Vaccine Safety > VSD
Vaccine Safety Datalink Project:
A New Tool for Improving Vaccine Safety Monitoring in the United States
As published in Pediatrics 1997; 99:765-73

¹ National Immunization Program (MS-E61), Centers for Disease
   Control and Prevention, Atlanta, GA 30333
² Center for Health Studies, Group Health Cooperative of Puget
   Sound, Seattle, WA 98101
³ Center for Health Research, Northwest Kaiser Permanente,
   Portland, OR 97227
⁴ Pediatric Vaccine Study Center, Northern California Kaiser
   Permanente, Oakland, CA 94611
⁵ Center for Vaccine Research, Harbor-UCLA Medical Center, 
   Torrance, CA 90502
⁶ Southern California Kaiser Permanente, Pasadena, CA 91188
⁷ Center for Biologics Evaluation and Research, Food and Drug
   Administration, Rockville, MD 20852
⁸ Division of Vaccine Injury Compensation, Health Resources 
   and Services Administration, Rockville, MD 20856

*Other Vaccine Safety Datalink Team Members by Site:
¹ Emmett Swint, M.A., Janet R. Hardy, M.Sc., M.P.H.
² Thomas Payne M.D., Virginia Immanuel, M.P.H., Patti Benson,
   Julie Drake
³ Lois Drew, B.A., Barbara Mendius, M.S.
⁴ Paula Ray, M.P.H., Ned Lewis, M.P.H., Bruce H. Fireman, M.A.
⁵ Jennie Jing M.A., Michael Wulfsohn, M.D., Ph.D.
⁶ Marlene M. Lugg, Dr.P.H., Patricia Osborne, M.S.
⁷ Suresh Rastogi, Ph.D., Peter Patriarca, M.D.; 
⁸ Vito Caserta, M.D., M.P.H.

Top of Page

Reprint Requests: Robert T. Chen, M.D., M.A., National Immunization Program (MS-E61), Centers for Disease Control and Prevention, Atlanta, GA 30333

Header: Vaccine Safety Datalink Project

Key Words: Vaccines, Immunization, Adverse Reactions, Databases, Record-Linkage, Vaccine Safety

Abbreviations:
CDC - Centers for Disease Control and Prevention
DTP - Diphtheria-Tetanus-Pertussis vaccine
Hib - Haemophilus influenzae type b vaccine
MMR - Measles-Mumps-Rubella vaccine
OPV - Oral Polio vaccine
HMO - Health Maintenance Organization
IOM - Institute of Medicine
LLDB - Large Linked Data Bases
GHC - Group Health Cooperative (of Puget Sound)
NWK - Northwest Kaiser
NCK - Northern California Kaiser
SCK - Southern California Kaiser
VAERS - Vaccine Adverse Event Reporting System
VSD - Vaccine Safety Datalink project

Abstract

Objective: To fill the large "gaps and limitations" in current scientific knowledge of rare vaccine adverse events identified in recent reviews of the Institute of Medicine.

Methods: Computerized information on immunization, medical outcomes, and potential confounders on over 500,000 children 0-6 years of age is linked annually at several health maintenance organizations to create a large cohort for multiple epidemiologic studies of vaccine safety.

Results: Analysis of 3 years of follow-up data shows that 549,488 doses of diphtheria-tetanus-pertussis (DTP) and 310,618 doses of measles-mumps-rubella (MMR) vaccines have been administered to children in the study cohort. Analyses for associations between vaccines and 34 medical outcomes are underway. Screening of automated data show seizures are associated with receipt of DTP on the same day (RR=2.1; 95% CI:1.1-4.0) and 8-14 days after receipt of MMR (RR=3.0, 95% CI:2.1-4.2). The diversity of vaccination exposures in this large cohort permits us to show that an apparent association of seizures 8-14 days after Haemophilus influenzae type b vaccine (RR=1.6, 95% CI:1.2-2.1) was attributable to confounding by simultaneous MMR vaccination; the association disappears with appropriate adjustment (RR=1.0; 95% CI:0.7-1.4).

Conclusion: Preliminary design, data collection, and analytic capability of the Vaccine Safety Datalink project has been validated by replication of previous known associations between seizures and DTP and MMR vaccines. The diversity in vaccine administration schedules permits potential disentangling of effects of simultaneous and combined vaccinations. The project provides a model of public health-managed care collaborations in addition to an excellent infrastructure for safety and other studies of vaccines.

Top of Page

Introduction
Immunizations are among the most cost-effective and widely used public health interventions.¹ The incidence rates of vaccine-preventable diseases in the United States and most countries worldwide² have decreased dramatically during recent decades (Table 1). No vaccine is perfectly safe, however. Increased vaccine use necessarily results in an increased number of true vaccine reactions as well as adverse medical events coincidentally associated with vaccinations.³ The number of both types of reports to the Vaccine Adverse Event Reporting System (VAERS) in the United States, approximately 10,000 per year, now exceeds the reported incidence of most vaccine-preventable childhood diseases combined (Table 1).

Since few vaccine-preventable diseases are currently eradicable, most immunizations must be continued indefinitely. One important way to minimize vaccine injuries is to improve our understanding of vaccine safety and thereby foster the development and use of safer vaccines.⁴ Close monitoring of vaccine safety should also help prevent the loss of public confidence in immunization programs and the subsequent resurgence of vaccine-preventable diseases, as experienced with pertussis in several countries^5-7 and more recently with diphtheria.⁸

Despite the importance of vaccine safety, the Institute of Medicine (IOM) recently found that serious "gaps and limitations" exist in both the knowledge and infrastructure needed to study vaccine adverse events.^9,10 Among the 76 types of vaccine adverse events reviewed by the IOM, the scientific evidence was inadequate to assess definitive vaccine causality for 50 (66%). The IOM also noted that "if research...[is] not improved, future reviews of vaccine safety will be similarly handicapped." These gaps in knowledge are attributable to several factors. Prelicensure controlled trials provide only limited safety data because of  their relatively small sample size, short duration, and population homogeneity. Postlicensure studies are therefore needed to provide a fuller understanding of the safety of vaccines in general use.⁴

Historically, postlicensure studies of safety have relied on passive surveillance systems such as VAERS.³ Because of methodologic weaknesses, such as the potential for biased reporting and under-reporting and lack of denominators or comparison groups, data from such case reports are usually not helpful in assessing risk or vaccine causality.⁴ Ad hoc retrospective epidemiologic studies of vaccine safety (eg, swine influenza vaccine and Guillain-Barré syndrome¹¹ and pertussis vaccine and encephalopathy⁵), although potentially informative about vaccine causality, are costly, time-consuming, and usually limited to assessment of a single event.

Recognizing the need to improve the capability to study vaccine safety, the Centers for Disease Control and Prevention (CDC) participated during the late 1980s in two pilot studies using large linked databases (LLDBs) of computerized vaccination and medical records.^12-14 These studies helped to validate the LLDB approach for vaccine safety studies. The need for a larger LLDB population for continuous assessment of vaccine safety prompted the CDC to initiate planning for the Vaccine Safety Datalink (VSD) project in 1989.¹⁵ This article provides an overview of the design of the VSD project and preliminary results, and reviews the prospects and the limitations of the VSD to address the vaccine safety issues identified by the IOM, as well as those of future vaccines.¹⁶

Vaccine Safety DataLink Project

Background
The need to improve post-licensure monitoring of drug safety became widely recognized after the thalidomide disaster.¹⁷ Faced with the methodologic limitations in passive surveillance for drug adverse events, pharmacoepidemiologists began during the 1980s to turn to LLDBs linking computerized pharmacy prescription and medical outcome records.¹⁸ These databases derive from defined populations such as members of health maintenance organizations (HMOs), single-provider health care systems, and Medicaid programs. Because the databases are usually generated in the routine administration of such programs and do not require completion of an vaccine adverse event reporting form, the problems of underreporting or recall bias are reduced. Because these programs have enrollees numbering from thousands to millions, large populations can be examined for relatively infrequent adverse events. Denominator data on doses administered and the ready availability of appropriate comparison groups are also very useful. Therefore, LLDBs can potentially provide an economical and rapid means of conducting postlicensure studies of safety of drugs and vaccines (Table 2).^19,20

Study Sites and Population
In 1991, the CDC began a partnership with four HMOs to evaluate vaccine safety in children in a large-scale prospective study. The HMOs include Group Health Cooperative (GHC) of Puget Sound in Washington, Northwest Kaiser (NWK) Permanente in Oregon, Northern California Kaiser (NCK), and Southern California Kaiser (SCK) Permanente Health Programs. These sites were chosen for their research experience and the existence of or willingness to create HMO-wide computerized vaccination databases for this project. Other Public Health Service agencies, including the Center for Biologics Evaluation and Research of the Food and Drug Administration and the Division of Vaccine Injury Compensation of the Health Resources and Services Administration, have been important contributors to this ongoing project.

The initial study focused on children 0-6 years of age but is being expanded to include adolescents and adults. To be eligible for the study, each child must be a member of the HMO, be within predefined age limits, live within the catchment area of a given site's participating clinics, and receive vaccine in a study clinic. The power to examine any particular vaccine and adverse event association within the VSD depends not only on the frequency of the vaccination but also the sensitivity and specificity of the case definition, the background rate for the event, and the magnitude of the risk. Previous LLDB studies reviewed adverse event experience after approximately 500,000 doses of diphtheria-tetanus-pertussis (DTP) vaccine in ten years. Our study accumulates similar exposure experience after two years. With time, we expect the VSD study should have adequate power to detect potential vaccine reactions with attributable risk of about 1 outcome per 100,000 vaccine doses (assuming a 3-dose vaccine, RR of 1.6, and background rate of 1.2 x 10^-5 to 1.6 x 10^-3). This magnitude of attributable risk is similar to that suggested by acute encephalopathy after whole-cell pertussis vaccination^5,9 or Guillain-Barré syndrome after swine influenza vaccination.¹¹

Top of Page

Data Collection
Health service use information for each patient is computerized and continuously compiled by each HMO indexed by an unique identifier. These data were initially used primarily for internal HMO administrative and clinical patient treatment purposes but has been adapted to this study. Data collection in a standardized VSD format began on March 1, 1991, for three HMOs (GHC, NWK, NCK) and October 1, 1992, for SCK. The data are organized into files containing demographic information, covariate information, vaccination records, and various types of medical outcomes data (Table 3). The automated outcome data are collected from various sources at each site, such as records of hospitalizations (all sites), emergency department visits (all sites), and outpatient clinic visits (GHC, NWK, NCK). Each site encodes their patients' clinical data with unique study identifiers before shipping the data to the CDC annually for merging and analysis, thereby preserving patient confidentiality. Institutional Review Boards at each HMO have approved this project in which only analyses with aggregate data are presented.

Vaccination Records
All vaccinations given within the HMO study population, either routinely or for special indications, are recorded and entered into a computer database. For all patients, automated data include: 1) the vaccine type, 2) the date of vaccination, and 3) concurrent vaccinations. For most patients, additional automated data available include whether vaccinations were obtained in or outside the HMO, as well as information required by the National Childhood Vaccine Injury Act of 1986:²¹ 1) the manufacturer, 2) lot number, and 3) site of vaccination.

Adverse Medical Events (Outcomes) of Interest
International Classification of Diseases (ICD)-9 codes for all hospitalizations and emergency department visits are compiled for the VSD study cohort. Automated diagnostic codes for routine outpatient clinic visits are currently available on approximately half of the cohort. This proportion will increase substantially as the HMO's switch to automated outpatient record systems. For initial study, the project identified 34 principal medical outcomes of possible association with vaccinations (Table 4) based on a thorough review of the literature and the IOM reports. In addition, the safety of certain vaccination practices are to be evaluated. These include simultaneous versus combined vaccination of various antigens and the relative adequacy of observation of contraindications to vaccinations. The list of research questions is amended yearly based upon evolving issues in the medical literature and new vaccination policy needs.

The 34 outcomes are identified in the medical outcomes files by one or more ICD-9 diagnostic codes. Additional outcome information is obtained from selected ancillary sources (eg, procedures, laboratory tests). These sources may be used both for case-finding and to supplement primary diagnostic codes. For example, positive blood cultures may enhance the accuracy of a discharge diagnosis of bacteremia. The case definitions for each of these 34 outcomes, consisting of one or more different ICD-9 and other diagnostic codes depending on source, have been determined iteratively and continue to evolve with the review of each year's analyses.

As a potential adverse event of immunization, death occurring soon (eg, 60 days) after vaccination is important to assess. However, deaths in children often occur in the home or outside of the routine health care system (eg, accident site or as the result of sudden infant death syndrome). Therefore, we maintain surveillance of state death reports in addition to monitoring hospitalizations and emergency department visits within the HMO. State death records are linked to LLDB cohort patients using probabilistic matching algorithm.²² Once identified, all deaths in study cohort patients are further validated by review of medical and autopsy records.

Potential Covariates
Factors that affect both vaccination status and incidence of medical events may confound observational studies of vaccine safety.²³ Therefore, we obtain from state birth certificate tapes relevant information, such as parental education and occupation, birth weight, and Apgar score. Similarly, additional information on socioeconomic status is obtained on the VSD study cohort by linking the zip codes and street addresses of the patients with their respective census tract block via "geocode".²⁴

Data Quality Control Procedures
To study potential rare associations between vaccines and adverse events, large and accurate databases are needed.²⁵ Routine procedures for assuring quality of HMO databases vary by type of database and HMO. Inpatient databases are important for hospital and financial management; therefore, data quality is high because of staff training, standardized coding protocols, reliability monitoring, and routine audits. Both routine data quality audits required by hospital accrediting agencies and special audits conducted by other research projects have found inpatient databases to be complete and accurate.²⁶ Drug, laboratory, radiologic, and referral databases are user-based data that involve clinical and administrative data essential for delivery of medical services. Such information is constantly monitored for accuracy and is used in other research projects.²⁷

In addition to routine quality checks for each of the databases, a random 2% sample of the study populations (1% at the larger sites: NCK and SCK) is selected periodically to review the quality of automated vaccination and diagnostic data. For these samples, vaccination and diagnostic data are abstracted from the medical records and compared with the automated data. Preliminary data from the first year of VSD found nearly perfect agreement between automated and abstracted hospital discharge diagnoses.²⁸ The percentage agreement between the dates of the abstracted and automated emergency department diagnoses ranged from 60% to 87%. The percentage agreement between abstracted and automated vaccination dates ranged from 70% to 98% across vaccines (with the exception of DT) and HMOs. The primary source of disagreement was the incomplete entry of all vaccinations into the database. Continuous feedback to HMOs are provided to identify potential means of improving the quality of the automated data.

Analytic Strategy
Inference that a vaccine causes an adverse event may be drawn if higher rates are consistently observed among vaccinees compared with nonvaccinees, especially if results are consistent for the different HMOs and over several study years. Because of  high vaccine coverage within the HMOs, for most outcomes of interest, there are too few unvaccinated persons, and those not vaccinated may not constitute a representative comparison group for epidemiologic analyses. Alternatively, an analysis of "risk interval" is used (Table 2). For each outcome of interest, time intervals after vaccination are selected during which an adverse event would be expected if an association exists. These intervals are defined a priori based on biological and clinical considerations. For the study population, incidence rates of adverse events within and outside the specific risk interval for the study population are then compared using appropriate statistical methods, after controlling for potential confounders.

Several statistical analytical designs are used in the VSD study to compare incidence rates, depending on the accuracy and the completeness of the automated data. If the quality of the automated data for an outcome of interest is high, multivariate cohort methods (eg, Poisson or proportional hazards regression) are used. Otherwise, the automated records will require validation by medical record review for all persons suspected of having the outcome. Similar validation of the medical records of the random 1% to 2% of the study population selected for quality control assessment permits a more efficient means of providing the comparison group for a case-cohort analysis.²⁹ Validation studies employing nested case-crossover³⁰ or case-control methods may also be done in parallel or sequentially, especially if a previously unknown association is detected. The medical records of cases, or cases and controls (also selected from the 1% to 2% samples if possible), will be thoroughly reviewed and children or their parents may be interviewed to identify other potential confounders.

Top of Page

Results

Descriptive Epidemiology
Because each HMO has its own set of medical and operating procedures, much of the first 2 years of the VSD study was devoted to developing protocols to standardize prospective data collection across sites. NCK and SCK incrementally expanded their automated vaccination registries throughout the HMOs. Consequently, the annual study population under surveillance grew from approximately 181,000 in 1991 to approximately 502,000 children younger than 7 (approximately 2% of the U.S. population in these age groups) by late 1995, encompassing 1,862,000 child-years of observation. Complete vaccination and other medical records are available now on a cohort of 242,000 children born into the study, which will grow by about 63,700 children annually. The 10 most common vaccines and vaccine combinations administered to the cumulative study cohort by late 1994 are shown in Table 5.

Figure 1 plots the vaccine coverage for specific vaccines by age for the VSD cohort. The delay between the recommended age for a vaccine dose and when 80% of the cohort actually receives it increases for older children. The lowest coverage of routine childhood vaccinations in the cohort was for hepatitis B (universal recommendations began after the start of the study) and the second dose of measles vaccine (administered at primary school entry at two HMOs and secondary school entry at the others). The highest coverage was for polio vaccination, exceeding pertussis-containing vaccines by about 5% to 10%; this may measure the proportion of children with concerns about the safety of pertussis vaccines.

The simultaneous administration of multiple vaccines is very common. For example, when children younger than 6 months in our study received DTP vaccine, 97% of them also received Haemophilus influenzae type b conjugate vaccine (Hib) at the same visit. Thus, at certain ages it is difficult, if not impossible, to differentiate the possible effects of certain vaccine combinations. The vaccination schedules at the four HMOs are not identical, however, and this provides opportunities for separating the possible adverse effects of some vaccine combinations. For example, in the second year of life, one HMO gives DTP-Hib-OPV-MMR at the same visit, whereas the other three sites commonly give MMR-Hib at one visit and DTP(or DTaP)-OPV at a later visit.

Analytical Studies
Other studies have shown that both DTP and MMR vaccines are associated with febrile seizures,^9,10,14 and this relationship was explored in the VSD study to illustrate its analytic capabilities. As it is difficult to differentiate between febrile and other types of seizures without chart review, we analyzed all seizure types combined with the automated data. Using a Cox regression model stratified by HMO and birthdate (children born in 3-day blocks), the relative rate of seizures in specific time windows after receipt of vaccine (same day, 1-3, 4-7, 8-14, and 15-30 days) was compared to periods before and more distant to the receipt of vaccine. Elevated rates of seizures, presumably mostly febrile, were found for both DTP and MMR, consistent with each vaccine's respective modes of biologic action (Figure 2). The risk varied for different periods after immunization. The risk of seizures after MMR, a live viral vaccine requiring a longer incubation period for viral replication, was delayed compared to DTP, a killed bacterial vaccine.

To examine the capability of the VSD cohort to differentiate the effects associated with simultaneous administration of vaccines, we examined the association between seizures and the administration of Hib and MMR vaccines. On crude analysis, a possible association was found 8 to 14 days after vaccination with both Hib (RR=1.4; 95% CI: 1.2-1.8) and MMR (RR=2.3; 95% CI:1.9-2.9) vaccines. Prior experience suggests that the association with Hib may be an artifact of the frequent coadministration of Hib with MMR during the second year of life and not a true association with Hib. Since the two vaccines are also frequently administered separately, we were able to adjust our analysis via regression to show that there is in fact no association between Hib and seizures (RR=0.9; 95% CI: 0.7-1.2), whereas the association with MMR persisted (RR=2.42; 95% CI: 1.8-3.2).

On screening of automated data, we found 8-14 days after immunization an apparent association between measles vaccine and invasive bacterial disease (RR=2.3; 95% CI: 1.1-4.6). This association was not validated by chart review, because the exposed cases were found to have undergone evaluation of fever of unknown origin (possibly caused by the vaccine) but did not actually have culture-proven sepsis. This example shows that the ICD-9 codes selected for this outcome had the desired high sensitivity for surveillance purposes, but needed validation.

Ad Hoc Studies
In addition to the planned vaccine safety studies, the infrastructure created by the VSD project permits timely investigation of new hypotheses. For example, when changes in vaccine policy are considered, it is often necessary to develop new information to evaluate such a potential change. The Advisory Committee on Immunization Practices recently considered lowering the age of the tetanus-diphtheria (Td) booster from 14-16 years of age to 10-12 years of age. However, information on the safety of the Td vaccine booster dose given to a younger age group was lacking. In the VSD study, we identified cohorts of 12,626 and 3,379 children in the two age groups, respectively, who had received Td boosters. Comparison of rates of emergency department and hospital use within 7, 14, and 30 days after Td showed some differences between the two groups, which disappeared when visits for trauma and suture removal are excluded (Table 6), supporting the safety of this schedule change. This analysis further illustrates the importance of adjusting for potential confounders in VSD studies. In this case, age itself effected rates of emergency room use independent of Td use.

Top of Page

Discussion
Vaccines are generally administered to healthy persons, frequently infants and children. Therefore, the acceptable risk of adverse reactions to vaccines is lower than that for therapeutic agents for ill persons. This lower tolerable risk translates into the need to conduct studies to detect rare reactions (eg, attributable risks on the order of 1 per 10⁵-10⁶ doses).⁴ Studies able to address such rare risks are possible only after licensure and general use, and they are large and expensive and may not provide conclusive results. For example, the National Childhood Encephalopathy Study was a case-control study that aimed to detect all hospitalizations in England and Wales for acute neurological illness in children 2 to 35 months of age over a 3-year period.⁵ The study findings were controversial, because the conclusion was based on only 7 cases of chronic encephalopathy observed within 3 days of DTP vaccination.³² These difficulties plus the limitations of passive surveillance^3,4 largely account for the relative sparsity of data on vaccine safety in the recent IOM review.^9,10

In recent years, developments in health care organization, health information systems, and pharmacoepidemiology methods have improved our capability to study rare drug reactions.¹⁸ Walker et al¹² and Griffin et al¹³ pioneered the use of such record linkage studies to evaluate vaccine safety. These studies were limited, however, by their relatively small sample sizes, retrospective design, and focus on the most severe reactions.⁹ The VSD study attempts to overcome these shortcomings by prospective collection of vaccination, medical outcome, and covariate data under joint protocol at multiple sites. Selection of prepaid health plans also minimized potential biases resulting from data generated from fee-for-service claims. Substantial efforts have been required to implement accurate automated vaccination record systems for our cohort, which represents approximately 2% of the children in the United States. A list of key research questions and how best to answer them within the VSD has been elaborated. Quality control procedures and methodologic approaches have also been developed. After all this development, does it work?

Although much remains to be done to improve the VSD, the early results are promising. Previously known associations between seizures and DTP and MMR vaccines have been validated in the prospective VSD cohort. This provides validation of the design, data collection, and analytic approaches of this project. The medical charts for many children with seizures identified from automated records are being abstracted. This will permit an evaluation of the accuracy of the automated system for a rigorous case-control analysis to distinguish between possible vaccine causation of first and subsequent seizures, as well as to characterize the types of seizures (eg, febrile versus other) associated with vaccinations.

In addition to studies to assess potential hypothesized vaccine associations, new ad hoc questions that arise from VAERS, from changes in immunization schedules (eg, new vaccines such as varicella or use of simultaneous vaccination) or from screening level cohort analyses in the VSD, can be addressed in a timely manner. For example, in response to concerns regarding a potential increased risk of arthropathy in adult women following rubella vaccination,³³ the VSD database was used to identify a cohort of women who had rubella immunity testing during pregnancy and their subsequent rubella immunization status. In a retrospective review of the women's charts, no association of any chronic arthritic condition was found with receipt of rubella vaccine.³⁴ The potential association between hepatitis B vaccination at birth and suspected neonatal sepsis work-up is being examined in another VSD study.

Each of the core databases created by the project (eg, vaccinations, medical outcomes, and potential covariates) have valuable applications. Each HMO in the VSD study uses its automated immunization records to set goals for improvement in vaccine coverage levels.^35,36 Children, clinics, and practices with inadequate immunization can be easily identified and strategies developed to improve coverage. Research into barriers, missed opportunities, and recall systems for immunization have been performed.³⁷ Documentation for school- entry immunization requirements is also easily retrievable. These records have been used to calculate the level of childhood immunizations as of the second birthday included as quality measures in the Health Plan Employer Data and Information Set (HEDIS).^38,39 Finally, the VSD databases provide excellent bases for construction of broader regional immunization registries.⁴⁰

Studies of many other pediatric illnesses via the VSD are also possible. Taking advantage of the cohort infrastructure created, plans are underway to expand the VSD study to examine: 1) vaccine safety issues in adolescents and adults, 2) the impact of vaccination programs on incidence of vaccine-preventable disease (eg, new varicella vaccine), 3) cost-effectiveness of specific vaccines, and 4) safety and immunogenicity of new combined vaccine schedules in prospective Phase II and III clinical trials nested within the cohort.⁴¹

The diversity in vaccination practice at the four HMOs and the clinic-to-clinic and day-to-day variations in practice permit useful contrasts in safety experiences. A study contrasting the safety of the second dose of measles vaccine administered at entry to primary school (as recommended by the Advisory Committee on Immunization Practices) versus entry to secondary school (as recommended by the American Academy of Pediatrics) is currently underway. As demonstrated by the Hib, MMR, and seizure example, the size of the VSD population may also permit separation of the risks associated with individual vaccines from those associated with vaccine combinations, whether given in the same syringe or simultaneously at different body sites. Such studies will be especially valuable in view of the new combined pediatric vaccines currently in development.⁴²

Should the VSD study identify a vaccine reaction, data on attributable risk will be available, thereby permitting accurate risk-benefit assessment by both the public and policymakers.⁴³ Subgroup analyses may permit identification of risk factors, which may be useful in identifying contraindications to vaccinations. Research may then be launched to understand the pathogenesis of the reaction in these individuals, potentially leading to the development of safer vaccines. The incidence rates of reactions identified in VSD should permit the evaluation and improvement of passive surveillance systems such as VAERS. The VSD data will also be invaluable to other Public Health Service agencies sharing responsibility for vaccine safety. The Food Drug Administration, in fulfillment of its regulatory responsibilities, is interested in potential product-specific differences in the vaccine safety profiles. The results of the VSD will also substantially enlarge the scientific basis for deciding whether to recommend compensation in alleged vaccine injury cases fundamental to a fair and efficient vaccine injury compensation program.⁴⁴

Amid these promises, a few caveats are appropriate. Although diverse, the population in the four HMOs currently in the VSD is not wholly representative of the United States. in terms of geography or socioeconomic status. With current changes in health care organization and additional resources, it may be possible to broaden the scope of the VSD. In the interim, there is little reason to believe that these factors significantly influence the risk of vaccine reactions. More importantly, because of the high rate of vaccine coverage attained in the HMOs, few nonimmunized controls are available. The VSD must therefore rely predominantly on some type of risk interval analysis. The capability of this approach to assess associations between vaccination and adverse events with delayed or insidious onset (eg, autism) is limited. Similarly, the ability of the VSD to fully distinguish effects of combined or simultaneous vaccination may be limited should such practices become universal.

The VSD also cannot easily assess adverse events not currently captured in existing HMO databases, either because they do not result in a health care consultations or because the data are not automated. Important nonautomated data sources relevant to the VSD study (eg, results of neurologic consultations) have required manual abstraction, coding, and computerization. The patient enrollment, health care practices, and health information systems at each HMO are dynamic, which may either aid or impede study of specific outcomes. Coding errors occurs inevitably in all data files to some extent, resulting in a decrease in our ability to detect a true association. The current VSD is also unable to examine the risk of extremely rare events after infrequent vaccinations, such as Guillain-Barré syndrome after each season's flu vaccine. Because the VSD relies on epidemiologic methods, it may not successfully control for confounding and bias in each analysis²³ and inferences on causality may be limited. Finally, even if findings from the VSD may often be "negative," (ie, show no elevations in risks in association with vaccination), one cannot absolutely "disprove" an alleged reaction.^10,45

Despite these potential shortcomings, the VSD provides a new, essential, powerful, and cost-effective complement to our ongoing evaluations of vaccine safety in the United States. The capability of VSD for reliable and consistent ascertainment should reassure the public of the adequacy of the surveillance for significant vaccine adverse events and the general safety of routine vaccine products. Enhanced public confidence is integral to maintaining or improving rates of vaccine acceptance at a time of rapid changes in vaccine schedule⁴⁶ and introduction of new vaccines.¹⁶

Top of Page

References

¹ World Bank. World Development Report 1993: Investing in Health. New York: Oxford University Press; 1993.

² Expanded Programme on Immunization. Global Advisory Group - Part 1. Weekly Epidemiological Record. 1994;69:21-27.

³ Chen RT, Rastogi SC, Mullen JR, et al. The Vaccine Adverse Event Reporting System (VAERS). Vaccine. 1994;12:542-550.

⁴ Chen RT. Special methodological issues in pharmacoepidemiology studies of vaccine safety. In: Strom BL, ed. Pharmacoepidemiology. Sussex, United Kingdom: John Wiley & Sons; 1994.

⁵ Miller DL, Alderslade R, Ross EM. Whooping cough and whooping cough vaccine: the risks and benefits debate. Epidemiol Rev. 1982;4:1-24.

⁶ Krantz I, Taranger J, Trollfors B. Estimating incidence of whooping cough over time: a cross-sectional recall study of four Swedish birth cohorts. Int J Epidemiol. 1989;18:959-963.

⁷ Kimura M, Kuno-Sakai H. Developments in pertussis immunisation in Japan. Lancet. 1990;336:30-32.

⁸ Galazka AM, Robertson SE, Oblapenko GP. Resurgence of diphtheria. Eur J Epidemiol. 1995;11:95-105.

⁹ Howson CP, Howe CJ, Fineberg HV, eds. Institute of Medicine. Adverse effects of pertussis and rubella vaccines: A report of the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines. Washington, D.C.: National Academy Press; 1991.

¹⁰ Stratton KR, Howe CJ, Johnston RB, eds. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington D.C.:National Academy Press; 1994.

¹¹ Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barré syndrome following vaccination in the national influenza immunization program, United States, 1976-1977. Am J Epidemiol. 1979;110:105-123.

¹² Walker AM, Jick H, Perera DR, et al. Diphtheria-tetanus-pertussis immunization and sudden infant death syndrome. Am J Public Health. 1987;77:945-951.

¹³ Griffin MR, Ray WA, Fough RL, et al. Monitoring the safety of childhood immunization: methods of linking and augmenting computerized data bases for epidemiologic studies. Am J Prev Med. 1988;4 (suppl): 5-14.

¹⁴ Walker AM, Jick H, Perera DR, et al. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatrics. 1988;81:345-349.

¹⁵ Wassilak SGF, Glasser JW, Chen RT, Black S, Mullooly JP, Thompson RS. Design of a multicenter study of adverse events following vaccination in childhood, J Clin Res Pharmacoepidemiol. 1991;5:294. Abstract

¹⁶ Frontiers in medicine: vaccines. Science. 1994;265:1371-1404.

¹⁷ Karch FE, Lasagna L. Adverse drug reactions. JAMA. 1975;234:1236-1241.

¹⁸ Strom BL, Carson JL. Use of automated databases for pharmacoepidemiology research. Epidemiol Rev. 1990;12:87-107.

¹⁹ Farrington CP, Pugh S, Colville A, et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet. 1995;345:567-569.

²⁰ Roberts JD, Roos LL, Poffenroth LA, et al. Surveillance of vaccine-related adverse events in the first year of life: A Manitoba cohort study. J Clin Epidemiol. 1996;49:51-58.

²¹ Centers for Disease Control. National Childhood Vaccine Injury Act: Requirements for Permanent Vaccination Records and for Reporting of Selected Events after Vaccination. MMWR. 1988;37:197-200.

²² Griffin MR, Ray WA, Livengood JR, et al. Risk of sudden infant death syndrome following diphtheria-tetanus-pertussis immunization. N Engl J Med. 1988;319:618-623.

²³ Fine PEM, Chen RT. Confounding in studies of adverse reactions to vaccines. Am J Epidemiol. 1992;136:121-135.

²⁴ Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health. 1992;92:703-710.

²⁵ Mullooly J. A misclassification model for person-time analysis of automated medical care database. Am J Epidemiol. 1996;144:782-92.

²⁶ Institute of Medicine. Reliability of National Hospital Discharge Survey Data. Report of a Study. Washington, DC: National Academy of Sciences, 1980.

²⁷ Fox LA, Stearns G, Imbiorski W, eds. The Administrator's Guide to Evaluating Records and the Medical Records Department. The Beacon Group. Chicago, IL: Care Communications; 1979.

²⁸ Mullooly JP, Black S, Thompson RS, Glasser JW, Chen RT and Rhodes P. Quality of Large, Linked HMO Databases: Estimation and Correction of Misclassification Bias in Screening Analyses of Childhood Vaccine Safety. Pharmacoepidemiolgy and Drug Safety 1994;3:S32. Abstract.

²⁹ Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika. 1986;73:1-11.

³⁰ Farrington CP, Nash J, Miller E. Case series analysis of adverse reactions to vaccines: a comparative evaluation. Am J Epidemiol. 1996;143:1165-73.

³¹ Griffin MR, Ray WA, Mortimer EA, et al. Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine. JAMA. 1990;263:1641-1645.

³² Marcuse EK, Wentz KR. The NCES reconsidered: summary of a 1989 workshop. Vaccine. 1990;8:531-535.

³³ Mitchell LA, Tingle AJ, Shukin R, Sangeorzan JA, McCune J, Braun DK. Chronic rubella vaccine-associated arthropathy. Arch Int Med. 1993;153:2268-2274.

³⁴ Ray P, Black S, Shinefield H et al. Retrospective cohort evaluation of chronic rubella vaccine arthropathy. Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC:American Society for Microbiology. 1994:240 [abstract].

³⁵ Davis R, Vadheim C, Black S, Shinefield H, Chen R, et al. Immunization tracking systems: experience of the CDC Vaccine Safety Datalink Sites. HMO Practice 1997;11:13-17.

³⁶ Payne T, Kanvik S, Seward R, et al. Development and validation of an immunization tracking system in a large health maintenance organization. Am J Prev Med. 1993;9:96-100

³⁷ Lieu T, Black S, Sorel M, et al. Missed opportunities for immunization in a HMO. Am J Public Health. 1994;84:1621-1625.

³⁸ Lieu TA, Black SB, Sorel ME, Ray P, Shinefield HR. Would better adherence to guidelines improve childhood immunization rates? Pediatrics. In press.

³⁹ Thompson RS, Taplin SH, McAfee TA, Mandelson MT, Smith AE. Primary and secondary preventive services in clinical practice. JAMA 1995;273:1130-1135.

⁴⁰ Cordero JF, Guerra FA, Saarlas KN, eds. Developing immunization registries: experience from the All Kids Count Program. Am J Prev Med 1997;13(Suppl 1): 1-128.

⁴¹ Centers for Disease Control and Prevention. Request for Proposals No. 200-95-0947(P) Comprehensive Linked Data Collection of Medical Events and Immunization (Vaccine Safety and Development Datalink); 1995.

⁴² Williams JC, Goldenthal KL, Burns DL, Lewis BP Jr, eds. Combined vaccines and simultaneous administration: current issues and perspective. New York: New York Academy of Science; 1995.

⁴³ Hinman AR, Orenstein WA. Public health considerations. In: Plotkin SA, Mortimer EA, eds. Vaccines. Philadelphia: WB Saunders, 1994:903-32.

⁴⁴ Evans G. Vaccine liability and safety: a progress report. Pediatr Infect Dis J 1996:15:477-8.

⁴⁵ Rothman KJ, ed. Causal inference. Chestnut Hill, MA: Epidemiology Resources, Inc; 1988.

⁴⁶ Centers for Disease Control and Prevention. Recommended childhood immunization schedule - United States, January-June 1996. MMWR. 1996;44:940-943.

Top of Page

Table 1.
Comparison of Maximum and Current Reported Morbidity from Vaccine-Preventable Diseases and Vaccine Adverse Events, United States

Pre-Vaccine era

* Provisional, subject to change due to late reporting
+ Estimated because no national reporting existed in prevaccine
   era.
++ This indicates the major increase in vaccine adverse events.

Top of Page

Table 2.
Example of Method for Risk-interval Analysis of Association Between a Universally Recommended 3-Dose Vaccine (with Few Unvaccinated Persons for Comparison) and Adverse Event: Vaccine Safety Datalink Project

1. Define "risk interval" for adverse event after vaccination (eg, 30 days after each dose).
2. Partition observation time for each child in the study into periods within and outside of risk intervals, and sum respectively. (e.g., for a child observed for 365 days during which 3 doses of vaccine were received; total risk interval time = 3 x 30 person-days = 90 person-days; total non-risk interval time = 365 - 90 = 275 person-days).

o-----------x====--------x====----------x====------//------>|

Birth           Dose 1           Dose 2              Dose 3       365 days

3. Add up a) total risk interval and non-risk interval observation times for each child in the study ( = Person-Time Observed; for mathematical convenience, example below uses 100 and 1000 person-months of observation), and b) adverse events occurring in each time period to complete 2x2 table (for illustration, example below uses 3 and 10 cases):

Incidence rate adverse event _vaccinated = 3/100 = 0.03
Incidence rate adverse event _unvaccinated =10/1000 = 0.01
Relative Risk vaccinated: unvaccinated = 0.03/0.01 = 3.0
Probability finding due to chance: <5/100

Conclusion: There is a 3-fold increase in risk for developing the adverse event within the interval following vaccination.

Top of Page

Table 3.
Data files created for Vaccine Safety Datalink Project

* Each study site obtains the necessary information for files from unique, site-specific administrative databases for health care delivery.

Top of Page

Table 4.
Outcomes of Primary Interest In Initial Evaluation of Vaccine Safety Datalink Project

Top of Page

Table 5.
Ten Most Common Vaccine and Vaccine Combinations Administered:  Vaccine Safety Datalink Project*

Analysis of first 3 years' data
**Whether used alone or administered simultaneously with 
    other vaccine(s).
+ "+" between vaccine denotes simultaneous administration at
    different sites.

Top of Page

Table 6.
Rates of Hospitalization and Emergency Room Visits After Tetanus-Diphtheria (Td) Toxoid Vaccination by Age: Vaccine Safety Datalink Project

* Rate per 1000 person-years
+ Excluding visits for trauma and/or suture removal

This page last modified on January 11, 2000