Invasive Hib Disease Research Articles

WITHDRAWN: Conjugate vaccines for preventing Haemophilus influenzae type B infections.

Haemophilus influenzae (H. influenzae) is an important cause of meningitis and pneumonia in children. Vaccine cost is a significant barrier to use in low income countries. Determining the size of the effects of the vaccine will enable cost-effectiveness comparisons with competing priorities in low income countries. 1. To determine the effects of conjugate Hib vaccine in preventing Hib disease or death in children under five years of age. 2. To determine any variation in effect with type of vaccine, number of doses, age at first dose, in children with known HIV infection, or in high and low income countries. 3. To determine any serious adverse outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2006, issue 4) which contains the Acute Respiratory Infections Group's specialized register; MEDLINE (January 1966 to December 2006); EMBASE (1990 to June 2006) and scanned reference lists and contacting of authors of trial reports. All randomised controlled trials (RCTs) or quasi-RCTs of conjugate H. influenzae type b vaccines compared with placebo or no treatment in children who were followed until at least two years of age. Two review authors independently selected eligible studies and extracted data. Six studies were included in the review, and four in the meta-analyses. The overall quality of the trials was good. The relative risk for invasive Hib disease was 0.20 (95% confidence interval (CI) 0.07 to 0.54; random-effects model), but there was statistically significant unexplained variation (heterogeneity) in the effects of the four trials in the meta-analysis (P = 0.002). The size of the effects did not appear to differ consistently with different vaccine types, the number of vaccine doses, age at first vaccination or use in high income versus low income countries, but the CIs for the effect estimates were wide. Hib-related mortality data showed a non-significant trend towards benefit (relative risk was 0.29; 95% CI 0.07 to 1.20; random-effects model). The relative risk for all cause mortality in the two trials from which data were available were 1.01 (95% CI 0.38 to 2.67, random-effects model) and 0.97. No serious adverse effects were reported in any of the trials. Hib vaccine is safe and effective. In resource-poor settings, decisions to use the vaccine will depend on its cost, the local burden of Hib disease and competing priorities.

Long‐Term Immunological Follow‐Up of Children withHaemophilus influenzaeSerotype b Vaccine Failure in the United Kingdom

It is not known how long children with Haemophilus influenzae serotype b (Hib) vaccine failure retain protective Hib antibody concentrations after infection. The objective of this study was to determine Hib antibody concentrations in children several years after infection and to identify risk factors for low antibody concentrations. The families of children from the United Kingdom who developed invasive Hib disease after prior immunization with Hib conjugate vaccine (i.e., Hib vaccine failure) from October 1992 through December 2005 were asked to complete a questionnaire. A blood sample was also obtained from each child. Of 323 families approached, 260 (80.5%) returned a completed questionnaire, and 175 (54.2%) children provided a blood sample. The median age at follow-up was 8.4 years (interquartile range [IQR], 6.2-15.4 years), and the median duration of follow-up was 4.1 years (IQR, 3.5-9.7 years). Twenty-seven children (16.1%) had been born prematurely and/or had an underlying medical condition, and 18 (10.8%) had immunoglobulin deficiency. The median Hib antibody concentration was 0.70 microg/mL (IQR, 0.22-5.8 microg/mL). Overall, 95 children (56.9%) had antibody concentrations <1.0 microg/mL, and 27 (16.2%) had antibody concentrations <0.15 microg/mL. All 3 children with Down syndrome and 10 (42%) of 24 children aged <5 years at follow-up had Hib antibody concentrations <0.15 microg/mL. An antibody concentration <0.15 microg/mL was independently associated with underlying conditions, young age at onset of Hib disease, and shorter time from Hib disease to follow-up. More than one-half of the children with Hib vaccine failure had antibody concentrations below those considered to confer long-term protection, which suggests that these children might be at further risk of invasive Hib disease and would benefit from another dose of Hib vaccine.

Epidemiology of Pertussis and Haemophilus influenzae type b Disease in Canada With Exclusive Use of a Diphtheria-Tetanus-Acellular Pertussis-Inactivated Poliovirus-Haemophilus influenzae type b Pediatric Combination Vaccine and an Adolescent-Adult Tetanus-Diphtheria-Acellular Pertussis Vaccine

During the decade 1998-2007, a combination DTaP(5)-IPV/Hib vaccine was used exclusively in Canada to immunize infants and young children against diphtheria, tetanus, pertussis, polio, and invasive Haemophilus influenzae type b (Hib) disease. Medline was used to search for publications during 1996-2008 related to the epidemiology and vaccine prevention of pertussis and invasive Hib disease in Canada. Related abstracts and presentations were reviewed, when available, and epidemiologic data since 1985 were obtained from the Public Health Agency of Canada public Web site. Reports of pertussis have declined substantially in preschool and school-aged children during the past decade, and cyclical peaks in disease incidence have been blunted or eliminated. In provinces and territories where Tdap(5) vaccine has been administered to 14- to 16-year-olds, marked reductions of pertussis have been documented in adolescents as well as younger age groups, possibly due to herd immunity. Incidence rates of invasive Hib disease among Canadian children <5 years declined markedly after introduction of Hib conjugate vaccines, and the disease has remained under control with exclusive use of DTaP(5)-IPV/Hib vaccine. Most cases of invasive Hib disease occur among unimmunized or only partially vaccinated children. The reduction of Hib case reports has been documented throughout Canada, including among Aboriginal children who are at high risk for this disease. The Canadian experience with DTaP(5)-IPV/Hib and Tdap(5) vaccines is relevant to the United States because immunization schedules, vaccination coverage rates, and epidemiologic patterns of pertussis and Hib diseases are similar in the 2 countries, and because both vaccines are licensed for use in the United States.

Haemophilus influenzae Type b Conjugate Vaccine Introduction in Mali: Impact on Disease Burden and Serologic Correlate of Protection

In Bamako, Mali, where surveillance revealed a high incidence of Haemophilus influenzae type b (Hib) invasive disease, Hib conjugate vaccine was introduced into the Expanded Program on Immunization and the impact assessed. Annual confirmed Hib hospitalizations for infants 0-11 months of age fell from 175/10(5) to 44/10(5) (P < 0.001); among infants 6-7 months of age Hib hospitalizations fell from 377/10(5) to 69/10(5), (82% decrease, P < 0.001). Invasive Streptococcus pneumoniae hospitalizations remained unchanged. In a baseline serosurvey, only 3/200 infants 6-7 months of age (1.5%) had protective anti-polyribosylribitol phosphate (PRP) titers > or = 0.15 microg/mL and 1(0.5%) had >or = 1.0 microg/mL. In serosurveys 18 and 30 months after vaccine introduction, 168/201 (84%) and 184/200 (92%) infants, respectively, had titers > or = 0.15 microg/mL and 141/201 (70%) and 163/200 (82%) had titers > or = 1.0 microg/mL. Introduction of Hib vaccine led to rises in anti-PRP seroprevalence, significant reductions in Hib disease, and all-cause hospitalizations, whereas S. pneumoniae disease remained unchanged.

Reduction of meningitis and impact on under-5 pneumonia after introducing the Hib vaccine in the Kingdom of Tonga

To document the impact of Hib vaccine on Haemophilus influenzae (Hi) invasive disease, meningitis and inpatient pneumonia in children under 5 in the Kingdom of Tonga. Cases of meningitis and pneumonia were sourced from the paediatric discharge book from 1 January 2000 to 2 November 2007 and from computerised discharge records from Vaoila Hospital on the island of Tongatapu where approximately 70% of the total population resides. Laboratory-confirmed cases were sourced from the microbiology laboratory register over the same period. Prior to the introduction of Hib vaccine in 2005, there were, on average, 5.6 cases of invasive Hi disease per year. In the 22 months after Hib vaccine introduction, there was only one case of invasive Hi disease. This corresponds to a fall in the annual incidence of invasive Hib disease from 54.3 to 5.1/100,000 children under 5 years of age. The annual incidence of inpatient pneumonia has fallen by 28.3% from 1007.6 to 722.8/100,000 children under 5 in the 22 months after introducing the vaccine. Hib vaccine has reduced invasive Hi disease and Hi meningitis in Tonga. The reduction in inpatient pneumonia is more likely a reflection of annual fluctuations in viral pneumonia than of a reduction in Hib pneumonia, but ongoing surveillance is recommended.

The Pediatric Infectous Disease Journal® Newsletter

The Pediatric Infectous Disease Journal® Newsletter

Burden of Invasive Disease Caused by &lt;i&gt;Haemophilus influenzae&lt;/i&gt; Type b in Asia

Globally, Haemophilus influenzae type b (Hib) is one of the leading causes of childhood meningitis and pneumonia. Vaccines against Hib have been developed and introduced into routine immunization programs in most industrialized nations, in which the burden of Hib disease has been clearly demonstrated. In Asia, the burden of Hib disease has been perceived as relatively low compared with other parts of the world. However, the results of several recent studies have allowed for a more cautious assessment of the disease burden in different populations and settings throughout Asia. These studies suggest that the true burden of Hib disease may have been underestimated, and point to several key factors that may have contributed to this problem, such as antibiotic use prior to the analysis of blood and cerebrospinal fluid in infants and children suspected of having invasive Hib disease. Trials evaluating Hib vaccines in Asian populations have shown that they are effective and safe. These results may aid in the decision about whether to implement routine Hib vaccination in Asia and help to track the impact of Hib vaccination in the future.

Invasive Haemophilus influenzae disease: Changing epidemiology and host–parasite interactions in the 21st century

Introduction of Haemophilus influenzae type b (Hib) conjugate vaccines in late 1980s–early 1990s made a dramatic effect on the incidence of invasive Hib disease among children in many industrialized countries with routine Hib immunization programs. However, cases of vaccine failure and an increased susceptibility to invasive Hib as well as non-type b H. influenzae disease have been consistently reported among individuals with various congenital and acquired immunodeficiencies. Remarkably, in the 21st century, diseases due to non-type b strains of H. influenzae are becoming relatively more frequent than before. Despite the overall successful immunization against Hib, some indigenous populations, i.e. Australian Aboriginal and North American Indian children still experience increased rates of invasive H. influenzae disease. In order to monitor the evolving nature of invasive H. influenzae disease, carefully documented surveillance data is required to capture the true magnitude of the problem. Developing new vaccines against non-type b H. influenzae is a potential solution to protect some vulnerable populations against the invasive disease.

Recommendations for the prevention of secondary Haemophilus influenzae type b (Hib) disease

Haemophilus influenzae serotype b (Hib) can cause severe life threatening disease in healthy individuals, with over 80% of cases in the pre-vaccine era occurring in children under five years of age. The introduction of Hib conjugate vaccine into routine childhood immunisation programmes has resulted in a dramatic reduction in the incidence of invasive Hib disease across all age groups. The objective of this paper is to update existing UK guidelines on the prevention of Hib disease among contacts of an index case by reviewing the original literature and the current epidemiology of Hib carriage and invasive disease. Household contacts of individuals who develop invasive Hib disease are at higher risk of developing secondary Hib infection themselves, particularly if the contact is a young child or is immunosuppressed. Pre-school contacts of young children with invasive Hib disease are also at higher risk of developing secondary Hib infection. Rifampicin at a dose of 20mg/kg/day for 4 days is highly effective in eradicating pharyngeal carriage of Hib and reducing the risk of invasive Hib disease among household and pre-school contacts. Children under 10 years of age who develop invasive Hib disease should also receive rifampicin chemoprophylaxis to eliminate carriage and have Hib antibody levels tested around four weeks after infection. Hib vaccine failure cases should additionally have immunoglobulin concentrations measured and be assessed for evidence of an immune deficiency. If there is a vulnerable individual (child younger than 10 years or an immunosuppressed or asplenic individual of any age) among the household contacts of a case, all members of that household, including the index case, should receive chemoprophylaxis. All children younger than 10 years in the household should be appropriately vaccinated against Hib. Where more than one case occurs in a pre-school or primary school setting, chemoprophylaxis should be offered to all room contacts (including staff), and unimmunised and partially immunised children younger than 10 years should complete their primary immunisations, including a booster dose, as soon as possible. Families of children attending the same pre-school or primary school as an index case should be advised to seek medical advice if their child becomes unwell.

Haemophilus influenzae type b vaccine impact in resource-poor settings in Asia and Africa

The Haemophilus influenzae type b (Hib) conjugate vaccine has been administered for almost 20 years in developed countries with remarkable success. More recently, the vaccine has been introduced in resource-poor settings, mainly those in Africa. African countries have documented large declines in Hib-invasive disease following universal vaccine introduction based on evaluation of routine surveillance data. As of 2007, only Mongolia in Asia had introduced the vaccine. Consequently, studies are limited to clinical trials in Bangladesh and Indonesia, and these also demonstrate substantial vaccine impact. Beyond invasive disease, three pivotal trials in Africa and Asia have demonstrated vaccine impact against clinical pneumonia end points. In all settings evaluated, Hib vaccine was shown to be cost effective, although the vaccine is not yet cost saving based on pentavalent vaccine prices in excess of US$3 per dose. Future issues include monitoring for serotype replacement and the effects of the HIV epidemic, evaluating the usefulness of a booster dose or new vaccine schedules and working to lower vaccine prices.

Is Hib Vaccine of Economic Value in South Korea?

We welcome the article from Shin and colleagues on the cost-benefit of Haemophilus influenzae type b (Hib) immunization in Korea (1). The introduction of Hib vaccine into national immunization programmes has increased considerably during the past few years. While 91 countries had introduced the vaccine in 2005, 138 had done so in 2008 (2). Thirty-three of these additional 46 countries receive support from the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunization) for Hib vaccine, while 13 countries have introduced the vaccine with government funds (3). In Asia, the large countries of India, Pakistan and Bangladesh are currently introducing the vaccine. The overall conclusion made by Shin et al. (1) is that Hib vaccine is not economically efficient enough to introduce in Korea, partly due to the relatively high price of Hib vaccine and also due to the low Hib disease incidence. We wish to question this conclusion and some of the assumptions made to derive it. Firstly, Shin et al. used a public sector Hib vaccine price of US$20 per dose which seems unrealistically high. There are no published records of governments paying such a high public sector price for Hib vaccine. The US public sector price is between US$9 and US$11 per dose (4). In Australia, the government pays US$8 per dose (5). Shin et al. (1) states that if the price was less than US$16 per dose the vaccine would be economically efficient. Hence, if the analysis in the paper had been based on a public sector price comparable to other countries, the overall conclusion would have been opposite to their conclusion. The vaccine is in fact cost-saving. Secondly, the assumption made about Hib pneumonia incidence is unclear. The authors cite a reference from the United States for the ratio of pneumonia to meningitis incidence (6), which included only the incidence for invasive Hib disease and not all Hib pneumonias, and indicated that the number of meningitis cases is far higher than the number of pneumonia cases. However, the calculations used to estimate the pneumonia burden of disease were not stated clearly, and there are problems in extrapolating data from countries with such different demographics. In fact, Hib pneumonia is commonly thought to be much more prevalent than Hib meningitis in Asia (7). Lastly, we disagree with the underlying notion of Shin et al. that economic efficiency is only achieved if an intervention is proven to be cost-saving. Governments and policy makers are normally prepared to pay for improvement in the health of their populations. Economic analysis should, therefore, be used as one of many factors to guide the decision to choose among alternative health technologies.

Progress in vaccination against Haemophilus influenzae type b in the Americas.

Worldwide, Haemophilus influenzae type b (Hib) causes at least 3 million cases of severe disease each year. Approximately 400,000 children die annually due to pneumonia or meningitis caused by Hib [1]. Severe neurological sequelae occur in 15% to 30% of those who survive Hib meningitis [2]. Other, less frequent, manifestations of Hib are epiglottitis, septic arthritis, osteomyelitis, and septicemia [1–3]. Current polysaccharide–protein conjugate Hib vaccines are highly efficacious and safe. Primary series of two or three doses protect approximately 95% of infants [4–8]. Universal infant Hib immunization has proven to dramatically reduce Hib invasive disease [9–13] through direct vaccine protection and an important herd effect related to the reduction in Hib nasopharyngeal carriage in the community [12,14–16]. Adverse events are rare, and Hib vaccine is contraindicated only for persons with hypersensitivity to any of the vaccine's components [8,17]. The World Health Organization (WHO) recommends the introduction of Hib vaccines worldwide [1]. Furthermore, the Global Alliance for Vaccines and Immunization (GAVI Alliance)—an organization that aligns public and private resources in a global effort to create greater access to the benefits of immunization—considers Hib vaccine introduction in the world's poorest countries to be a top priority [18]. Prior to vaccine introduction, an estimated 20,000 cases of Hib meningitis were estimated to occur in countries of Latin America and the Caribbean (LAC) annually, based on an overall Hib meningitis incidence of 35 per 100,000 children aged 0–4 years [19]. Another 20,000 cases of invasive Hib disease were estimated to occur in the United States annually [20]. Most cases occurred in children aged less than 24 months, with at least 60% of cases occurring in children aged 0–11 months in half of the studies. The annual mortality rate for Hib meningitis in children aged less than five years was estimated to be around two per 100,000 in the Western Hemisphere [21]. Summary Points Hib vaccine introduction in countries of Latin America and the Caribbean has substantially reduced morbidity and mortality due to invasive Hib infections. All Latin American and Caribbean countries but one include Hib vaccine in their routine immunization schedule for infants. Factors that favored this region-wide Hib vaccine adoption include strong political will, data supporting Hib disease burden and impact in early adopting countries, and experience exchange among countries. Financial sustainability when introducing the more expensive Hib vaccine was critical for ensuring successful vaccine introduction in all countries. Efforts are still needed to improve vaccination coverage and to strengthen invasive bacterial disease surveillance in developing countries. In this article, we review the progress of vaccine introduction, lessons learned, and remaining challenges regarding Hib vaccination in the Americas, with emphasis on LAC countries. We expect that this updated and summarized information on Hib vaccination will serve as a useful reference to public health officials and policy makers from other regions who face the challenge of introducing Hib and other new or underutilized vaccines.

Effectiveness of hexavalent vaccines against invasive Haemophilus influenzae type b disease: Germany's experience after 5 years of licensure

Vaccine effectiveness (VE) was determined with a case-cohort approach using Cox regression. Cases with confirmed systemic Hib infections in children born from 1 August 2000 to 31 December 2004 were ascertained through two independent nationwide active surveillance systems. A representative cohort of 1303 children born in the same time frame was randomly sampled in a nationwide immunisation survey. Thirty cases were eligible for VE calculation; 19 were unvaccinated and 11 vaccinated with hexavalent vaccines. VE was 68.4% (95% CI: 19.0-87.6) for incomplete primary series and 90.4% (95% CI: 70.6-96.8) for the full primary series. For full immunisation VE was 100.0% (95% CI: 52.7-100.0). Hexavalent vaccines show a high effectiveness against invasive Hib disease in Germany.

Haemophilus influenzae Type b Vaccine Failure in Children Is Associated with Inadequate Production of High-Quality Antibody

Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects. Serum samples from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the samples using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution. Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection. Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.

Two variants among Haemophilus influenzae serotype b strains with distinct bcs4, hcsA and hcsB genes display differences in expression of the polysaccharide capsule

BackgroundDespite nearly complete vaccine coverage, a small number of fully vaccinated children in the Netherlands have experienced invasive disease caused by Haemophilus influenzae serotype b (Hib). This increase started in 2002, nine years after the introduction of nationwide vaccination in the Netherlands. The capsular polysaccharide of Hib is used as a conjugate vaccine to protect against Hib disease. To evaluate the possible rise of escape variants, explaining the increased number of vaccine failures we analyzed the composition of the capsular genes and the expressed polysaccharide of Dutch Hib strains collected before and after the introduction of Hib vaccination.ResultsThe DNA sequences of the complete capsular gene clusters of 9 Dutch Hib strains were assessed and two variants, designated type I and type II were found. The two variants displayed considerable sequence divergence in the hcsA and hcsB genes, involved in transport of capsular polysaccharide to the cell surface. Application of hcsA type specific PCRs on 670 Hib strains collected from Dutch patients with invasive Hib disease showed that 5% of the strains collected before 1996 were type II. No endogenous type II Hib strains were isolated after 1995 and all type II strains were isolated from 0–4 year old, non-vaccinated children only. Analysis of a worldwide collection of Hib strains from the pre-vaccination era revealed considerable geographic differences in the distribution of the type I and type II strains with up to 73% of type II strains in the USA. NMR analysis of type I and type II capsule polysaccharides did not reveal structural differences. However, type I strains were shown to produce twice as much surface bound capsular polysaccharide.ConclusionType II strains were only isolated during the pre-vaccination era from young, non-vaccinated individuals and displayed a lower expression of capsular polysaccharide than type I strains. The higher polysaccharide expression may have provided a selective advantage for type I strains resulting in the rapid elimination of type II from the Dutch Hib population after introduction of nationwide Hib vaccination. However, this phenomenon does not explain the increase in the number of Hib vaccine failures in the Netherlands.

Anticapsular Polysaccharide IgG Concentrations in Mexican Children Formerly Immunized with Haemophilus Influenzae b Prp-T Vaccine

Background: In 1999 H. influenzae b (Hib) PRP-T vaccine was introduced into primary immunization schedule in Mexico. There have been no studies evaluating antibody response after widespread immunization in our country. It is now recognized that Hib conjugates induce significant initial antibody levels that in some cases wane over time. This study relies on the measurement of IgG serum antibody concentrations to Hib capsular polysaccharide (PS) and is interpreted in the light of the accepted levels ≥ 0.15 µg/mL for short-term protection against Hib invasive disease and ≥ 5.0 µg/mL for protection against Hib oropharyngeal carriage. Methods: Using a validated ELISA assay, we measured the IgG serum antibody concentrations in 115 children between 7 and 93 months of age who had received three doses of PRP-T. We used the standard reference serum US FDA 1983 for quantification of PS antibody levels. Concentrations were estimated using 3rd degree polynomial regression lines. As there was no unvaccinated group available (>95% of Mexican children have received the Hib vaccine), the study was designed as a cross-sectional. Results: All children had serum IgG concentrations ≥ 0.15 µg/mL [range 0.24-54.64 µg/mL]; 69.6 % (80/115) had ≥1.0 µg/mL and 14% (16/115) showed concentrations ≥5.0 µg/mL. The vaccine elicited geometric mean concentrations (GMC) of 4.0, 1.6, 1.4 and 2.4 µg/mL in groups of 7-12, 13-24, 25-48 and 49-93 month-old respectively. Conclusions: PRP-T vaccination in this group of Mexican children has resulted in serum IgG concentrations ≥ 0.15 µg/mL, suggesting that Hib immunization has conferred protection against invasive disease.

Responses to immunisation with Hib conjugate vaccine in Australian breastfed and formula‐fed infants

There are conflicting reports as to whether breastfed infants respond with higher antibody levels to conjugate Haemophilus influenzae type b (Hib) vaccine compared with formula-fed infants. These observations prompted us to investigate the effect of feeding method on the antibody concentration to Hib polyribosylribitol (PRP) both prior to and 3 months after the primary course of immunisation with Hib (PRP-OMP). We measured plasma concentrations of IgG antibody to Hib PRP by enzyme-linked immunosorbent assay in blood samples from a total of 272 breastfed and formula-fed infants prior to immunisation (7 weeks of age, n = 82 and n = 148, respectively) and again 3 months after completion of the primary course of immunisation with Hib PRP-OMP (7 months of age, n = 88 and n = 132, respectively). Breastfeeding was associated with lower plasma antibody titres at both times (P < 0.01, T-test) with 49% of breastfed infants having anti-PRP concentrations below 1.0 microg/mL at age 7 months. There was no reported invasive Hib disease in this cohort of infants, and nationally the effectiveness of the Hib vaccination programme remains high. These data suggest that breastfeeding may be associated with immunomodulation of infant Hib immunisation responses with this immunisation regime. Further research is needed to determine whether differences in antibody concentration described here are primarily determined by factors directly attributed to breastfeeding or whether other environmental factors may play a significant role.

Epidemiology of invasive Haemophilus influenzae type b disease in Singapore children, 1994–2003

Invasive Haemophilus influenzae type b (Hib) diseases are major causes of childhood morbidity and mortality. For the period from 1994 to 2003, we retrospectively identified 53 children with invasive Hib disease including 31 with meningitis, 14 with pneumonia, 2 with septic arthritis, 2 with epiglottitis, 1 with neutropenic sepsis, and 3 who were bacteraemic without a focus. Two children died and 22 had serious sequelae; significantly, survivors with sequelae had presented with meningitis (P-value<0.001) or sepsis (P-value=0.001). During the 11-year period, the annual incidence of invasive Hib disease was estimated to be 4.4/100,000 children <5 years old. With rising affluence, decreasing costs of vaccines, and increased costs in caring for survivors, universal infant immunization with Hib vaccine may need to be reconsidered in Singapore.

Economic evaluation of delivering Haemophilus influenzae type b vaccine in routine immunization services in Kenya.

Haemophilus influenzae type b (Hib) vaccine was introduced into routine immunization services in Kenya in 2001. We aimed to estimate the cost-effectiveness of Hib vaccine delivery. A model was developed to follow the Kenyan 2004 birth cohort until death, with and without Hib vaccine. Incidence of invasive Hib disease was estimated at Kilifi District Hospital and in the surrounding demographic surveillance system in coastal Kenya. National Hib disease incidence was estimated by adjusting incidence observed by passive hospital surveillance using assumptions about access to care. Case fatality rates were also assumed dependent on access to care. A price of US$ 3.65 per dose of pentavalent diphtheria-tetanus-pertussis-hep B-Hib vaccine was used. Multivariate Monte Carlo simulations were performed in order to assess the impact on the cost-effectiveness ratios of uncertainty in parameter values. The introduction of Hib vaccine reduced the estimated incidence of Hib meningitis per 100,000 children aged < 5 years from 71 to 8; of Hib non-meningitic invasive disease from 61 to 7; and of non-bacteraemic Hib pneumonia from 296 to 34. The costs per discounted disability adjusted life year (DALY) and per discounted death averted were US$ 38 (95% confidence interval, CI: 26-63) and US$ 1197 (95% CI: 814-2021) respectively. Most of the uncertainty in the results was due to uncertain access to care parameters. The break-even pentavalent vaccine price--where incremental Hib vaccination costs equal treatment costs averted from Hib disease--was US$ 1.82 per dose. Hib vaccine is a highly cost-effective intervention in Kenya. It would be cost-saving if the vaccine price was below half of its present level.

Re-emergence of Haemophilus influenzae type b (Hib) disease in The Gambia following successful elimination with conjugate Hib vaccine

Invasive Hib disease, which remains a major cause of childhood mortality and morbidity in most of the developing world, was eliminated in The Gambia by 2002 following the introduction of conjugate Hib vaccine in 1997. Formal disease surveillance was stopped in 2002 but five cases (including three of meningitis) were detected non-systematically between July 2005 and April 2006. This equates to an incidence of 3 per 100,000 annually for meningitis, a likely underestimate. The age distribution of cases (median 15 months, range 0-36 months) was older than previously seen and there were examples of apparent vaccine failure, but the cause for this re-emergence is not clear. No evidence was found of the emergence of a hypervirulent strain. The re-establishment of continuing surveillance is required to answer the questions raised by this report, and is particularly important in settings like The Gambia, where a booster dose is not given, to determine long-term effects of national immunisation with Hib vaccine.