[Uncertainties with starting new vaccinations: a comparison between polio and covid-19 vaccination]. / Onzekerheden bij invoering nieuwe vaccinaties.

In 1956 The Netherlands experienced a major outbreak of poliomyelitis with over 2200 patients. A vaccine was in reach, and it was used. Now, polio is nearly eradicated globally with vaccinations. In 2020 a similar situation occurred with COVID-19. Large-scale vaccinations form an essential tool to combat the epidemic. This article describes uncertainties to start both mass vaccination campaigns, and reflects on similarities and differences then and now.

[Diphtheria: a 'forgotten' disease?] / Difterie: een 'vergeten' ziekte?

Respiratory diphtheria is an acute respiratory tract infection. The high mortality rates (5-10%) are related to airway obstruction and local and systemic effects of the diphtheria toxin. Vaccination against diphtheria has been available through the Dutch national vaccination programme since the 1950s. The disease has now become rare as a result of herd immunity by these vaccinations. As a consequence, the disease has largely been forgotten, which can result in it not being recognised and treated in time. In addition, diphtheria antitoxin is not always available. In this article, we are drawing attention to the need for immunisation. We also look back at how diphtheria prevention started in the Netherlands.

Elevated Immune Response Among Children 4 Years of Age With Pronounced Local Adverse Events After the Fifth Diphtheria, Tetanus, Acellular Pertussis Vaccination.

BACKGROUND: In the Netherlands, acellular pertussis vaccines replaced the more reactogenic whole-cell pertussis vaccines. This replacement in the primary immunization schedule of infants coincided with a significant increase in pronounced local adverse events (AEs) in 4 years old children shortly after the administration of a fifth diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV) vaccine. The objective of this study was to investigate possible differences in vaccine antigen-specific immune responses between children with and without a pronounced local AE after the fifth DTaP-IPV vaccination. METHODS: Blood was sampled in 2 groups of 4-year-olds: a case group reporting pronounced local swelling and/or erythema up to extensive limb swelling at the injection site (n = 30) and a control group (n = 30). Peripheral blood mononuclear cells were stimulated with individual vaccine antigens. Plasma antigen-specific IgG, IgG subclass and total IgE concentrations and T-cell cytokine [interferon-gamma, interleukin (IL)-13, IL-17 and IL-10] production by stimulated peripheral blood mononuclear cells were determined by multiplex bead-based fluorescent multiplex immunoassays. RESULTS: In children with AEs, significantly higher total IgE and vaccine antigen-specific IgG and IgG4 responses as well as levels of the T-helper 2 (Th2) cytokine IL-13 were found after pertussis, tetanus and diphtheria stimulation compared with controls. CONCLUSIONS: Children with pronounced local reactions show higher humoral and cellular immune responses. Acellular vaccines are known to skew toward more Th2 responses. The pronounced local AEs may be associated with more Th2 skewing after the fifth DTaP-IPV vaccination, but other biologic factors may also impact the occurrence of these pronounced local reactions.

Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age.

OBJECTIVES: This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects. METHODS: Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 µg antigen with half a standard dose of MF59 adjuvant, 7.5 µg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 µg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months). RESULTS: A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event. CONCLUSIONS: An MF59-adjuvanted influenza vaccine containing 3.75 µg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old.

Adverse events and association with age, sex and immunological parameters of Q fever vaccination in patients at risk for chronic Q fever in the Netherlands 2011.

BACKGROUND: Following a large Q fever outbreak in the Netherlands, patients at risk for chronic Q fever received a whole-cell Q fever vaccine. Sensitized people were excluded based on pre-vaccination screening with skin test (ST) and serology. An investigational IFN-γ-production assay was added. No previous experience existed for Q fever vaccination in this patient risk-group with predefined cardiac valvular anomalies or aortic aneurysm/prosthesis and many co-morbidities. We studied the adverse events (AE) and their association with patient characteristics and immunological parameters. METHODS: AE registration covered the week after skin test and 90 days following vaccination, with the use of diaries, interviews and spontaneous reports. Serious (S)AE were assessed immediately to ensure safety. We coded AE according to reported severity. Univariate and multivariate analysis addressed associations. RESULTS: Pre-vaccination screening led to exclusion of 182 patients with positive serology and 207 patients with positive skin test-reading. The skin test did not lead to any causally related SAE. Subsequent vaccination of 1370 patients did not reveal unexpected AE; however, 80% of vaccinees reported local AE (in 26% of these pronounced or extensive). The two causally related SAE (0.1%) both concerned a persistent subcutaneous injection site mass. AE were more frequent in women, younger patients, and those without immunosuppressive co-morbidity/medication. The occurrence of local AE after skin test was associated with pre-vaccination positive serology and high IFN-γ production. This was also true for local AE following vaccination, with a strong association with local AE after skin test as well. The proportion of vaccinees with positive serology and positive IFN-γ values 6 months after vaccination was higher in those with local AE after skin test or after vaccination (non-significant, probably due to small numbers). CONCLUSION: Q fever vaccination was safe but reactogenic in this high-risk patient-group. Rates of local AE were higher in women, younger age groups and in those with positive immunological parameters. Vaccinees with local AE after skin test or after vaccination appear to have more pronounced post-vaccination immune responses.

Immunogenicity and tolerability of an MF59-adjuvanted, egg-derived, A/H1N1 pandemic influenza vaccine in children 6-35 months of age.

BACKGROUND: Vaccines against pandemic A/H1N1 influenza should provide protective immunity in children, because they are at greater risk of disease than adults. This study was conducted to identify the optimal dose of an MF59®-adjuvanted, egg-derived, A/H1N1 influenza vaccine for young children. METHODS: Children 6-11 months (N = 144) and 12-35 months (N = 186) of age received vaccine formulations containing either 3.75 µg antigen with half the standard dose of MF59 or 7.5 µg antigen with a standard dose of MF59, or a nonadjuvanted formulation containing 15 µg antigen (children 12-35 months only). Participants were given 2 primary vaccine doses 3 weeks apart, followed by 1 booster dose of MF59-adjuvanted seasonal influenza vaccine 1 year later. Immunogenicity was assessed by hemagglutination inhibition and microneutralization assays. RESULTS: All vaccine formulations were highly immunogenic and met all 3 European licensure criteria after 2 doses. MF59-adjuvanted vaccines met all licensure criteria after 1 dose in both age cohorts, while nonadjuvanted vaccine did not meet all criteria after 1 dose in children 12-35 months. A single booster dose was highly immunogenic, and stable antibody persistence was observed in response to all vaccines. All vaccines were well tolerated. CONCLUSIONS: In this study, a single dose of 3.75 µg antigen with half the standard dose of MF59 was shown to be optimal, providing adequate levels of immediate and long-term antibodies in pediatric subjects 6-35 months of age. These data demonstrated that MF59 adjuvant allowed for reduced antigen content and promoted significant long-term antibody persistence in children, with a satisfactory safety profile.

[Reported adverse events following influenza vaccination]. / Gemelde bijwerkingen na influenzavaccinatie.

OBJECTIVE: Review of case reports of possible adverse events following immunization (AEFI) after vaccination with an influenza vaccine in the past three years. DESIGN: Descriptive, retrospective. METHOD: Lareb (Netherlands Pharmacovigilance Centre) investigated and reviewed reports of possible AEFI after vaccination with an influenza vaccine over seasons 2010-2011, 2011-2012 and 2012-2013. RESULTS: Over the three seasons we received a total of 531 reports after administration of seasonal influenza vaccination. Each year the number of reports increased, especially the reports directly from vaccinees. In 32 cases (6%) the report was considered 'serious', in most cases it was associated with hospitalization. Two reports mentioned that the patient died but a causal relationship with the vaccination was considered unlikely. There were three reports of acute severe reactions, with anaphylaxis, angio-oedema and cardiac arrest. A total of 961 possible AEFI were reported. In 256 (over 25%) AEFI inflammatory symptoms occurred at the injection site. Besides the injection site reactions, headache (101), myalgia (90) and pyrexia (86) were the most reported AEFI. Notably, there were 26 reports of extensive limb swelling, in which injection site inflammation extends beyond shoulder or elbow or around the upper arm. The clinical picture resembles cellulitis or an allergic reaction and usually disappears with symptomatic treatment. Its aetiology is unknown. CONCLUSION: Apart from extensive swelling of the limb, we did not find signs of unknown side effects of influenza vaccination. Based on the reported AEFI, influenza vaccines seem to be safe.

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

BACKGROUND: Improved 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. METHODS: This 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 (AS03(C), AS03(B) or AS03(A), 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. RESULTS: In 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 AS03(A)-MPL25, AS03(B)-MPL25 and AS03(B)-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 (AS03(C) and AS03(B)-MPL25). Reactogenicity increased with increasing AS03 dosage, and with MPL. No safety concerns were raised. CONCLUSIONS: Five formulations containing AS03(A) or AS03(B) were identified as potential candidates to improve immune responses to influenza vaccination; AS03(B) without MPL showed the best balance between improved immunogenicity and acceptable reactogenicity. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT00540592.

Implementation of a Q fever vaccination program for high-risk patients in the Netherlands.

BACKGROUND: Between 2007 and 2011 the Netherlands was faced with an unprecedented Q fever outbreak with more than 4000 people affected. Dairy goats were considered the main source of infection. In addition to taking veterinary measures, the Dutch government offered an unlicensed vaccine against the causative bacterium Coxiella burnetii to patient groups at high-risk of Q fever complications. This article describes the complexity of the vaccination program for Q fever in 2010-2011. METHODS: High-risk patients were selected and referred mainly by their general practitioner to a publicly funded centralized screening and vaccination program. In addition, cardiovascular specialists and the public were informed. Patients were screened for previous infection with C. burnetii by serology and skin-tests. Patients who tested positive were excluded from vaccination. RESULTS: Of the 2741 referred high-risk patients (1669 male, 1957 from the high-risk area), 955 were excluded because vaccination was considered unnecessary or the distance to the vaccination clinic too far. 388 (22% of those screened) were excluded because of a positive skin-test or serology. 1368 patients (77% of those screened) were vaccinated between January and June 2011. Two-thirds of the vaccinees reported an adverse event. 89 patients (6.6%) reported serious adverse events. In just one patient, with an injection site reaction, a possible causal relationship was considered. CONCLUSION: This Q fever vaccination program posed challenges to the Dutch Health Care system. Creating clarity on the roles and responsibilities of those involved precluded timely vaccination. Targeting the high-risk population through GPs was challenging but appeared to be efficient. The vaccination was considered to be safe and compliance of the screened patients was high.

Specific interferon γ detection for the diagnosis of previous Q fever.

BACKGROUND: Current practice for diagnosis of Q fever, caused by the intracellular pathogen Coxiella burnetii, relies mainly on serology and, in prevaccination assessment, on skin tests (STs), which both have drawbacks. In this study, C. burnetii-specific interferon γ (IFN-γ) production was used as a new diagnostic tool for previous Q fever, circumventing most of these drawbacks. Our aim was to compare this test to serology and ST. METHODS: One thousand five hundred twenty-five individuals from an endemic area with a risk for chronic Q fever were enrolled. IFN-γ production was measured after in vitro stimulation of whole blood with C. burnetii antigens. Various formats using different C. burnetii antigens were tested. Serology and ST were performed in all individuals. RESULTS: In all assay formats, C. burnetii-specific IFN-γ production was higher (P < .0001) in seropositive or ST-positive subjects than in seronegative and ST-negative subjects. Whole blood incubated for 24 hours with C. burnetii Nine Mile showed optimal performance. After excluding subjects with equivocal serology and/or borderline ST results, IFN-γ production was 449 ± 82 pg/mL in the positive individuals (n = 219) but only 21 ± 3 pg/mL in negative subjects (n = 908). Using Bayesian analysis, sensitivity and specificity (87.0% and 90.2%, respectively) were similar to the combination of serology and ST (83.0% and 95.6%, respectively). Agreement with the combination of serology and ST was moderate (84% concordance; κ = 0.542). CONCLUSIONS: Specific IFN-γ detection is a novel diagnostic assay for previous C. burnetii infection and shows similar performance and practical advantages over serology and ST. Future studies to investigate the clinical value in practice are warranted.

Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ≥ 70 years: a randomized study of a single dose vs. two different two-dose schedules.

Disease protection provided by herpes zoster (HZ) vaccination tends to reduce as age increases. This study was designed to ascertain whether a second dose of the HZ vaccine, Zostavax(®), would increase varicella zoster virus (VZV)-specific immune response among individuals aged ≥ 70 y. Individuals aged ≥ 70 y were randomized to receive HZ vaccine in one of three schedules: a single dose (0.65 mL), two doses at 0 and 1 mo, or two doses at 0 and 3 mo. VZV antibody titers were measured at baseline, 4 weeks after each vaccine dose, and 12 mo after the last dose. In total, 759 participants (mean age 76.1 y) were randomized to receive vaccination. Antibody responses were similar after a single dose or two doses of HZ vaccine [post-dose 2/post-dose 1 geometric mean titer (GMT) ratios for the 1-mo or 3-mo schedules were 1.11, 95% confidence interval (CI) 1.02-1.22 and 0.78, 95% CI 0.73-0.85], respectively). The 12-mo post-dose 2/12-mo post-dose 1 GMT ratio was similar for the 1-mo schedule and for the 3-mo schedule (1.06, 95% CI 0.96-1.17 and 1.08, 95% CI 0.98-1.19, respectively). Similar immune responses were observed in participants aged 70-79 y and those aged ≥ 80 y. HZ vaccine was generally well tolerated, with no evidence of increased adverse event incidence after the second dose with either schedule. Compared with a single-dose regimen, two-dose vaccination did not increase VZV antibody responses among individuals aged ≥ 70 y. Antibody persistence after 12 mo was similar with all three schedules.

The burden of varicella from a parent's perspective and its societal impact in The Netherlands: an Internet survey.

BACKGROUND: Varicella is a common childhood disease. Only 5% of first varicella-zoster-virus infections occur asymptomatically. Most data on the burden of varicella stem from health service databases. This study aims to provide insight in the burden of varicella from a parent's perspective including cases outside the healthcare system. METHODS: An internet questionnaire was developed for parents in the Netherlands to report health care resource use and productivity losses during the varicella episode in their child younger than 6 years. 11,367 invitations were sent out to members with children of an internet panel of a market research agency. 4,168 (37%) parents started the questionnaire (response rate), of which 360 (9%) stopped before completion and 1,838 (44%) were out of the target group. In total 1,970 parents completed the questionnaire. The questionnaire provided a symptom list ranging from common symptoms, such as skin vesicles, itching to fits or convulsions. A posteriori, in the analyses, the symptoms 'skin infections', 'fits/convulsions', 'unconsciousness', and 'balance and movement disorders' were labelled as complications. There was no restriction to time since the varicella episode for inclusion in the analyses. RESULTS: The 1,970 respondents had in total 2,899 children aged younger than six years, of which 2,564 (88%) children had had varicella. In 62% of the episodes the parent did not seek medical help. In 18% of all episodes symptoms labelled as complications were reported; in 11% of all episodes parents visited a medical doctor (MD) for a complication. Reporting of complications did not differ (X2 ; p = 0.964) between children with a recent (≤ 12 months ago) or a more distant (> 12 months) history of varicella. Prescription drugs were used in 12% of the children with varicella; OTC drugs in 72%. Parents reported work loss in 17% of the varicella-episodes (23% when MD visit; 14% when no MD-visit) for on average 14 hours, which equals to 2.5 hours of work loss for any given varicella-episode. CONCLUSIONS: This study shows the full spectrum of varicella-episodes and associated healthcare use, including the large proportion of cases not seeking medical care and the societal impact associated with those cases.

[Vaccination against chickenpox, shingles and rotavirus-infection]. / Vaccineren tegen waterpokken, gordelroos en rotavirus-infectie.

The Dutch National Immunisation Programme (NIP) has been very successful over the past 50 years. In future, this programme shall not include all new vaccines. Such vaccines can, however, be individually administered. At present there are 3 vaccines available in the Netherlands that have not been included in the NIP to date: against varicella (chickenpox), herpes zoster (shingles) and rotavirus infections. These vaccines are safe and effective. Chickenpox is not always a harmless childhood disease. A chickenpox vaccine is now available as well as a combined vaccine against mumps, measles, rubella and chickenpox. Shingles (herpes zoster) is a common disease in the elderly people. For many patients it is a considerable burden with significant complications, mainly postherpetic neuralgia and herpes zoster ophthalmicus. Vaccination may be considered for people 60 years and older. Rotavirus is much more associated with severe symptoms of diarrhoea than other pathogens. More than 95% of children experience one or more episodes of rotavirus gastroenteritis before their 5th birthday. In the Netherlands about 3400 children are hospitalised each year for rehydration following rotavirus infection. The vaccine is given orally.

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.

Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant.

PURPOSE: In female individuals 15-25-years of age, the AS04-containing human papillomavirus (HPV)-16/18 vaccine is highly immunogenic and provides up to 100% protection against HPV-16/18 persistent infection and associated cervical lesions up to 4.5 years. Optimal cervical cancer prevention will require prophylactic vaccination against oncogenic HPV 16 and 18 before the onset of sexual activity in early adolescent girls. To establish the feasibility of vaccination in girls 10-14 years of age, we compared the immunogenicity and safety in early adolescent female individuals to those 15-25 years in whom vaccine efficacy has been demonstrated. METHODS: We enrolled 773 female participants aged 10-14 years and 15-25 years to receive the HPV-16/18 L1 VLP AS04 vaccine, which was administered at months 0, 1, and 6. Serum samples were collected at months 0 and 7; antibodies to HPV 16 and 18 VLPs were measured by enzyme-linked immunosorbent assay. Vaccine safety was assessed at 7 or 30 days after each dose; serious adverse events were recorded during the entire study period. RESULTS: Both age groups achieved 100% seroconversion for HPV 16 and 18. Participants in the group aged 10-14 years were not only noninferior to those 15-25 years in terms of HPV 16 and 18 seroconversion rates but also had approximately twice as high geometric mean titers. The vaccine was generally safe and well tolerated. CONCLUSIONS: These findings suggest that HPV vaccination during early adolescence is generally safe, well tolerated, and highly immunogenic. The observed higher antibody titers in the group 10-14 years of age are likely to result in longer antibody persistence. Overall, these data support the implementation of prophylactic HPV vaccination in this age group.

Combination vaccine against invasive meningococcal B and pneumococcal infections: potential epidemiological and economic impact in the Netherlands.

BACKGROUND: Streptococcus pneumoniae and Neisseria meningitidis group B are among the main causes of invasive bacterial meningitis infections in infants. Worldwide, these diseases lead to significant mortality, morbidity and costs. The societal impact is especially severe since the majority of cases occur in very young infants. A combination vaccine consisting of 9-valent conjugated pneumococcal and meningococcal B components is currently being developed. The aim of this study was to estimate the potential impact and cost effectiveness from the societal perspective of vaccinating infants in The Netherlands with this combination pneumococcal and meningococcal B vaccine versus no vaccination. METHODS: A Markov cycle model was developed using epidemiological and healthcare resource use data from 1996 to 2001. This model was used to project the annual costs, benefits and health gains associated with vaccinating all newborns. The base year for the costing was 2003 and all costs and health effects were discounted at 4%. The results of the analysis are expressed in costs per QALY and both probabilistic and univariate sensitivity analyses were used to identify the robustness of the results. RESULTS: Annually, an average of 755 cases of invasive pneumococcal and meningococcal B infection occurred in infants aged 0-10 years in The Netherlands. Introduction of the combination vaccine would prevent 201 cases of meningococcal B meningitis and 165 cases of invasive pneumococcal disease per year. Additionally, 3410 cases of pneumococcal pneumonia and 46,350 cases of otitis media would be prevented. Vaccination would save 35 lives per year and prevent 71 cases of severe sequelae. This translates into 860 life-years gained, or 1128 QALYs gained. Alongside these health gains, vaccination would prevent euro 17,681,370 of direct medical and indirect costs attributable to meningococcal and pneumococcal infections in The Netherlands. Depending on vaccine price, cost effectiveness varied from euro 3160 (vaccine price per dose euro 20) to euro 32,170 (vaccine price euro 60 per dose) per QALY. Base-case cost effectiveness (vaccine price euro 40) was euro 17,700 per QALY. The model was most sensitive to changes in incidence, vaccine price and duration of protective efficacy. CONCLUSION: Our results suggest that the introduction of a combination meningococcal B and pneumococcal vaccine into the Dutch infant vaccination programme is potentially cost effective compared with no vaccination.

Reactogenicity of acellular pertussis vaccine in 4-year-olds in The Netherlands.

AIM: To observe reactogenicity of a three-component acellular pertussis (aP) vaccine simultaneously given with dT-IPV vaccine at the age of 4 years. RESULTS: Of 813 subjects 36% had no adverse events. At the first day the score for pain was 47-55% (aP versus dT-IPV), for redness 3-4% and for swelling 5-6%. Irritability and loss of appetite had a score of 20%. In 3% of the children fever was present. Most symptoms disappeared within 3 days. CONCLUSION: Boostervaccination with an aP vaccine simultaneously given with dT-IPV vaccine at the age of 4 years is well tolerated.