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Immunization Issues

Vaccine Safety Datalink

Updated: 04/21/2005

Vaccine safety monitoring is conducted both before and after a vaccine is licensed. Prelicensure trials typically involve thousands to tens of thousands of participants. Common adverse events can be identified by comparing the incidence of those events in vaccine recipients with the incidence rate in placebo recipients. A rate significantly higher in the vaccine recipients is supportive of vaccine playing a causal role in the illness.

However, adverse events that are rare (for example, 1 in 10,000 or lower) may not be detected because the numbers of participants in the prelicensure trials are not large enough to find these rare events. (1) For example, to identify a rare adverse event that occurs 1 time per every 10,000 vaccinees may require 30,000 vaccinees plus 30,000 controls or more. (2)

Postlicensure or postmarketing evaluation of vaccine safety is done through passive reporting systems such as the Vaccine Adverse Event Reporting System (VAERS) or non passive systems such as the Clinical Immunization Safety Assessment (CISA), as well as large linked databases, such as the Vaccine Safety Datalink (VSD) project.

The VSD project was created in 1990 by the Centers for Disease Control and Prevention (CDC) and currently involves partnerships with 8 large health maintenance organizations (HMOs) to continually monitor vaccine safety. (3)

The VSD is a large-linked database that is used to analyze vaccine related information pertaining to more than seven million people affiliated with the partner HMOs. The HMOs include Group Health Cooperative of Puget Sound in Washington, Northwest Kaiser Permanente in Oregon, Northern California Kaiser, Southern California Kaiser Permanente health programs, Marshfield Clinic, Kaiser Permanente Colorado, Health Partners Healthcare Minneapolis, and Harvard Vanguard. (4)

Although originally the VSD surveyed only children between 0 and 6 years of age, it has been expanded to include information on adolescents and adults.

The VSD database allows researchers to access already gathered data on:

  • vaccine type 
  • date of vaccination 
  • concurrent vaccinations (those given during the same visit) 
  • the manufacturer 
  • lot number 
  • injection site  
  • potential adverse events (3)

The VSD has several advantages over other methods of post-licensure vaccine safety monitoring. First, it is a comprehensive medical database. All or almost all significant medical encounters should be in the available information. Thus, the VSD does not rely on a physician or parent recognizing that a given clinical illness might be related to vaccine and making a report. All medical illnesses whether vaccine related or not are already in the data base.

Second, all or almost all information on vaccination is also available. Thus, investigators can determine the most valid incidence rate of an illness following vaccination. Most importantly, the VSD allows the comparison of the incidence rate of a given clinical illness after vaccination with the incidence of the same event among unvaccinated individuals. Significantly higher rates after vaccination are supportive of a potential causal role for the vaccine in the illness. On the other hand, if the rates are similar between vaccinees and nonvaccinees, the vaccine is unlikely to be playing a causal role in the event. Neither VAERS nor CISA has the capacity to make these types of comparisons.

Further, when there is concern that a vaccine may be causing an illness in a certain time frame after vaccination, the incidence during this period can be compared with the incidence at other times to see if it is significantly higher in the period of concern. Finally, the electronic records of diagnoses can be validated through actual review of the medical charts to assure the information is as accurate as possible.

Thus, the VSD allows researchers to plan vaccine safety studies and examine hypotheses generated from the medical literature, study possible signals from the passive VAERS program, and evaluate changes in the immunization schedule or from the introduction of new vaccines. (3)

For example, VSD data were used to study the rate of Sudden Infant Death Syndrome (SIDS) after anecdotal evidence suggested a possible link to the DTP vaccine. The risk of SIDS was found to be the same for vaccinated children as for unvaccinated children enrolled in the participating health maintenance organizations. (5)

Over 30 studies have used or are using the VSD to examine vaccine safety issues, including the safety of inactivated influenza vaccine among children, and the relation between immunizations and conditions such as asthma and neonatal death. (6, 7)

The VSD project, however, has some limitations:

  • The population in the participating HMOs is not wholly representative of the United States in terms of geography and socioeconomic status. 
  • Vaccine coverage rates for most vaccines are very high in the participating HMOs, and thus few nonvaccinated controls are available to do a comprehensive comparison. 
  • The VSD cannot easily assess mild adverse events that may escape medical attention such as fever. 
  • The project is not large enough to examine the risk of extremely rare events (such as 1 in a million vaccinees) such as Guillain-Barré Syndrome after each influenza season. (3
  • Because the database contains clinical information, it can only be accessed under circumstances which maintain patient confidentiality. (8)

Despite the above caveats, the VSD project is a powerful and cost-effective tool for the constant monitoring of vaccine safety. Studies performed using these data sets—along with many other studies—were used by the Institute of Medicine’s Vaccine Safety Review of thimerosal and autism to favor the rejection of a cause-effect relationship.


1. Chen RT, Davis RL and Sheedy KM (2004). Safety of Immunizations. In: Plotkin SA, Orenstein WA (Eds). Vaccines (4th Edition, chapter 61). Philadelphia, PA: W.B. Saunders Company.

2. Jacobson RM, Adegbenro A, Pankratz VS and Poland GA. Adverse events and vaccination-the lack of power and predictability of infrequent events in pre-licensure study. Vaccine, 2001;19(17-19):2428-2433. 

3. CDC National Immunization Program (2004). Vaccine Safety Data-Sharing Process. 

4. Chen RT, Glasser J, Rhodes P, et al (1997). The Vaccine Safety Datalink Project: A New Tool for Improving Vaccine Safety Monitoring in the United States. Pediatrics, 99:765-73. 

5. Institute of Medicine. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: National Academies Press 2003. 

6. DeStefano F, Gu D, Kramarz P et al (2002). Childhood vaccinations and risk of asthma. Pediatric Infectious Diseases Journal, 21(6):498-504.

7. Eriksen EM, Perlman JA, Miller A et al (2004). Lack of Association between Hepatitis B Birth Immunization and Neonatal Death: A Population-Based Study from the Vaccine Safety Datalink Project. The Pediatric Infectious Disease Journal, 23(7):656-662.

8. Institute of Medicine. Vaccine Safety Research, Data Access, and Public Trust. Washington, DC: National Academies Press 2005. 

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