The costs and effectiveness of large Phase III pre-licensure vaccine clinical trials.

Prior to the 1980s, most vaccines were licensed based upon safety and effectiveness studies in several hundred individuals. Beginning with the evaluation of Haemophilus influenzae type b conjugate vaccines, much larger pre-licensure trials became common. The pre-licensure trial for Haemophilus influenzae oligosaccharide conjugate vaccine had more than 60,000 children and that of the seven-valent pneumococcal conjugate vaccine included almost 38,000 children. Although trial sizes for both of these studies were driven by the sample size required to demonstrate efficacy, the sample size requirements for safety evaluations of other vaccines have subsequently increased. With the demonstration of an increased risk of intussusception following the Rotashield brand rotavirus vaccine, this trend has continued. However, routinely requiring safety studies of 20,000-50,000 or more participants has two major downsides. First, the cost of performing large safety trials routinely prior to licensure of a vaccine is very large, with some estimates as high at US$200 million euros for one vaccine. This high financial cost engenders an opportunity cost whereby the number of vaccines that a company is willing or able to develop to meet public health needs becomes limited by this financial barrier. The second downside is that in the pre-licensure setting, such studies are very time consuming and delay the availability of a beneficial vaccine substantially. One might argue that in some situations, this financial commitment is warranted such as for evaluations of the risk of intussusception following newer rotavirus vaccines. However, it must be noted that while an increased risk of intussusception was not identified in large pre-licensure studies, in post marketing evaluations an increased risk of this outcome has been identified. Thus, even the extensive pre-licensure evaluations conducted did not identify an associated risk. The limitations of large Phase III trials have also been demonstrated in efficacy trials. Notably, pre-licensure trials of pneumococcal conjugate severely underestimated their true effect and cost-effectiveness. In fact, in discussions prior to vaccine introduction in the USA for PCV7, the vaccine was said to be not cost-effective and some counseled against its introduction. In reality, following introduction, PCV7 has been shown to be highly cost-effective. In the last decade, new methods have been identified using large linked databases such as the Vaccine Safety Datalink in the USA that allow identification of an increased risk of an event within a few months of vaccine introduction and that can screen for unanticipated very rare events as well. In addition, the availability of electronic medical records and hospital discharge data in many settings allows for accurate assessment of vaccine effectiveness. Given the high financial and opportunity cost of requiring large pre-licensure safety studies, consideration could be given to 'conditional licensure' of vaccines whose delivery system is well characterized in a setting where sophisticated pharmacovigilance systems exist on the condition that such licensure would incorporate a requirement for rapid cycle and other real-time evaluations of safety and effectiveness following introduction. This would actually allow for a more complete and timely evaluation of vaccines, lower the financial barrier to development of new vaccines and thus allow a broader portfolio of vaccines to be developed and successfully introduced.

The impact of residency and urbanicity on Haemophilus influenzae Type b and pneumococcal immunization in Shanghai Children: a Retrospective Cohort Study.

BACKGROUND: Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugate vaccine (PCV) are relatively expensive, newly introduced vaccines in China. This study evaluates the impact of residency and urbanicity on Hib vaccine and PCV coverage for children aged 2 to 7 years living in Shanghai, China, in August 2012. METHODS: In this exploratory cohort study, a sample of children aged 2 to 7 years, all of whom were eligible to have received the complete series of Hib vaccine and PCV, was obtained from the Shanghai Immunization Program Information System. Three measures of vaccination coverage for Hib vaccine and PCV were examined: dose 1 coverage, series completion, and timeliness of dose 1 vaccination. Multivariable binomial regression was used to estimate the difference in vaccination coverage between locals and the floating population. RESULTS: Dose 1 coverage was 50.9% for Hib vaccine and 11.4% for PCV for the 28,141 abstracted pediatric records. For both vaccines, dose 1 coverage was higher in locals than in the floating population. The disparity in coverage between locals and the floating population was greater in suburban areas than urban areas. Of all children who received dose 1, 79.7% completed the Hib vaccine series, and 91.3% completed the PCV series. Timely dose 1 coverage was 8.2% for Hib vaccine and 0.5% for PCV. CONCLUSION: Low vaccination coverage and extremely low levels of timely dose 1 vaccination indicate that current vaccination efforts are inadequate to reduce the burden of Hib and pneumococcal disease among Chinese children, especially infants. Government funding of the Hib vaccine and PCV through the Expanded Program on Immunization would increase uptake and could also ensure that improvement in the timeliness of administration and series completion is targeted for all demographic groups.

Assessment of immunogenicity and safety following primary and booster immunisation with a CRM197 -conjugated Haemophilus influenzae type B vaccine in healthy Chinese infants.

BACKGROUND: Invasive meningitis and pneumonia caused by Haemophilus influenzae type b (Hib) is an important cause of childhood mortality in countries where Hib vaccination is not routine. We evaluated the non-inferiority of a licensed Hib vaccine, PRP-CRM(197) compared with a second licensed Hib vaccine, PRP-T, following the recommended Chinese immunisation schedule for infants between 6 months and 1 year of age. METHODS: In the first study phase, 6-12 month-old infants received two primary doses of either PRP-CRM(197) (n = 335) or PRP-T (n = 335) vaccine administered 1 month apart. In the second study phase 8 months later, the same children received a single booster dose of vaccine identical to that use for priming (PRP-CRM(197), n = 327; PRP-T, n = 333). Serum levels of anti-polyribosylribitol phosphate (PRP) antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Non-inferiority of primary and booster doses was assessed in terms of percentages of subjects with anti-PRP antibody levels associated with providing short-term (≥ 0.15 µg/ml) and long-term (≥ 1.0 µg/ml) protection; the non-inferiority margin was set at -5%. RESULTS: PRP-CRM(197) was demonstrated to be non-inferior to PRP-T. Anti-PRP antibodies levels ≥ 0.15 µg/ml and ≥ 1.0 µg/ml were achieved by 97% of infants in the PRP-CRM(197) group and 98% of infants in the PRP-T group 1 month after primary immunisation, and by all subjects (100%) in both vaccine groups 1 month after booster administration. Safety profiles for both vaccines were similar; no serious adverse events, deaths or adverse events leading to withdrawal occurred during the study. CONCLUSION: PRP-CRM(197) was well-tolerated and immunologically non-inferior to a licensed comparator Hib vaccine in Chinese infants (Clinicaltrials.gov: NCT01044316 & NCT01226953).

Impact and cost-effectiveness of Haemophilus influenzae type b conjugate vaccination in India.

OBJECTIVE: To estimate the potential health impact and cost-effectiveness of nationwide Haemophilus influenzae type b (Hib) vaccination in India. STUDY DESIGN: A decision support model was used, bringing together estimates of demography, epidemiology, Hib vaccine effectiveness, Hib vaccine costs, and health care costs. Scenarios favorable and unfavorable to the vaccine were evaluated. State-level analyses indicate where the vaccine might have the greatest impact and value. RESULTS: Between 2012 and 2031, Hib conjugate vaccination is estimated to prevent over 200 000 child deaths (∼1% of deaths in children <5 years of age) in India at an incremental cost of US$127 million per year. From a government perspective, state-level cost-effectiveness ranged from US$192 to US$1033 per discounted disability adjusted life years averted. With the inclusion of household health care costs, cost-effectiveness ranged from US$155-US$939 per discounted disability adjusted life year averted. These values are below the World Health Organization thresholds for cost effectiveness of public health interventions. CONCLUSIONS: Hib conjugate vaccination is a cost-effective intervention in all States of India. This conclusion does not alter with plausible changes in key parameters. Although investment in Hib conjugate vaccination would significantly increase the cost of the Universal Immunization Program, about 15% of the incremental cost would be offset by health care cost savings. Efforts should be made to expedite the nationwide introduction of Hib conjugate vaccination in India.

Naturally acquired and conjugate vaccine-induced antibody to Haemophilus influenzae type b (Hib) polysaccharide in Malian children: serological assessment of the Hib immunization program in Mali.

Haemophilus influenzae type b (Hib) conjugate vaccine for infants (6, 10, and 14 weeks of age) was introduced into the Malian Expanded Program on Immunization in July 2005, to diminish invasive Hib disease in young children. Antibodies to Hib capsular polysaccharide (PRP) were measured in infants and toddlers from an area already served by the Hib immunization program (Bamako) and in unimmunized children of the same age in a district (Kangaba) where Hib immunization had not yet begun. Among vaccinated Bamako children 6-23 months of age, 77-93% exhibited PRP titers ≥ 1.0 µg/mL, indicating long-term protection, versus only 10-23% of Kangaba children of that age. High PRP antibody titers in immunized children persisted through 2 years of age. Moreover, ∼50% of Bamako children exhibited anti-PRP titers ≥ 5.0 µg/mL; a level that impedes Hib upper respiratory carriage, and may thereby diminish the Hib transmission to the unimmunized susceptible population (i.e., providing indirect protection).

Accelerating introduction of new vaccines: barriers to introduction and lessons learned from the recent Haemophilus influenzae type B vaccine experience.

Adoption of new vaccines in developing countries is critical to reducing child mortality and meeting Millennium Development Goal 4. However, such introduction has historically suffered from significant delays that can be attributed to various factors including (i) lack of recognition of the value of a vaccine, (ii) factors related to weak health systems, and (iii) policy considerations. Recently, the Global Alliance for Vaccines and Immunization (GAVI) supported efforts to accelerate the introduction of Haemophilus influenzae type b (Hib) vaccines in developing countries, which resulted in a significant surge in vaccine adoption by these countries. The experience with Hib vaccines, as well as similar efforts by GAVI to support the introduction of new pneumococcal and rotavirus vaccines, provides a strategy for new vaccine adoption that is reviewed in this paper, providing a useful model to help accelerate the uptake of other life-saving vaccines. This strategy addresses barriers for vaccine adoption by focusing on three major areas: (i) communications to increase awareness about the various factors needed for evidence-based decisions that meet a country's health goals; (ii) research activities to answer key questions that support vaccine introduction and long-term programme sustainability; and (iii) coordination with the various stakeholders at global, regional and country levels to ensure successful programme implementation.

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.

[Assessment of effectiveness of immunization against Hib-infection].

AIM: To assess effectiveness of Act-HIB vaccine forprevention of acute respiratory diseases. MATERIALS AND METHODS: Nine hundred immunized children 1 - 5 years old as well as not immunized children of the same age were followed-up. Criteria for clinical effectiveness of the vaccine were rate of acute respiratory infection episodes, duration of disease episode, and rate of complications development. Level of nasopharyngeal coverage were also studied by bacteriological tests of nasopharyngeal secretion samples. RESULTS: Obtained data showed that immunization leads to increase of host's resistance capabilities, decrease of acute respiratory disease incidence and changes in structure of complications due to infection. CONCLUSION: Prevention of Hib-infection using Act-HIB vaccine leads to decrease of acute respiratory disease rates and severity of infections. Total incidence of acute respiratory infections in children aged 1 - 5 years decreased by 27%, whereas incidence of pneumonia, bronchitis, and sinusitis - by 50%. Vaccination resulted in decrease of antibiotic use, number of pediatric consultations.

Economic evaluations of Haemophilus influenzae type b vaccine: systematic review of the literature.

With the arrival of new, more expensive vaccines, economic evaluation has become an important tool for assessing the feasibility of introducing a new vaccine into a country's routine immunization schedule. Haemophilus influenzae type b (Hib) vaccine has been available since the early 1990s, but uptake of the vaccine was slow in low-income countries until the GAVI Alliance started offering financial support for it. However, at some point, GAVI Alliance-supported countries will have to identify other sources of financing for Hib vaccine, meaning cost-effectiveness evidence will be important to support resource allocation decisions. Several middle-income countries have not yet introduced the vaccine. Thus, the aim of this literature review was to identify and evaluate the published evidence on the cost-effectiveness of the Hib vaccine, with particular emphasis on low- and middle-income countries. It is concluded that there are only few studies available from resource-poor countries and some of these are of low quality.

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.

Vaccine-preventable haemophilus influenza type B disease burden and cost-effectiveness of infant vaccination in Indonesia.

BACKGROUND: Most of Asia, including Indonesia, does not use Haemophilus influenzae type b (Hib) conjugate vaccines. We estimated total vaccine-preventable disease burden and the cost-effectiveness of Hib conjugate vaccine in Indonesia. METHODS: Hib pneumonia and meningitis incidences for children with access to health care were derived from a randomized vaccine probe study on Lombok Island, Indonesia during 1998-2002. Incidences were adjusted for limited access to care. Health system and patient out-of-pocket treatment cost data were collected concurrent with the probe study. For Hib vaccine in monovalent and combined (with DTP-HepB) presentations, we used 2007 UNICEF vaccine prices of US$3.30 and $3.75 per dose. RESULTS: For the 2007 Indonesian birth cohort, Hib vaccine would prevent meningitis in 1 of every 179 children, pneumonia in 1 of every 18 children, and 4.9% of mortality among those younger than 5 years. The total incremental societal costs of introducing Hib vaccine in monovalent and pentavalent presentations were, respectively, US$11.74 and $8.93 per child vaccinated. Annual discounted treatment costs averted amounted to 20% of pentavalent vaccine costs. For the pentavalent vaccine, the incremental costs per discounted death and disability adjusted life-year averted amounted to US$3102 and $74, respectively, versus $4438 and $102 for monovalent vaccine. CONCLUSIONS: Routine infant Hib vaccination would prevent a large burden of pediatric illness and death in Indonesia. Even without external funding support, Hib vaccine will be a highly cost-effective intervention in either a monovalent or pentavalent presentation based on commonly used benchmarks.

Immunogenicity and safety of four different doses of Haemophilus influenzae type b-tetanus toxoid conjugated vaccine, combined with diphtheria-tetanus-pertussis vaccine (DTP-Hib), in Indonesian infants.

Widespread use of Haemophilus influenzae type b (Hib) conjugated vaccine in industrialized countries has resulted in a dramatic decline in the incidence of invasive Hib diseases, but the vaccine's cost has prevented its inclusion in basic immunization programs in developing countries. To overcome this problem, combination with diphtheria-tetanus-pertussis (DTP) vaccine or reduction in the dose of Hib vaccine has been proposed. To evaluate the immunogenicity and adverse reactions from lower doses of Hib-polyribosylphosphate (PRP) conjugated with tetanus toxoid (PRP-T), a double-blind study was conducted in Jakarta, Indonesia, and its suburbs. A total of 1048 infants 6 weeks to 6 months of age received three doses of DTP vaccine combined with the usual 10 microg dose or with a reduced dose of 5, 2.5 or 1.25 microg of PRP-T at two-monthly intervals. Antibodies were measured prior to the first dose and 4-6 weeks following the third dose. Adverse reactions were similar among all four groups. The only significant difference was a higher rate of irritability (p<0.02) and of temperature elevation >38 degrees C (p<0.009) after doses 1 and 2 in the lowest dose group (1.25 microg PRP-T) compared to the other groups. All participants tested had a 4-fold increase in antibodies against all DTP antigens. In addition, after a fourth booster dose of Hib, 99.6% of infants produced >or=0.15 microg/ml of antibody to Hib-PRP, and 96.4% showed levels >or=1.0 microg/ml after primary immunization, level that correlate with short- and long-term immunity, respectively. Antibody titers to the PRP antigen showed no significant differences among dosage groups with the exception of the 5.0 microg group, which had a significantly higher GMC than the 1.25 microg group (p<0.012). This study demonstrates that primary vaccination with half, one-fourth, or one-eighth of the usual dose of PRP-T, combined with DTP vaccine, produces protective immune responses, and has side effects that are comparable to DTP vaccination alone. In these lower dosages, PRP-T conjugate vaccine can lower vaccine costs to a level that is affordable for infant immunization programs in developing countries.

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.

Impact of universal Haemophilus influenzae type b vaccination starting at 2 months of age in the United States: an economic analysis.

OBJECTIVE: To evaluate the economic impact of universal Haemophilus influenzae type b (Hib) vaccination starting at 2 months of age. METHODS: Decision-tree-based analysis was conducted of a hypothetical US birth cohort of 3 815 469 infants using population-based vaccination coverage and disease incidence data. All costs were estimated from both the direct cost (medical and nonmedical) and societal perspectives. Net present value, cost-effectiveness ratios, and benefit-cost ratios of the US Hib vaccination program were evaluated. RESULTS: The results of these analyses showed that the universal vaccination program using the Hib conjugate vaccines in the United States in 2000 was cost-saving from both the direct and societal perspectives, with the benefit of the Hib vaccination program (net present value) from the direct cost and societal perspectives of $0.95 billion and $2.09 billion, respectively. Without a Hib vaccination program, the direct and societal costs of Hib invasive cases would be $1.35 billion and $2.58 billion, respectively. The direct and societal costs of the Hib vaccination program were estimated at $0.39 billion and $0.48 billion, respectively. The direct and societal benefit-cost ratios for the Hib vaccination program were 3.4 and 5.4, respectively. Varying the proportion of vaccines purchased and administered in the public versus the private sector and the proportion of combination vaccine versus monovalent vaccine administered did not have much effect on the results. CONCLUSIONS: Regardless of the perspective (direct cost or societal) and the assumptions used, the benefit-cost ratios of the US vaccination program are >1.0. Potential changes in the program, including use of more or less Hib combination vaccines, would not significantly alter the benefit-cost ratio. The national Hib vaccination program is highly cost beneficial and results in substantial cost savings.

Standard and alternative regimens of Haemophilus influenzae type b conjugate vaccine (polyribosylribitol phosphate-tetanus toxoid conjugate vaccine) elicit comparable antibody avidities in infants.

BACKGROUND: Haemophilus influenzae type b conjugate vaccines are relatively expensive in the developing world. Previous study of the type b conjugate vaccine polyribosylribitol phosphate-tetanus toxoid conjugate vaccine showed that two dose and fractional three dose schedules elicit protective antibody concentrations equivalent to three full doses. METHODS: Antibody avidity was measured in 73 of these vaccinees with a modified enzyme-linked immunosorbent assay using NH(4) SCN as the chaotrope. Avidity index (AI) is the molarity causing a 50% reduction in OD(405). RESULTS: The postprimary series AI was similar for all dosing regimens. Preboost AI was highest in those receiving three half-doses, although there was no statistical difference among groups. Rises in avidity from age 8 to 12 months were also similar among regimens. Our data support the equivalence of anti-polyribosylribitol phosphate IgG avidity in infants primed with these alternative regimens. CONCLUSIONS: Given the known correlation of avidity with assays of bacterial killing and memory priming, these potentially more economical alternative schedules should be studied in the developing world.

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.

Economic evaluation of Haemophilus influenzae type b vaccination in Slovenia.

The objective of the present study was to assess the economical impact of invasive Haemophilus influenzae type b infections in Slovenia, where the annual incidence of these infections is 16.4/100000 in children less than 5 years of age, and to compare it with the costs of a vaccination programme. The lifetime costs and benefits were estimated for the annual birth cohort of 18200 children. In the base-case model, the calculated benefit-to-cost ratios were 0.15, 0.98 and 1.38 taking into account 95% of savings in acute care costs, medical costs, and medical and non-medical costs, respectively. From the point of view of the Institute of Health Insurance of Slovenia, who pays all healthcare and vaccination costs, the vaccination programme per annual birth cohort of 18200 children would require an extra 7023 EUR or 0.40 EUR per cohort-child. The savings to society would represent 118410 EUR, indicating the rationale for inclusion of H. influenzae type b vaccination in the routine childhood immunisation programme in Slovenia.

Age- and cause-specific childhood mortality in Lombok, Indonesia, as a factor for determining the appropriateness of introducing Haemophilus influenzae type b and pneumococcal vaccines.

Using age and cause-specific childhood mortality in Lombok, Indonesia, as a factor for determining the appropriateness of introducing Haemophilus influenzae type b (Hib) and pneumococcal vaccines, the study describes a cross-sectional, hamlet-level mortality survey in 40 of 305 villages in Lombok Island, Indonesia. Causes of death were assessed with a standardized verbal-autopsy questionnaire. One thousand four hundred ninety-nine births and 141 deaths occurring among children aged less than 2 years were identified, with 43% of deaths occurring during the first 2 months of life. The infant mortality rate was 89 (95% CI: 75, 104) per 1,000 live-births. All mortality rates are reported per 1,000 live-births. To examine children whose deaths could potentially have been prevented through vaccination with Hib or pneumococcal vaccine, deaths due to acute respiratory infection (ARI) and central nervous system (CNS) infections among children, aged 2-23 months, were analyzed. ARI and CNS infections caused 58% (mortality rate: 31 per 1,000 live-births; 95% CI: 23, 41) and 17% (mortality rate: 9 per 1,000 live-births; 95% CI: 5, 16), respectively, of all deaths within this age group. Between the ages of 2 and 23 months, 5% of all babies born alive died of ARI, and another 1% died of CNS infections. Our results indicate that current efforts to reduce childhood mortality should focus on reducing ARI and meningitis. These efforts should include evaluating the impact of Hib and pneumococcal vaccines within the routine Expanded Programme on Immunization system.