[BCG: an almost 100-year-old vaccine]. / BCG: een bijna 100 jaar oud vaccin.

There has been a vaccine against tuberculosis (TB) since 1921. This vaccine contains Bacillus Calmette-Guérin (BCG), a live attenuated strain of the tubercle bacterium Mycobacterium bovis. The vaccine is fairly effective in children, but protection is poor in adults. Protection lasts about 15 years. The vaccine is safe for immunocompetent people, provided it is administered intracutaneously and at the correct dose. This article looks back at the development of the tuberculin skin test and BCG vaccine, and their use in the Netherlands.

[Vaccination against Haemophilus influenzaetype b; why and how?] / Vaccinatie tegenHaemophilus influenzaetype b.

After a development period of around 13 years, in 1993 the vaccination against infections caused by Haemophilus influenzae type b (Hib) was introduced into the Dutch National Immunisation Programme. Before the introduction of the vaccination, the burden of disease was high; every year around 700 children acquired an invasive Hib infection, half of whom developed meningitis. Of those children with Hib-related meningitis, 2% died and more than 8% were left with severe residual symptoms. Furthermore, at least one-third of those who recovered developed learning and concentration problems. Hib also caused other infections such as epiglottitis, osteomyelitis and arthritis. Initially, the conjugated Hib vaccine PRP-T was given as a separate injection. From 2005 onwards PRP-T was included in the combination DTaP-IPV-Hib vaccine, and since 2011 PRP-T has been part of the DTaP-IPV-Hib-HepB vaccine. Although H. influenzae is still around, invasive Hib infections in children now occur only very rarely.

[Measles vaccination: why and how?] / Mazelenvaccinatie: waarom en hoe?

The measles virus is highly contagious and may hit non-immune populations very hard, as observed on remote islands. The first live-attenuated measles virus vaccine was registered in the United States in 1963, and was imported to the Netherlands from 1968 onwards. Production was taken over by the National Institute for Public Health (RIV). Because the burden of disease was still high, measles vaccination was introduced into the Dutch National Immunisation Programme in 1976; since 1987 this has been in the form of the combined measles, mumps and rubella (MMR) vaccination. The MMR vaccine was also initially imported and later manufactured by the National Institute for Public Health and the Environment (RIVM). Since then, measles epidemics have almost exclusively affected unvaccinated populations. Vaccinated individuals are thus well-protected, as are unvaccinated individuals as long as the rate of vaccination in the surrounding population is sufficiently high. Unvaccinated individuals who travel to countries where measles is endemic are still at a higher risk. Recent studies show that measles not only has the classical symptoms, but also damages the immune system.

[Hypersensitivity reactions and vaccines]. / Overgevoeligheidsreacties en vaccins.

- A lot of questions are being asked in the Netherlands about the safety of vaccination. More knowledge among care providers helps with regard to good medical practice and information.- Severe hypersensitivity reactions to vaccines are rare. Chicken-egg protein, gelatine and thiomersal are the most important vaccine components that may provoke severe reactions.- Acute treatment of patients with severe hypersensitivity reactions consists of intramuscular adrenaline.- In case of a severe reaction to a vaccine or a vaccine component, the subsequent course of action is determined by the physician referred to: the allergist or paediatric allergist. For most patients, vaccination or revaccination is possible in a setting where acute treatment is possible.- Slight side effects and delayed hypersensitivity reactions are not good reasons for additional measures with respect to vaccination.- It is important to record hypersensitivity reactions completely and unambiguously in the patient file.

A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged ≥65 years.

This randomized, double-blind study evaluated concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (TIV) in adults aged ≥65 years who were naïve to 23-valent pneumococcal polysaccharide vaccine. Patients (N=1160) were randomized 1:1 to receive PCV13+TIV followed by placebo, or Placebo+TIV followed by PCV13 at 0 and 1 months, with blood draws at 0, 1, and 2 months. Slightly lower pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G geometric mean concentrations were observed with PCV13+TIV relative to PCV13. Concomitant PCV13+TIV demonstrates acceptable immunogenicity and safety compared with either agent given alone.

Immunogenicity and safety of a measles-mumps-rubella-varicella vaccine following a 4-week or a 12-month interval between two doses.

BACKGROUND: The MMRV combination vaccine, Priorix-Tetra™, is currently licensed in several European countries using a two-dose schedule in infants aged ≥9 months, with a preferred 6-week to 3-month interval between doses. This study was undertaken to generate safety and immunogenicity data for two doses of MMRV vaccine administered according to dose schedules using the shortest permitted interval of 4 weeks versus a longer interval of 12 months, which would allow flexible adaptation to local immunization calendars. METHODS: Healthy children aged 11-13 months were randomized (1:1:1) to receive 2 doses of either: MMRV vaccine with a 4-week interval between doses (MMRV-4W group, N=188), MMRV vaccine with a 12-month interval between doses (MMRV-12M group, N=184), or MMR vaccine with a 4-week interval between doses (MMR group, N=187). Blood samples were taken prior to, and 4-6 weeks after each vaccination. RESULTS: Post-Dose 2, both MMRV groups exhibited an adequate immunogenic response for all components; however the MMRV-12M group showed significantly greater geometric mean titers for mumps, rubella and varicella. Two varicella breakthrough cases occurred within the 12-month interval between doses in the MMRV-12M group. Local and general reactogenicity results were similar for all groups except for the MMRV-4W group, which had a greater incidence of fever during Days 0-14 post-Dose 1. CONCLUSIONS: Two doses of MMRV vaccine administered in the second year of life elicited adequate immunogenicity and were well-tolerated whether administered with a dose interval of 4 weeks or 12 months.

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).

Economic evaluation of meningococcal serogroup C conjugate vaccination programmes in The Netherlands and its impact on decision-making.

The cost-effectiveness of one time vaccination of all persons aged 14 months to 18 years (catch-up programme) and of routine childhood immunisation at either ages 2 + 3 + 4 months, 5 + 6 months, or 14 months with a meningococcal C conjugate vaccine was estimated for The Netherlands, from a societal and a health care payer perspective. A decision analysis cohort model was employed (time horizon 77 years), direct and indirect costs (friction cost method) were considered and future costs and effects were discounted at 4%. The results showed that all vaccination options yield a substantial health gain and that the catch-up programme and routine vaccination at 14 months render favourable cost-effectiveness ratios: between about 13,200 and 17,700 per life year gained for the catch-up programme and between about 2200 and 2400 per life year gained for routine childhood vaccination at 14 months, depending on the perspective. In comparison to vaccination at 14 months, routine childhood vaccination during the first year of life is much less cost-effective: each additional life year gained costs approximately 147,000 (2 + 3 + 4 months) or 102,000 (5 + 6 months), from both perspectives. Additionally, inclusion of the likely herd immunity effect of the catch-up programme increases these incremental cost-effectiveness ratios. These results played a major role in the decision to add meningococcal C vaccination to the routine childhood immunisation schedule at 14 months and to implement a catch-up vaccination programme in The Netherlands in 2002.

No epidemiological evidence for infant vaccinations to cause allergic disease.

CONTEXT: The prevalence of allergic diseases has increased considerably over the last decades. The hygiene hypothesis has emerged, linking reduced microbial exposure and infections early in life with the development of allergic diseases. Especially some of currently available non-replicating infant vaccines are unlikely to mimic a natural infection-mediated immune response that protects against the development of allergic diseases. Moreover, several studies suggested infant vaccinations to increase the risk of allergic diseases. OBJECTIVE: To determine whether infant vaccinations increase the risk of developing allergic disease. DATA SOURCES: We searched MEDLINE from 1966 to March 2003 and bibliography lists from retrieved articles, and consulted experts in the field to identify all articles relating vaccination to allergy. STUDY SELECTION AND DATA EXTRACTION: We selected epidemiological studies with original data on the correlation between vaccination with diphtheria, pertussis, tetanus (DPT), measles, mumps, rubella (MMR) and Bacillus Calmette-Guérin (BCG) vaccine in infancy and the development of allergic diseases, and assessed their quality and validity. DATA SYNTHESIS: Methodological design and quality varied considerably between the studies we reviewed. Many studies did not address possible confounders, such as the presence of lifestyle factors, leaving them prone to bias. The studies that offer the stronger evidence, including the only randomized controlled trial at issue published to date, indicate that the infant vaccinations we investigated do not increase the risk of developing allergic disease. Furthermore, BCG does not seem to reduce the risk of allergies. CONCLUSIONS: The reviewed epidemiological evidence indicates that, although possibly not contributing to optimal stimulation of the immune system in infancy, current infant vaccines do not cause allergic diseases.

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.

Evaluation of diphtheria convalescent patients to serve as donors for the production of anti-diphtheria immunoglobulin preparations.

AIMS: The study was conducted to evaluate the possibility of selecting convalescent diphtheria patients to serve in emergency situations as donors for the production of anti-diphtheria immunoglobulin. To select suitable donors, the criterion of an antitoxin titer >/=3.0 IU/ml was used. In addition, the effects of treatment and the effect of immunization with diphtheria toxoid on the level of anti-diphtheria toxin antibodies were evaluated. SCOPE: Three groups of diphtheria patients were included in the study. The first group (n = 23) consisted of patients who had a basic antibiotic treatment, with or without serotherapy using horse antitoxin and/or human immunoglobulin. The second group (n = 12) comprised patients examined immediately after the onset of disease. The immunological history of this group was not known. The third group (n = 20) included patients with a known immunization history, treated only with antibiotics but having received a booster immunization with diphtheria toxoid. Antitoxin titers were measured using the toxin binding inhibition (ToBI) assay. CONCLUSIONS: In the first group, 47.8% (11/23) of the patients had a diphtheria antibody titer >/=3.0 IU/ml. For most of them, however, the antibody titers could have resulted from treatment with exogenous antibodies from horse antitoxin or human immunoglobulin (18/23). Only two of the 11 high-titer subjects had received antibiotics only. Among the second group, only two (16.76%) of the patients had an antibody titer of >/=3.0 IU/ml. In the third group 50% (10/20) of the patients showed an antibody titer of >/=3.0 IU/ml prior to vaccination, and therefore could be directly considered as donors. Three weeks after booster vaccination, 70% (14/20) had an antibody titer of >/=3.0 IU/ml and 1 year after booster vaccination, 28.6% (2/7) of the subjects still had titers of >/=3.0 IU/ml. In 40% of these patients, a decrease was observed 3-4 weeks after the booster dose. It was concluded that convalescent diphtheria patients could be considered as donors in an emergency situation, since approximately half of them showed antitoxin titers of >/=3.0 IU/ml.

Pneumococcal vaccines: an update on current strategies.

Streptococcus pneumoniae is a major cause of morbidity and mortality in infants, children and the elderly. Despite the availability of excellent antimicrobial therapy and adequate health care systems, respiratory diseases and invasive infections caused by pneumococci still comprise a major health problem. The emerging resistance to penicillin and other commonly used antibiotics underscores the importance of the development of novel vaccine strategies to combat pneumococcal disease. Although the 23-valent polysaccharide (PS) vaccine is immunogenic and protective in most adults and children over 5 years of age, they fail to protect children under 2 years of age. Fortunately, the recent conjugate vaccines have shown to be highly efficacious in preventing invasive diseases in this risk group. Moreover, promising results regarding prevention of pneumonia and acute otitis media have been published. Unfortunately, protection is raised against a limited number of pneumococcal serotypes, and serotype replacement and subsequent vaccine failure have become a serious concern. Currently, several pneumococcal surface proteins are considered as alternative vaccine candidates because of their serotype-independence. Thus far, pneumococcal surface adhesin A (PsaA) has proven to be highly protective against colonization in animal models. Moreover, pneumococcal surface protein A (PspA) and pneumolysin have shown to elicit protection against invasive diseases. Future research will elucidate their true potential in protecting humans. In this paper we discuss the present knowledge on pneumococcal vaccines and the current status of novel vaccine strategies.

[Childhood vaccinations anno 2004. I. Effectiveness and acceptance of the Dutch National Vaccination Programme]. / Vaccinaties op de kinderleeftijd anno 2004. I. Effectiviteit en acceptatie van het Rijksvaccinatieprogramma.

Vaccinations are the most effective measures in public health. In the Netherlands after the second world war the morbidity and mortality of infectious diseases were a great problem. Nowadays these diseases are gone or reduced at a minimal level and for the greater part under control. The Dutch National Vaccination Programme aims at 10 infectious diseases. In the Netherlands there has always been a relatively small group of religious people who live together and reject vaccinations. Since the start of the vaccination programme in this group several small epidemics of poliomyelitis and measles have been observed. The other dispersed living non-vaccinated people are protected by herd-immunity, as long as the vaccination coverage is above 90%. During recent years an increasing number of people have doubts over the use and safety of vaccinations. There is a worldwide anti-vaccination movement, in the Netherlands represented by the 'Nederlandse Vereniging Kritisch Prikken'. The finding that there is now a greater spread of areas with a low or insufficient vaccination coverage, is cause for concern because experiences in several countries have shown that infectious diseases with all complications will recur when the vaccination percentage decreases. There is no scientific support for the hypothesis that vaccinations overwhelm or weaken the immune system of infants and there is no objection to start with vaccination at the age of two months. Anthroposofic and homeopathic arguments are neither scientifically, nor practically supported. Good promotion and education about the vaccination programme is of great importance and can be improved. Parents should make decisions based on good, objective information. Possible risks and side effects of vaccination should not be concealed.

[Childhood vaccinations anno 2004. II. The real and presumed side effects of vaccination]. / Vaccinaties op de kinderleeftijd anno 2004. II. Echte en vermeende bijwerkingen.

Vaccinations protect to a high degree against infectious diseases, but may cause side effects. In the Netherlands since 1962 the adverse events following immunizations are registered and analysed by the National Institute of Health and Environment (RIVM). Since 1983 a permanent Committee of the Dutch Health Council reviews adverse events reported to the RIVM. With the so-called killed vaccines the side effects are mainly local (redness, swelling, pain) or general (fever, listlessness, irritability, sleep and eating problems). They are seen mainly after DPT-IPV vaccination against diphtheria, pertussis, tetanus and poliomyelitis. Some side effects occur rarely (collapse reactions, discoloured legs, persistent screaming and convulsions) and very rarely serious neurological events are reported. After MMR vaccination against measles, mumps and rubella, cases of arthritis, thrombocytopenia and ataxia are reported sporadically. Usually, they have a spontaneous recovery. During recent years a scala of diseases or symptoms have been associated with vaccination (presumed side effects). Careful and extensive investigations have shown that such hypotheses could not be supported. Examples are allergic diseases as asthma, diabetes mellitus, multiple sclerosis (after hepatitis B vaccination), autism and inflammatory bowel disease (after MMR vaccination) and sudden infant death syndrome. The total number of cases where at least a possible relation between side effects and vaccination is observed--apart from local reactions and moderate general symptoms--is very rare (about 0.25 per 1000 vaccinations) and does not balance the benefits from vaccination. There appears increasing doubt about the use and safety of vaccinations. More research is needed about the motives of people to choose for and against vaccination. The education about vaccination for parents and professionals who are involved with vaccination has to be improved. Internet can play an important role.

Poliovirus circulation among schoolchildren during the early phase of the 1992-1993 poliomyelitis outbreak in The Netherlands.

During the 1992-1993 outbreak of poliomyelitis in The Netherlands, we examined 866 childrenat 7 schools for evidence of infection with the outbreak virus, poliovirus type 3(PV3), to determine the extent of the outbreak and the protection of the herd immunity. Seventy-seven children (8.9%) showed evidence of recent wild-type PV3 infection, as determined by virus isolation and/or poliovirus type-specific IgM assay. Most infected children lived in the same area as the index case patient, attended an orthodox-reformed (OR) primary school, and had not been vaccinated. At the OR school, as many as 22% of children immunized with inactive poliovirus vaccine were found to have evidence of recent infection, which is a significantly lower rate than that among unvaccinated children (59.5%). No evidence of vaccination was seen in 25.5%-43.1% of children at OR schools. Seroprevalence of antibodies against the 3 types of poliovirus suggested that no poliovirus circulation had occurred between the 1978 and 1992-1993 outbreaks.

Vaccine-induced antibody responses as parameters of the influence of endogenous and environmental factors.

In laboratory animals, an adequate way to assess effects of environmental exposures on the immune system is to study effects on antigen-specific immune responses, such as after sensitization to T-cell-dependent antigens. This probably also applies to testing effects in the human population. It has thus been suggested that antibody responses to vaccination might be useful in this context. Vaccination responses may be influenced by a variety of factors other than environmental ones. One factor is the vaccine itself; a second is the vaccination procedure used. In addition, the intrinsic capacity of the recipient to respond to a vaccine, which is determined by sex, genetic factors, and age, is important. Psychological stress, nutrition, and (infectious) diseases are also likely to have an impact. We reviewed the literature on vaccine response. With regard to exogenous factors, there is good evidence that smoking, diet, psychological stress, and certain infectious diseases affect vaccination titers, although it is difficult to determine to what extent. Genetic factors render certain individuals nonresponsive to vaccination. In general, in epidemiologic studies of adverse effects of exposure to agents in the environment in which vaccination titers are used, these additional factors need to be taken into consideration. Provided that these factors are corrected for, a study that shows an association of exposure to a given agent with diminished vaccination responses may indicate suboptimal function of the immune system and clinically relevant diminished immune response. It is quite unlikely that environmental exposures that affect responses to vaccination may in fact abrogate protection to the specific pathogen for which vaccination was performed. Only in those cases where individuals have a poor response to the vaccine may exogenous factors perhaps have a clinically significant influence on resistance to the specific pathogen. An exposure-associated inhibition of a vaccination response may, however, signify a decreased host resistance to pathogens against which no vaccination had been performed.

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.