Hans C. Rümke

Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children

A trial with a 7-valent pneumococcal-conjugate vaccine in children with recurrent acute otitis media showed a shift in pneumococcal colonisation towards non-vaccine serotypes and an increase in Staphylococcus aureus-related acute otitis media after vaccination. We investigated prevalence and determinants of nasopharyngeal carriage of Streptococcus pneumoniae and S aureus in 3198 healthy children aged 1-19 years. Nasopharyngeal carriage of S pneumoniae was detected in 598 (19%) children, and was affected by age (peak incidence at 3 years) and day-care attendance (odds ratio [OR] 2.14, 95% CI 1.44-3.18). S aureus carriage was affected by age (peak incidence at 10 years) and male sex (OR 1.46, 1.25-1.70). Serotyping showed 42% vaccine type pneumococci. We noted a negative correlation for co-colonisation of S aureus and vaccine-type pneumococci (OR 0.68, 0.48-0.94), but not for S aureus and non-vaccine serotypes. These findings suggest a natural competition between colonisation with vaccine-type pneumococci and S aureus, which might explain the increase in S aureus-related otitis media after vaccination.

Immunogenicity and reactogenicity in UK infants of a novel meningococcal vesicle vaccine containing multiple class 1 (PorA) outer membrane proteins.

The development of effective vaccines against serogroup B meningococci is of great public health importance. We assessed a novel genetically engineered vaccine containing six meningococcal class 1 (PorA) outer membrane proteins representing 80% of prevalent strains in the UK. 103 infants were given the meningococcal vaccine at ages 2, 3 and 4 months with routine infant immunisations, with a fourth dose at 12-18 months. The vaccine was well tolerated. Three doses evoked good immune responses to two of six meningococcal strains expressing PorA proteins contained in the vaccine. Following a fourth dose, larger bactericidal responses to all six strains were observed, suggesting that the initial course had primed memory lymphocytes and revaccination stimulated a booster response. This hexavalent PorA meningococcal vaccine was safe and evoked encouraging immune responses in infants. Vaccines of this type warrant further development and evaluation.

Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2-3 and 7-8 years of age.

To study the reactogenicity and immunogenicity of a hexavalent meningococcal outer-membrane-vesicle vaccine (OMV), two different dosages of this vaccine (7.5 and 15 microg of individual PorA proteins) consisting of vesicles expressing class 1 outer-membrane proteins (OMPs) of subtypes P1.7,16; P1.5,2; P1.19,15 and P1.5(c), 10; P1.12,13; P1.7(h),4 were administered to a group of 7-8 year (n=165) and a group of 2-3 year old children (n=172). Control groups of children with similar ages were vaccinated against hepatitis B. All participants received three injections. Pre- and postimmunisation sera were tested for bactericidal antibodies against six isogenic meningococcal vaccine strains expressing different PorA proteins. Antibody titres against OMP of the two different vesicles (PL16215 and PL10124) were measured by ELISA. The meningococcal hexavalent OMV vaccine was well tolerated. No statistically significant differences were seen between the high and low dose of hexavalent meningococcal OMV vaccine. The percentage of children showing a fourfold increase of bactericidal antibody titres against the specific serosubtype varied in toddlers from 28 to 98% and in older children from 16 to 100%. Both ELISA antibody titres and bactericidal activity showed the highest level in the youngest age-group.

Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial

A multicentre, randomized, phase III clinical trial in 5071 healthy adults was conducted to evaluate the safety and reactogenicity of a 15 microg HA dose of a candidate oil-in-water emulsion-based adjuvant system (AS)-adjuvanted split-virion H5N1 (AS-H5N1) vaccine compared to a licensed seasonal influenza vaccine, Fluarix.(1) Stringent criteria were used to evaluate adverse events and reactogenicity profile. Overall, 96.7% of the 5071 vaccinated subjects completed the study. Significantly more participants in the AS-H5N1 vaccine group reported general or local adverse events. Pain was the most common symptom in both treatment groups. Less than 1% of subjects withdrew from the study due to adverse events and no withdrawals were due to serious adverse events related to vaccination. The safety and reactogenicity profile of the AS-H5N1 candidate vaccine can be considered clinically acceptable in the context of its use against pandemic influenza.

Epidemiologic impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands

BACKGROUND Streptococcus pneumoniae is one of the main causes of bacterial meningitis, bacteremia, pneumonia, and otitis media in the Netherlands. These diseases lead to substantial mortality, morbidity, and costs. The societal impact is especially severe because most cases occur in very young infants. OBJECTIVE The aim of this study was to estimate the epidemiological impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands. METHODS Decision analysis was performed using epidemiological data and data on health care resource use from 1996 to 2001. A model was used to project the impact of pneumococcal vaccination on the incidence of pneumococcal infections in infants and children from birth to age 10 years. Costs, benefits, and health gains were estimated, and cost-effectiveness was calculated. All analyses were performed from a societal perspective. RESULTS On average, 339 cases per year of invasive pneumococcal infection occurred in infants and children from birth to age 10 years in the Netherlands from 1996 to 2001. The model predicted that introduction of the 7-valent conjugated pneumococcal vaccine would prevent 48 cases of bacterial meningitis and 88 cases of pneumococcal bacteremia per year, as well as 42,695 cases of pneumococcal otitis media and 3411 cases of invasive pneumococcal pneumonia. The model also predicted that vaccination would save 13 lives per year and prevent 31 cases of lifelong sequelae, rendering 382 discounted quality-adjusted life-years (QALYs) gained or 329 discounted life-years gained per year. Considering these health gains, vaccination would prevent Euro 9,453,600 of direct and indirect medical costs of meningococcal and pneumococcal infections in the Netherlands, including acute medical care, management of sequelae, and lost time at work. With a vaccine price of Euro 40 per dose, the base-case cost-effectiveness ratio would be Euro 71,250 per QALY. The model was sensitive to changes in incidence of infections, vaccine effectiveness, and vaccine price. CONCLUSIONS Our analytic model predicted that universal pneumococcal vaccination of infants in the Netherlands could prevent a large number of pneumococcal infections and considerably reduce related mortality and morbidity. However, the baseline cost-effectiveness ratio of such a vaccination program would be relatively unfavorable compared with other interventions implemented in the Netherlands.

Serum bactericidal activity and isotype distribution of antibodies in toddlers and schoolchildren after vaccination with RIVM hexavalent PorA vesicle vaccine

A clinical phase II trial with the RIVM hexavalent OMV vaccine containing six different PorAs was carried out in toddlers (2-3 years) and schoolchildren (7-8 years) in The Netherlands. Children were vaccinated three times (0, 2, 8 months). Sera after two and three vaccinations were analysed for serum bactericidal activity (SBA) and isotype distribution in whole cell enzyme linked immunosorbent assay (ELISA). The SBA after vaccination against the six PorAs was significantly different. We investigated whether the age specific and PorA specific differences in SBA titers correlated with differences in PorA specific IgG isotype distribution. The SBA titers were higher in toddlers compared with schoolchildren. After vaccination, IgG1 antibodies dominated the response followed by IgG3 antibodies. IgG2 levels were low, whereas IgG4 was not detected. Irrespective of PorA, IgG total and isotype specific titers after two and three vaccinations were significantly higher in toddlers than in schoolchildren. A weak correlation was found between IgG total or IgG1 and SBA. Although the immunogenicity of the six PorAs is very different, the isotype distribution was similar for all six tested PorAs. We conclude that the RIVM hexavalent PorA vesicle vaccine induces bactericidal antibodies mainly of the IgG1 and IgG3 isotypes that are considered to be most important for protection against disease. The isotype distribution of the response is not age-dependent.

Health economics of a hexavalent meningococcal outer-membrane vesicle vaccine in children : potential impact of introduction in the Dutch vaccination program

The cost-effectiveness of universal vaccination of infants with a new hexavalent meningococcal B outer-membrane vesicle vaccine is projected for The Netherlands by applying decision analysis. The societal perspective is taken and direct and productivity costs (friction costs method) are considered. Future costs and effects are discounted at 4% (base year 1998). In this simulation model, vaccination would prevent 19 deaths and eight cases with severe long-term sequelae per year, rendering 526 additional quality adjusted life years (QALYs) per year. Yearly costs of acute phase of illness due to meningococcal infections in children are estimated at 1,426,634, while the future costs due to sequelae are estimated at 3,801,121 per year. Of all these costs, the vaccination program could prevent 3,334,052 per year. The program costs of meningococcal vaccination are estimated at 11,601,356, resulting in a cost-effectiveness ratio (CER) of 15,721 per QALY. These results are sensitive to the vaccine dose price (conservatively estimated at 10), efficacy, and coverage of meningococcal sero-subtypes.

Epidemiology of Nasopharyngeal Carriage of Neisseria meningitidis in Healthy Dutch Children

We investigated the prevalence and determinants of nasopharyngeal carriage of Neisseria meningitidis in 3200 healthy children aged 1-19 years. The incidence of meningococcal carriage was, on average, 1.5%. Peak incidences were seen at age 1 year and after age 15 years. The independent determinants of meningococcal carriage included age, regular visits to youth clubs (odds ratio [OR], 2.2) and discotheques (OR, 4.3), and pneumococcal carriage (OR, 4.1).

Prevention of Meningococcal Serogroup B Infections in Children: A Protein-Based Vaccine Induces Immunologic Memory

Immunologic memory against meningococci was studied in 177 children (100 children were 10-11 years old and 77 were 5-6 years old) 2.5 years after vaccination with hexavalent meningococcal outer membrane vesicle (OMV) vaccine or hepatitis B (HepB) vaccine. Children were revaccinated with monovalent P1.7(h),4 meningococcal OMV vaccine. Serum bactericidal antibodies (SBAs) were measured before revaccination and after 4-6 weeks. A minimum 4-fold increase in SBAs against serosubtype P1.7(h),4 was detected in 48.5% of the children after hexavalent meningococcal vaccine and in 8.9% after HepB vaccine. Of the initial responders given hexavalent meningococcal vaccine, 78% had > or =4-fold increase in SBAs against strain P1.4. Thus, immunologic memory is present in toddlers and school-aged children previously given 3 hexavalent meningococcal vaccinations. Booster vaccination with monovalent P1.7(h),4 meningococcal OMV vaccine induces a significant increase in SBAs against serosubtype P1.7(h),4 and cross-reactivity against other serosubtypes in the hexavalent vaccine.

Selection of an adjuvant for seasonal influenza vaccine in elderly people: modelling immunogenicity from a randomized trial

BackgroundImproved influenza vaccines are needed to reduce influenza-associated complications in older adults. The aim of this study was to identify the optimal formulation of adjuvanted seasonal influenza vaccine for use in elderly people.MethodsThis observer-blind, randomized study assessed the optimal formulation of adjuvanted seasonal influenza vaccine based on immunogenicity and safety in participants aged ≥65 years. Participants were randomized (~200 per group) to receive one dose of non-adjuvanted vaccine or one of eight formulations of vaccine formulated with a squalene and tocopherol oil-in-water emulsion-based Adjuvant System (AS03C, AS03B or AS03A, with 2.97, 5.93 and 11.86 mg tocopherol, respectively) together with the immunostimulant monophosphoryl lipid A (MPL, doses of 0, 25 or 50 mg). Hemagglutination-inhibition (HI) antibody responses and T-cell responses were assessed on Day 0 and 21 days post-vaccination. The ratio of HI-based geometric mean titers in adjuvanted versus non-adjuvanted vaccine groups were calculated and the lower limit of the 90% confidence interval was transformed into a desirability index (a value between 0 and 1) in an experimental domain for each vaccine strain, and plotted in relation to the AS03 and MPL dose combination in the formulation. This model was used to assess the optimal formulation based on HI antibody titers. Reactogenicity and safety were also assessed. The immunogenicity and safety analyses were used to evaluate the optimal formulation of adjuvanted vaccine.ResultsIn the HI antibody-based model, an AS03 dose–response was evident; responses against the A/H1N1 and A/H3N2 strains were higher for all adjuvanted formulations versus non-adjuvanted vaccine, and for the AS03A-MPL25, AS03B-MPL25 and AS03B-MPL50 formulations against the B strain. Modelling using more stringent criteria (post hoc) showed a clear dose-range effect for the AS03 component against all strains, whereas MPL showed a limited effect. Higher T-cell responses for adjuvanted versus non-adjuvanted vaccine were observed for all except two formulations (AS03C and AS03B-MPL25). Reactogenicity increased with increasing AS03 dosage, and with MPL. No safety concerns were raised.ConclusionsFive formulations containing AS03A or AS03B were identified as potential candidates to improve immune responses to influenza vaccination; AS03B without MPL showed the best balance between improved immunogenicity and acceptable reactogenicity.Trial registrationThis trial is registered at ClinicalTrials.gov, NCT00540592