Recent Submissions

  • Preclinical and clinical safety studies on DNA vaccines.

    Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G (2007-01-03)
    DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and clinical studies about the safety of DNA vaccines. Here we review current knowledge about the safety of DNA vaccines. Safety concerns of DNA vaccines relate to genetic, immunologic, toxic, and environmental effects. In this review we provide an overview of findings related to the safety of DNA vaccines, obtained so far. We conclude that the potential risks of DNA vaccines are minimal. However, their safety issues may differ case-by-case, and they should be treated accordingly.
  • Performance of the Brighton collaboration case definition for hypotonic-hyporesponsive episode (HHE) on reported collapse reactions following infant vaccinations in the Netherlands.

    Vermeer-de Bondt, Patricia E; Dzaferagić, Aida; David, Silke; Maas, Nicoline A T van der (2006-11-30)
    We reviewed collapse (sudden onset of pallor, limpness and hyporesponsiveness) following the first infant (DPTP+Hib) vaccination reported to the enhanced passive surveillance system of the Netherlands in 1994-2003. All 1303 reports identified by the current RIVM (National Institute for Public Health and Environment) case definition were captured by the Brighton Collaboration (BC) case definition, with in 17 (1.3%) reports insufficient information. Over the years the proportion of the highest level of diagnostic certainty (level 1) increased due to more complete data from 70% to over 90%. We checked the BC case definition also on a sample of cases (with pallor or hyporesponsiveness) not meeting RIVM's case definition for collapse at the time. Sixty out of 200 cases were captured by BC but again rejected by RIVM. The sensitivity BC levels 2 and 3 appeared too high. We recommend a more restrict case definition by the Brighton Collaboration with certain exclusion criteria to make it more specific. Furthermore a change in the specifications for levels 2 and 3 will increase specificity and accommodate for the loss of sensitivity.
  • Programme of the Community Network of Reference Laboratories for Human Influenza to improve Influenza Surveillance in Europe.

    Meijer, Adam; Brown, Caroline; Hungnes, Olav; Schweiger, Brunhilde; Valette, Martine; Werf, Sylvie van der; Zambon, Maria (2006-11-10)
    All laboratories participating in the Community Network of Reference Laboratories for Human Influenza in Europe (CNRL) co-ordinated by the European Influenza Surveillance Scheme (EISS) should be able to perform a range of influenza diagnostics. This includes direct detection, culture, typing, subtyping and strain characterisation of influenza viruses, diagnostic serology and the creation of archives for clinical specimens and virus isolates. To improve the capacity and quality of the laboratories of the CNRL and to increase the consistency in performance among all 25 European Union countries plus Norway, Romania, and Switzerland, five task groups were set up in February 2005. These task groups developed work programmes in the areas of virus isolation, antibodies, molecular virology, quality control assessment and antiviral susceptibility testing. This report outlines the programmes and the results achieved in the first half-year of operation of the task groups. The action plans are challenging and it is expected that these efforts will lead to considerable improvements in the performance of the laboratories and in the standardisation of methods employed in Europe with regard to routine influenza surveillance and early warning for emerging viruses.
  • Use of oseltamivir in Dutch nursing homes during the 2004-2005 influenza season.

    Sande, Marianne A B van der; Ruijs, Wilhelmina L M; Meijer, Adam; Cools, Herman J M; Plas, Simone M van der (2006-11-10)
    To assess the implementation of guidelines for using neuraminidase inhibitors in the control of influenza outbreaks in Dutch nursing homes, data were collected on prophylactic and therapeutic use of anti-viral medication, indications for use and criteria for prescribing, based on experiences during the influenza season 2004-2005 in a retrospective cross-sectional survey among Dutch nursing homes after the 2004-2005 season. Ninety/194 (49%) participating nursing homes reported an outbreak of influenza-like illness; in 57/194 (29%) influenza was laboratory confirmed. In 37/57 homes (65%) oseltamivir had been used as prophylaxis. Prophylactic use was extended to all residents and staff in 6/37 (16%) of homes, but limited in the others. In 9/37 (24%) no staff were issued prophylaxis. Among clinicians with laboratory confirmed influenza, 41/46 (89%) had used oseltamivir therapeutically. Main reasons for not prescribing oseltamivir for prophylaxis and/or therapy were lack of scientific evidence, high costs, and absent or delayed laboratory confirmation. Logistical bottlenecks in diagnosis, cost-effectiveness concerns, and lack of an evidence-base hamper full integration in policy and should be addressed.
  • Assessing the introduction of universal varicella vaccination in the Netherlands.

    Boot, Hein J; Melker, Hester E de; Stolk, Elly A; Wit, G Ardine de; Kimman, Tjeerd G (2006-09-11)
    Although varicella is seen as a benign disease in the Netherlands, about 40,000 visits to a general practitioner (GP) are made, over 200 hospital admission occur, and 2.3 persons die on average each year. Most of this burden of disease can be prevented by universal varicella childhood vaccination. Ten years after the introduction of the single-shot, single-component varicella childhood vaccination in the USA, a major reduction in hospitalization, mortality, and burden of disease has been reported. Using our recently vaccine evaluation model for the introduction of a new vaccine in our national immunization program, we have analyzed the feasibility of universal varicella vaccination by replacing the measles-mumps-rubella (MMR) vaccine with a measles-mumps-rubella-varicella (MMRV) vaccine. After structuring and reviewing the available data, two major points of uncertainty remain: (1) the influence of universal childhood vaccination on the incidence of zoster later in life; (2) the cost-effectiveness ratio for the Dutch situation. Despite these uncertainties it is clear that universal childhood vaccination will prevent most of the varicella related GP-visits, hospitalizations, and deaths.
  • Frequency of Adverse Events after Vaccination with Different Vaccinia Strains.

    Kretzschmar, Mirjam; Wallinga, Jacco; Teunis, Peter F M; Xing, Shuqin; Mikolajczyk, Rafael (2006-08-22)
    BACKGROUND: Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus. METHODS AND FINDINGS: We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0-6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0-31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains. CONCLUSIONS: Previous analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
  • Vaccinaties in het eerste levensjaar en gerapporteerde allergische aandoeningen bij kinderen van 8-12 jaar

    Bernsen, R M D; Jongste, Johan C de; Koes, B W; Aardoom, H A; Wouden, J C van der (RIVM, 2006-06-01)
    Evidence for the relationship between the diphtheria tetanus pertussis (DTP) vaccination and allergic disorders is inconclusive, because the available studies that constitute the evidence are liable to confounding by indication. Further the Haemophilus influenzae type b (Hib) vaccination was added recently to most existing vaccination programmes and therefore no conclusive data on the relationship with allergic disorders are yet available. Objective of the study was to assess the relationship between vaccinations in the first year of life and reported allergic disorders at primary school age. We conducted a cross sectional study in 1875 children attending Orthodox Reformed (Protestant) primary schools in the Netherlands. The parents returned questionnaires with data on vaccination status, allergic symptoms and lifetime allergic disorders (asthma, hay fever, eczema and food allergy), and possible confounders. In the diphtheria tetanus pertussis (inactivated) poliomyelitis (DTP-IPV) vaccinated group Hib vaccinated and Hib unvaccinated children were compared as to allergic disorders. No clinically or statistically significant differences in the prevalence of asthma, hay fever, eczema and food allergy appeared between vaccinated and unvaccinated groups. The DTP-IPV vaccination and the Hib-vaccination, administered in the first year of life, do not increase the risk of allergic disorders in 8-12 years-old, Dutch children.
  • Long-term protection against carriage of hepatitis B virus after infant vaccination.

    Sande, Marianne A B van der; Waight, P; Mendy, M; Rayco-Solon, P; Hutt, P; Fulford, T; Doherty, C; McConkey, S J; Jeffries, D; Hall, A J; Whittle, H C (2006-06-01)
    BACKGROUND: Carriage of hepatitis B virus (HBV) is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Infant vaccination has been effective in preventing horizontal transmission during early childhood. It is unknown whether protection is maintained into early adulthood. METHODS: In 1984, early childhood vaccination was introduced in 2 rural Gambian villages. In 2003, serological assessment of 81.5% of 1,350 eligible participants 1-24 years old was done, to determine vaccine efficacy against infection and carriage. RESULTS: Overall vaccine efficacy against infection and carriage was 83.4% (95% confidence interval [CI], 79.8%-86.6%) and 96.5% (85% CI, 93.9%-98.9%), respectively. Vaccine efficacy against infection was similar when restricted to primary responders (85.3%), but a significant effect of peak antibody concentration was found. Both vaccine efficacy and levels of hepatitis B surface antibody (anti-HBs) decreased with age, resulting in a vaccine efficacy against infection and carriage among 20-24-year-old participants of 70.9% (95% CI, 60.4%-80.5%) and 91.1% (95% CI, 75.8%-100%), respectively. Fifteen years after vaccination, fewer than half of the vaccinees had detectable anti-HBs. The prevalence of carriage in the unvaccinated population was similar to the prevalence 20 years earlier. CONCLUSIONS: HBV vaccination early during life can provide long-lasting protection against carriage, despite decreasing antibody levels. The role played by subclinical boosting and the necessity of a booster need to be evaluated.
  • Developing a vaccination evaluation model to support evidence-based decision making on national immunization programs.

    Kimman, Tjeerd G; Boot, Hein J; Berbers, Guy A M; Vermeer-de Bondt, Patricia E; Wit, G Ardine de; Melker, Hester E de (2006-05-29)
    Among all public health provisions national immunization programs (NIPs) are beyond doubt one of the most effective in reducing mortality, morbidity, and costs associated with major infectious diseases. To maintain their success, NIPs have to modernize in response to many new and old demands regarding efficacy, safety, availability of new vaccines, emerging and evolving pathogens, waning immunity, altered epidemiological situations, and the public's trust in the program. In this paper we present an evaluation model in the form of a checklist that may help in collecting relevant scientific information that is necessary for evaluation and decision making when considering changes in a NIP. Such a checklist points to relevant information on the vaccine-preventable disease, the pathogen causing it, the vaccine, and the cost-effectiveness ratio of the vaccine. However, the final judgment on a potential change in the NIP cannot be based on a simple algorithm, as the relevant information reflects factors of a very different kind and magnitude, to which different value judgements may be added, and which may have certain degrees of uncertainty. Because any change in the NIP may be accompanied by more or less unforeseen changes in the vaccine's efficacy, evolutionary consequences, including the antigenic composition of the pathogen, and the vaccine's safety profile, an intensive surveillance program should accompany any NIP. Elements thereof include clinical-epidemiological surveillance, surveillance of vaccination coverage, immune surveillance, surveillance of microbial population dynamics, and surveillance of adverse events and safety issues. We emphasize that the decision to introduce a vaccine in the NIP should be taken as seriously, both scientifically and ethically, as the decision to withhold a vaccine from the NIP. In the latter case one might be responsible for vaccine-preventable disease and mortality.
  • WHO informal consultation on scientific basis for regulatory evaluation of candidate human vaccines from plants, Geneva, Switzerland, 24-25 January 2005.

    Laan, Jan Willem van der; Minor, Philip; Mahoney, Richard; Arntzen, Charles; Shin, Jinho; Wood, David (2006-05-15)
    In January 2005, WHO convened a meeting of leading experts in plant-derived vaccines and experts from regulatory authorities for an informal discussion on the state-of-the-art and to analyse whether specific guidance might be needed for plant-derived vaccines that is not yet provided by regulatory authorities. After a series of individual presentations, a general discussion was held to obtain a consensus on the need for further guidance. Both the presentations and the conclusions are presented. The meeting concluded that existing guidelines for the development, evaluation, and use of vaccines made by traditional methods can be applied to plant-derived vaccines. For plant-derived vaccines some specific issues will have to be addressed. These include, but are not restricted to, containment of the plants including disposal of waste materials. It was noted that plant-derived vaccines have been produced and clinically tested under US investigational new drug application, and all applicable regulatory and good manufacturing practice requirements are in place for this type of product. An innovator wishing to bring a plant-derived vaccine to market should consult closely with regulatory authorities to ensure that all appropriate studies are undertaken.
  • The epidemiology of varicella and herpes zoster in The Netherlands: implications for varicella zoster virus vaccination.

    Melker, Hester E de; Berbers, Guy A M; Hahné, Susan J M; Rümke, Hans; Hof, Susan van den; Wit, G Ardine de; Boot, Hein J (2006-05-01)
    We studied the epidemiology of varicella (chickenpox) and herpes zoster (shingles) in The Netherlands to assess the desirability to implement routine varicella zoster virus vaccination in The Netherlands. Data on seroprevalence of varicella zoster virus in the general population (1995-1996), consultations of general practitioners for varicella (2000-2002) and herpes zoster (1998-2001) and hospital admissions due to varicella (1994-2001) and herpes zoster (1994-2001) in The Netherlands were analysed. The seropositivity increased sharply with age from 18.4% for both 0- and 1-year-olds, to 48.9%, 59.0%, 75.7% and 93.0% for 2-, 3-, 4- and 5-year-olds, respectively, and varied between 97.5% and 100% for older age groups. The average annual incidence of GP-consultations amounted to 253.5 and 325.0 per 100,000 for varicella and herpes zoster, respectively. The incidence of hospital admission due to varicella and herpes zoster was 1.3 (2.3 including side diagnosis) and 2.7 (5.8) per 100,000, respectively. Whilst for varicella, the incidence of GP-consultations and hospital admissions were highest in childhood, for herpes zoster, these were highest in elderly. Insight into epidemiology of varicella zoster is needed for the assessment of the desirability of introduction of routine varicella zoster vaccination.
  • Stable isotope tagging of epitopes: a highly selective strategy for the identification of major histocompatibility complex class I-associated peptides induced upon viral infection.

    Meiring, Hugo D; Soethout, Ernst C; Poelen, Martien C M; Mooibroek, Dennis; Hoogerbrugge, Ronald; Timmermans, Hans; Boog, Claire J; Heck, Albert J R; Jong, Ad P J M de; Els, Cécile A C M van (2006-05-01)
    Identification of peptides presented in major histocompatibility complex (MHC) class I molecules after viral infection is of strategic importance for vaccine development. Until recently, mass spectrometric identification of virus-induced peptides was based on comparative analysis of peptide pools isolated from uninfected and virus-infected cells. Here we report on a powerful strategy aiming at the rapid, unambiguous identification of naturally processed MHC class I-associated peptides, which are induced by viral infection. The methodology, stable isotope tagging of epitopes (SITE), is based on metabolic labeling of endogenously synthesized proteins during infection. This is accomplished by culturing virus-infected cells with stable isotope-labeled amino acids that are expected to be anchor residues (i.e. residues of the peptide that have amino acid side chains that bind into pockets lining the peptide-binding groove of the MHC class I molecule) for the human leukocyte antigen allele of interest. Subsequently these cells are mixed with an equal number of non-infected cells, which are cultured in normal medium. Finally peptides are acid-eluted from immunoprecipitated MHC molecules and subjected to two-dimensional nanoscale LC-MS analysis. Virus-induced peptides are identified through computer-assisted detection of characteristic, binomially distributed ratios of labeled and unlabeled molecules. Using this approach we identified novel measles virus and respiratory syncytial virus epitopes as well as infection-induced self-peptides in several cell types, showing that SITE is a unique and versatile method for unequivocal identification of disease-related MHC class I epitopes.