Assessment of bacterial exposure on phagocytic capability and surface marker expression of sputum macrophages and neutrophils in COPD patients.

Defective phagocytosis has been shown in chronic obstructive pulmonary disease (COPD) bronchoalveolar lavage and blood monocyte-derived macrophages. Phagocytic capabilities of sputum macrophages and neutrophils in COPD are unknown. We investigated phagocytosis in these cells from COPD patients and controls. Phagocytosis of Streptococcus pneumoniae or fluorescently labelled non-typeable Haemophilus influenzae (NTHi) by sputum macrophages and neutrophils was determined by gentamycin protection assay (COPD; n = 5) or flow cytometry in 14 COPD patients, 8 healthy smokers (HS) and 9 healthy never-smokers (HNS). Sputum macrophages and neutrophils were differentiated by adherence for the gentamycin protection assay or receptor expression (CD206 and CD66b, respectively), by flow cytometry. The effects of NTHi on macrophage expression of CD206 and CD14 and neutrophil expression of CD16 were determined by flow cytometry. There was greater uptake of S. pneumoniae [~10-fold more colony-forming units (CFU)/ml] by sputum neutrophils compared to macrophages in COPD patients. Flow cytometry showed greater NTHi uptake by neutrophils compared to macrophages in COPD (67 versus 38%, respectively) and HS (61 versus 31%, respectively). NTHi uptake by macrophages was lower in HS (31%, p = 0.019) and COPD patients (38%, p = 0.069) compared to HNS (57%). NTHi uptake by neutrophils was similar between groups. NTHi exposure reduced CD206 and CD14 expression on macrophages and CD16 expression on neutrophils. Sputum neutrophils showed more phagocytic activity than macrophages. There was some evidence that bacterial phagocytosis was impaired in HS sputum macrophages, but no impairment of neutrophils was observed in HS or COPD patients. These results highlight the relative contributions of neutrophils and macrophages to bacterial clearance in COPD.

Intranasal coinfection model allows for assessment of protein vaccines against nontypeable Haemophilus influenzae in mice.

PURPOSE: Nontypeable Haemophilus influenzae (NTHi) is a commensal in the human nasopharynx and the cause of pneumonia, meningitis, sinusitis, acute exacerbations of chronic obstructive pulmonary disease and acute otitis media (AOM). AOM is the most common ailment for which antibiotics are prescribed in the United States. With the emergence of new strains of antibiotic-resistant bacteria, finding an effective and broad coverage vaccine to protect against AOM-causing pathogens has become a priority. Mouse models are a cost-effective and efficient way to help determine vaccine efficacy. Here, we describe an NTHi AOM model in C57BL/6J mice, which also utilizes a mouse-adapted H1N1 influenza virus to mimic human coinfection. METHODOLOGY: We tested our coinfection model using a protein vaccine formulation containing protein D, a well-studied NTHi vaccine candidate that can be found in the 10-valent Streptococcus pneumoniae conjugate vaccine. We verified the usefulness of our mouse model by comparing bacterial loads in the nose and ear between protein D-vaccinated and control mice. RESULTS: While there was no measurable difference in nasal bacterial loads, we did detect significant differences in the bacterial loads of ear washes and ear bullae between vaccinated and control mice. CONCLUSION: The results from this study suggest that our NTHi AOM coinfection model is useful for assessing protein vaccines.

Cost-effectiveness of a potential vaccine candidate for Haemophilus influenzae serotype 'a'.

The preceding decade has witnessed the emergence of severe community-acquired acute infections caused by Haemophilus influenzae serotype a (Hia), with alarming incidence rates in North America, particularly among indigenous populations. The remarkable success of Hib conjugate vaccine over the past 20 years signify the development of an Hia vaccine candidate as a prevention measure to reduce the incidence of invasive Hia disease. However, quantifications of the long-term epidemiologic and economic impacts of vaccination are needed to inform decision on investment in Hia vaccine development and immunization programs. We sought to evaluate the cost-effectiveness of an Hia vaccine with a similar routine infant immunization schedules currently in practice for Hib in Canada. We developed and parameterized an agent-based simulation model using age-specific incidence rates reported for Nunavut, a Canadian territory with predominantly aboriginal populations. Our results, based on statistical analyses of the incremental cost-effectiveness ratio, show that an Hia conjugate vaccine is highly cost-effective. Sustaining an immunization program with vaccine coverages of 77% for primary series and 93% for booster dose over a 10-year period reduces the incidence of invasive disease by 63.8% on average from 9.97 to 3.61 cases, per 100,000 population. The overall costs of disease management in year 10 are reduced by 53.4% from CDN $1.863 million (95% CI: $1.229-$2.519 M) to CDN $0.868 million (95% CI: $0.627-$1.120 M). The findings suggest an important role for a conjugate vaccine in managing Hia disease as a growing public health threat.

Cost-effectiveness analysis of infant pneumococcal vaccination with PHiD-CV in Korea.

BACKGROUND: Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) can cause invasive pneumococcal diseases (IPD), pneumonia, and acute otitis media (AOM). Both the 10-valent pneumococcal NTHi protein D conjugate vaccine (PHiD-CV) and the 13-valent pneumococcal conjugate vaccine (PCV-13) are included in the National Immunization Program for infants in Korea. This study aimed to evaluate the cost-effectiveness of the 3+1 schedule of PHiD-CV versus that of PCV-13 for National Immunization Program in Korea. METHODS: A published Markov model was adapted to evaluate the cost-effectiveness of vaccinating the 2012 birth cohort with PHiD-CV vs. PCV-13 from the Korean government perspective over 10 y. Best available published data were used for epidemiology, vaccine efficacy and disutilities. Data on incidence and direct medical costs were taken from the national insurance claims database. Sensitivity analyses were conducted to explore the robustness of the results. RESULTS: PHiD-CV was projected to prevent an additional 195,262 cases of pneumococcal diseases and NTHi-related diseases vs. PCV-13, with a substantially greater reduction in NTHi-related AOM and a comparable reduction in IPD and community-acquired pneumonia. Parity-priced PHiD-CV generated a health gain of about 844 quality-adjusted life years and a total cost-saving of approximately 4 million United States Dollars (USD) over 10 y. 93% of probabilistic simulations found PHiD-CV 3+1 to be the dominant vaccine option. CONCLUSION: Compared to PCV-13, PHiD-CV was projected to provide similar prevention against IPD and community-acquired pneumonia but would prevent more cases of AOM. Parity-priced PHiD-CV was anticipated to generate substantial cost-savings and health benefits vs. PCV-13 in Korea.

Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study.

BACKGROUND: The relationship between early-life antibiotic use and the development of wheeze and asthma has been reported in several studies but might arise as a consequence of bias rather than causal relationship. We investigated the association between antibiotic prescription and subsequent development of atopy, wheeze, and asthma exacerbations, and the relation of early life antibiotic prescription with anti-infective immunity and genetic variants on asthma susceptibility locus 17q21. METHODS: Children in a population-based birth cohort were followed from birth to age 11 years. Information on antibiotic prescription, wheeze, and asthma exacerbations was extracted from medical records, and the effect of antibiotic prescription assessed with longitudinal analyses. We assessed immune responses of peripheral blood mononuclear cells, taken at age 11 years, to viruses (rhinovirus and respiratory syncytial virus; RSV) and bacteria (Haemophilus influenzae and Streptococcus pneumoniae) in children who either received at least one or no antibiotic prescriptions in infancy. Finally, we assessed the association of 17q21 polymorphisms with antibiotic prescription. FINDINGS: Of 984 families who gave consent, we extracted data for 916 children. We noted significantly higher risk of physician-confirmed wheezing after antibiotic prescription (hazard ratio [HR] 1·71, 95% CI 1·32-2·23; p<0·0001) and severe wheeze or asthma exacerbation after antibiotic prescription (HR 2·26, 95% CI 1·03-4·94; p=0·041). In children who wheezed, the hazards of exacerbations (2·09, 1·51-2·90; p<0·0001) and admissions to hospital (2·64, 1·49-4·70; p=0·0009) were significantly increased in the 2 years after the first antibiotic prescription. Children who received antibiotics in infancy had significantly lower induction of cytokines, which are important in host defence against virus infections to both RSV and rhinovirus; there were no differences in antibacterial responses. Variants in 17q21 were associated with an increased risk of early life antibiotic prescription. INTERPRETATION: The association between antibiotics and asthma might arise through a complex confounding by indication. Hidden factors that may increase the likelihood of both early life antibiotic prescription and later asthma are an increased susceptibility to viral infections consequent upon impaired antiviral immunity and genetic variants on 17q21. FUNDING: Moulton Charitable Foundation and Medical Research Council.

Burden and cost of hospital admissions for vaccine-preventable paediatric pneumococcal disease and non-typable Haemophilus influenzae otitis media in New Zealand.

INTRODUCTION: Streptococcus pneumoniae (Sp.) is a leading cause of paediatric bacterial meningitis, pneumonia and acute otitis media, as is non-typable Haemophilus influenzae (NTHi) for acute otitis media. In 2008, a 7-valent conjugated pneumococcal vaccine (PCV7) was included in the New Zealand (NZ) childhood immunization schedule. OBJECTIVE: To estimate the potentially vaccine-preventable annual hospital admissions and cost to the NZ Government of paediatric admissions for pneumococcal disease and NTHi otitis media prior to the immunization programme. METHODS: Admissions (2000-7) and deaths (2000-5) in children aged<20 years with pneumococcal meningitis or bacteraemia, pneumonia or otitis media were identified in national datasets and linked by unique patient identifiers. New episodes of illness were defined as admissions occurring >30 days after discharge from a previous admission. Informed by the literature, pneumococcal pneumonia episodes were estimated at 33% of all-cause pneumonia admissions; Sp. and NTHi otitis media episodes were estimated jointly at 72% of otitis media admissions. Each episode was assigned a single diagnosis according to the following hierarchy: meningitis>bacteraemia>pneumonia>otitis media. Incidence rates for episodes were determined for 2000-7 (meningitis, bacteraemia and pneumonia) and 2006-7 (otitis media). Annual DRG-based costs for pneumococcal meningitis, bacteraemia, pneumonia and otitis media were estimated as (episode rate)x(DRG cost weight per episode)x(2007 population)x(national price per cost weight). RESULTS: Episode rates for pneumococcal meningitis, bacteraemia and pneumonia were stable in 2000-7, highest in the second 6 months of life and declined steeply over the first 5 years of life. Mean rates per 100000 in 2000-7 were 18.4, 27.6 and 464 for pneumococcal meningitis, bacteraemia and pneumonia, respectively, for children aged<2 years; 8.4, 14.9 and 295 for children aged<5 years (including those aged<2 years); and 2.2, 4.4 and 97 for children aged<20 years (including those aged<5 years). Mean rates per 100000 in 2006-7 for Sp. and NTHi otitis media combined were 631 (surgical) and 197 (medical) for children aged<2 years; 691 and 116 for children aged<5 years; and 281 and 35 for children aged<20 years. Pacific Island and indigenous Maori children generally had higher rates than European/other children. Rates increased with socioeconomic disadvantage, across all diagnoses. The annual cost to Government of pneumococcal disease and NTHi otitis media admissions for children aged<20 years was estimated at New Zealand dollars ($NZ)9.95 million (range 7.7-12.2 million) [about $US7.1 million]. Most of this cost was shared between pneumococcal pneumonia (48%) and otitis media (45%), and 78% was incurred in the first 2 years of life. Estimated annual paediatric mortality rates per 100 000 for children aged<5 years were 0.48, 0.30 and 0.54 for pneumococcal meningitis, bacteraemia and pneumonia, respectively. The analysis predicted four or five pneumococcal deaths per year (range 1-8) for children aged<5 years. CONCLUSIONS: Prior to the introduction of a national Sp. immunization programme, hospital admissions for Sp. disease and NTHi otitis media in NZ cost about $NZ10 million annually, mostly for children aged<2 years and particularly for those living in relative socioeconomic deprivation and for Pacific Island and Maori children. There were about five pneumococcal deaths annually. With adjustment for local serotypes, vaccine serotype coverage and uptake, immunization with any of the three available pneumococcal vaccines would reduce this burden substantially.

Global reduction of Hib disease: what are the next steps? Proceedings of the meeting Scottsdale, Arizona, September 22-25, 2002.

On September 22 to 25, 2002, a group of infectious disease specialists, public health officials, and vaccine experts from 33 countries gathered in Scottsdale, Arizona, to discuss the epidemiology and control of disease caused by Haemophilus influenzae type b (Hib) in the era of Hib conjugate vaccines. This supplement is a synthesis of the major themes and key lessons identified at the meeting. The objectives of the conference were to review the 10-year experience with Hib conjugate vaccines, discuss strategies to reduce Hib disease rates to lowest possible levels in industrialized countries, review impediments to the introduction of Hib vaccine in developing countries, and discuss strategies for disseminating lessons learned from countries using to those not using Hib conjugate vaccines. Over 10 years of international experience with Hib conjugate vaccines has demonstrated that they are safe and effective. Routine use of Hib conjugate vaccine has consistently led to decreases in the incidence of invasive Hib disease of 90% or more across a wide range of epidemiologic situations in industrialized countries. In some countries, the vaccine has caused a near-disappearance of invasive Hib disease through a combination of direct protection and herd immunity. Developing countries that have implemented routine vaccination (eg, The Gambia, Chile) have also had substantial disease reduction. In countries where Hib conjugate vaccine is being used, reducing Hib disease incidence to the lowest possible level will depend on maintaining high vaccine coverage levels, conducting surveillance for Hib disease, and investigating Hib disease cases. The optimal Hib vaccination strategy will depend on many factors, including local epidemiology and programmatic considerations. In countries that are not using Hib conjugate vaccine, information on the local burden of Hib disease will be essential for leaders considering vaccine introduction. Where disease burden is high, a multifaceted approach is urgently needed to evaluate and overcome barriers to vaccine introduction. In areas where Hib disease burden is not well characterized, additional work will be needed to understand the epidemiology of Hib disease and to communicate the value of Hib conjugate vaccine.

Functional antibody activity elicited by fractional doses of Haemophilus influenzae type b conjugate vaccine (polyribosylribitol phosphate-tetanus toxoid conjugate).

We evaluated the functional activities of antibodies, serum bactericidal activity (SBA), and immunoglobulin G (IgG) antibody avidity indices, using sodium thiocyanate (NaSCN) elution, elicited after vaccination with fractional doses of the Haemophilus influenzae type b conjugate (polyribosylribitol phosphate [PRP] conjugated to tetanus toxoid [PRP-T]) vaccine. A cohort of 600 infants from the Dominican Republic were randomized to receive one of three regimens of the PRP-T vaccine at ages 2, 4, and 6 months: full doses (10 microg of PRP antigen), one-half doses (5.0 microg), and one-third doses (3.3 microg) (J. Fernandez et al., Am. J. Trop. Med. Hyg. 62:485-490, 2000). Sixty serum samples, collected at age 7 months, with > or =2.0 microg of anti-PRP IgG per ml were randomly selected for avidity determinations. Geometric mean IgG concentrations were 13, 14, and 17 microg/ml for infants who received the full-dose (n = 19), one-half-dose (n = 19), and one-third-dose (n = 22) regimens, respectively. SBA geometric mean titers (1/dilution) were 85.0, 82.0, and 76.1 in sera from infants receiving the full-, one-half-, and one-third-dose regimens, respectively. Avidity indices (mean +/- standard error weighted average of NaSCN molar concentration x serum dilution factor) were 71.9 +/- 9.4, 123.6 +/- 26.8, and 150.9 +/- 24.9 for the full-, one-half-, and one-third-dose regimens, respectively. Upon comparison, the only significant difference (P = 0.024) found was a greater avidity index for sera from infants receiving the one-third-dose regimen than for sera from infants receiving the the full-dose regimen. We conclude that fractional doses elicit similar functional antibody activities in infants with > or = 2 microg of anti-PRP IgG per ml, corresponding to 89, 90, and 97% of infants receiving three doses of either the full concentration or one-half or one-third of the labeled concentration, respectively. This approach offers an alternative strategy for the prevention of H. influenzae type b disease in countries with limited resources.

Clinical efficacy and antimicrobial pharmacodynamics.

Changes in the susceptibility of bacterial pathogens and the availability of new antimicrobial drugs mean that physicians need to understand the underlying pharmacodynamics of each antimicrobial therapy. Antimicrobial pharmacodynamics determine clinical efficacy and should therefore be carefully considered when selecting appropriate antibiotic agents in the therapeutic setting.

Cost-effectiveness evaluation of vaccination against Haemophilus influenzae invasive diseases in France.

A cost-effectiveness analysis of a vaccination program against Haemophilus influenzae type b (Hib) was conducted using French epidemiological data. The vaccine would be added as a fifth valence to the tetravalent vaccines (DTCP) widely used in France. The permanent sequelae of the Hib invasive diseases which might be avoided by vaccination were weighted to determine Quality Adjusted Life Years gained. In a stable French population of 3,746,000 children aged < 5 years old (1990), and for a followup period of ten years, the cost-effectiveness ratio of such a program for the French national health insurance system would equal 54,084 FF per year of life added or 34,050 FF per QALY. The net cost of the program during that period would be 1.02 billion FF for the French national health insurance system and 920 million FF for patients' families. Comparison of these projections with available information supports, a posteriori, the decision of the French government to authorize the licensing of the pentavalent vaccine.

Impact of immunization on Haemophilus influenzae type b disease.

Epidemiological surveillance programs have shown that before the introduction of effective vaccines, Haemophilus influenzae type b (Hib) was the primary pathogen associated with bacterial meningitis in children. Vaccines composed of the bacterium's polysaccharide conjugated onto protein carriers began to be introduced into routine health care practices for infants as early as 1989 in some European countries. Continued introduction in industrialized nations, including the United States in late 1990, has resulted in the rapid decline in the incidence of reported invasive Hib disease. Follow-up surveillance studies show that (a) the decline in the incidence of Hib disease is temporally related to the introduction of effective vaccines, (b) the decline in Hib epiglottitis preceded the decline in meningitis in the United States, (c) the incidence of disease declined in children under the age of 5 years but remained constant in older children and adults, (d) other bacterial pathogens are now the primary causative agents of infant meningitis and epiglottitis even though the incidence of disease caused by these other pathogens has not changed, and (e) the pharyngeal carriage rate of Hib in children has declined without any evidence of an increase in the carriage of non-type b strains or other pathogens. The introduction of effective conjugate vaccines appears to protect at-risk children from invasive Hib disease as well as reduce the opportunities for interpersonal transmission of this bacterium. In addition, Hib conjugate vaccine utilization has benefited society through economic savings.

Laboratory correlates of protection against Haemophilus influenzae type b disease. Importance of assessment of antibody avidity and immunologic memory.

The concentration of serum antibody to the Haemophilus influenzae type b polysaccharide sufficient to confer protection against Hib disease has been estimated to range from 0.15 to 1.0 microgram/ml as measured by conventional antigen binding assays. However, the ability of these serologic tests to predict vaccine equivalence and/or protective efficacy is limited since there are important qualitative differences in vaccine-induced anti-PRP antibody, such as isotype, variable region usage, and antibody avidity. These differences may profoundly affect the biologic activity of the antibody. Also, Hib conjugate vaccination primes infants for memory antibody responses to a subsequent encounter with PRP, and immunologic priming can occur in infants with very low serum anti-PRP antibody responses to conjugate vaccination, or in those whose antibody concentrations have declined after vaccination. Primed infants are likely to be protected against Hib disease in the absence of "protective" serum antibody concentrations because priming permits a rapid serum anti-PRP antibody response upon encountering the organism. Thus, quantitative assessment of immunogenicity, by itself, is insufficient to predict vaccine equivalence or protective efficacy. In defining surrogate serologic tests for prediction of vaccine efficacy, assessments of antibody avidity and induction of immunologic memory should be included. Ideally, these assessments should be supplemented with antibody functional assays such as complement-mediated bactericidal activity, opsonic activity, or passive protection in animal models of disease.

Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants.

OBJECTIVE: To evaluate the safety and immunogenicity of two Haemophilus influenzae type b (Hib) conjugate vaccines when administered in serial combination. These vaccines consisted of Hib capsular polysaccharide polyribosyl-ribitol phosphate (PRP) conjugated to the meningococcal outer membrane protein (OMP) complex (PRP-OMP) and H influenzae oligosaccharide conjugated to a mutant toxin (CRM197) isolated from Corynebacterium diphtheriae (HbOC). DESIGN: Randomized, double-blind, clinical trial evaluating five Hib vaccination regimens. SETTING: Vaccine Treatment and Evaluation Units and affiliated private pediatric practices at Saint Louis (Mo) University, Vanderbilt University, Nashville, Tenn, and Baylor College of Medicine, Houston, Tex. PATIENTS: A total of 497 healthy 2-month-old infants scheduled to receive routine immunization. INTERVENTION: Participants received either PRP-OMP or HbOC given as recommended by the manufacturer, PRP-OMP at 2 and 6 months, HbOC at 2 months, then PRP-OMP at 4 and 6 months, or PRP-OMP at 2 months and then HbOC at 4 and 6 months. Unconjugated PRP was given at 15 months to evaluate priming. RESULTS: Geometric mean antibody concentrations differed significantly among the groups following the second and third immunizations of the primary series and following booster immunization with unconjugated PRP. On each occasion, the groups receiving serial combinations of PRP-OMP and HbOC achieved mean antibody concentrations that equalled or exceeded those of the groups receiving a single product. Adverse reactions did not vary by group. CONCLUSIONS: The studied sequential combinations of Hib vaccines were safe and at least as immunogenic as either vaccine alone.

The costs and benefits of a vaccination programme for Haemophilus influenzae type B disease.

Haemophilus influenzae type b (Hib) infection is a major cause of severe bacterial infection in young children in South Africa and world-wide. These diseases can be prevented by immunisation with conjugate Hib vaccines. In South Africa, unlike some developed countries, Hib vaccines are not part of the routine immunisation schedule. The objective of this study was to measure the expected net benefits from a hypothetical programme of vaccination of the 1992 Cape Town birth cohort (N = 46,537). Costs were calculated by summing the estimated direct medical care costs together with the indirect costs of Hib disease. The latter were calculated by valuing human life using alternative, and conservative human capital and willingness-to-pay measures. The difference between Hib disease costs (i.e. the benefits which would be gained from a successful vaccination programme) and the costs of the vaccination programme itself (HibTITER, Praxis Biologicals) defined the expected net benefits. In the absence of an immunisation programme, the estimated economic costs of Hib disease in the 1992 Cape Town cohort ranged from R10.7 million to R11.8 million. The costs of introducing the vaccine would have amounted to R8.3 million. Had the vaccine been administered to the 1992 birth cohort, benefits would have exceeded costs by between R2.4 million and R3.5 million.

Cost of treatment and prevention of Haemophilus influenzae type b disease. An international perspective.

On the basis of immunogenicity and protective efficacy studies, 4 Haemophilus influenzae type b (Hib) conjugate vaccines have been licensed for administration to infants and children. Population based studies of Hib disease from Australia, Chile, Finland, Gambia, Israel, Switzerland, UK and US show that the relative and absolute incidence of Hib disease varies significantly. These differences in Hib epidemiology, and associated sequelae and hospital costs affect the cost-benefit analysis of preventive vaccination, necessitating unique calculations for each country. Published papers on the cost of Hib disease and the cost-benefit relationship of Hib vaccination have been based primarily on reports from the US, but more recently also on studies from Australia, Finland, Israel, Switzerland, UK, Sweden and Chile. All studies to date have produced favourable cost-benefit ratios. The implementation of Hib vaccination has led to the virtual disappearance of Hib disease in some of these countries. The lessons gained from these analyses are instructive not only for better understanding of the epidemiology of Hib disease, but also as a template for assessing the cost-benefit ratio of the implementation of preventive vaccination for other diseases.

Clinical usefulness of cerebrospinal fluid bacterial antigen studies.

A retrospective chart review was performed to evaluate the effect that positive results of cerebrospinal fluid bacterial antigen tests had on the care of patients with presumed bacterial meningitis. Of 901 tests ordered, costing $26,000 per year, 29 showed positive results--and only four of these affected patient care. By using cerebrospinal fluid bacterial antigen testing only when another test does not identify an organism, or in an attempt to determine central nervous system infection late in therapy for presumed sepsis, one can greatly reduce costs with no detrimental effect on patients.

[Costs and benefits of vaccination against Haemophilus influenzae type b]. / De kosten en baten van vaccinatie tegen Haemophilus influenzae type b.

In the Netherlands, Haemophilus influenzae type b (Hib) causes invasive disease in hundreds of children every year; meningitis is the most frequent and most severe infection. Children from the age of 6 months can be protected against Hib-diseases by conjugated vaccines. The financial consequences of the introduction of such vaccine into the state vaccination programme are considered in a cost-effectiveness analysis. Some elements in the analysis are still uncertain, such as the price and the schedule and method of administration of the vaccine. Presumably, the costs and benefits will be in balance, if one vaccine dose will cost about 7 US $+ and if the administration can be combined with the present programme of vaccinations against diphtheria, whooping cough, poliomyelitis and tetanus.