Special Theme ± Safety The Safety Datalink: immunization research in health maintenance organizations in the USA R.T. Chen,1 F. DeStefano,1 R.L. Davis,2 L.A. Jackson,2 R.S. Thompson,2 J.P. Mullooly,3 S.B. Black,4 H.R. Shinefield,4 C.M. Vadheim,5 J.I. Ward,5 S.M. Marcy,6 & the Vaccine SafetyDatalink Team 7

The is a collaborative project involving the National Immunization Program of the Centers for Disease Control and Prevention and several large health maintenance organizations in the USA. The project began in 1990 with the primary purpose of rigorously evaluating concerns about the safety of . Computerized data on , medical outcome (e.g. outpatient visits, emergency room visits, hospitalizations, and deaths) and covariates (e.g. birth certificates, census data) are prospectively collected and linked under joint protocol at multiple health maintenance organizations for analysis. Approximately 6 million persons (2% of the population of the USA) are now members of health maintenance organizations participating in the Vaccine Safety Datalink, which has proved to be a valuable resource providing important information on a number of vaccine safety issues. The databases and infrastructure created for the Vaccine Safety Datalink have also provided opportunities to address vaccination coverage, cost-effectiveness and other matters connected with immunization as well as matters outside this field.

Keywords: reporting systems; health maintenance organizations; vaccines, combined, adverse effects; viral vaccines, adverse effects; United States.

Voir page 191 le reÂsume en francËais. En la pa gina 192 figura un resumen en espanÄ ol.

Introduction safety concern arise, for example the Guillain±Barre syndrome after administration of , As immunization continues to reduce the incidence ad hoc epidemiological studies are conducted for of vaccine-preventable diseases, there is increasing validation (5, 6 ). Such studies, while potentially interest in vaccine safety (1). There are inherent informative about vaccine causality, are costly, limitations in prelicensing clinical trials with respect time-consuming and usually limited to the assess- to sample size, duration of follow-up and population ment of a single event. heterogeneity. Consequently, postlicensing (also The need to improve postlicensing monitoring called postmarketing) evaluation of safety, when of pharmaceutical products became widely recog- vaccines are administered to millions of persons, is nized following the thalidomide disaster (7). During needed to assess rare, delayed or unusual reactions the 1980s, faced with the methodological limitations (2). Postlicensing safety monitoring is also necessary of passive surveillance for adverse events caused by in order to maintain public confidence, as vaccines drugs, pharmacoepidemiologists began turning to are usually administered to healthy persons, mostly large linked databases (LLDBs) linking computerized children, on an almost universal basis, with few alternatives (3). Postlicensing monitoring in most 7 countries has relied on passive surveillance systems Other members of the Vaccine Safety Datalink team (by site): J. Glasser, P. H. Rhodes, S. Wassilak, P. Kramarz, E. Swint, D. Walker, such as the Reporting System C. Okoro, P. Gargiullo, D. Baughman, D. King (National Immunization (VAERS) (4 ). Should evidence of a potential vaccine Program, Centers for Disease Control and Prevention, Atlanta, GA, USA); P. Benson, V. Immanuel, W. Barlow, K. Bohlke, P. L. Poy, V. Rebolledo, D. Rubanowice, L. Mell, M. LaFrance, L. Huggins, J. Dhillon, A. Zavitkovsky, A. Salazar, E. Adams, M. Shafer, 1 National Immunization Program, Centers for Disease Control and M. Sunderland, J. Habanangas, J. Drake, J. Kramer (Group Health Prevention, Atlanta, GA 30333, USA. Requests for reprints should Cooperative of Puget Sound, Seattle, WA, USA); L. Drew, K. Olson, be addressed to Robert T. Chen at this address (e-mail: [email protected]). J. Mesa, J. A. Pearson, M. Allison, A. Bauck, N. Redmond (Northwest 2 Center for Health Studies, Group Health Cooperative of Puget Sound, Kaiser Permanente, Portland, OR, USA); T. A. Lieu, P. Ray, E. Lewis, Seattle, WA, USA. B. H. Fireman (Northern California Kaiser Permanente, Oakland, 3 CA, USA); H. Lee, J. Jing, N. Goff (Center for Vaccine Research, Harbor± Center for Health Research, Northwest Kaiser Permanente, Portland, UCLA Medical Center, Torrance, CA, USA); S. M. Marcy, M. Lugg OR, USA. (Southern California Kaiser Permanente, Los Angeles, CA, USA); 4 Pediatric Vaccine Study Center, Northern California Kaiser M. M. Braun, R. P. Wise, M. E. Salive (Center for Biologics Evaluation Permanente, Oakland, CA, USA. and Research, Food and Drug Administration, Rockville, MD); 5 Center for Vaccine Research, Harbor-UCLA Medical Center, Torrance, V. Caserta (Division of Vaccine Injury Compensation, Health Resources CA, USA. and Services Administration, Rockville, MD). 6 Southern California Kaiser Permanente, Pasadena, CA, USA. Ref. No. 0338

186 # World Health Organization 2000 Bulletin of the World Health Organization, 2000, 78 (2) The Vaccine Safety Datalink pharmacy prescription (and later, immunization) to has been expanded to include older children, medical outcome records (8). These databases derive adolescents and adults, totalling about 6 million from defined populations such as members of health persons (2% or the population of the USA). maintenance organizations (HMOs), single-provider Computerized databases are the initial source health care systems, and Medicaid programmes. of data for most VSD studies. Vaccination data are Since the databases are usually generated in the derived from computerized immunization tracking routine administration of such programmes and do systems maintained by each HMO. Quality control not require completion of a vaccine adverse event comparisons of the computerized immunization data reporting form, the problems of underreporting or with information recorded in paper medical records recall bias are reduced. Because the numbers of have shown high levels of agreement (17). For people enrolled in these programmes range from medical encounters, each HMO maintains compu- thousands to millions, large populations can be terized databases on all hospital discharges and examined for relatively infrequent adverse events. emergency room visits. Diagnoses from outpatient Denominator data on doses administered and the clinic encounters are available from some of the ready availability of appropriate comparison groups HMOs for certain years. Automated pharmacy and are also very useful. LLDBs therefore have the laboratory data on, for example, seizure medications potential to provide an economical and rapid means and anticonvulsant blood levels, provide valuable of conducting postlicensing studies on the safety of cross-references for identifying diagnoses that may drugs and vaccines (9±11). have been related to immunization but were During the late 1980s the Centers for Disease miscoded or overlooked. Records are kept of Control and Prevention (CDC) in the USA partici- diagnostic procedures, e.g. electroencephalography pated in two pilot vaccine safety studies using LLDBs and radiography, and these provide another source in Medicaid and HMO populations (12±15). These for establishing the presence of such conditions. investigations, while validating this approach for Paper medical records are often abstracted to vaccine safety studies and providing scientifically confirm diagnoses and vaccination histories. Patients rigorous results, were limited by relatively small or their parents are occasionally interviewed to obtain sample sizes, retrospective design, and focus on the additional information. Each site encodes its patients' most severe reactions (16 ). These limitations, the clinical data with unique study identifiers before constraints of VAERS, and recognition of the need sending data to CDC annually for merging and for improved monitoring of vaccine safety prompted analysis, thereby preserving patient confidentiality. CDC to initiate the Vaccine Safety Datalink(VSD) The refinement of study methods and the prioritiza- project in 1991 (11). tion of research projects take place during monthly In this article we review several completed conference calls and annual meetings. VSD studies, summarize key findings, and illustrate The specific methods for each of the studies the potential of the project to address many types of outlined below are described in the accompanying question related to immunization research and policy. respective citations. However, an unusual aspect of Discussed also are some of the lessons, strengths and many vaccine safety analyses is worth highlighting weaknesses of VSD during its first 10 years of here. For vaccines that are universally recommended, operation. e.g. most childhood vaccines, the number of persons unexposed is too small to compare adverse outcomes between vaccinated and unvaccinated people (typical Methods cohort studies) or vaccination between cases and non-cases (typical case±control studies). An alter- The VSD methodology has been described pre- native definition of exposure is therefore used. A risk viously (11). VSD was created in 1991 by CDC's window is defined a priori after vaccination for the National Immunization Program. The project links specific event of interest, based on current under- medical event information, vaccine history and standing of the most plausible biological mechanism selected demographic information from the compu- should such an association actually exist. Incidences terized clinical databases of four model HMOs: the inside and outside the riskwindow, for exposed and Group Health Cooperative of Puget Sound, Seattle, unexposed individuals, respectively, or recent ex- WA, USA; Kaiser Permanente Northwest, Portland, posures among cases and non-cases, are then OR, USA; Kaiser Permanente Medical Care Program compared. Sources of covariates used to control for of Northern California, Oakland, CA; and Southern potential confounders include birth certificates and California Kaiser Permanente Health Care Program, the decennial census, linked by subscribers' postal zip Los Angeles, CA, USA. These HMOs are essentially codes. Alternatively, the data are analysed using the mini-national health services. Once a subscriber has case-series design (18) to minimize confounding. paid the insurance fee to an HMO, care is provided by the HMO's health clinics and providers. Members have unique identification numbers that can be used Results to linkdata on their medical services within the HMO. Data were initially obtained only for infants A considerable number of VSD studies have been and children aged up to 6 years, but data collection published (see Annex). The topics covered range

Bulletin of the World Health Organization, 2000, 78 (2) 187 Special Theme ± Immunization Safety

over vaccine coverage, disease incidence, methodol- previous seizures or were well-child care visits by ogy, vaccine safety and cost-effectiveness. In these children with pre-existing seizure disorders. investigations, advantage has been taken of various aspects of the VSD infrastructure. Details on the Risk of chronic arthropathy among women results of several of these studies are presented after rubella vaccination below. This study was based on computerized laboratory data and a medical record review comparing women Risk of hospitalization because of aseptic who had been vaccinated with and after ±±rubella unvaccinated women. After at least one year of vaccination of children aged 1±2 years follow-up there was no evidence of an increased risk Vaccines containing the Urabe strain of mumps of chronic joint problems associated with vaccination vaccine are associated with an increased riskof (21). A regional laboratory database at one of the aseptic meningitis. A VSD analysis, however, showed HMOs enabled the identification and selection of that the measles±mumps±rubella (MMR) vaccine women for study according to rubella serological used in the USA, containing the Jeryl±Lynn strain of status. A detailed chart review was conducted in , is not associated with an increased order to verify diagnoses, determine onset dates and riskof aseptic meningitis ( 19). A matched case± obtain rubella vaccination histories. The records of control study was performed in which cases of 4884 women were reviewed and those of 4316 were aseptic meningitis were ascertained by reviewing retained after various exclusions. During a one-year hospitalization data files for the period 1984±93 follow-up period the of chronic joint among children aged 1±2 years. Of the 59 confirmed symptoms did not vary significantly in relation to cases hospitalized for aseptic meningitis, 3 had rubella vaccination status (Table 2). received MMR vaccine within 30 days before illness developed, whereas 7 of the 118 matched controls Safety of revaccination with pneumococcal had been hospitalized for the same reason, resulting polysaccharide vaccine in an odds ratio of 0.84 (95% confidence interval, Each of the HMOs had the clinical and research 0.2±3.5). The incidence of hospitalization for aseptic infrastructure necessary for the enrolment and meningitis was therefore similar for MMR vaccinees follow-up of participants in prospective studies, and controls. including studies on vaccine immunogenicity and . A study of this kind was conducted at Safety of second dose of measles±mumps± one of the HMOs with a view to determining whether rubella vaccine for children aged 4±6 and the revaccination of adults with pneumococcal 10±11 years polysaccharide vaccine at least 5 years after primary A comparison of adverse event rates in the VSD vaccination was associated with an increased riskof project showed that children aged 10±12 years were adverse reactions (22). more likely to have a clinical event after a second dose The participants were required to be in the age of MMR vaccination than were children who range 50±74 years and to have been continuously received their second MMR dose at 4±6 years of enrolled in the HMO for at least 13 years. Participants age (20). These results favoured policy recommenda- under 65 years of age had to have at least one chronic tions indicating that in the USA the second dose of medical condition that was an indication for MMR vaccine should be given to children aged 4±6 pneumococcal vaccination. In order to compare years. The study compared the frequency of clinical adverse events following revaccination with those events after, and possibly related to, the second MMR following first vaccination, patients who had been dose at two HMOs with different vaccination vaccinated once at least 5 years previously and policies. At each HMO a cohort of children who patients who had never been vaccinated were had received MMR vaccination was identified and the identified for recruitment. The identification and rates of medical encounters overall and for specific recruitment of individuals who met the eligibility conditions were compared for the 30-day period criteria were greatly facilitated by the availability of following vaccination and the 30-day period before computerized databases with information on demo- vaccination. In the HMO that administered the graphic characteristics, medical histories and vacci- second dose of MMR vaccine at 10±12 years of age nation histories, as well as on their whereabouts. The the rates of medical encounters increased by about 1463 participants were asked to record systemic and 45%aftervaccinationcomparedwithbefore, local symptoms for 13 days after vaccination, and to whereas in the HMO that administered the vaccine measure any redness or swelling at the injection site at 4±6 years the medical encounter rates decreased using a standard tool. The riskof a sizable local after vaccination (Table 1). The increase among the injection site reaction, i.e. redness or swelling children aged 10±12 years was primarily attributable 510.2 cm in diameter within three days after to visits for rashes and joint pains. The computerized vaccination, was significantly higher in revaccinees data suggested that there was an increase in visits for (Table 3). However, the riskof such a reaction was seizures but chart review revealed that, for the most not associated with the time that had elapsed since part, they were follow-up visits associated with the first vaccination. Thus one of the policy

188 Bulletin of the World Health Organization, 2000, 78 (2) The Vaccine Safety Datalink implications is that extending the minimum interval Table 1. Number and rates of medical care visits 30 days before and between initial vaccination and revaccination beyond 30 days after the second measles±mumps±rubella vaccination five years may not influence the riskof a local reaction. by age at vaccination (Vaccine Safety Datalink)

Age at vaccination Impact of the inactivated poliovirus vaccine/oral poliovirus vaccine sequential 4±6 years 10±12 years schedule on vaccination coverage 30 days 30 days 30 days 30 days The automated vaccination data have been of value in before after before after monitoring vaccination coverage and the impact of Rash 32 17 18 25 changes. Thus, for example, an Joint pain 0 0 12 19 evaluation was made of the impact of the sequential Seizures 3 3 8 14 inactivated poliovirus vaccine/oral poliovirus vac- Pyrexia 7831 cine (IPV/OPV) schedule implemented in the USA Lymphadenopathy 6215 in 1997 (23). The study was undertaken because of Malaise/fatigue 0034 concerns that the new schedule might lead to reduced Nervous/musculoskeletal 0010 vaccination coverage, given the requirement for an Oedema 0110 extra injection. It emerged that the introduction of Total 48 31 47 68 IPV was fairly rapid and that, at 12 months of age, Visits/1000 person-months 5.6 3.6 2.1 3.8 a b infants who received IPV did not have lower Odds ratio 0.64 (0.40±1.01) 1.45 (1.00±2.10) coverage levels for the routine infant vaccines than a Odds ratio comparing the 30-day period after vaccination with the 30-day period before infants who received OPV only. vaccination. Beginning in April 1997, one of the HMOs b Figures in parentheses are 95% confidence intervals. adopted the Advisory Committee on Immunization Practices guidelines for the IPV/OPV sequential schedule as an option for physicians and families. Up- to-date status, defined as the receipt of two poliovirus Table 2. Prevalence of nontraumatic arthropathies during a one- , three diphtheria and and year follow-up period by rubella serological and immunization pertussis/acellular pertussis (DTP/DTaP) vaccina- status (Vaccine Safety Datalink) tions, and two Haemophilus influenzae type b and hepatitis B vaccinations administered after the age of Prevalence (%) for P-value 3 weeks, was measured at the age of 12 months. The ABC percentage of children who received their first Seronegative + Seronegative + Seropositive + A vs B A vs C poliovirus vaccine as IPV increased from 18% during vaccinated no vaccine no vaccine the fourth quarter of 1996 to 19%, 34% and 82%, (n = 971) (n = 924) (n =2421) respectively, in the first, second and third quarter of 1997. Among children who received IPV as their first 5.7 6.2 6.8 0.64 0.24 poliovirus vaccination, the up-to-date status by the age of 12 months for routinely recommended vaccines was 82%, 83% and 82% in the first three a quarters following implementation, while for those Table 3. Risk of a sizable local reaction by pneumococcal receiving OPV the corresponding values were 82%, polysaccharide vaccination status (Vaccine Safety Datalink) 81% and 79%. Number (%) with reaction following Varicella serology among school-age First vaccination Revaccination Relative risk P-value children with a negative or uncertain (n = 901) (n = 513) history of chickenpox 29 (3)b 55 (11) 3.3; 2.1±5.1c < 0.001 VSD data have proved valuable in cost-effectiveness a studies of different vaccination policy options. For 510.2 cm of redness or swelling within three days after vaccination. b example, a study was designed to determine the most Figures in parentheses are percentages. cost-effective strategy for dealing with school-age c Figures in italics are the 95% confidence interval. children who had a negative or uncertain history of chickenpox (24). The workwas possible because the Parents were interviewed by telephone about their HMO that conducted the study had issued a general children's varicella history. The cost-effectiveness recommendation that children aged 7±12 years with estimates depended on the results relating to positive such a history should have their varicella serology varicella serology according to age and on informa- determined before the decision to vaccinate was tion given by parents on whether their children had taken. All serology specimens were tested at the had chickenpox (Table 4). Among children aged HMO's regional laboratory so that children who had 7±12 years with negative or uncertain histories of specimens submitted from any of the HMO's chickenpox, varicella seroprevalence ranged from 32 paediatric clinics could be quickly identified. 9% to 68%, depending on age and clinical history. Of

Bulletin of the World Health Organization, 2000, 78 (2) 189 Special Theme ± Immunization Safety

feasible and desirable epidemiological method for Table 4. Proportion of children with positive varicella serology, detecting the adverse effects of vaccines (28). by age and parents' history of whether child had had chickenpox The VSD project was established to benefit (Vaccine Safety Datalink) from the advantages offered by HMOs for efficient population-based health research (3, 11). VSD Parents' history of whether child had had chickenpox focused its initial efforts on examining potential Age of child (years) Not sure Probably not Definitely not associations between and 34 serious 7 0.20 0.21 0.09 neurological, allergic, haematological, infectious, 8 0.39 0.17 0.25 inflammatory and metabolic conditions (29). In- 9 0.50 0.33 0.23 creasingly, VSD is being used to test new ad hoc 10 0.50 0.45 0.28 vaccine safety hypotheses in addition to planned 11 0.68 0.30 0.33 vaccine safety studies. These hypotheses may arise 12 0.52 0.39 0.33 from the medical literature (21), passive surveillance, All 0.48 0.32 0.25 e.g. VAERS (30, 31), changes in immunization schedules (20) or the introduction of new vaccines (31, 32). Many completed VSD studies have in- formed various matters connected with vaccination policy in the USA, including: Table 5. Studies in progress or planned, Vaccine Safety Datalink, ± the recommended age for administering the 1999 second MMR dose; ± the vaccination of seronegative women against . Hepatitis B vaccination and risk of multiple sclerosis and other demyelinating rubella; disorders ± revaccination with pneumococcal polysaccharide . Timing of hepatitis B vaccination and risk of type 1 (juvenile) diabetes vaccine; . Mortality risk following vaccination, including hepatitis B ± initial poliovirus vaccination with IPV; . Ataxia following vaccination ± the riskof intussusception following rotavirus . Encephalopathy associated with vaccination vaccination. . Wheezing and asthma associated with vaccinations . Hepatitis B vaccination and risk of rheumatoid arthritis The number and scope of studies in the project has . Rick of inflammatory bowel disease associated with measles±mumps±rubella continued to grow with the increasing importance of vaccine vaccine safety monitoring in maintaining public . Hepatitis B vaccination and risk of systemic lupus erythematosis and other confidence in vaccines. Continuing and planned autoimmune disorders studies are listed in Table 5. . Risk of following vaccination The diversity of vaccination practices in the . Possible health effects of four HMOs facilitates making useful contrasts in . Incidences and risk factors for intussusception safety experience (20). The size of the VSD population may also permit separation of the risks associated with individual vaccines from those the parents whose children had been serotested, 73% associated with vaccine combinations, whether given said they would prefer to have the blood test first in the same syringe or simultaneously at different rather than presumptive vaccination. For the study body sites. Such studies would be especially valuable population it was projected that it would be most in view of the combined paediatric vaccines currently cost-effective to recommend testing before vaccinat- undergoing development (33). Should VSD identify ing children aged 9±12 years with uncertain histories an adverse event as being caused by a vaccine, data on of chickenpox and to vaccinate presumptively in all the incidence attributable to the vaccine would be other groups. available, permitting accurate risk±benefit assess- ment by both the public and policy-makers. Subgroup analyses may permit identification of risk Discussion factors for adverse events, which may be useful in identifying contraindications to vaccination. Data No vaccine is perfectly safe or effective. With high from VSD should be useful in calculating back- rates of vaccination and a low incidence of vaccine- ground rates of illness in the absence of vaccination, preventable diseases, adverse events after vaccination which could serve as expected rates when comparing are understandably of concern and have received rates of vaccine-associated events in passive reports. increasing attention from the medical community Incidence rates of vaccine-associated adverse events and the public (1). Unfortunately, this concern has derived from VSD can be used to evaluate the often affected the stability of vaccination pro- sensitivity of passive reporting systems. VSD data grammes (25±27). Current knowledge about vaccine can aid the regulatory authorities in their evaluation of safety is incomplete, and in the early 1990s it was VAERS data (30) and the Vaccine Injury Compensa- reported that research capability was insufficient tion Program in determining which events should be (16, 28). The existence of large databases for defined compensated as vaccine injuries (34). Furthermore, populations means that cohort studies have become a the cohort infrastructure created by the VSD project

190 Bulletin of the World Health Organization, 2000, 78 (2) The Vaccine Safety Datalink easily lends itself to a wide range of vaccine-related riskof extremely rare events such as Guillain±Barre studies outside the safety field (11). syndrome after seasonal administration of influenza A few words of caution are appropriate. The vaccine. Because VSD relies on epidemiological HMO membership at all VSD sites is perpetually methods it may not successfully control for con- changing as people enrol and leave. Keeping an founding and bias in each analysis (35) and inferences accurate record of members' enrolment histories is a on causality may be limited (36). However, we are laborious matter. The computerized HMO databases becoming increasingly aware that well-executed case- used by VSD were developed for clinical care and control or other non-experimental designs can meet administrative functions, not for research purposes. most of the necessary conditions for dealing with Furthermore, they are continuously changing as the causality (16, 23, 37). Finally, while VSD is more data systems and requirements of the organization efficient than conducting individual large epidemio- evolve. Consequently, using these databases for logical studies de novo, the resources needed to research purposes can be more onerous than was maintain VSD are considerable. However, invest- initially expected. Concerns about confidentiality are ment in this vaccine safety infrastructure may be also prominent. While diverse, the population in the necessary if we are to take full advantage of the four HMOs covered here is not wholly representative promise of biotechnology for new vaccines (1). of the USA in terms of geography and socioeconomic Despite these potential shortcomings, VSD status, being skewed towards the West Coast and the provides a new, essential, powerful and cost-effective middle class. complement to the continuing evaluations of vaccine More importantly, because of the high cover- safety in the USA. The methodological and logistic age attained in the HMOs for most vaccines, few advantages have led Canada, the United Kingdom, unvaccinated controls are available. VSD must and other countries to develop LLDBs linking therefore rely predominantly on some type of risk immunization registries with medical files (9, 10). interval analysis (12±15). The capability of this However, given the relatively limited number of approach to assess associations between vaccination vaccines used worldwide and the costs associated and adverse events with delayed or insidious onset, with establishing and operating LLDBs, it is unlikely e.g. , is limited. Nor can VSD easily assess that all countries will have the ability or necessity to adverse events that are not currently captured in establish their own LLDBs. The results from existing HMO databases, either because they do not scientifically rigorous vaccine safety studies con- result in a health care consultation, as with fever, or ducted in VSD and other LLDBs should provide a because the data are not automated, as with X-ray firm foundation for accurate risk-benefit assessment results (11). VSD is not large enough to examine the by both the public and policy-makers (38). n

Re sume Vaccine Safety Datalink : recherche sur la vaccination dans les caisses de sante des Etats-Unis d'Ame rique On connaõÃt bien les effets secondaires courants des n'est pas associeÂaÁ un risque accru de meÂningite aÁ vaccins, mais on sait peu de choses des effets indeÂsirables liquide clair ; rares ou exceptionnels. Pour combler ces lacunes, le ± administre e entre 10 et 12 ans, la seconde dose de Centers for Disease Control and Prevention des Etats-Unis vaccin antirougeoleux/antiourlien/antirubeÂoleux peut d'AmeÂrique a creÂe le projet Vaccine Safety Datalink, en entraõÃner davantage de re actions indeÂsirables que si partenariat avec quatre grandes caisses de sante HMO elle est administreÂe entre 4 et 6 ans ; (« Health Maintenance Organizations »), pour proceÂder aÁ ± le vaccin antirougeoleux/antiourlien/antirubeÂoleux l'eÂvaluation continue de la seÂcurite des vaccins. On n'augmente pas le risque d'arthropathie chronique recueille preÂalablement des donneÂes informatiseÂes sur la chez la femme ; et vaccination, l'issue meÂdicale de cette dernieÁre (par ex. ± la revaccination des adultes par le vaccin anti- sortie de l'hoà pital, consultations externes, urgences, pneumococcique polysaccharidique cinq ans au deÂceÁs) et des donneÂes relatives aÁ des co-variables (par moins apreÁs la primovaccination est associeÂe aÁun ex. certificats de naissance, donneÂes du recensement), que risque accru de re actions indeÂsirables. l'on relie ensuite pour les analyser selon un protocole Les bases de donne es et l'infrastructure creÂeÂes conjoint pour les quatre caisses de santeÂ. Vaccine Safety pour Vaccine Safety Datalink ont eÂgalement fourni Datalink couvre plus de 6 millions d'adheÂrents des caisses l'occasion de s'atteler aÁ des questions en rapport avec la de sante (2 % de la population des Etats-Unis d'AmeÂ- vaccination mais ne concernant pas l'innocuite . Les rique). Ce projet permet d'effectuer des eÂtudes planifieÂes exemples preÂsente s concernent : sur l'innocuite des vaccins et de mener en temps utile des ± le fait de savoir si la mise en úuvre de l'administration travaux sur les probleÁmes qui se font jour concernant la seÂquentielle du vaccin antipoliomyeÂlitique inactiveÂ/ seÂcurite des vaccins. Dans le preÂsent article, on examine vaccin antipoliomyeÂlitique buvable risque d'entraõÃner les reÂsultats marquants du projet, aÁ savoir : une diminution de la couverture du fait de la ne cessite ± le vaccin antirougeoleux/antiourlien/antirubeÂoleux de proce der aÁ une injection de plus ; et contenant la souche Jeryl-Lynn de vaccin antiourlien

Bulletin of the World Health Organization, 2000, 78 (2) 191 Special Theme ± Immunization Safety

± la strateÂgie de vaccination contre la varicelle, qui a le eÂtudes scientifiquement rigoureuses meneÂes dans le meilleur rapport couà t/efficacite pour les enfants d'aÃge cadre du Vaccine Safety Datalink et de bases de donneÂes scolaire ayant des anteÂce dents douteux ou n'ayant analogues devraient eÃtre pour le public et les deÂcideurs pas eu la varicelle. une base solide aÁ partir de laquelle eÂvaluer preÂciseÂment A une eÂpoque ouÁlase curite des vaccins est une le rapport avantages/risques de la vaccination. preÂoccupation publique croissante, les reÂsultats des

Resumen Vaccine Safety Datalink: investigaciones sobre inmunizacio n en las organizaciones para el mantenimiento de la salud en los Estados Unidos Se sabe mucho de los efectos secundarios comunes de ± una segunda dosis de la vacuna SPR puede dar lugar las vacunas, pero nuestros conocimientos de los a una mayor frecuencia de episodios adversos en los episodios adversos raros o inusuales son limitados. Para ninÄ os de 10-12 anÄ os que en los de 4-6 anÄos; colmar esa laguna, los Centros de Control y PrevencioÂn ± la vacuna SPR no aumenta la incidencia de artropatõÂa de Enfermedades de los Estados Unidos lanzaron el cro nica entre las mujeres; y proyecto Vaccine Safety Datalink, asociacio n establecida ± la reinmunizacio n de los adultos con la vacuna con cuatro grandes organizaciones de mantenimiento de antineumococo cica de polisaca ridos cada cinco anÄos la salud para evaluar permanentemente la seguridad de tras la primera dosis se asocia a un mayor riesgo de las vacunas. La informacio n computarizada sobre episodios adversos. vacunacio n, resultados meÂdicos (p. ej., altas hospitala- Las bases de datos y la infraestructura creadas por rias, consultas de pacientes ambulatorios, visitas a VaccineSafetyDatalink tambieÂnhandadoocasio npara urgencias, defunciones), y datos covariables (certificados tratar aspectos de la inmunizacio n no relacionados con de nacimiento, datos censales) se reu nen y ponen en la seguridad. Los ejemplos facilitados se refieren a: relacio n de forma prospectiva para someterlos a ana lisis ± la posibilidad de que la aplicacio n de la secuencia de conforme a un protocolo comuÂn de las cuatro vacuna antipoliomielõÂtica inactivada/vacuna antipo- organizaciones de mantenimiento de la salud. Vaccine liomielõÂtica oral, al exigir una inyeccio n suplementa- Safety Datalink cuenta con ma s de 6 millones de ria, conduzca a una disminucio n de la cobertura de miembros (el 2% de la poblacio n de los Estados Unidos). vacunacioÂn;y El proyecto preve la realizacio n de estudios planificados ± la estrategia ma s econo mica de inmunizacio n contra sobre la seguridad de las vacunas, asõ como de las la varicela para tratar a los ninÄ os en edad escolar con investigaciones necesarias para abordar los nuevos un historial negativo o impreciso de esa enfermedad. problemas surgidos al respecto. En el presente artõÂculo se En una eÂpoca de creciente preocupacioÂn pu blica examinan algunas conclusiones importantes del proyec- por la seguridad de las vacunas, los resultados de los to, entre ellas las siguientes: estudios rigurosamente cientõÂficos realizados en Vaccine ± la vacuna contra el sarampio n ± parotiditis ± rubeÂola Safety Datalink y en bases de datos similares deberõÂan (SPR) que contiene la cepa Jeryl-Lynn de la vacuna facilitar al pu blico y a los formuladores de polõÂticas una antisarampionosa no se asocia a un mayor riesgo de base so lida para poder sopesar con exactitud los riesgos meningitis aseÂptica; y los beneficios asociados.

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Annex Published Vaccine Safety Datalink studies by topic area

Vaccine coverage health maintenance organizations. Pediatric Infectious Davis RL et al. Impact of the sequential IPV/OPV Disease Journal, 1998, 17: 605±611. schedule on vaccination coverage levels in the United States, 1997. Morbidity and Mortality Weekly Report, Methodology 1998, 47: 1017±1019. Barlow W. Measurement of interrater agreement DavisRLetal.Immunization levels among with adjustment for covariates. Biometrics, 1996, 52: premature and low-birth-weight infants and risk 695±1162. factors for delayed up-to-date immunization status. Barlow WE. Global measures of local influence for Journal of the American Medical Association, 1999, 282: proportional hazards regression models. Biometrics, 547±553. 1997, 53: 1157±1162. Lieu TA et al. Riskfactors for delayed immunization Chen RT et al. The Vaccine Safety Datalinkproject: among children in a health maintenance organization. a new tool for improving vaccine safety monitoring in American Journal of , 1994, 84: 1621±1625. the United States. Pediatrics, 1997, 99: 765±773. Lieu TA et al. Would better adherence to guidelines Davis RL et al. Utility of immunization tracking improve childhood immunization rates? Pediatrics, systems for self-assessment, improvement, research 1996, 98: 1062±1068. and evaluation, and linkage with statewide networks: experience of the CDC Vaccine Safety Datalinksites. Disease Incidence HMO Practice, 1997, 11: 13±17. Parashar UD et al. Epidemiology of diarrheal Mullooly J et al. Quality of HMO vaccination disease among children enrolled in four West Coast databases used to monitor childhood vaccine safety. American Journal of Epidemiology, 1999, 149: 186±194.

Bulletin of the World Health Organization, 2000, 78 (2) 193 Special Theme ± Immunization Safety

Mullooly JP. Misclassification model for person- Niu MT et al. Comparative safety of two time analysis of automated medical care databases. recombinant hepatitis B vaccines in children: data American Journal of Epidemiology, 1996, 144: 782±792. from the Vaccine Adverse Event Reporting System Wassilak SGF et al. Utility of large-linked databases (VAERS) and Vaccine Safety Datalink(VSD). Journal in vaccine safety, particularly in distinguishing of Clinical Epidemiology, 1998, 51: 503±510. independent and synergistic effects. Annals of the Ray P et al. Riskof chronic arthropathy among New York Academy of Sciences, 1995, 754: 377±382. women after rubella vaccination. Journal of the American Medical Association, 1997, 278: 551±556. Vaccine safety Black S et al. Riskof hospitalization because of Cost-effectiveness aseptic meningitis after measles-mumps-rubella vac- Lieu TA et al. Computer-generated recall letters for cination in one-to-two-year-old children: an analysis underimmunized children: how cost-effective? Pedia- of the Vaccine Safety Datalink(VSD) project. tric Infectious Disease Journal, 1997, 16: 28±33. Pediatric Infectious Disease Journal, 1997, 16: 500±503. Lieu TA et al. Varicella serology among school age Davis RL et al. MMMR2 at 4±5 years and 10±11 children with a negative or uncertain history of years of age. A comparison of adverse event rates in chickenpox. Pediatric Infectious Disease Journal, 1998, the Vaccine Safety Datalink(VSD) project. Pediatrics, 17: 120±125. 1997, 100: 767±771. Lieu TA et al. Effectiveness and cost-effectiveness Jackson LA et al. Safety of revaccination with of letters, automated telephone messages, or both for pneumococcal polysaccharide vaccine. Journal of the underimmunized children in a health maintenance American Medical Association, 1999, 281: 243±248. organization. Pediatrics, 1998, 101 (4): E3.

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