Hib Disease Research Articles

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

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

Utilization pattern of Haemophilus influenza type b vaccine in eight provinces of China

ABSTRACTObjective: 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.

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

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

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

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

Haemophilus influenzae type b carriage and burden of its related diseases in Chinese children: Systematic review and meta-analysis.

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 (P<0.001). 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 (P<0.001). 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.

Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b

BackgroundHaemophilus influenzae serotype b (Hib) has yet to be eliminated despite the implementation of routine infant immunization programs. There is no consensus regarding the number of primary vaccine doses and an optimal schedule for the booster dose. We sought to evaluate the effect of a booster dose after receiving the primary series on the long-term disease incidence.MethodsA stochastic model of Hib transmission dynamics was constructed to compare the long-term impact of a booster vaccination and different booster schedules after receiving the primary series on the incidence of carriage and symptomatic disease. We parameterized the model with available estimates for the efficacy of Hib conjugate vaccine and durations of both vaccine-induced and naturally acquired immunity.ResultsWe found that administering a booster dose substantially reduced the population burden of Hib disease compared to the scenario of only receiving the primary series. Comparing the schedules, the incidence of carriage for a 2-year delay (on average) in booster vaccination was comparable or lower than that observed for the scenario of booster dose within 1 year after primary series. The temporal reduction of symptomatic disease was similar in the two booster schedules, suggesting no superiority of one schedule over the other in terms of reducing the incidence of symptomatic disease.ConclusionsThe findings underscore the importance of a booster vaccination for continued decline of Hib incidence. When the primary series provides a high level of protection temporarily, delaying the booster dose (still within the average duration of protection conferred by the primary series) may be beneficial to maintain longer-term protection levels and decelerate the decline of herd immunity in the population.

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

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

Recognizing the Importance of Vaccine Confidence

In the past thirty years we have seen dramatic advances in vaccine technology and development that have yielded vaccines to protect against the pneumococcus, Hib, rotavirus, HPV, and meningococcal disease amongst others (Parashar et al., 1998, Gessner and Adegbola, 2008, Khatami and Pollard, 2010, Lynch and Zhanel, 2010). We have also seen a paradigm shift in the availability of these vaccines in the developing world through the efforts of the Gavi alliance and WHO (Fund V). In addition, new vaccines are being developed to target diseases whose primary impact is in developing countries such as the malaria (Wilby et al., 2012) and meningococcal A vaccines (Kristiansen et al., 2013). These changes in technology and the distribution of vaccines have saved many lives and have the potential to save millions more if widespread vaccine use is sustained. Unfortunately, vaccines safety scares and loss of public and political confidence in vaccines and vaccination programs have the potential to negate these public health gains. As we have seen with the polio eradication program in Africa and Asia, bogus vaccine safety concerns and loss of public confidence in the polio vaccination program, whatever the scientific reality, can derail successful programs (Jegede, 2007). Similarly, unfounded vaccine safety concerns regarding the hepatitis B vaccine in France have led to low hepatitis B vaccination rates and persistent disease there (Marshall, 1998).

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

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

Impact of Haemophilus influenzae Type B Conjugate Vaccines on Nasopharyngeal Carriage in HIV-infected Children and Their Parents From West Bengal, India

In addition to reducing Haemophilus influenzae type b (Hib) disease in vaccinated individuals, the Hib conjugate vaccine (HibCV) has indirect effects; it reduces Hib disease in unvaccinated individuals by decreasing carriage. Human immunodeficiency virus (HIV)-infected children are at increased risk for Hib disease and live in families where multiple members may have HIV. The aim of this study is to look at the impact of 2 doses of the HibCV on nasopharyngeal carriage of Hib in HIV-infected Indian children (2-15 years) and the indirect impact on carriage in their parents. This prospective cohort study was conducted in HIV-infected and HIV-uninfected families. Nasopharyngeal swabs were collected from children and parents before and after vaccination. HIV-infected children 2-15 years of age got two doses of HibCV and were followed up for 20 months. Uninfected children 2-5 years of age got 1 dose of HibCV as catch-up. 123 HIV-infected and 44 HIV-uninfected children participated. Baseline colonization in HIV-infected children was 13.8% and dropped to 1.8% (P = 0.002) at 20 months. Baseline carriage in HIV-uninfected children was 4.5% and dropped to 2.3% after vaccination (P = 0.3). HIV-infected parents had 12.3 times increased risk of Hib carriage if their child was colonized (P = 0.04) and had 9.3 times increased risk if their child had persistent colonization postvaccine (P = 0.05). No parent of HIV-uninfected children had Hib colonization at any point. Pneumococcal colonization was associated with increased Hib colonization. Making the HibCV available to HIV-infected children could interrupt Hib carriage in high-risk families.

Children with Haemophilus influenzae type b (Hib) vaccine failure have long-term bactericidal antibodies against virulent Hib strains with multiple capsular loci

Children who develop invasive Haemophilus influenzae serotype b (Hib) disease after immunisation with a highly-effective conjugate vaccine are more likely to have been infected with Hib strains possessing multiple copies of the capsulation locus. Using a recently-validated serum bactericidal antibody (SBA) assay, we tested convalescent sera from 127 Hib vaccine failure cases against clinical Hib strains expressing 1–5 copies of the capsulation locus. SBA titres correlated weakly with anti-capsular IgG antibody concentrations and there was no association between SBA geometric mean titres and number of capsulation locus copies. After infection, children with Hib vaccine failure were equally protected against Hib strains with 1–5 copies of the capsulation locus.

IgE anti-Haemophilus influenzae type b (Hib) antibodies detected in serum of Hib-vaccinated asthmatic and non-asthmatic pediatric patients.

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. 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. We found that: 1) total serum IgE levels were higher in asthmatic compared with non-asthmatic subjects (389±125 vs. 125±129, P<0.001); 2) IgE and IgG anti-Hib antibody responses were similar in both asthmatic and non-asthmatic subjects (0.722±0.279 and 0.681±0.280, respectively; P=0.65; 0.450±0.505 and 0.573±0.779, respectively; P=0.580). The universal Hib vaccine antigen did not result in either increased IgE, or IgG anti-Hib antibody responses in asthmatic or non-asthmatics subjects. Thus, in this cohort, no association between Hib vaccination and asthma status was identified.

Laboratory characterization of invasive Haemophilus influenzae isolates from Nunavut, Canada, 2000–2012

BackgroundWith invasive Haemophilus influenzae serotype b (Hib) disease controlled by vaccination with conjugate Hib vaccines, there is concern that invasive disease due to non-serotype b strains may emerge.ObjectiveThis study characterized invasive H. influenzae (Hi) isolates from Nunavut, Canada, in the post-Hib vaccine era.MethodsInvasive H. influenzae isolates were identified by conventional methods at local hospitals; and further characterized at the provincial and federal public health laboratories, including detection of serotype antigens and genes, multi-locus sequence typing and antibiotic susceptibility.ResultsOf the 89 invasive H. influenzae cases identified from 2000 to 2012, 71 case isolates were available for study. There were 43 serotype a (Hia), 12 Hib, 2 Hic, 1 Hid, 1 Hie, 2 Hif and 10 were non-typeable (NT). All 43 Hia were biotype II, sequence type (ST)-23. Three related STs were found among the Hib isolates: ST-95 (n=9), ST-635 (n=2) and ST-44 (n=1). Both Hif belonged to ST-124 and the 2 Hic were typed as ST-9. The remaining Hid (ST-1288) and Hie (ST-18) belonged to 2 separate clones. Of the 10 NT strains, 3 were typed as ST-23 and the remaining 7 isolates each belonged to a unique ST. Eight Hib and 1 NT-Hi were found to be resistant to ampicillin due to β-lactamase production. No resistance to other antibiotics was detected.ConclusionDuring the period of 2000–2012, Hia was the predominant serotype causing invasive disease in Nunavut. This presents a public health concern due to an emerging clone of Hia as a cause of invasive H. influenzae disease and the lack of published guidelines for the prophylaxis of contacts. The clonal nature of Hia could be the result of spread within an isolated population, and/or unique characteristics of this strain to cause invasive disease. Further study of Hia in other populations may provide important information on this emerging pathogen. No antibiotic resistance was detected among Hia isolates; a small proportion of Hib and NT-Hi isolates demonstrated resistance to ampicillin due to β-lactamase production.

Haemophilus influenzae Type f Hijacks Vitronectin Using Protein H To Resist Host Innate Immunity and Adhere to Pulmonary Epithelial Cells.

The incidence of invasive Haemophilus influenzae type b (Hib) disease has significantly decreased since the introduction of an efficient vaccine against Hib. However, in contrast to Hib, infections caused by H. influenzae serotype f (Hif) are emerging. We recently did a whole genome sequencing of an invasive Hif isolate, and reported that Hif interacts with factor H by expressing protein H (PH). In this study, upon screening with various human complement regulators, we revealed that PH is also a receptor for vitronectin (Vn), an abundant plasma protein that regulates the terminal pathway of the human complement system in addition to being a component of the extracellular matrix. Bacterial Vn binding was significantly reduced when the lph gene encoding PH was deleted in an invasive Hif isolate. The dissociation constant (KD) of the interaction between recombinant PH and Vn was 2.2 μM, as revealed by Biolayer interferometry. We found that PH has different regions for simultaneous interaction with both Vn and factor H, and that it recognized the C-terminal part of Vn (aa 352-362). Importantly, PH-dependent Vn binding resulted in better survival of the wild-type Hif or PH-expressing Escherichia coli when exposed to human serum. Finally, we observed that PH mediated an increased bacterial adherence to alveolar epithelial cells in the presence of Vn. In conclusion, our study reveals that PH most likely plays an important role in Hif pathogenesis by increasing serum resistance and adhesion to the airways.

Safety and reactogenicity of the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b (DTPa-IPV/Hib) vaccine in healthy Vietnamese toddlers: An open-label, phase III study

abstractThe introduction of combination vaccines plays a significant role in increasing vaccine acceptance and widening vaccine coverage. Primary vaccination against diphtheria, tetanus, pertussis, poliomyelitis and Haemophilus influenza type b (Hib) diseases has been implemented in Vietnam. In this study we evaluated the safety and reactogenicity of combined diphtheria-tetanus-pertussis-inactivated polio (DTPa-IPV)/Hib vaccine when administered as a booster dose in 300 healthy Vietnamese children <2 years of age (mean age: 15.8 months). During the 4-day follow-up period, pain (31.7%) and redness (27.3%) were the most frequent solicited local symptoms. Pain (2%) was also the most frequent grade 3 local symptom. One subject reported 2 serious adverse events that were not causally related to the study vaccine. DTPa-IPV/Hib conjugate vaccine was well tolerated as a booster dose in healthy Vietnamese children aged <2 years.

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

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

Increased Disease due to Haemophilus influenzae Type b

In 1997, The Gambia became the first African country to introduce conjugate Haemophilus influenzae type b (Hib) vaccine with good disease control through to 2010. Culture-based surveillance for invasive bacterial disease in eastern Gambia, specifically the Basse Health and Demographic Surveillance System (BHDSS) area, was conducted from 12 May 2008 and in Fuladu West district from 12 September 2011 until 31 December 2013. In 2011, Hib serology was measured in 5-34-year-olds. In all, 16,735 of 17,932 (93%) eligible patients were investigated. We detected 57 cases of invasive H. influenzae disease; 24 (42%) were type b. No cases of Hib disease were detected in the BHDSS area in 2008-2009; 1 was detected in 2010, 2 in 2011, 4 in 2012 and 7 in 2013. In 2013, the incidence of Hib disease in those aged 2-11 and 2-59 months in the BHDSS area was 88 [95% confidence interval (CI): 29-207] and 22 (95% CI: 9-45) cases per 10⁵ person-years, respectively. In 2013, disease incidence in Fuladu West among those aged 0-59 months was 26 (95% CI: 7-67) cases per 10⁵ person-years. Nine of 24 Hib cases were vaccine failures (2 HIV positive) and 9 were too young to have been vaccinated. The proportion of children aged 5-6 years (n = 223) with anti-Hib IgG ≥1.0 μg/mL was 67%; the antibody nadir was in 9-14-year-olds (n = 58) with 55% above threshold. Hib disease in eastern Gambia has increased in recent years. Surveillance in developing countries should remain alert to detect such changes.

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

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

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

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

Pneumococcal conjugate vaccine and changing epidemiology of childhood bacterial meningitis

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