<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

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<pre></pre>

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<pre>Aan de Minister van Volksgezondheid, Welzijn en Sport
Onderwerp      :   Aanbieding advies
Uw kenmerk     :   GZB/GZ 1.002.207
Ons kenmerk    :   3236/JS/sg/144/6-E
Bijlagen       :   1
Datum          :   28 juni 2000
Op 12 november 1999 verzocht de Minister van Volksgezondheid, Welzijn en Sport de
Gezondheidsraad om een advies waarin de recente ontwikkelingen met betrekking tot
kinkhoest worden beschreven en waarbij tevens wordt ingegaan op de stand van
wetenschap sinds het uitbrengen van het advies 'Pertussis: a critical appraisal' in 1997.
Het advies 'Pertussis; a critical appraisal (2)', dat door de commissie Kinkhoest is
opgesteld, bied ik u - gehoord de Beraadsgroep Infectie en Immuniteit - hierbij aan.
w.g.
prof. dr JJ Sixma
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<pre></pre>

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<pre>Pertussis: a critical appraisal (2)
to:
The Minister of Health, Welfare and Sport
No. 2000/14, The Hague, June 28, 2000
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<pre>Preferred citation:
Health Council of the Netherlands. Pertussis: a critical appraisal (2). The Hague: Health
Council of the Netherlands, 2000; publication no. 2000/14
all rights reserved
ISBN: 90-5549-325-2
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<pre>    Contents
    Executive summary 9
    Samenvatting 11
1   Introduction 13
2   The current situation on pertussis in the Netherlands 15
2.1 Epidemiology/surveillance 15
2.2 Antigenic variants in B pertussis strains 16
2.3 The ‘96 improved RIVM whole-cell pertussis vaccine 17
2.4 Booster vaccination at four years of age 17
3   The follow up of recommendations made in the 1997 report 19
4   Recommendations 21
4.1 Data collection 21
4.2 The booster vaccination at four years of age 21
4.3 The primary vaccination with pertussis vaccine in the first year of life 22
4.4 The vaccination scheme 23
    Literature 25
7   Contents
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<pre>  Annexes 27
A The request for an advisory report 29
B The Committee 31
C  33
8 Pertussis: a critical appraisal (2)
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<pre>  Executive summary
  In 1997 a Health Council Committee produced a report entitled “Pertussis a critical
  appraisal”. This report was an initial response to the epidemic of whooping cough in
  1996 and 1997. Possible explanations were discussed. Due to the fact that many children
  with the disease had a history of vaccination, special attention was given to the
  whole-cell vaccine against whooping cough. The intention was that the conclusions of
  this 1997 report should be reviewed after a given period of time. In this second report
  special attention is devoted to the efforts to modify the current whole-cell vaccine with a
  greater immunogenicity and to study the protection given by the vaccine. Introducing,
  again, revaccination against whooping cough at the age of four years is expected to have
  an important effect on the incidence of the disease and should be effected as soon as
  possible. In view of adverse reactions the Committee prefers an acellular vaccine for this
  revaccination. For the primary vaccination during the first year of life the development
  of a combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis vaccine
  should be given priority.
9 Executive summary
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<pre>10 Pertussis: a critical appraisal (2)</pre>

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<pre>   Samenvatting
   In 1997 stelde een commissie van de Gezondheidsraad een advies op onder de titel
   Pertussis: a critical appraisal (kinkhoest: een beoordeling). Dit advies gaf een eerste
   bespreking van een epidemie van kinkhoest die zich voordeed in 1996 en 1997.
   Mogelijke verklaringen van deze epidemie werden besproken. Omdat veel kinderen die
   aan de ziekte leden tegen kinkhoest gevaccineerd waren, werd daarbij in het bijzonder
   aandacht gegeven aan de kwaliteit van het heelcel vaccin gericht tegen kinkhoest. In dit
   advies werd het voornemen uitgesproken om de conclusies na verloop van enige tijd nog
   eens te bezien. In het voorliggende (tweede) advies wordt met name aandacht gegeven
   aan de pogingen om het bestaande heelcel vaccin om te vormen tot een grotere
   immunogeniteit en aan de bescherming die door het vaccin gegeven wordt. Van
   herinvoering van de revaccinatie tegen kinkhoest op de leeftijd van vier jaar wordt een
   belangrijk effect verwacht op de incidentie van de ziekte. Deze revaccinatie dient zo
   spoedig mogelijk te worden ingesteld. Bij deze revaccinatie wordt aan het gebruik van
   een acellulair vaccin de voorkeur gegeven, dit in verband met de kans op bijwerkingen.
   Ten behoeve van de vaccinatie in het eerste levensjaar dient aan de ontwikkeling van een
   gecombineerd difterie, tetanus, acellulair pertussis, geïnactiveerd poliomyelitis vaccin
   grote prioriteit gegeven worden.
11 Samenvatting
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<pre>12 Pertussis: a critical appraisal (2)</pre>

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<pre>Chapter 1
        Introduction
        Since 1996 there has been an increase in the incidence of reported pertussis in the
        Netherlands. The peak incidence is in the age group 5-9 years, but there are also many
        cases in the age groups 1-4 years, 10-14 years and > 20 years. Most patients in the age
        group 1-15 years were children who had been vaccinated against pertussis.
             In 1997 the Health Council’s Standing Committee on Infectious Diseases and
        Immunology consulted a working party of experts and produced an advisory report
        entitled ‘Pertussis: a critical appraisal’ (GR97). The most important recommendations
        were:
             to improve the acquisition of clinical and microbiological data from pertussis
             patients
             to improve the Dutch whole-cell pertussis vaccine
             to investigate the potential benefits of a booster vaccination with acellular pertussis
             vaccine at four years of age
             to further the plans to introduce an acellular pertussis vaccine for the vaccination in
             the first year of life.
        The Standing Committee recommended a re-evaluation of the situation at some point in
        the future. The present report is the result of this re-evaluation. A Committee was
        installed by the President of the Health Council. This Committee met during a two day
        conference and had fruitful and stimulating discussions with a group of staff members
        from the National Institute for Public Health and the Environment (RIVM). The
        following presentations were held:
13      Introduction
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<pre>       Epidemiology of pertussis in the Netherlands (JFP Schellekens)
       Comparison of whole-cell and acellular vaccines in four year old children: the
       ‘Apeldoorn’ study (WAM Berbers)
       Pertussis vaccines: current concepts and RIVM developments (M Thalen)
       Variations in B. pertussis antigens and its immunological relevance (FR Mooi)
       Summary of RIVM activities on improvement of DTP-IPV-vaccine (diphtheria,
       tetanus, pertussis, inactivated poliomyelitis-vaccine) (BAM van der Zeijst).
   The request from the Minister of Health, Welfare and Sport for this re-evaluation is
   presented in Annex A. The membership of the Committee is presented in Annex B.
14 Pertussis: a critical appraisal (2)
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<pre>Chapter 2
        The current situation on pertussis
        in the Netherlands
2.1     Epidemiology/surveillance
        Following a long period of relatively low incidence of pertussis (Hof98, Mel96) the
        Netherlands experienced an epidemic from autumn 1996 till spring 1997 especially
        among children in the age group 4-7 years. Many of the patients concerned had been
        vaccinated against pertussis (GR97, Mel97). Until 1999 the scheme of vaccination
        against pertussis was 3, 4, 5, 11 months. In the second half of 1997 and in 1998 the
        incidence of pertussis declined, but it increased again in 1999 (Mel00b, Nep99a). In the
        third quarter of 1999 the total number of pertussis notifications was 2223, as compared
        with 925 (1998), 856 (1997) and 1522 (1996) in former third-quarter periods.
        Surveillance data in the Netherlands are based on notifications to the Health Care
        Inspectorate, laboratory data from the National Institute of Public Health and the
        Environment (RIVM), isolation of Bordetella pertussis strains from regional public
        health laboratories and national registration of hospital admissions and of deaths
        (Nep99b). Cases are ascertained using both positive one-point serology (high titre in the
        first serum sample) and positive two-point serology (fourfold increase or more in
        antibody-titre) (Mel00a). Since 1997, data from the Netherlands Paediatric Surveillance
        Centre (NSCK) have also been available (Nep99b).
        There are several epidemiological pitfalls and bias factors when comparing the
        surveillance data. For example criteria for notification and case-definitions have changed
15      The current situation on pertussis in the Netherlands
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<pre>    during the surveillance period. However, the Committee feels that there is a definite
    increase since the mid 90’s and there is an important public health problem.
    The age-specific distribution of pertussis notifications in 1999 shows a peak incidence in
    the age group 5-9 years. Most patients in the age group 1-15 years were children who
    had been vaccinated against pertussis. The real number of cases is higher than the
    number of notifications, but difficult to estimate precisely. The circulation of Bordetella
    pertussis in the population can roughly be estimated by measuring the serum IgG-PT
    (immunoglobulin G anti-pertussis toxin) levels in blood samples. An increased level of
    IgG-PT is an indication of a recent (re)infection with Bordetella pertussis (Mel00a).
    Based on the results of a recent study by the RIVM, the number of re-infections can be
    estimated at between 1000 and 5000/100 000 population per year (Mel00a).
    The efficacy rate of the pertussis whole-cell vaccine used in the Netherlands appears to
    have been low for at least a number of years and surveillance data show that a decline in
    this rate had already started in 1994 (Mel00b).
    The Committee concludes that the present vaccination programme against pertussis
    (annex c) does not apparently provide sufficient protection, particularly not to children
    in the age group 1-10 years.
2.2 Antigenic variants in B pertussis strains
    Bordetella pertussis, the aetiological agent of whooping cough, produces many virulence
    factors. A number of these factors: pertussis toxin, filamentous haemagglutinin,
    pertactin and fimbriae, are proteins involved in intoxication or adhesion processes to
    host tissues and are critical antigens responsible for inducing immunity to B. pertussis.
    Results obtained in experimental studies with animals showed that these antigens are
    effective in preventing B. pertussis infections. The resurgence of pertussis experienced
    during recent years in countries with a long tradition in pertussis vaccination (not only
    the Netherlands but also the United States, Canada and Australia) evoked discussions as
    to whether or not vaccination had affected the genetic structure of B. pertussis and had
    resulted in antigenic shifts (Moo98). The results of recent studies indicate a shift in the
    structure of strains isolated over successive time periods and a divergence in the
    pertussis toxin and pertactin proteins between vaccine strains and clinical isolates
    (Mas99, Moo96, Mor98).
    The Committee recognises the potential importance of the findings of B. pertussis strains
    which are structurally different from the vaccine strains. There is only some indirect
16  Pertussis: a critical appraisal (2)
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<pre>    evidence (in animals) of immunological consequences with the currently used RIVM
    whole-cell vaccine. However, the apparent mismatch between vaccine strains and
    cultured circulating strains has thus far not resulted in proven clinical consequences for
    humans. Therefore, the Committee feels that it is too early to suggest that the decline of
    vaccine efficacy since 1994 and the increased incidence of pertussis since 1996 are
    related to antigenic changes of B. pertussis over time. The Committee possesses no
    convincing evidence that the mutations of strains directly result from vaccination
    pressure, since other countries where the same mutations occurred do not have the same
    vaccination pressure. There the vaccines continue to give satisfactory protection against
    all circulating strains (Mas99).
    The monitoring of further developments is important. The RIVM has a leading position
    in this field of research and should be strongly supported in continuing this work.
2.3 The ‘96 improved RIVM whole-cell pertussis vaccine
    The RIVM is continuously working to improve the quality of its pertussis vaccine, in
    accordance with the recommendations made by the working party in 1997 (GR97). An
    improved vaccine was introduced in 1997. Till 1996 the pertussis vaccine, (called
    RVP93) was cultured in 350 litre containers. In 1996 the culture volume was enlarged.
    The so called RVP96 vaccine is now cultured in 1000 litre containers. This vaccine was
    tested in a booster vaccination trial on four year old children (Ber99). The results of this
    so called Apeldoorn study are discussed later on in this report.
    RIVM is engaged in further improving the manufacture of the whole-cell pertussis
    vaccine, for example, culturing the two vaccine strains in a chemically well defined and
    stable medium (the so called THIJS-medium).
2.4 Booster vaccination at four years of age
    Recently RIVM studied the immunogenicity and adverse effects of three commercial
    acellular pertussis vaccines and the ’96 improved RIVM whole-cell vaccine combined
    with diphtheria, tetanus and poliomyelitis vaccine as a booster in a randomised
    controlled study in four year old children after primary vaccination with whole-cell
    vaccine (WCV): the Apeldoorn study (Ber99). The immune response of the children in
    this study (each group 21-24 children) is a reflection of the composition of the vaccines
    which had different concentrations of pertussis antigens.
17  The current situation on pertussis in the Netherlands
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<pre>   The number of participants who responded with a fourfold increase in the immune
   response (IgG antibody titre) to the pertussis antigens: pertussis toxin (PT), filamentous
   haemagglutinin (FHA) and pertactin (PRN) was clearly higher in the groups with the
   acellular vaccines (except for one of those vaccines which did not contain pertactin).
   Only 45 percent of the children with whole-cell vaccine had a fourfold increase in PT
   titre. For the acellular vaccines this percentage was at least 90. The incidence of adverse
   events in the recipients of the whole-cell pertussis vaccine was much higher (factor 4-12)
   than in the acellular pertussis vaccine recipients. Systemic and local reactions — both of
   minor importance — were prominent in the WCV recipients, both in frequency and in
   duration.
   The Committee feels that the results of this Apeldoorn study demonstrate that a booster
   pertussis vaccination at four years of age with acellular vaccine has preference above a
   booster with WCV.
18 Pertussis: a critical appraisal (2)
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<pre>Chapter 3
        The follow up of recommendations
        made in the 1997 report
        The Committee evaluated the follow-up of recommendations made in the first report on
        the subject (GR97):
        1 Improvements to the collection of clinical and microbiological data from the
            epidemic are needed. The Committee notes that the present pertussis surveillance
            system in the Netherlands is of a high quality, is an example for other countries and
            has been improved since 1997 (Nep99a, Nep99b).
        2 The current vaccine should be improved. At the end of 1997 an improved pertussis
            whole-cell vaccine was introduced by the RIVM (Moo00). The results were
            compared with three acellular vaccines in the Apeldoorn study (see 2.4) (Ber99).
        3 The bacterial strains used should be compared with those used in the French
            vaccine (which originally used the same parental strains); this may indicate ways
            in which the vaccine can be improved. The Dutch whole-cell vaccine parent strains
            509 and 134 were sent to the Institut Pasteur in Paris and compared with the French
            vaccine parent strains. The DNA patterns were similar, but not identical. The
            French whole-cell vaccine is produced by Pasteur Merieux Connaught. Additional
            information is not available.
        4 Expression of the various pertussis antigens should be identified as part of the in
            process-control procedures performed during preparation of the vaccine. The
            improved 1996 Dutch whole-cell vaccine — as used in the Apeldoorn study — still
            has a low concentration of pertussis toxin (PT) and filamentous haemagglutonin
            (FHA) as compared with the acellular vaccines. The in-process control procedures
            have been improved (Ber99, Moo00).
19      The follow up of recommendations made in the 1997 report
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<pre>   5   An investigation should be conducted into the potential benefits of a booster
       vaccination using an acellular pertussis vaccine, to be given at the age of four. If
       this could be shown to be of genuine benefit then a suitable immunisation
       programme should be introduced. A randomised controlled study with whole-cell
       and three acellular pertussis vaccines had been completed (Apeldoorn study, see 2.4)
       (Ber99).
   6   It is recommended that the current primary vaccination scheme is left unchanged,
       since any changes would have limited value. In 1998 the Dutch primary
       immunisation scheme was been changed: the first vaccination against diphtheria,
       pertussis, tetanus, poliomyelitis and Haemophilus influenzae type b is now given at
       the age of two months instead of three months (GR99). The main reason for this
       change was the fact that many children received their first three vaccinations later
       than on the intended 3, 4 and 5 months of age. This leads to a delay in the building
       up of immunity against particularly B. pertussis and Haemophilus influenzae.
   7   The introduction of an acellular pertussis vaccine for primary vaccination should
       go ahead as planned and start with field studies. Little progress has been made
       between 1997 and 2000.
   8   A re-evaluation should be carried out after a period of 9-12 months, by which time
       the cause of the epidemic may have become clear. This re-evaluation took place at
       the end of January 2000. The results are presented in this report.
20 Pertussis: a critical appraisal (2)
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<pre>Chapter 4
        Recommendations
4.1     Data collection
        The Committee feels that the current surveillance programmes should be continued.
        There is a need for more precise data on the number of vaccination doses that each child
        receives, so that the efficacy rate of the primary vaccination and of the booster
        vaccination at the age of four years can be more accurately calculated. Also more data
        on the circulation of B pertussis in the population is needed. The Committee suggests
        that such surveillance studies should be carried out in conjunction with future vaccine
        trials. In these studies also B pertussis strains should be collected and analysed.
4.2     The booster vaccination at four years of age
        The Committee strongly recommends a booster vaccination at four years of age with an
        acellular pertussis vaccine. It is difficult to assess the health benefits of such a booster
        vaccination, but a considerable reduction in the number of pertussis cases in the age
        group 5-9 years can be expected. Another effect will be a general decrease in the
        circulation of B. pertussis. Mathematical modelling studies are needed to analyse more
        accurately the latter effect. Further reduction of the circulation will be accomplished by
        efficacious primary vaccination in the first year of life. There is no proof of an increased
        risk for disease in unvaccinated young children due to transmission from adults (parents)
        as a result of the booster at four years of age.
21      Recommendations
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<pre>    The booster vaccination at four years has to be performed with a registered acellular
    vaccine. The Committee prefers a vaccine with three or more immunogenic components.
    These vaccines in general have better efficacy than one- or two-component vaccines,
    although some exemptions exist (Hal99, Kle96, Sim97). The combination of an acellular
    vaccine given with the now used diphtheria-, tetanus-, poliomyelitis (DT-IPV) vaccine at
    four years will make a second injection necessary. There are no real objections to this in
    view of the very low frequency of adverse effects of the acellular vaccines, as was shown
    in the Apeldoorn study (Ber99) and many studies from abroad (Hal99, Oli97, Sim97,
    Wil96). A second injection could be avoided by using a combined commercial vaccine.
    The Committee does not prefer that option.
    The Committee does not recommend the use of the RIVM-whole-cell pertussis vaccine
    for the booster, in view of the adverse effects and the low antibody response as
    compared with the acellular vaccines (Ber99).
4.3 The primary vaccination with pertussis vaccine in the first year of life
    The Committee strongly supports the RIVM-plans for the future of primary pertussis
    vaccination. It is the Committee’s understanding that there will be three tracks of
    development:
         development of a combined DT-polio acellular pertussis vaccine
         development of a new DT-polio whole-cell pertussis vaccine
         development of a pertussis vaccine made based on genetically modified strains in
         view of the mutation findings.
    The Committee emphasises that a direct approach to tackle the pertussis problem in the
    Netherlands would be the introduction of an effective and safe pertussis vaccine to be
    administered in the first year of life. High priority should be given to developing a
    combined DT-polio acellular pertussis vaccine (track a) as soon as possible. An
    acellular vaccine should be incorporated that has been proven to be safe and efficacious
    in clinical trials. In the long term such a primary vaccine can also be used for the booster
    vaccination at four years of age. The Committee strongly feels that in this way it will be
    possible to reduce the pertussis problem in the Netherlands to an acceptable level as well
    as solving the current public health problem.
    In the Committee’s opinion, the development of a new DT-polio and whole-cell pertussis
    combined vaccine (track b) should not be given any priority. It will be difficult to assess
    the efficacy of such a vaccine compared to the combined acellular vaccine.
22  Pertussis: a critical appraisal (2)
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<pre>    In future, it may be possible that a new effective whole-cell vaccine will be developed
    with minimal adverse effects, based on genetically modified strains. The Committee
    believes that track c is a long term approach.
    The Committee acknowledges the great expertise in RIVM in the field of B pertussis
    mutations. Further research is needed and RIVM — which has a leading position
    internationally — should be strongly supported in continuing this research.
4.4 The vaccination scheme
    The Committee recommends that the current vaccination scheme in the Netherlands,
    dating from January 1999, be retained. In this scheme the vaccinations in the first year
    of life (including pertussis vaccine) take place at 2, 3, 4 and 11 months of age. As
    mentioned before, a booster pertussis vaccination at four years of age should be
    implemented in conjunction with the current DT-Polio booster.
    The Hague, 28 June 2000,
    for the Committee
    J Sekhuis, arts                            Professor dr HKA Visser,
    scientific secretary                       chairman
23  Recommendations
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<pre>24 Pertussis: a critical appraisal (2)</pre>

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<pre>      Literature
Ber99 Berbers GAM, Lafeber AB, Labadie J, et al. A randomized controlled study with whole-cell or acellular
      pertussis vaccines in combination with regular DT-IPV vaccine and a new poliomyelitis (IPV-Vero)
      component in children 4 years of age in the Netherlands. Bilthoven: RIVM, 1999; (RIVM report no.
      105000 001).
GR97  Health Council of the Netherlands. Pertussis: a critical appraisal. Rijswijk: Health Council of the
      Netherlands, 1997; publication no. 1997/16.
GR99  Gezondheidsraad. Wijziging Rijksvaccinatieprogramma; vervroegde vaccinatie. Den Haag:
      Gezondheidsraad, 1999; publikatie nr 1999/09.
Hal99 Halperin SA. Developing better paediatric vaccines. The case of pertussis vaccine. Bio Drugs 1999; 12;
      175-91.
Hof98 van den Hof S, Conyn-van Spaendonck MAE, de Melker HE, et al. The effects of vaccination, the
      incidence of the target diseases. Bilthoven: RIVM, 1998; (RIVM report no. 213676008).
Kle96 Klein DL Heilman C. The new pertussis vaccines. In: Kaufmann SHE, de Gruyter W, eds. Concepts in
      Vaccine Development. Berlin: Publisher unknown, 1996: 89-115.
Mas99 Mastrantonio P, Spigaglia P, van Oirschot H, et al. Antigenic variants in Bordetella pertussis strains
      isolated from vaccinated and unvaccinated children. Microbiology 1999; 145: 2069-75.
Mel96 de Melker HE, Conyn-van Spaendonck MAE, Schellekens JFP. Pertussis surveillance 1989-1995.
      Bilthoven: RIVM, 1996; (RIVM report no. 128507004).
Mel97 de Melker HE, Conyn-van Spaendonck MAE, Rümke HC, et al. Pertussis in the Netherlands: an
      outbreak despite high levels of immunisation with whole-cell vaccine. Emerg Infect Dis 1997; 3: 175-8.
25    Literature
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<pre>Mel00a de Melker HE, Versteegh FGA, Conyn-van Spaendonck MAE, et al. Specificity and sensitivity of high
       levels of IgG antibodies against pertussis toxin in a single serum sample for diagnosis of infection with
       Bordetella pertussis. J Clin Microbiol 2000; 38: 800-6.
Mel00b de Melker HE, Schellekens JFP, Neppelenbroek SE, et al. Re-emergence of pertussis in the Netherlands:
       observations on surveillance data (submitted). Emerg Infect Dis 2000; (in press).
Moo96  Mooi FR, van Oirschot H, Peeters J, et al. Antigenic variation of the acellular vaccine component in the
       Dutch B. pertussis population. In: RIVM. RIVM annual scientific report 1995. Bilthoven: RIVM, 1996:
       74-5.
Moo98  Mooi FR, van Oirschot H, Heuvelman K, et al. Polymorphism in the Bordetella pertussis virulence
       factors P. 69/pertactin and pertussis toxin in the Netherlands: temporal trends and evidence for
       vaccine-driven evolution. Infect Immun 1998; 66: 670-5.
Moo00  Mooi F, Thalen M, Schellekens J, et al. The pertussis component in the DTP-IPV vaccine. “Dynamical
       balance between the infectious agent and humans”. Bilthoven: RIVM, 2000: 1-15.
Nep99a Neppelenbroek SE, de Melker HE, Schellekens JFP, et al. Pertussis; description and evaluation based on
       surveillance data of 1997 and 1998. Bilthoven: RIVM, 1999; (RIVM report no. 128507007).
Nep99b Neppelenbroek SE, de Melker HE, Schellekens JFP, et al. Severity of pertussis. Paediatric surveillance
       and notification study in the Netherlands in 1997. Bilthoven: RIVM, 1999; (RIVM report no.
       128507006).
Oli97  Olin P, Rasmussen F, Gottfarb P. Schedules and protection, simultaneous vaccination and safety:
       experiences from recent controlled trials. Int J Infect Dis 1997; 1: 143-7.
Sim97  Simonian S, Voordouw ACG. Acellulaire pertussisvaccins zijn in aantocht. Pharm Wkbl 1997; 132:
       700-8
Wil96  Willems RJL, Mooi FR. From whole-cell to acellular pertussis vaccines. Rev Med Microbiol 1996; 7:
       13-21.
26     Pertussis: a critical appraisal (2)
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<pre>A  The request for an advisory report
B  The Committee
C  Vaccination scheme of the National Vaccination Programme since 1 January 1999
   Annexes
27
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<pre>28 Pertussis: a critical appraisal (2)</pre>

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<pre>Annex A
      The request for an advisory report
      The President of the Health Council of the Netherlands received the following letter,
      dated 12 November 1999, from the Minister of Health, Welfare and Sport.
      On 30 June 1997, following a whooping cough epidemic in the Netherlands, the Health Council produced
      a report, at my request, entitled “Pertussis: a critical appraisal”, being an assessment of an earlier report,
      (“Whooping cough epidemic 1996-1997. Present position, possible causes and responses”), produced by
      the National Institute of Public Health and Environment (RIVM). In your report, you indicated that you
      would eventually like to issue a re-evaluation of your findings. In response to your report, improved
      quality assurance arrangements were introduced for the present cellular whooping cough vaccine and a
      number of studies were carried out. For example, circulating pertussis strains have been investigated and
      a study to determine the value of administering acellular booster vaccinations to four-year-olds has been
      carried out. Field studies involving the use of a DT-IPV vaccine containing an acellular whooping cough
      vaccine and improved cellular component have also been prepared.
      In view of the developments that have taken place in this field, I would like you to review the conclusions
      of your earlier report in the light of the latest scientific thinking. In particular, please indicate whether
      booster immunisation of four year olds using acellular vaccine may be expected to provide better
      protection and what the health benefits are likely to be, bearing in mind the other measures already
      taken. The short-term and long-term effects of such revaccination on the transmission of B. pertussis,
      especially to unvaccinated infants, should also be addressed.
29    The request for an advisory report
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<pre>   Please take the following into consideration:
        the reduction in the age at which vaccination under the National Immunization Programme is carried
        out by one month, with effect from 1999
        the present epidemiological situation with regard to whooping cough
        the report by the RIVM entitled ”A randomized controlled study with whole-cell or acellular
        pertussis vaccines in combination with regular DT-IPV vaccine and a new poliomyelitis (IPV-Vero)
        component in children 4 years of age in the Netherlands”.
   Minister for Health, Welfare and Sport
   (signed )
   Dr E Borst-Eilers
30 Pertussis: a critical appraisal (2)
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<pre>Annex B
      The Committee
         HKA Visser, chairman
         emeritus professor of paediatrics, Erasmus University Rotterdam (the Netherlands)
         Ph Duclos
         epidemiologist; World Health Organisation, Geneva (Switzerland)
         J Huisman
         emeritus professor of epidemiology and control of infectious diseases, Rotterdam
         (the Netherlands)
         JWM van der Meer
         professor of internal medicine, Catholic University Nijmegen (the Netherlands)
         P Olin
         paediatrician; Swedish Institute for Infectious Disease Control, Solna, Stockholm
         (Sweden)
         CH Wirsing von König
         professor of microbiology; Institute for Hygiene and Laboratory Medicine; Krefeld
         (Germany)
         JK van Wijngaarden, advisor
         Inspectorate for Health Care, The Hague (the Netherlands)
         J Sekhuis, scientific secretary
         Health Council, The Hague (the Netherlands)
31    The Committee
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<pre>   The Committee consulted the following scientific staff members from the National
   Institute of Public Health and the Environment (RIVM), Bilthoven (the Netherlands):
        WAM Berbers
        G Elzinga
        FR Mooi
        JFP Schellekens
        BAM Van der Zeijst
32 Pertussis: a critical appraisal (2)
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<pre>Annex C
      Vaccination scheme of the National
      Vaccination Programme since 1 January
      1999
      age                  vaccinations
      2 months             DTP-IPVa –1 + Hibb-1
      3 months             DTP-IPV –2 + Hib-2
      4 months             DTP-IPV –3 + Hib-3
      11 months            DTP-IPV –4 + Hib-4
      14 months            MMRc-1
      4 years              DT-IPVd -5
      9 years              DT-IPV –6 + MMR-2
      a
           DTP-IPV: Diphtheria toxoid, Tetanus toxoid, Pertussis vaccine, Inactivated Polioviruses
      b
           Hib: Haemophilus influenzae type b
      c
           MMR: Measles, Mumps, Rubella
      d
           DT-IPV: Diphtheria toxoid, Tetanus toxoid, Inactivated Polioviruses
33    Vaccination scheme of the National Vaccination Programme since 1 January 1999
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