microbes being researched at the institute. Studies comparing these employees with a control group found a few significant differences in immunologic parameters, including elevated levels of antibodies in their blood. These differences increased as more time passed following immunization, but the findings are of questionable clinical significance. Researchers are conducting another study that will evaluate a number of immunologic parameters in retired and current employees at the institute, most of whom received a half dozen vaccines over a 6to 9-month period.

RESEARCH OPPORTUNITIES22

A number of questions remain unanswered regarding risks for adverse events following vaccination and ways to lower such risks. Several speakers, including a parent representing a consumers organization focused on vaccine safety, suggested research avenues that might prove fruitful in this regard.

Hanson pointed out that although children with genetic disorders or other chronic conditions represent between 5 and 15 percent of all children (Warkany, 1971), the effects of vaccination on these children are not known because they were either excluded from or not present in large enough numbers in the studies that initially tested the effects of vaccines. He suggested that researchers assess the risk of adverse events associated with vaccination in populations with specific genetic makeups.

Identifying families with several members who experience similar adverse events after vaccination, the speaker added, could provide a highly enriched sample of families suitable for studies of genetic factors associated with the adverse effects of vaccines. These families could be identified by using the LLDB, which could also be used to identify twins useful in the study of genetic differences associated with the risk of adverse events following vaccination. To prioritize which genetic populations should be studied, the speaker suggested creating ranked categories of conditions on the basis of the most frequent claims under the Vaccine Injury Compensation Program, and among those, the conditions most likely to have a genetic susceptibility component worthy of study. These studies could use genetic markers of development of disease identified from other studies. The use of such markers, however, requires researchers to develop ways to protect research subjects from discrimination on the basis of their genetic makeup, the speaker noted.

22  

This section is based on information presented by James Hanson, Marcel Kinsbourne, Burton Waisbren, Barbara Loe Fisher, and other forum members.



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Vaccine Safety Forum: Summaries of Two Workshops microbes being researched at the institute. Studies comparing these employees with a control group found a few significant differences in immunologic parameters, including elevated levels of antibodies in their blood. These differences increased as more time passed following immunization, but the findings are of questionable clinical significance. Researchers are conducting another study that will evaluate a number of immunologic parameters in retired and current employees at the institute, most of whom received a half dozen vaccines over a 6to 9-month period. RESEARCH OPPORTUNITIES22 A number of questions remain unanswered regarding risks for adverse events following vaccination and ways to lower such risks. Several speakers, including a parent representing a consumers organization focused on vaccine safety, suggested research avenues that might prove fruitful in this regard. Hanson pointed out that although children with genetic disorders or other chronic conditions represent between 5 and 15 percent of all children (Warkany, 1971), the effects of vaccination on these children are not known because they were either excluded from or not present in large enough numbers in the studies that initially tested the effects of vaccines. He suggested that researchers assess the risk of adverse events associated with vaccination in populations with specific genetic makeups. Identifying families with several members who experience similar adverse events after vaccination, the speaker added, could provide a highly enriched sample of families suitable for studies of genetic factors associated with the adverse effects of vaccines. These families could be identified by using the LLDB, which could also be used to identify twins useful in the study of genetic differences associated with the risk of adverse events following vaccination. To prioritize which genetic populations should be studied, the speaker suggested creating ranked categories of conditions on the basis of the most frequent claims under the Vaccine Injury Compensation Program, and among those, the conditions most likely to have a genetic susceptibility component worthy of study. These studies could use genetic markers of development of disease identified from other studies. The use of such markers, however, requires researchers to develop ways to protect research subjects from discrimination on the basis of their genetic makeup, the speaker noted. 22   This section is based on information presented by James Hanson, Marcel Kinsbourne, Burton Waisbren, Barbara Loe Fisher, and other forum members.

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Vaccine Safety Forum: Summaries of Two Workshops A CDC epidemiologist noted that no unique laboratory diagnosis or clinical syndrome has been identified for most of the rare, serious outcomes associated with vaccination. Without the ability to define uniquely such adverse events, it will be difficult to link them to specific genetic markers. He added, however, that such analysis is feasible for adverse events that are more common, such as seizures, with the use of the LLDB. By genetically analyzing tissue or blood samples from those individuals who developed seizures following vaccination with DPT, for example, and comparing them with samples from matched controls who did not react adversely to vaccination, researchers might discern a genetic marker for susceptibility to seizures following vaccination with DPT. Fisher delineated five research areas that she felt, from a parent's perspective, were important to pursue. One was research to evaluate, on a molecular biology level, the impact over time of repeatedly manipulating the human immune system with single and multiple antigens. Parents who are being asked or required by law to vaccinate their children with increasing numbers of vaccines, she pointed out, want it known what exactly is happening in the human body at the molecular level when several vaccines are given simultaneously or over a short period of time, compared to physiologic responses to naturally-presented antigens, such as those found in the viruses or bacteria against which the vaccines are directed. The way in which an antigen is presented to the body, including whether in a vaccine or through natural infection, could affect the immune response. The route of immunization with DNA vaccines, for instance, could influence the type of cytokine response elicited by the vaccine. 23 In addition, the immune response to multiple antigens given simultaneously could be different than the response to the same antigens given individually (Goldenthal et al., 1995). A representative of a vaccine manufacturer said that studies are being conducted to assess some of the short-term immunologic effects of vaccines given separately versus the effects of those given simultaneously. Consumer advocates also question whether there are differences in long-term immunologic function and health status between children who receive vaccinations and those who do not. Several vaccine manufacturer representatives and biomedical researchers noted that it would be a challenge to conduct studies aimed at assessing the long-term immunologic effects of vaccination versus nonvaccination. It is difficult to find for such studies a group of nonvaccinated children who are similar in all relevant aspects to vaccinated children, an epidemiologist pointed out. Other researchers noted that even if immunologic differences are detected between vaccinated and nonvaccinated 23   Based on data presented at the International Meeting on Nucleic Acid Approaches for the Prevention of Infectious Diseases, Bethesda, Md., February 5–7, 1996.

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Vaccine Safety Forum: Summaries of Two Workshops children, it would be difficult to assess whether those differences are due to the dozen or so antigens encountered in vaccines or to the myriad of antigens a child encounters through infections or diet. There are several immunologic parameters that one could study, a vaccine manufacturer pointed out, and it is not known which are of the highest priority for documenting potential changes with respect to vaccination. It is not practical and there are not enough resources, he said, to evaluate all immune parameters. Ultimately, the immune parameters selected should relate to protection from the agent as well as related to adverse events. One researcher noted that vaccines have mainly been evaluated in terms of their ability to generate antibodies. She suggested conducting more studies that determine T-cell response or other immune parameters besides antibody response, as is already being done for AIDS vaccines. Even if immunologic differences were found when individuals are exposed to an antigen via a vaccine versus via natural infection, a researcher noted, those differences will be difficult to interpret in terms of their implication for susceptibility to disease or the development of subsequent disease. The second important area of research, Fisher said, is to assess whether vaccinations in conjunction with antibiotic use and exposure to environmental toxins make people more vulnerable to new and more virulent viruses and bacteria or more prone to adverse effects from vaccines or infections. Others questioned the scientific basis for this hypotheses. Third, she suggested that studies be conducted to investigate the possible link between vaccination and learning disabilities or attention deficit disorder. More than 2.5 million children with specific learning disabilities have been identified in the United States (U.S. Dept. of Education, 1996). She and Kinsbourne, a pediatric neurologist, noted that a vaccine that might, in rare cases, cause severe brain damage might more frequently cause milder forms of brain damage that could manifest itself as a learning disability or attention deficit disorder. This hypothesis is based on evidence that some causes of brain damage, such as low oxygen conditions during birth, not only cause severe mental retardation or cerebral palsy but are also associated with an increased risk of the hyperactive impulsive behavior that is seen in children with attention deficit disorder (Nichols and Chen, 1981; Astbury et al., 1987). If a vaccine causes mild brain damage, the effects of such damage may not be apparent for several years following vaccination, Kinsbourne pointed out. Deficits in such skills as learning to read, spell, write, or concentrate, for example, will not become apparent until the child has reached a level of development where such skills are expected. Kinsbourne also noted that there are several different kinds of learning disabilities and that there are no established causes for any of them.

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Vaccine Safety Forum: Summaries of Two Workshops Kinsbourne suggested conducting a study to assess whether learning disabilities occur more frequently in vaccinated children who suffered adverse reactions (particularly neurological) as compared to those who did not. The other logical comparison of vaccinated with unvaccinated children might be more difficult in terms of obtaining a sufficiently large unvaccinated sample matched for age, sex. and SFS. Such a study would, in particular, focus on pertussis vaccine, the well recognized adverse reactions of seizures, hypotonic/hyperesponsive episodes and prolonged inconsolable crying within 72 hours of the vaccination. Potential outcome variables of particular interest would be attention deficit-hyperactivity disorder, selective learning disabilities, and clumsiness with motor soft signs. Fisher's fourth research priority was that researchers conduct studies to investigate the possible link between vaccines and autism. Autism affects 1 in 1,000 children (Bryson, 1996). Some autistic children have been found to have abnormally high levels of rubella antibodies. When these children were given intravenous immune globulin (known as IVIG), their rubella antibody levels fell and their autism seemed to improve (Gupta et al., 1996). It was suggested that a study comparing a number of measures of immune function in autistic versus nonautistic children would be worthwhile. Others pointed out, however, even if an immunologic abnormality is found in autistic children, it will be difficult to establish whether vaccines rather than other factors such as infectious diseases or toxic exposures trigger this abnormality. Fisher's fifth research priority was studies that will, on a continuing long-term basis, scientifically reevaluate each of the 10 vaccines being given to children. These would include full evaluation of the safety of the growth media, adjuvants, preservatives and other additives, as well as identification of genetic and other risk factors, to screen out children at high risk for experiencing an adverse event after vaccination. She expressed concern that viruses in the animal tissues used to produce some vaccines might be introduced into the body via vaccines, and some of these might cause disease. Vaccine manufacturers currently screen the tissues that they use in vaccine production for known infectious agents, but it is possible, Fisher pointed out, that viruses previously unknown might be present in the growth media used in vaccine production. A practicing internist had several suggestions of ways to assess whether particular disorders can be stimulated by specific vaccines and, if so, ways to avoid such stimulation. Because there have been several reports the development of MS or other syndromes characterized by a loss of myelin following vaccination with HBV (Shaw et al., 1988; Herroelen et al., 1991; Nadler, 1993), he suggested contacting 1,000 hospitals and having each of them determine whether a randomly selected sample of 100 of their nurses vaccinated with HBV developed any symptoms suggesting a demyelinating autoimmune

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Vaccine Safety Forum: Summaries of Two Workshops disorder. A workshop participant noted that any findings from such a study would not be applicable to the general population because, by the nature of their occupation, health care workers have different exposures than the general public. In addition, health care workers are adults, and thus may not be informative to the infant immunization issues. It was noted that because HBV was initially given predominantly to health care workers, if there is a link between the vaccine and demyelinating disorders such as MS or GBS, the incidence of these disorders should be significantly greater in health care workers than in the general public. This could be relatively easily assessed with epidemiologic studies with data collected in other established studies of health care workers. A CDC representative pointed out, however, that MS initially occurs most often in young women. A higher frequency of the disorder in vaccinated nurses, who are predominantly young women, may reflect a higher incidence of the disease in this population and may not be directly due to vaccination. Waisbren also suggested testing all present and projected vaccines for antigens that are similar in molecular structure to human myelin and assessing whether these antigens induce in an animal model a demyelinating condition called allergic encephalomyelitis (EAE). If they do, he suggested their removal from present and future vaccines with the use of genetic engineering or other techniques (Sela and Amon, 1992). A FDA representative noted that although it would be relatively easy to remove antigens from genetically engineered vaccines and assess whether those antigens can induce EAE, it is more difficult to do so in vaccines made up of live whole viruses, in which all the antigenic components are not clearly isolated. A drug company representative noted that the three-dimensional structure of an antigen is often critical to the effects that it can have on the body. This three-dimensional structure is dependent on the connections that the antigen has to other components in the vaccine. Consequently, whether or not the antigen, in isolation, induces EAE may not indicate whether it would be able to do so in the three-dimensional conformation that it would have in the vaccine. However, such an analysis may be useful for some antigens whose functions are not as dependent on their three-dimensional structures. Other forum members voiced concern about the applicability of the EAE model because it uses an adjuvant that stimulates the immune system to a greater degree than most adjuvants used in vaccines. Waisbren also suggested testing the MAMA hypothesis as an explanation for why some people develop GBS or MS after vaccination with HBV by determining if vaccinated patients showed an increase in the number of antimyelin T cells in their circulating blood (Shaw et al., 1988; Herroelen et al., 1991; Zhang et al., 1994). Vaccines could also be checked for homology

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Vaccine Safety Forum: Summaries of Two Workshops between their polypeptides and human myelin and for complimentarity of their antigens with other viruses or bacterial cell wall substances that might be present in vaccine recipients (Westall and Root-Bernstein, 1983). In summary, a number of questions remain unanswered regarding risks for adverse events following vaccination and ways to lower such risks. Several speakers suggested research avenues that might prove fruitful in this regard, including studies that assess the risk of adverse events after vaccination in specific genetic populations; on a molecular biology level, the impact over time of multiple vaccination; whether there is a link between learning disabilities and vaccination; whether autistic children have different immune responses than nonautistic children; whether health care workers vaccinated with the hepatitis B virus vaccine (HBV) experience more autoimmune disorders; and whether the antigens in vaccines are likely to cause demyelinating disorders. Several forum members and other workshop participants voiced concern that some of these studies would be difficult to design or impractical to conduct because of a lack of standard definitions or reactions, rarity, and lack of clear diagnostic tests for risk states such as autism. Others felt that information that they would provide, if the studies are successfully carried out, would be valuable in determining risk for adverse events following vaccination.

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