PEDIATRICS Vol. 121 No. 3 March 2008, pp. 625-626 (doi:10.1542/10.1542/peds.2007-3846)
COMMENTARY |
Toward Better Vaccine Safety Data and Safer Vaccination
Division of Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration
In 1994 the Institute of Medicine's Vaccine Safety Committee concluded that "the evidence establishes a causal relation between measles-mumps-rubella vaccine (MMR) and thrombocytopenia. On the basis of data from Finland and Sweden, the incidence seems to be on the order of 1 per 30 000 to 40 000 vaccinated children.1" Although data available at that time were not optimal, the Committee's conclusions have stood the test of time and are supported by the accretion of evidence in subsequent studies, including the study by France et al published in this issue of Pediatrics2 that found an attributable risk of 1 case of immune thrombocytopenic purpura (ITP) per 40 000 doses of MMR administered in the second year of life. Given that the annual US birth cohort is >4 million and that the first dose of MMR is routinely recommended by the Centers for Disease Control and Prevention (CDC) early in the second year of life, then 
100 cases of ITP per year would be attributable to MMR vaccination in the United States' setting of nearly universal immunization with this vaccine.
Current evidence does not suggest substantial clinical differences between ITP after MMR vaccination and ITP due to other causes. ITP is frequently treated with corticosteroids and/or intravenous immunoglobulin, and then the condition usually resolves. Chronic ITP occurs in a small percentage of cases, 2 of 20 ITP cases post-MMR among children 12 to 23 months of age in the study by France et al.2 Hemorrhages requiring blood transfusion occur rarely, and reports of intracranial hemorrhage or death are very rare.3–6
The study by France et al used data from the CDC's Vaccine Safety Datalink. This innovative project began in the early 1990s and is an invaluable and essential pillar of the US system to monitor the safety of licensed vaccines.7 An early contribution of the project was the establishment of a central repository for accumulating data on patients that could be queried to answer questions of clinical and public health significance. In recent years, the large databases have not resided at the CDC. Instead, each of the member managed care organizations stores its own data and shares summary tables or analyses centrally. The data are composed of medical claims information and, increasingly, electronic medical records. Since 2005, the project has made significant strides and undertaken routine rapid safety assessments, called "rapid cycle analyses," of new vaccines postlicensure.8 The Vaccine Safety Datalink has also been an early adopter of powerful and clever novel analytic techniques, used in the France et al study and others. Techniques such as the self-controlled case series approach, in which each case acts as its own control, have the particular strength of eliminating confounding by variables that do not vary among the time intervals compared in the study. The value of the Vaccine Safety Datalink can be appreciated by noting its contributions to addressing important safety issues such as intussusception after Rotashield vaccination9 and the risk of seizures after MMR or whole-cell pertussis vaccine.10 Another extremely valuable contribution of the Vaccine Safety Datalink is that it provides a mechanism to conduct preliminary assessments of vaccine safety concerns much more rapidly than formal studies can be mounted. Examples of such concerns include Rotashield vaccine and intussusception11 or meningococcal conjugate vaccine and Guillain-Barre syndrome.12 These preliminary assessments can be of great assistance to public health policy decision makers.
The Vaccine Safety Datalink can be seen as a model program and paradigm for the larger field of drug safety studies. It has been cited in the Food and Drug Administration Amendments Act of 2007 as a complementary approach to the envisaged postmarket risk identification and analysis system that would have data from over 100 million patients available for study.13 The medical care experiences of 5.5 million people included in the Vaccine Safety Datalink databases may at first seem sufficient in number for virtually all study purposes, but actually more data are necessary to provide definitive answers to important questions about rare events such as whether there is an association between the meningococcal conjugate vaccine and Guillain-Barre syndrome. The ability to study the experiences of substantially larger numbers of individuals than is now possible, as called for in the recently enacted Food and Drug Administration Amendments Act of 2007, is essential to answering some of the current and future key safety questions in the realm of vaccine and drug safety. Although establishment of such a large postmarket risk identification and analysis system will mark an important step forward, studies based on such data still have limitations and should always be carefully designed, analyzed and interpreted to minimize the potential for bias and confounding from various sources; in addition, validation of computerized data by examining medical charts is often important.14
What is the etiology of postvaccination ITP? Given that ITP has been associated with both wild type measles and rubella infections,15 it is reasonable to infer a role for the vaccine in the pathogenesis of this condition. Thus, in effect, MMR is not fully attenuated with regard to ITP. Although the vast majority of ITP cases resolve without sequelae, the rare serious and even rarer fatal adverse events raise several questions: 1) What are the immunogenetic causes of ITP after MMR, as well as after measles and rubella? Basic science and clinical work on this question may lead to better understanding of ITP, including the vast majority of ITP that is unrelated to vaccination. 2) Could MMR-associated ITP be prevented by identifying those at risk, for example if there were genetic predisposition that could be identified through genomic studies? 3) Might it be feasible to engineer a safer vaccine? Although the benefits of MMR vaccine clearly exceed its risks, there remains potential room for improvement.
Multiple hypothetical associations of immunization with diseases believed to involve immune dysregulation have not been confirmed by rigorous studies; examples include type 1 diabetes and multiple sclerosis. In contrast, ITP is an autoimmune disease that can rarely be triggered by MMR and possibly by multiple other causes. Focusing 21st century science on MMR vaccine-associated cases of ITP may help us better understand, prevent or treat both MMR-related and other cases of ITP. Comparison of individuals who have developed post MMR ITP with other individuals who have not, coupled with the collection of biological specimens (eg, blood, genetic material), could lead to significant progress in understanding potential genetic, immunologic, and environmental factors that alone or in combination may have causal roles. It also might ultimately be possible to design candidate MMR vaccines that decouple the protective from the potentially deleterious immunogenic components of the vaccine.
The threat of measles still exists in the United States.16 Measles is still a leading cause of childhood mortality worldwide,17 and the US "universal" immunization recommendations are clearly still indicated. Indeed, the vaccine stopped endemic measles transmission in the US18; however, the vaccine will not completely eliminate ITP that would have been caused by measles and rubella as routine childhood diseases. Epidemiologic studies have quantified the risk of ITP attributable to MMR in the second year of life as 1 in 40 000 vaccine recipients. The vast majority of such reactions resolve without sequelae, but such resolution does not occur in all cases. Therefore, we should support studies that may lead to new strategies or vaccines that may further enhance the favorable risk/benefit ratio of MMR immunization by reducing the risk of MMR-related ITP.
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ACKNOWLEDGMENTS |
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I would like to thank Drs Jesse Goodman, Robert Ball, Hector Izurieta, Robert Davis, Judy Beeler, and Ann Gaines for helpful comments.
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FOOTNOTES |
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Accepted Jan 7, 2008.
Address correspondence to M. Miles Braun, MD, MPH, Division of Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, HFM-220, 1401 Rockville Pike, Rockville, MD 20852. E-mail: miles.braun{at}fda.hhs.gov
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
The author has indicated that he has no financial relationships to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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