemophilus influenzae type b (Hib) was eliminated in Oman after the introduction of Hib vaccine in 2001. However, a case of H. influenzae type a meningitis was diagnosed in a child from Oman in 2015, which highlights the need to monitor the incidence of invasive non-Hib H. influenzae disease.

Haemophilus influenzae type b (Hib) is an important cause of invasive bacterial disease in children worldwide. The limited awareness of disease burden is a major barrier to the introduction of Hib vaccine into China's National Immunization Program. Therefore, we conducted a systematic review and meta-analysis to estimate carriage of Hib and burden of its related diseases in Chinese children.We systematically searched Pubmed, Web of Science, Ovid, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases for studies published up to December 31, 2016, reporting Hib carriage and burden of Hib diseases among children in Mainland China. Pooled estimates were obtained using random-effects models.We included 27 studies with 15783 children across 14 provinces. The pooled carriage of Hib was 5.87% (95% CI 3.42-8.33) for healthy children. The pooled proportion of disease due to Hib were 4.06% (95% CI 3.29-4.83) for acute lower respiratory tract infection (ALRI) and 27.32% (95% CI 0.41-54.24) for bacterial meningitis. The proportion of ALRI caused by Hib was higher in northern China than that in the south. Significant heterogeneity was noted across and within regions (P0.001). After the induction of Hib vaccine, meta-regression showed that carriage of Hib changed little (P=0.725), but the proportion of ALRI caused by Hib in children decreased (P0.001).Hib carriage persists at low levels among children in China. The proportion of ALRI due to Hib infection decreased with year. Incorporation of Hib vaccine into the National Immunization Program could reduce the burden of Hib disease in China.

Aims Botswana is a country in Southern Africa with a UNAIDS estimated adult HIV prevalence of 25% but a PMTCT program that has limited mother-to-child transmission to an estimated 3%. Haemophilus influenza type B (Hib) vaccination was rolled out nationally in 2011, with WHO estimating coverage of 95% by 2012. This study aims to describe the culture-confirmed causes of meningitis in children in Botswana, a setting with high HIV prevalence and recent introduction of Hib vaccination. Methods We conducted a retrospective laboratory-based surveillance study reviewing paediatric cerebrospinal fluid (CSF) records at the country’s main referral hospital. Microbiology reports from all CSF samples collected from inpatients aged 0–14 years between February 2012 and December 2014 were retrospectively reviewed. Results Over the 3 year period, 1036 samples CSF samples were collected from patients aged 0–14 years. 67 samples were culture positive. Cryptococcus neoformans was the most commonly cultured organism, grown in 27 unique patients. This compared with 10 cases of culture-confirmed Streptococcus pneumoniae and 6 cases of Klebsiella pneumoniae. Haemophilus influenzae was not cultured from any CSF samples during this period. Half of all microbiologically confirmed cases of cryptococcal meningitis occurred in children aged 0–1 years. Conclusion Cryptococcus neoformans was the most common microbiologically confirmed cause of meningitis in Botswana children. It was cultured twice as frequently as Streptococcus pneumoniae, traditionally the most common causative organism of paediatric meningitis. Literature is limited on the epidemiology of paediatric meningitis in settings of high HIV prevalence, although our single-centre study found this to be the predominant isolated pathogen. Following countrywide Hib vaccine rollout, no cases of Hib meningitis were observed during the surveillance period.

Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV-IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12–15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1–3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued.

The objective of this study was to evaluate the immunogenicity and safety of the novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroup A and C-tetanus toxoid conjugate vaccine (Hib-MenAC).We conducted a non-inferiority, randomized, observer-blind, positive control clinical trial in 900 healthy infants aged between 3-5 months in Funing County, Jiangsu Province, China. Participants were randomly allocated, in a ratio of 2:1 (block = 6), to receive experimental combined Hib-MenAC vaccines co-administrated with placebo or the co-administration of licensed Hib vaccine and MenAC vaccine, according to a three-dose immunization schedule. The seroconversion of antibody titer against meningococcal serogroups A, C and Hib was the primary endpoint.The experimental vaccines was non-inferior to the licensed two control vaccines. Participants receiving experimental Hib-MenAC vaccines showed a seroconversion rate of 99.0%, 96.1% and 97.7% for rSBA-MenA, rSBA-MenC and anti-PRP antibodies, respectively. The Hib-MenAC vaccine did not result in an increase in adverse reaction, and no serious adverse event was judged to be related to the vaccination.The novel combined Hib-MenAC conjugate vaccine was safe and highly immunogenic in infants aged between 3 to 5 months.

Infants with history of prematurity (37 weeks gestation) and low birth weight (LBW,2500 g) are at high risk of infection due to functional immaturity of normal physical and immunological defense mechanisms. Despite current recommendations that infants with history of prematurity/LBW should receive routine immunization according to the same schedule and chronological age as full-term infants, immunization is often delayed.Here we summarize 10 clinical studies and 15 years of post-marketing safety surveillance of GSK's hexavalent vaccine (DTPa-HBV-IPV/Hib), a combined diphtheria-tetanus-acellular-pertussis-hepatitis-B-inactivated-poliovirus-Haemophilus influenzae-type-b (Hib) conjugate vaccine, when administered alone, or co-administered with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with history of prematurity/LBW in clinical trials.At least 92.5% of infants with history of prematurity/LBW as young as 24 weeks gestation in clinical studies were seropositive to all vaccine antigens after 3-dose primary vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine, with robust immune responses to booster vaccination. Seropositivity rates and antibody concentrations to hepatitis B and Hib appeared lower in infants with history of prematurity/LBW than term infants. Between 13-30% of medically stable infants with history of prematurity developed apnea after vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine; usually after dose 1. The occurrence of post-immunization cardiorespiratory events appears to be influenced by the severity of any underlying neonatal condition. Most cardiorespiratory events resolve spontaneously or require minimal intervention. GSK's hexavalent DTPa-HBV-IPV/Hib vaccine was well tolerated in co-administration regimens.GSK's hexavalent DTPa-HBV-IPV/Hib vaccine alone or co-administered with other pediatric vaccines has a clinically acceptable safety and immunogenicity profile when used in infants with history of prematurity/LBW for primary and booster vaccination. Additional studies are needed in very premature and very LBW infants. However, currently available data support using GSK's hexavalent DTPa-HBV-IPV/Hib vaccine to immunize infants with history of prematurity/LBW according to chronological age.

Haemophilus influenzae type b (Hib), a Gram-negative capsulated bacterium, is a causative agent of meningitis worldwide. The capsular polysaccharide, a high molecular mass polymer consisting of the repeated units of the polyribosyl-ribitol-phosphate, is considered the main virulence factor and it is used as an antigen to vaccines, conjugated to a carrier protein. The industrial production of the polysaccharide requires the cultivation of Hib in rich medium, which impacts process costs and product recovery. In this study, a central composite rotational experimental design strategy was used to access the influence of key components of culture medium (soy peptone, yeast extract and glucose) on biomass formation and polysaccharide production in shake-flasks. The optimized medium formulation, containing half of the usual yeast extract and soytone concentrations, was further validated in batch bioreactor cultivations. High polysaccharide production (∼500 mg/L) was obtained in a cheaper and more competitive production process for use in Hib vaccine production. In addition, simulations of a metabolic model describing Hib central metabolism were used to assess the role of key amino acids on growth. A chemically defined medium supplemented only with amino acids from α-ketoglutarate and oxaloacetate families as well as phenylalanine was suggested as a promising alternative for reduced acetate accumulation and enhanced polysaccharide production in Hib cultures. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1508-1519, 2017.

Background In sub-Saharan Africa, systematic surveillance of young children with suspected invasive bacterial disease (e.g., septicemia, meningitis) has revealed non-typhoidal Salmonella (NTS) to be a major pathogen exhibiting high case fatality (~20%). Where infant vaccination against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae has been introduced to prevent invasive disease caused by these pathogens, as in Bamako, Mali, their burden has decreased markedly. In parallel, NTS has become the predominant invasive bacterial pathogen in children aged, Author Summary A surveillance program at Gabriel Touré Hospital in Mali observed a high burden of invasive disease caused by non-typhoidal Salmonella (iNTS). This surveillance program was originally instituted to measure the amount of invasive disease (e.g., septicemia, meningitis) caused by two bacteria that invade the respiratory tract: Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (pneumococcus). While documenting the burden of these pathogens, the surveillance program also found that serotypes of iNTS, mainly Salmonella Typhimurium and Salmonella Enteritidis, were common causes of severe invasive disease. As the number of cases of Hib and pneumococcus markedly decreased following the introduction of relevant vaccines, the relative threat of iNTS increased. Little is known about the reservoir of iNTS, whether it resides in humans, animals, or the environment, or how it is spread to susceptible children. Without this knowledge, it is not possible to employ certain disease control methods useful in interrupting the transmission of other pathogens. Therefore, vaccination remains the one promising control strategy for this disease. Our research modeled the potential effects of introducing an iNTS vaccine. The findings are of great importance to Mali and other developing countries where young children are at a high risk of developing iNTS disease.

Background Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugated vaccine (PCV) have been widely used since 2010 in Japan when both vaccines were supported by the regional governments, and they were covered as routine recommended vaccines in 2013. The incidence of bacterial meningitis due to these organisms decreased in 2011 and 2012, but meningitis due to Streptococcus agalactiae and Escherichia coli remained unchanged. Objectives We planned to confirm whether the incidence also decreased in subsequent years. Methods We analyzed the epidemiological and clinical data for 2013–2015, and compared the information obtained in the previous nationwide survey database and our previous reports. We also investigated the risk factors for disease outcome. Results In the 2013–2015 surveys, 407 patients from 366 hospitals from all prefectures were evaluated. S. agalactiae (33%), Streptococcus pneumoniae (25%), and E. coli (10%) were the main organisms. The total number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.19 in 2009–2010 to 0.37 in 2013–2015 (p H. influenzae and S. pneumoniae meningitis significantly decreased from 0.66 in 2009–2010 to 0.01 in 2013–2015, and from 0.30 to 0.09, respectively (p Neisseria meningitidis were reported each year throughout 2001–2015. The fatality rates for H. influenzae, S. pneumoniae, S. agalactiae, and E. coli in 2013–2015 were 0.0, 4.1, 3.1, and 2.6%, respectively. Risk factors for death and sequelae were consciousness disturbance, convulsion, low CSF glucose, and Staphylococcus sp. as a causative organism (p Conclusions Hib vaccine and PCV have decreased the rate of bacterial meningitis. S. agalactiae has subsequently become the most common cause of bacterial meningitis in Japan.