August 1998
Unanswered QuestionsPanel says more research is needed to answer the following:
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ATLANTA - The possible connection between insulin-dependent type 1 diabetes mellitus and childhood immunizations has been a controversial topic since the 1980s, but a panel convened by the National Institutes of Health (NIH) recently suggested there is no reason for concern.
The workshop participants concluded that existing studies in humans do not indicate an increase in type 1 diabetes attributable to any vaccine or the timing of vaccine administration. However, various promising areas of research in diabetes and infectious diseases were defined. Studies that may provide additional data are ongoing at the University of Colorado and at the Centers for Disease Control and Prevention, said Regina Rabinovich, MD, MPH, chief of the clinical studies section in the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID).
The meeting, held recently at the NIH, was designed to evaluate the role of vaccines and infectious diseases in autoimmune disease, specifically insulin dependent type 1 diabetes mellitus, also known as juvenile onset diabetes. A multidisciplinary group was called upon to evaluate publicized hypotheses linking vaccination and diabetes in the context of changing epidemiology and concepts of diabetes.
The group consisted of experts from the specialties of diabetes, infectious diseases, pediatrics, vaccine, immunology and epidemiology, public health and vaccine safety.
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Numerous investigators have conducted studies of genetically susceptible, non-obese diabetic mice and rats that with little provocation developed diabetes, Rabinovich said.
"This is a useful model to evaluate what kinds of factors can modulate that immune response," she said.
The mice and rats developed diabetes at a high rate. The relevance of this animal model for diabetes in humans is that Major Histocompatibility Complex (MHC) class 2 genes are essential for expression of the disease and that T cell function is essential for the disease.
"These are thought to be parallels to how the disease is expressed in humans," Rabinovich said.
A number of antigens and other non-specific stimuli including food and environmental conditions, changes in lighting and temperature can prevent or modulate the rate at which diabetes is expressed in these animals - especially in the short term, she said. There are a number of aspects about the models that are unknown and could affect extrapolation to humans: the nature of the primary autoantigen and the method by which class 2 genes prevent diabetes mellitus.
Diabetes as a potential adverse event from immunizations has been a controversial topic since its mention during a television news program in 1982. Numerous related article have since been published.
Ecologic analyses of diabetes rates and national immunization schedules in several selected countries have also been published, along with several secondary analyses of vaccine trials. These analyses afforded the opportunity for long-term follow-up with the caveats that come along with secondary analyses of data that is not the original endpoint, Rabinovich said.
The consensus is that juvenile diabetes is an immune-mediated disease. Evidence from various parts of the world indicate increased disease rates over the past decade in many countries.
In addition, evidence suggests specific antibodies to pancreatic cells precede disease in more than 90% of cases, sometimes from nine months to many years prior to onset of diabetes.
Emerging data over the past decade has suggested a strong genetic influence, and susceptibility and resistance alleles may be necessary and sometimes sufficient. Environmental factors, including infectious diseases in general, are multiple and likely non-specific influences, Rabinovich said.
A Haemophilus influenzae type b (Hib) vaccine trial held in Finland was the topic of extensive panel discussion, she said. Because of the country's unique health care system, detailed vaccination data from a randomized cohort to Hib vaccine given at infancy or at 2 years of age to a national diabetes registry was linked. The review of the vaccine trial data by Finnish investigators did not attribute the rise in type 1 diabetes rates in Finland to differences in the timing of childhood vaccination in the study, Rabinovich said.
Two independent reviews were presented. A full report of the meeting is being prepared, and publication of the independent reviews is pending, Rabinovich said. Increasing public and provider awareness of the panel's consensus is also expected to help clear up the controversy.
Suggestions from the panel included improved methodological analyses of available data. The panel believed it was a reasonable approach to do an ecological analysis, but rigorous statistical and analytical approaches need to be taken.
The conclusions were not evident at the beginning of the workshop, Rabinovich said. However, based on the strength of the evidence, the group felt very comfortable with the conclusion that immunization a is safe and effective tool that should continue, but that targeted areas of research should also proceed.
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