respiratory infections have been associated with increased risks (Nafstad et al., 2000), as has early exposure to antibiotics (Droste et al., 2000).

The prevalence of asthma has increased in the United States and other countries over the past 30 years (Grant et al., 1999). An international study of asthma in children found that prevalence was higher in more developed countries (Asher and Weiland, 1998). In the United States, the prevalence rates of self-reported asthma rose from 3.1 percent in 1980 to 5.4 percent in 1994, an increase of 74 percent (Mannino et al., 1998). For children age 0–4 years, rates increased by 159 percent during this period (from 2.2% to 5.7%). Increases in asthma prevalence were seen in all race, sex, age, and regional groups in the United States. No national estimates of the incidence of new asthma cases in the United States are available.

SCIENTIFIC ASSESSMENT

Causality

As has been specified, the committee’s review of the safety of multiple immunizations focused on three possible adverse outcomes: heterologous infections; autoimmune disease in the form of type 1a diabetes; and allergy, especially asthma. For each of these outcomes, the epidemiological evidence is summarized (in the text and in accompanying Tables 2, 3, and 4) and the committee’s conclusion regarding causality is presented. The search strategies used to identify relevant published reports are described in Appendix D.

Heterologous Infections
Controlled Epidemiological Studies

Guinea-Bissau. Kristensen and colleagues (2000) studied the relationship between vaccination and childhood survival in a population of 8,752 children born to mothers participating in a longitudinal mortality study in Guinea-Bissau. Recommended childhood vaccines in Guinea-Bissau include BCG, OPV, DTP, and measles. Vaccination status was determined by inspection of immunization cards kept by the children’s parents. Children were excluded if the card could not be examined, which was the case for more than a third of children.

Vaccine exposure for BCG, OPV, and DTP was assessed during a first visit when children were 0–6 months of age. Mortality was assessed at a subsequent visit approximately 6 months later. For surviving children, vaccination status, including measles vaccine exposure as well as that of BCG, OPV, and DTP, was updated. Mortality was assessed again at a third visit, approximately 6 months after the second visit.



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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction respiratory infections have been associated with increased risks (Nafstad et al., 2000), as has early exposure to antibiotics (Droste et al., 2000). The prevalence of asthma has increased in the United States and other countries over the past 30 years (Grant et al., 1999). An international study of asthma in children found that prevalence was higher in more developed countries (Asher and Weiland, 1998). In the United States, the prevalence rates of self-reported asthma rose from 3.1 percent in 1980 to 5.4 percent in 1994, an increase of 74 percent (Mannino et al., 1998). For children age 0–4 years, rates increased by 159 percent during this period (from 2.2% to 5.7%). Increases in asthma prevalence were seen in all race, sex, age, and regional groups in the United States. No national estimates of the incidence of new asthma cases in the United States are available. SCIENTIFIC ASSESSMENT Causality As has been specified, the committee’s review of the safety of multiple immunizations focused on three possible adverse outcomes: heterologous infections; autoimmune disease in the form of type 1a diabetes; and allergy, especially asthma. For each of these outcomes, the epidemiological evidence is summarized (in the text and in accompanying Tables 2, 3, and 4) and the committee’s conclusion regarding causality is presented. The search strategies used to identify relevant published reports are described in Appendix D. Heterologous Infections Controlled Epidemiological Studies Guinea-Bissau. Kristensen and colleagues (2000) studied the relationship between vaccination and childhood survival in a population of 8,752 children born to mothers participating in a longitudinal mortality study in Guinea-Bissau. Recommended childhood vaccines in Guinea-Bissau include BCG, OPV, DTP, and measles. Vaccination status was determined by inspection of immunization cards kept by the children’s parents. Children were excluded if the card could not be examined, which was the case for more than a third of children. Vaccine exposure for BCG, OPV, and DTP was assessed during a first visit when children were 0–6 months of age. Mortality was assessed at a subsequent visit approximately 6 months later. For surviving children, vaccination status, including measles vaccine exposure as well as that of BCG, OPV, and DTP, was updated. Mortality was assessed again at a third visit, approximately 6 months after the second visit.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction A Cox proportional hazards model was used to calculate the mortality ratio for vaccinated and unvaccinated children. The overall mortality for any vaccine was nonsignificant (RR = 0.74, 95% CI 0.53–1.03). Receipt of BCG vaccine was associated with lower mortality (adjusted RR = 0.55, 95% CI 0.36–0.85), as was measles vaccine (adjusted RR=0.48, 95% CI 0.27–0.87). The mortality ratio for one dose of DTP vaccine versus none was 1.84 (95% CI 1.10–3.10), but the ratio for two to three doses was not significantly elevated (RR=1.38, 95% CI 0.73–2.61). The pattern was similar for OPV, with an elevated mortality ratio for one dose (RR = 1.81, 95% CI 1.07–3.05), and nonsignificant ratio for two to three doses (RR = 1.39, 95% CI 0.73–2.64). The authors conclude that receipt of BCG and measles vaccines may have a protective effect against mortality, while receipt of a single dose of DTP and polio vaccines may carry a higher mortality risk compared with receiving no vaccinations. The results also suggest that DTP vaccine may negate the positive effects associated with BCG vaccine. However, the interpretation of these findings warrants caution. The vaccination status of some children was unclear and more than a third of the children did not have records available. Many children may have been underimmunized, contributing to the increased mortality rates and reflecting limited access to health care. Vaccinated children were also more likely to receive health care than unvaccinated children, which may mean that getting vaccinated is associated with access to or use of other interventions that improve survival. Mothers of children vaccinated with DTP were younger than mothers of children vaccinated with BCG or measles vaccine, which means maternal age may have contributed to infant mortality risk. The adjustment procedure for potential confounders was also unclear. For the United States, the findings regarding BCG vaccine are not relevant since the vaccine is not routinely used in this country. United States-Boston. In a case-control study, Burstein and Fleischer (1994) examined the relationship between vaccination and the risk of occult bacteremia. Cases and controls were patients treated in the emergency department at Children’s Hospital in Boston between November 1987 and December 1990. Cases were 54 children age 3 to 36 months who participated in a multicenter antibiotic study. Pathogens isolated from these children included S. pneumoniae, E. coli, S. aureus, H. influenzae, or Salmonella spp. The 108 controls were matched to cases according to age. Each case had two controls. One control group included febrile nonbacteremic children. The other group included nonfebrile children who were treated for symptoms not related to infectious diseases. Vaccination history, including DTwP, was obtained from medical records. The authors found no significant difference between cases and controls for time since last vaccination of any type, or for time since last DTwP vaccination. Limitations of this study included weak statistical power. It was also unclear which vaccines, other than DTwP, the children received.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction United States-Tennessee. Griffin and others (1992) examined the association between DTwP immunization and the risk of invasive bacterial infection. The incidence of invasive bacterial diseases (H. influenzae, N meningitidis, Streptococcus pneumoniae, group B Streptococcus, or Listeria monocytogenes) was measured in a cohort of 64,591 children who received at least one dose of DTwP vaccine through any of the four largest Tennessee county health clinics from 1986 to 1987. Based on surveillance data, 158 children diagnosed with invasive bacterial infection after receiving DTwP vaccine were identified in this cohort. Using a Poisson regression model and controlling for age, the relative risk for infections during the early post-immunization periods (0–7, 8–14, 15–28 days) compared with the later period (29 or more days) was nonsignificant. The authors concluded that there was no increase in the risk for invasive bacterial infection following receipt of DTwP vaccine, especially during the early post-immunization period. Interpretation of the study is limited by the lack of an unvaccinated comparison group. In addition, the analysis was limited to cases of serious culture-confirmed infections. United States-Kaiser Permanente Northern California. In a case-control study, Black and colleagues (1991) examined the relationship between vaccination and the risk of heterologous invasive bacterial disease. Cases and controls were identified from member records in the Kaiser Permanente Medical Care Program of Northern California. As cases, 223 children between 1 month and 2 years of age who were diagnosed with invasive bacterial disease (Pneumococcus, H. influenzae, E. coli, and Meningococcus) between 1986 and 1988. Invasive bacterial disease status was identified from a computerized microbiology laboratory database. The 446 controls were matched according to age, sex, zip code, and length of plan membership. For cases, all vaccines received within three months prior to disease onset were identified through medical chart review. For matched controls, the date of diagnosis for the corresponding case was the reference date used to obtain vaccination histories. Children had received one or more of the following vaccines: DTP, OPV, and MMR. A conditional logistic regression model was used to estimate the effect of recent immunization on disease; odds ratios were calculated from the regression results for each vaccine. A separate analysis controlled for the effect of well care visits and day care attendance (information available for 72 percent of the subjects). Odds ratios were calculated for separate time intervals from date of vaccine receipt to date of disease diagnosis: 0–7 days, 8–30 days, 31–60 days, and 61–90 days. Receipt of individual vaccines was associated with a lower risk of disease in all time intervals, with significant effects for DTP at any interval after 7 days and for OPV at 8–30 days and 31–60 days. After adjustment for day-care attendance and well-care visits, however, no individual vaccine had a significant effect on risk of disease. But there was a significant protective effect in the adjusted analysis from the receipt of any vaccine within 30 days (OR = 0.26, 95% CI 0.09–0.76) or 90 days (OR = 0.31, 95% CI 0.13–0.73).

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction The authors conclude that vaccines do not increase the risk for invasive bacterial disease and that they may provide a protective effect against disease, especially within 3 months after vaccination. However, children who received well care visits were also less likely to develop invasive bacterial disease than those who did not receive them. A health care effect may account for the observed protection of vaccines against heterologous invasive bacterial disease. United States-Alaska. In a two-part study, Davidson and colleagues (1991) examined risk of disease following receipt of DTwP vaccine among Alaskan Native children. They first conducted a case-control study to examine the risk of invasive bacterial disease. The 186 cases were children 2 to 24 months old who received at least one DTwP vaccine and were identified through surveillance reports for H. influenzae type b and S. pneumoniae diseases. There were 186 controls matched according to age, sex, residence, and number of DTwP vaccines received. The time interval between last DTwP vaccination and date of disease diagnosis (the reference date for controls) was obtained. There were no significant differences in DTwP vaccine intervals for Hib disease cases. For S. pneumoniae disease, significantly more cases had been immunized 31–60 days earlier (OR = 3.3, 95% CI 1.1–10.0), but differences were not significant for shorter or longer intervals. The authors conclude that there was no clear association between the timing of DTwP vaccination and risk of invasive bacterial disease. The authors note that a possible explanation for the lack of difference observed in the study is overmatching. Overmatching is where cases and controls closely resemble each other on factors related to the exposure of interest. In this study, matching based on the number of DTP vaccines received may have resulted in the lack of difference in the timing of DTwP immunization between cases and controls. However, the authors observed that matching according to the number of DTP vaccines was necessary and reduced potential confounders such as those related to health status. Subjects in the second part of the study included 104 cases and controls from the earlier part who had complete medical records available. Cases and controls were combined to compare the occurrence of any illnesses within 30 days before and after receipt of DTwP vaccine. Comparisons were made for the occurrence of any illness, any infectious disease, otitis media, other respiratory infections, temperature greater than 38°C, or hospitalization. There was a higher incidence of any illness during the 30 days prior to DTP vaccination than in the 30 days following vaccination (53% versus 43%, p = .004). There were no significant differences between the pre- and post-vaccination periods for the other indicators of illness. The authors again conclude that DTwP vaccination does not increase the risk of other illnesses. The authors note that the higher frequency of disease in the pre-DTP group compared to the post-DTP group may have resulted from a “well-child effect,” whereby immunization of children with illnesses was postponed until they were well.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction Randomized Controlled Trial Germany. Otto and colleagues (2000) examined differences between vaccinated and unvaccinated children in the risk of morbidity associated with infectious diseases. A total of 662 children, born between January 1995 and December 1996, were randomized to receive their first vaccine (against diphtheria, pertussis, tetanus, Haemophilus influenzae type B, and poliomyelitis) at either 60 days or 90 days after birth.5 Children were observed during the third month of life, beginning at the sixth day after vaccine receipt. Mothers kept a daily journal and recorded any occurrence of symptoms. Morbidity was assessed in terms of the incidence of coughing, signs of rhinitis, restlessness, vomiting, rash, pain, poor food or fluid intake, fever, and respiratory embarrassment. A total of 166 children were excluded from the analysis, mostly because of missed vaccination. The authors observed a significant (p<0.01) increase in vomiting, cough, rhinitis, restlessness, rash, and pain in the unvaccinated group compared with the vaccinated group. Hospitalization was more frequent among unvaccinated children (n = 4) than vaccinated children (n = 1). The authors concluded that children who received vaccinations during the third month of life did not demonstrate an increased risk of infectious-disease symptoms and may experience some protective effect from vaccination. Study limitations included observer bias in that the mothers, who were responsible for monitoring morbidity, were not blinded as to vaccination status. The high exclusion and dropout rate (39% versus 11% in the unvaccinated group), especially in the vaccinated group, may also effect interpretation of the study results. Other Studies The committee reviewed additional articles that reported adverse events after receipt of multiple immunizations. These studies helped inform the committee’s assessment of risk for heterologous infection but did not contribute to the causality argument. Most of these articles reported on randomized controlled trials that primarily investigated the safety, efficacy, and/or immunogenicity of various vaccines. They did not specifically examine the incidence of heterologous infections in children post-immunization, compare the incidence of such infections between different exposure groups, or report statistical analyses from which to make inferences or extrapolations related to heterologous infections. The articles reviewed are briefly summarized below. Shinefield and colleagues (1999) examined the safety and immunogenicity in infants of a heptavalent pneumococcal CRM197 conjugate vaccine administered concurrently with DTwP, Hib, and OPV vaccines. Hepatitis B vaccine was 5   In Greiswald, Germany, immunization recommendations call for children to receive their first vaccine during the third month of life. Children participating in the study received their vaccines on either the first day (60 days after birth) or the 30th day of the third month (90 days after birth), complying with the recommended immunization schedule.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction administered concurrently or at least two weeks earlier or later. Children received DTaP vaccine at a later stage of the study. The authors reported on adverse events observed following immunization. In the study, 302 infants age 2 months were randomized to receive the pneumococcal vaccine or meningococcal Group C conjugate vaccine. During the study, 12 emergency room visits occurred within 30 days of any vaccine dose. These visits were for croup, otitis, febrile illness, and urinary tract infection, but none were considered vaccine-related. Following the primary doses of vaccines, eight children were hospitalized, two within 30 days after vaccination. Following the booster doses, there were four emergency department cases (of viral illness, otitis media [two cases], and burn) and four hospitalizations (pneumonia, otitis media, elective surgery, asthma, and cough). The authors did not believe that these events were vaccine-related. Olin and others (1997) compared the efficacy of three types of DTaP vaccine to the DTwP vaccine used in the United Kingdom. A sample of close to 83,000 infants age 2–3 months were randomized to different DTP vaccine exposures and also given Hib and IPV vaccines. The authors reported on adverse events following vaccine receipt. Those that may have involved heterologous infections included two deaths from pneumonia within 4–7 days of a trial vaccine dose, 20 cases of invasive bacterial infections, and one case of suspected encephalitis Afari and colleagues (1996) examined the immunogenicity and reactogenicity of two types of DTaP vaccine (a freeze-dried, heat-stable product and a liquid product) and DTwP vaccine. Of the 403 infants who were studied, 136 were randomized to receive the freeze-dried DTaP, 130 to receive liquid DTaP product, and 137 to receive DTwP. The authors reported that three children who received the freeze-dried vaccine died of measles or malaria, two children who received liquid DTaP died of malaria or diarrheal disease, and two children who received DTwP died of multiple boils or malaria. Differences in mortality rates between either DTaP group and the DTwP group were not statistically significant. Simondon and colleagues (1996) compared the safety and immunogenicity of DTaP and DTwP vaccines in a randomized clinical trial involving 286 Senegalese infants. Children also received BCG and IPV during the study. Six deaths occurred within 2 months after vaccination. On the basis of verbal autopsies, the four deaths in the DTwP group were attributed to diarrhea, malaria, and pneumonia. The two deaths in the DTaP group were attributed to meningitis and diarrhea. The authors suggested caution in drawing conclusions regarding the number and causes of deaths in the study. The infant mortality rate in the study region is high, and verbal autopsies are an imprecise means of determining cause of death. Riordan and colleagues (1995) reported two cases of bacterial meningitis after receipt of MMR vaccine. Fever and rash occurred in two children, age 12 months and 13 months, within 4 days after MMR vaccine, and were initially attributed to the vaccine. After diagnostic tests, both children were found to have

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction a high level of C-reactive protein and were diagnosed with a bacterial infection. Meningococcal infection was confirmed in one case and suspected in the other. The authors noted that the median age of children admitted to their hospital with meningococcal disease is 14 months. Avendano and colleagues (1993) evaluated the safety and immunogenicity of a Hib vaccine made with purified polyribosylribitol phosphate conjugated to tetanus toxoid (PRP-T). The 287 infants in the study were randomized to receive either the Hib vaccine combined in a single injection with DTP, separate injections of Hib vaccine and DTP, or separate injections of DTP and a placebo. The one death during the study, resulting from pneumonia and sepsis, occurred 38 days after the second dose of combined DTP and PRP-T. Cultures obtained from the infant were positive for Streptococcus pneumoniae. Chazono and colleagues (1991) described the side effects following use of DTaP vaccine in Japan and compared that experience with the side effects reported in a Phase III trial of the acellular pertussis vaccine component in Sweden in 1986. Pediatricians in four health centers in Japan collected information on the number of children diagnosed with any infectious diseases after receiving DTaP vaccine, as well as information on cases of pertussis or abnormal reactions such as febrile seizures. Information was obtained from medical charts or from parents or guardians contacted by telephone or mail. Of the 940 infants for whom information was available, three children had an infectious disease (one case each of measles, mumps, and varicella). The authors contrasted their findings with those from the Phase III acellular pertussis trial in Sweden, where three deaths from severe invasive bacterial infection (i.e., Hib, pneumococcal, and meningococcal infections) occurred among 1,385 children. Ruuskanen and colleagues (1980) examined antibody responses and adverse reactions following receipt of inactivated polio vaccine. Children in the study received 2 doses of IPV as well as 4 doses of DTP between the ages of 3 months and 24 months. Information on reactions following receipt of IPV was obtained from questionnaires returned by parents of 225 of 380 children in the study. Fever (greater than or equal to 37.5°C) was reported for about 17 percent of children and was clinically significant (greater than or equal to 38.5°C) in 5 percent of the children. Fevers usually began the same day as vaccination and lasted up to 2 days. In a few children (exact number unspecified), fevers started 6 or more days following vaccination. The authors believed that these fevers were caused by infection, and not vaccination, although the basis for their belief was not stated. Causality Argument The committee reviewed several case-control or cohort studies (Black et al., 1991; Burstein and Fleisher, 1994; Davidson et al., 1991; Griffin et al., 1992; Kristensen et al., 2000) and a randomized controlled trial (Otto et al., 2000) (see

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction Table 2). Vaccine exposure varied among the studies but fit the committee’s definition of exposure to “multiple immunizations.” The studies examined the effects of the addition of one vaccine to an existing immunization schedule, of one vaccine consisting of antigens from more than one infectious agent or strain of virus (e.g., DTP, OPV, or MMR), or of several vaccines received at the same time. Outcome measures in the studies also varied, with the “disease” group including subjects who had a positive culture to invasive bacterial disease, who had symptoms related to infectious diseases, or who had died. Limitations of the studies included a potential health care utilization bias and high dropout rates. Despite these variations and limitations, the overall findings from the studies consistently demonstrated either no effect or a beneficial effect of multiple immunizations on heterologous disease. Therefore, the committee concludes that the epidemiological and clinical evidence favors rejection of a causal relationship between multiple immunizations and an increased risk of heterologous infections. Autoimmune Disease: Type 1 Diabetes Uncontrolled Observational Studies An ecological analysis by Hyoty and colleagues (1993) and an update by Hiltunen et al. (1999) examined the incidence of type 1 diabetes before and after introduction of MMR vaccine in Finland in 1982. Periodic mumps epidemics had been suggested as a contributing factor in the incidence of Type 1 diabetes, and the introduction of MMR vaccine resulted in almost complete disappearance of mumps. Data on the incidence of type 1 diabetes among children ages 0–14 years was obtained from a national registry for the years 1966–1996. The authors found a continuing increase in the incidence of diabetes over the period, especially among children ages 0–4 years and 5–9 years, but no cohort effect associated with the introduction of MMR vaccine was observed. The authors concluded that neither wild-type mumps nor MMR vaccine were related to the continuing increase in diabetes. In a letter reporting on an ecological analysis, Classen (1996) examined IDDM incidence in children born before and after the introduction of a hepatitis B immunization program in New Zealand in 1988. At the time, children in New Zealand were also routinely immunized with DTP, MMR, and OPV vaccines. Exposure was based on birth year, and diabetes cases were identified through the diabetes registry in Christchurch. The author reported an increase in average annual incidence of diabetes after introduction of hepatitis B vaccine, although no control was made for the general secular trend of increasing diabetes incidence rates. The incidence rate for 1982–1987 was 11.2 cases per 100,000 per year, and the rate increased to 18.2 cases per 100,000 per year for 1989–1991. The authors proposed a possible link between the hepatitis B vaccine, and the timing of its

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction administration, and the rising incidence of type 1 diabetes, but the ecological nature of the study limits the ability to make inferences about causation. Controlled Epidemiological Studies Vaccine Safety Datalink. In a case-control study, DeStefano and colleagues (2001) examined the association between childhood vaccines and the risk of developing type 1 diabetes. Data for both cases and controls were obtained from the four health maintenance organizations (HMOs) that participate in CDC’s Vaccine Safety Datalink project. The cases were 252 children diagnosed with type 1 diabetes and the 768 controls were matched to individual cases on HMO, sex, date of birth (within 7 days), and length of health plan enrollment. For each case, vaccination history prior to the date of diabetes diagnosis was gathered from a medical chart review. The same reference date was used to obtain vaccination histories for the matched controls. The vaccines evaluated included DTaP, DTwP, MMR, varicella, Hib, and hepatitis B. Oral polio vaccine was not included in the analysis because so few children had not received it (one case and three controls). Also tested was the effect of the timing of the first hepatitis B vaccine (never vaccinated; birth to 14 days, 15 to 55 days, or 56 or more days). In addition, the effect of differences in the schedule of Hib immunization (one dose at 21 to 27 months of age versus 3 doses in the first 8 months plus a fourth dose at 12 to 18 months) was examined. On the basis of a conditional logistic regression model stratified by the matching variables, the odds ratio for each of the vaccines was nonsignificant. However, after adjusting for race/ethnicity and family history of type 1 diabetes, the odds ratio for whole-cell pertussis was 0.23 (95% CI 0.06–0.93). The highest adjusted odds ratio was for MMR (1.43, 95% CI 0.71–2.86) but was not statistically significant. Variations in the timing of hepatitis B vaccine produced no significant differences in the risk of type 1 diabetes. Similarly, there were no significant differences among various Hib immunization schedules. However, the ability to compare the different Hib schedules was limited, since only a few children received either no Hib vaccine or received one dose at 21 to 27 months. The authors concluded that neither the receipt of routine childhood vaccines nor the timing of certain vaccines was associated with an increased risk of type 1 diabetes. EURODIAB. In a case-control study, a group examined infections and vaccinations as risk factors for type 1 diabetes (EURODIAB, 2000). Cases and controls were identified through seven European centers, each of which operates a population-based diabetes registry. As cases, there were 900 children with diabetes onset before age 15. The 2,302 controls were matched to the cases by age distribution. Vaccination history was obtained from parents through interviews or questionnaires and validated by official sources or entries in child health records held by the parent. Vaccines received included BCG, polio, tetanus, diphtheria, pertussis, rubella, measles, mumps, and Hib.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction The odds ratios for all nine vaccines were nonsignificant using either a Mantel Haenszel analysis stratified by center, or a logistic regression analysis with adjustment for center, age group, breast feeding, birth weight, maternal age, jaundice at birth, asthma, and vitamin D supplementation. There was no evidence, the authors concluded, that vaccinations increase the risk of type 1 diabetes. The study may have been compromised by ascertainment bias. About 75% of responders had validated vaccination records available. Validation was based on either a review of official records or on parental recall of exact vaccination dates, even if the investigator did not see a record. The latter may have contributed to imprecision in assigning vaccine status. Finland. Karvonen and colleagues (1999a) studied the relationship between multiple vaccines and type 1 diabetes by examining the effect of adding Hib vaccine to the routine childhood immunization schedule. Incidence of type 1 diabetes was compared in cohorts of Finnish children born before or after a Hib vaccine efficacy trial and followed for 10 years. One cohort of 128,936 children was born between October 1983 and September 1985, prior to the Hib vaccine trial and thus was not exposed to the vaccine. Children born between October 1985 and August 1987 participated in the Hib vaccine efficacy trial. These children were divided into two cohorts: 59,238 children who were born on odd days were vaccinated with Hib at 3, 4, 6, and 14 to 18 months; 57,114 children born on even days were vaccinated at 24 months only. All children were assumed to have received BCG, diphtheria-tetanus-pertussis, polio, and measles-mumps-rubella vaccines. Newly diagnosed cases of diabetes among all three cohorts were ascertained from a national hospital discharge registry (1983–1986) or a nationwide prospective childhood diabetes registry (1987–1997). There was no significant difference in the risk of diabetes by age 10 between the children who did not receive the Hib vaccine and children who were vaccinated at 24 months of age. Similarly, no difference in risk was found between the children first vaccinated at 3 months of age and those vaccinated at 24 months. For each of the comparisons, the relative risk was near 1.0. The authors concluded that neither the addition of Hib vaccine to the immunization schedule nor the timing of Hib vaccine increased the risk of type 1 diabetes in children. Estimates of both vaccine exposure and diabetes cases were based on aggregate data from three cohorts and from the population as a whole. Thus, interpreting the results at the level of the individual is difficult. Sweden. Heijbel and colleagues (1997) examined the effect of pertussis vaccination in infancy on the risk of developing type 1 diabetes. Cumulative incidence of type 1 diabetes at ages 0 to 12 years was compared in cohorts of children born before or after the pertussis vaccine was removed from the routine immunization schedule in Sweden. Specifically, cohorts of children born in 1977 (96,057 children) and in 1978 (93,248 children) received pertussis vaccine

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction TABLE 2 Evidence Table: Controlled Epidemiological Studies—Vaccines and Heterologous Infections Citation Design Population Exposure Measure Outcome Measure Results Comment Contributions to Causality Kristensen et al. (2000) Cohort; two visits required 8,752 children born to women participating in a longitudinal mortality study (Guinea-Bissau) Vaccine status by inspection of immunization card. Vaccines included BCG, polio, diphtheria-tetanus-pertussis,* and measles vaccines Mortality by parental report RR (95% CI) mortality Any vaccine = 0.74 (0.53–1.03) BCG = 0.55 (0.36–0.85) Measles = 0.48 (0.27–0.87) DTP = 1.84 (1.10–3.10) Polio = 1.81 (1.07–3.05) vaccination status unclear; records not available for more than one-third; vaccinated children more likely to receive health care; maternal age differences in cohorts; adjustment for potential confounds not clear; DTP may negate the positive effect of BCG weak evidence relevant to causality; favors beneficial effect of measles and BCG and negative effect of DTP in country with a high infant mortality of uncertain relevance to U.S.; BCG data not relevant to U.S. Otto et al. (2000) Randomized controlled trial comparing vaccinated and unvaccinated children 662 children born between Jan 1995 to Dec 1996 at a single hospital; 166 children excluded from final analysis (most missed vaccination) (Germany) Vaccinated: 1st vaccination (diphtheria, pertussis,* tetanus, (ital.)Haemophil us influenzae type B, and poliomyelitis) 60 days after birth Unvaccinated: 1st vaccination at 90 days after birth Any “Unspecific morbidity” from parental diary on days 66 to 90 after birth. Unspecific morbidity= coughing, signs of rhinitis, restlessness, vomiting, rash, pain, poor Vomiting, cough, rhinitis, restlessness, rash, pain more common in unvaccinated group (all p<0.01); 4 hospitalizations in unvaccinated group vs. 1 in vaccinated group Not blinded; drop out/exclusion rate 25%, disproportionately in early-vaccination group Weak evidence relevant to causality; favors no effect or beneficial effect of vaccines

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction and favor a Th1 response and production of IgG1 antibodies (but not IgG4 antibodies). The vaccine also contains inactivated pertussis toxin and alum, which are adjuvants that favor a Th2 response and production of IgE and IgG4 antibodies (reviewed in Gruber et al., 2001). Some human studies have been interpreted as showing that DTwP, and pertussis infection itself, induced the development of IgE antibodies to vaccine antigens and might have a similar effect on responses to environmental antigens, thereby predisposing to allergy and presumably impeding risk of autoimmunity (Farooqi and Hopkin, 1998; Nilsson et al., 1998; Odelram et al., 1994; Odent et al., 1994; Pershagen, 2000). More recent studies suggest that the antibody responses to tetanus and diphtheria antigens in children given DTwP vaccine are similar for IgG but significantly lower for IgE and IgG4 (a correlate in humans of Th2 responses) when compared with responses in children given DT vaccine (Gruber et al., 2001b). There was no significant effect on IgE antibody response to environmental antigens, suggesting that DTwP may shift the Th1-Th2 balance modestly in the Th1 direction, but only for coadministered antigens (Gruber et al., 2001a). The relative contribution of alum to the Th1-Th2 balance in response to immunization with DT seems to be minor, as the amounts of IgE induced in those given DT with or without alum were similar in one study (Mark et al., 1995). It is important to note, such results do not necessarily mean this would apply to all of the other vaccines in which alum is employed as an adjuvant (e.g., hepatitis B, various conjugate vaccines). These studies, in which the outcome measure was IgE antibodies, parallel the findings of T-cell responses in infants with pertussis infection or in those who have received DTwP: the T cell response is dominated by the Th1 cytokine interferon-γ, with very weak production of Th2 cytokines, such as IL-5. Conversely, DTaP, which contains acellular pertussis antigens, including inactivated pertussis toxin, but not the Th1-inducing components of B. pertussis whole cells, induces a mixed Th1-Th2 response. The Th2 response is more prominent and persistent in children with a family history of allergy (Ausiello et al., 1997; Rowe et al., 2001; Ryan et al., 1997a, 1997b, 1998). Thus there is some evidence of a bystander effect associated with vaccines, but this effect is relatively modest, most evident with coadministered vaccine antigens rather than other environmental antigens or infections, and inconsistently shown. Current vaccines have, on balance, weak or no Th1-inducing activities. BCG appears to demonstrate the principle for co-administered antigens. However, BCG is not used in the United States, so the relevance for this mechanism in the effects of the U.S. recommended schedule is not demonstrated. Viral vaccines carry some potential for bystander activation, but likely would have a small effect, if it occurs at all. The data on DTaP vaccine indicates that Th1 dominance is not prominent. There is also no evidence in humans that vaccine antigens lead to the pathophysiological disease state. The limited evidence from humans that does exist regards surrogates of the disease process, that is, just

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction some components of the events that would need to take place for the appearance of clinically relevant pathophysiology. Given the dominant Th1 nature of type 1 diabetes, MS, and most other autoimmune diseases, the prediction is that even if multiple immunizations had a cumulative bystander effect on potentially autoreactive T cells, the current vaccine program would be biased against the generation of Th1-dominated responses. And it is noted that this bias would be stronger now than at any time in the past. The committee concludes that there is weak evidence for bystander activation, alone or in concert with molecular mimicry, as a mechanism by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of autoimmunity. Moreover, the current routine childhood immunization schedule in the United States appears even less likely to act as an initiator or facilitator of autoimmunity than in the past. Multiple Immunizations and Infectious Diseases That Protect from Autoimmunity The mechanisms described above posit that immunizations play a direct role in the initiation or amplification of autoimmune processes. An alternative hypothesis is that immunizations increase the risk of autoimmunity by preventing infectious diseases that have protective effects. The theoretical deleterious effect might be specific to the infection prevented by the vaccine (a homologous effect), or result from a non-antigen-specific effect on the overall nature of the immune response (a heterologous effect). In either case, the notion is that a heretofore protective effect of infection has been lost by immunization. Homologous effects. The nature of a homologous effect can be illustrated by changes in the epidemiology of poliomyelitis, although this example does not involve autoimmune disease or vaccine-induced effects. The poliomyelitis epidemics that commenced in developed countries near the end of the 19th century are thought to have followed improvements in hygiene that postponed exposure to the virus beyond infancy (Plotkin and Orenstein, 1999; Wilson and Marcuse, 2001). Previously, wild-type poliovirus exposure most commonly occurred in infancy, at a time when passive maternally derived antibody provided partial protection. Thus, a child was first exposed under conditions in which acute paralytic disease was blocked but infection sufficient to immunize against disease on subsequent encounters resulted. Improved hygiene is believed to have reduced circulation of wild-type poliovirus sufficiently to delay exposure in many children until after passively acquired antibody was lost and they were fully susceptible. Further, reduced circulation of wild-type poliovirus would be predicted to result in lower levels of maternal antibody because of less frequent boosting, so that the magnitude of passive antibody transferred and duration of passive protection would be shorter (Zinkernagel, 2001). An immunization program might also be expected to leave infants more susceptible if

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction vaccine-induced immunity did not induce protective levels of passive maternal antibody and herd immunity sufficient to reduce wild-type virus spread. This potential problem was overcome by actively immunizing infants. A similar situation may apply to other vaccine-preventable diseases. In the case of measles, mumps, and rubella, the amount of passively-acquired antibody in infants born to mothers whose immunity is due to vaccination is less than and falls more quickly than in infants born to mothers whose immunity is due to wild-type virus infection. As a result, the age at which immunization induces protective antibody responses to measles is younger now than before the widespread use of MMR vaccine (Gans et al., 2001; Redd et al., 1999). For loss of homologous protection that results from multiple immunizations to be a factor in autoimmunity, a vaccine-preventable infection must cause autoimmune disease. The relative risk will also be affected by the extent to which wild-type infection still occurs in the community; herd immunity will reduce the risk of infection and therefore increase the risk of autoimmune disease. Of the vaccine-preventable diseases, only congenital rubella, which has been noted as inducing type 1 diabetes in about 20 percent of affected individuals, has been causally linked with a chronic autoimmune disorder. Mumps virus infection has been linked to type 1 diabetes in rare cases (IOM, 1994), but causality has not been established. Even though waning of immunity following immunization may delay the age of onset of vaccine-preventable infections, and thus may be a factor in the chronic rubella viral arthritis in adolescent females, there is no evidence that waning immunity and delayed infection increases the potential for induction or acceleration of type 1 diabetes by wild-type rubella or mumps virus. Furthermore, the incidence of type 1 diabetes has increased most in children in the youngest age group (age 0–4 years) (Karvonen et al., 1999b; Podar et al., 2001), arguing against waning immunity as the basis for the increased incidence. The same theoretical considerations apply to the vaccine-preventable diseases that are capable of inducing acute neurological autoimmune injury, including ADEM and Guillain-Barré syndrome. In the absence of experimental or human evidence regarding loss of protection against a homologous infection as a mechanism by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of autoimmunity, the committee concludes that this mechanism is only theoretical. Heterologous effects and the hygiene hypothesis. Possible heterologous effects of vaccination on autoimmunity can be considered in the context of the larger theoretical construct of the hygiene hypothesis, introduced earlier in the report. As noted previously, this hypothesis was first developed as a model to explain the rising increase in asthma and allergic diseases in the developed world (Strachan, 2000), and has been broadened recently to address the apparently

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction parallel increase in certain autoimmune diseases, including type 1 diabetes and MS (Rook, 2000; Rook and Stanford, 1998; reviewed in Wills-Karp et al., 2001). The hygiene hypothesis. The hygiene hypothesis is based on the notion that the human immune system (and that of other mammals) evolved in concert with constant exposure to a diverse and changing array of nonpathogenic environmental and commensal microbes, as well as under the persistent threat of lethal infectious diseases caused by microbial pathogens. This microbial exposure is thought to have conditioned the human immune system to respond vigorously to pathogenic microbes but not to harmless environmental antigens (allergens), normal microbial flora and environmental commensals, or self-antigens. Because birth is associated with a rapid switch from a sterile environment to a microbe-rich environment, to which the immune system must learn to respond properly, a component of the hypothesis is that the immune system may be particularly dependent on receiving appropriate conditioning through microbial exposure in early childhood. During the past century, the developed world has seen improvements in hygiene, the development of effective immunizations, and the advent of antibiotics. These changes have altered the relationships between humans and microbes and, by inference, the challenges that the immune system must meet to provide protection from infection. The magnitude of the change in these relationships over the past century is arguably greater than the total change over all previous millennia of human existence. The original hygiene hypothesis, developed as a model to explain the rising incidence of asthma and allergy, relied on the then recently elucidated Th1-Th2 paradigm that describes the ability of T cells to differentiate into cells with divergent effector functions. Th1 T cells produce interferon-γ and mediate or regulate cellular immunity and protection against viruses, bacteria, and invasive protozoans. Th2 T cells produce IL-4, IL-5, and IL-13, induce B cells to secrete IgE antibodies, and promote the development of eosinophils, which together mediate allergy and immunity to worms or helminthic parasites. As noted above, a number of microbial components stimulate cells of the innate immune system to produce IL-12 and other cytokines that cause T cells to differentiate into Th1 T cells and inhibit the development of Th2 T cells. The logic of the hygiene hypothesis is that constant microbial exposure has a bystander effect that impedes the development of Th2 T cells and allergic responses to harmless environmental antigens such as foods and pollens. Therefore the reduced microbial exposure that infants now experience is associated with reduced constraints on the development of Th2 T cells. The hygiene hypothesis also fits well with the notion (Adkins, 2000; Prescott et al., 1998; Rowe et al., 2001; Siegrist, 2001), not yet firmly established as fact (Delespesse et al., 1998; Hassan and Reen, 2000; Lewis and Wilson, 2001; Marchant et al., 1999), that T cell responses of the human fetus and young infant are Th2-biased and

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction gradually switch to a more balanced pattern over the first year or two of life in nonallergic children. Although these mechanisms were consistent with observed increases in allergic diseases, they ran counter to two other observations. First, the incidence of autoimmune diseases, particularly type 1 diabetes and MS, appears to have increased in the same or overlapping populations. These diseases, however, are characterized primarily by Th1 T cell responses. Second, although worms or helminthic parasites induce robust Th2 and IgE responses, children in the developing world with large worm burdens have a lower incidence of asthma or allergic diseases (van den Biggelaar et al., 2000). Moreover, in certain mouse models intestinal worms can protect from allergic diseases (Wang et al., 2001), and conversely Th1 promoters can exacerbate allergic disease, depending on the context in which they are administered (Bryan et al., 2000; Hansen et al., 1999). To address these apparent inconsistencies, modifications of the hygiene hypothesis posit that microbial exposure primarily acts not by deviating the immune response from Th2 to Th1, but by inducing the production of immunoregulatory cytokines (including IL-10 and TGF-ß) and T cells that dampen the immune response broadly, including both Th1 and Th2 responses (Rook et al., 2000; Wills-Karp et al., 2001). Many microbes, including worms or helminthic parasites, bacteria, and viruses, induce IL-10 and/or TGF-ß production (Letterio and Roberts, 1998; Moore et al., 2001; Rook et al., 2000; Wills-Karp et al., 2001). For example, increased IL-10 production in response to chronic parasitic infection with Schistosoma haematobium has been correlated with reduced evidence of allergic sensitization (van den Biggelaar et al., 2000). IL-10 and TGF-ß can impede antigen-specific T cell responses directly, by impairing antigen presenting cell function, or by the induction of anergic or regulatory T cells. When stimulated via the T-cell receptor, regulatory T cells suppress the responses of other T cells in a nonspecific manner by contact-dependent mechanisms and by production of IL-10 or TGF-ß. Mice that lack these regulatory cytokines or regulatory T cells develop inflammatory bowel disease or inflammatory or autoimmune disease in other tissues (Ermann and Fathman, 2001; Maloy and Powrie, 2001; Roncarolo and Levings, 2000; Rook et al., 2000; Shevach, 2000; Singh, 2000; Wills-Karp et al., 2001; Zhang et al., 2001). Various findings suggest that that the human neonate can produce regulatory cytokines and T cells, supporting the notion that the neonate’s immune system has the requisite immunoregulatory potential if the proper environmental signals are provided. Regulatory T cells are present and inducible in the blood of neonates (Roncarolo and Levings, 2000). Although the conditions required for their induction may differ somewhat from those in adults, it is not known at present if these differences are reproducible or biologically important. In addition, peripheral blood mononuclear cells and monocytes from the blood of human neonates can produce IL-10 and TGF-ß in response to microbes or their components (reviewed in Lewis and Wilson, 2001). Although the magnitude of the

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction response may be reduced compared with that in adults, the production of proinflammatory cytokines is also reduced in neonates, suggesting no imbalance in the production of pro- and anti-inflammatory cytokines. Thus the extent, nature, and timing of contact with microbes are proposed to play an important role in establishing a proper balance in the immune response in early childhood and in maintaining this balance thereafter. A balanced immune response fosters the development of protective immune responses against pathogenic microbes, while preventing both a deleterious Th1 response to self antigens or harmless commensal microbes and a Th2-mediated allergic response to harmless environmental antigens. The type of microbial exposure that is important in establishing this balance is not currently known. Proposed candidates include various gut microbial commensals, chronic infections with intestinal worms or helminthic parasites or Mycobacterium tuberculosis, frequent exposure to environmental mycobacteria or other soil organisms, and the timing, number, and nature of acute infections. Factors such as breast feeding, number of siblings and birth order, day care attendance, contact with animals, antibiotic use, and the timing and nature of immunizations have been proposed to affect risk for autoimmune (or allergic) diseases through their effects on the extent and nature of microbial contact (Rook, 2001; Rook and Stanford, 1998; Singh, 2000; Strachan, 2000; Wills-Karp et al., 2001). Whether the sum of all microbial exposure, some specific combination of exposures, or one particular type of exposure is the important factor, or whether these are surrogates for an as yet undefined factor that is important, is uncertain. Possible impact of vaccines on autoimmunity. On a numerical basis, vaccine-preventable infections represent a minute fraction of the overall infectious and microbial exposure in childhood. For immunization to have an impact on autoimmunity under the hygiene hypothesis, it would be necessary for one or more vaccine-preventable diseases to be particularly important for conditioning immunoregulatory immune responses. The gastrointestinal tract is proposed to play a particularly critical role in this process, so it would follow that immunizations that affect infection or colonization of the gut would be good candidates, but none of the childhood vaccines currently in use do so. (The rotavirus vaccine, which did affect the gut, was in use for too short a time to influence rates of autoimmunity.) Data from animal models suggest that no one infection is likely to be key, but, rather, a global reduction in microbial contact could be a factor. For example, prior exposure to or infection with a variety of microbes can prevent type 1 diabetes in non-obese diabetic (NOD) mice, as can certain vaccines (reviewed in Bach, 2001; Bach and Chatenoud, 2001; Hiltunen et al., 1999; Singh, 2000). The role of infection is complex in the EAE model. The potentially protective effect of prior mycobacterial or B. pertussis exposure (Bach, 2001; Ben-Nun et al., 1993, 1997; Hempel et al., 1985; Mostaricka-Stojkovic et al., 1988) may be related directly to their use as adjuvants at the time of subsequent immunization

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction with myelin proteins; thus the effect is not generalizable to autoimmune disease developing through more natural mechanisms, as in humans with MS. Nonetheless, if prior infection with one or both of these agents is assumed to be particularly important in establishing protection from autoimmune disease, the immunization schedule in the United States would have had no effect; use of BCG vaccine has never been recommended and, by analogy to the studies of EAE, administration of whole-cell B. pertussis vaccine—even as given in alum along with DT (Hempel et al., 1985)—should have been protective. It is possible that the acellular pertussis vaccines might lack the key components needed to provide protection against human autoimmune diseases, but even if this is so, the apparent increase in autoimmune disease began much earlier than the use of the acellular vaccine. If immunoregulatory cytokines and regulatory T cells play an essential role in impeding the untoward inflammatory responses to normal microbial flora that result in autoimmunity and allergy, and their generation or function depends on microbial contact, it follows that the necessary microbial cues must be established early in postnatal life, in parallel with the development of effector T and B cell responses. Furthermore, such cues must either be persistent or sufficiently frequent to maintain these protective immunoregulatory mechanisms. Because these mechanisms have presumably been operative in all human populations for millennia and only recently perturbed, the associated microbial exposure must be both universally present and long established. None of the diseases prevented by the current U.S. immunization program meets those conditions, nor does tuberculosis or measles, the two candidates proposed from studies of heterologous vaccine-induced protection in Africa (Kristensen et al., 2000). Although tuberculosis may induce persistent infection, fulfilling one requirement, it has not been endemic worldwide until the relatively recent past, nor has measles (Cherry, 1998; Daniel et al., 1994). The more likely candidates are commensal bacteria and ubiquitous environmental microbes, the richness and diversity of which are reduced in hygienic urban environments, or the cumulative exposure to these nonpathogenic microbes and to various invasive infections rather than any specific infection. The hygiene hypothesis is a model originally proposed based on epidemiological data. The biological mechanisms by which this model could explain an increase in incidence of autoimmune (or allergic) disease are substantial, and the biological evidence in support of the model is moderate to strong. However, the potential contribution of vaccine-preventable diseases as part of this model is minimal. In the absence of experimental or human evidence regarding mechanisms related to the hygiene hypothesis as a means by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of autoimmunity, the committee concludes that this mechanism is only theoretical.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction In theory, molecular mimicry, bystander activation, and impaired immunoregulatory mechanisms might act in an additive or synergistic manner to affect the risk of autoimmunity. Considering molecular mimicry, bystander activation, and impaired immunoregulation collectively rather than individually, the committee concludes that there is weak evidence for these mechanisms as means by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of autoimmunity. Multiple Immunizations and Allergy Allergic responses are directed against environmental antigens rather than self-antigens as in autoimmunity. In allergic disease, harmless environmental agents evoke Th2 responses and IgE antibody, which otherwise mediate useful protective responses to infections with worms or helminthic parasites. Allergic responses, such as anaphylaxis, are known to occur following vaccination and are reactions either to the vaccine antigens themselves or to other vaccine components. However, the major concern addressed here is whether there are biologically plausible mechanisms by which multiple immunizations might increase the risk of allergic responses to environmental antigens other than those contained in the vaccines—that is, heterologous allergic responses. By analogy to the theoretical frameworks in which the potential effects on autoimmunity were considered, multiple immunizations might influence heterologous allergic responses through a bystander mechanism that modifies the magnitude or quality of the immune response to environmental antigens, or they might prevent infectious diseases that do so. Bystander Effects The elimination of smallpox vaccine in 1972 and the substitution of DTaP (containing acellular pertussis vaccine) for DTwP (containing formalin-inactivated B. pertussis whole cells) in the 1990s removed two vaccine-based sources of microbial signals favoring Th1 and opposing Th2 responses (Ausiello et al., 1997; Rowe et al., 2001; Ryan et al., 1998). In theory, the replacement of the oral polio vaccine with an injected vaccine given in alum, along with the addition of other vaccines given in alum and administered as early as birth, favors the development of Th2 responses relative to Th1 responses. In mouse neonates (which have a developmentally less mature immune system than that of the human neonate), such a Th2 bias has clearly been shown in response to antigens in alum compared with antigens administered with microbial adjuvants (Adkins, 2000; Barrios et al., 1996; Siegrist, 2001). Alum also induces IL-4 production

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction from human mononuclear cells (Ulanova et al., 2001). However, except for evidence supporting a more Th2-directed immune response to components of DTaP than to DTwP (both of which are administered in alum), direct evidence is lacking that alum-containing vaccines deviate the immune response of human infants to environmental antigens toward Th2 responses. (For more details regarding this point, see the discussion of Th1 versus Th2 responses related to bystander effects of immunization and autoimmunity.) If such a deviation were to occur, whether it would be sufficient to result in clinically manifest allergy to these antigens would depend on other factors that are as yet incompletely elucidated. Nonetheless, the biological mechanisms by which immunizations that contain microbial stimuli favor Th1 responses and immunizations containing alum favor Th2 responses are well established. Although the impact of immunization on heterologous allergic responses is unknown, on balance the current routine childhood immunization schedule in the United States is less likely to favor Th1 responses to heterologous antigens and more likely to favor Th2 responses. The committee concludes that there is weak evidence for bystander activation as a mechanism by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of allergy. Prevention of Protective Infections: The Hygiene Hypothesis. The hygiene hypothesis is discussed in detail in the above autoimmunity section on “Heterologous Effects and the Hygiene Hypothesis”. In the context of allergic diseases, either a shift of the Th1-Th2 balance, a loss of immunoregulatory mechanisms that block untoward immune responses to environmental antigens, or both, could result in an increase in allergy. All but the first of these mechanisms are compatible with a parallel increase in allergic and autoimmune diseases. The same reasoning applied to the potential role of vaccine-preventable diseases in reducing risk of autoimmunity can be applied to the question of allergy, with one modification. If a specific type of infection or microbial exposure impaired heterologous Th2 responses, even if it did not play an important role in the generation of immunoregulatory cytokines or regulatory T cells, a vaccine that prevented the disease but was not an effective surrogate for the infection could contribute to the increased incidence of allergy. It does not appear that this occurs. Tuberculosis and measles infection have been proposed as agents that impair heterologous Th2 responses, although, unlike tuberculosis which is a strong Th1-inducing microbe, measles virus is unlikely to have such an effect (Wills-Karp et al., 2001) and neither disease meets the requirement of having been a long-time, ubiquitous infection of all human populations. Although the evidence is conflicting, it has also been proposed that the vaccines against these two diseases are effective surrogates for the infections in the prevention of allergy.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction The hygiene hypothesis is a theoretical model, originally proposed on the basis of epidemiological data. The biological mechanisms by which this model could explain an increase in incidence of allergic diseases are substantial, and the model is considered to be moderately to strongly plausible. However, the potential contribution of vaccine-preventable diseases as part of this theory is minimal. In the absence of experimental or human evidence regarding mechanisms related to the hygiene hypothesis as a means by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of allergy, the committee concludes that this mechanism is only theoretical. The committee concludes that there is weak evidence for the existence of any biological mechanisms, collectively or individually, by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk of allergy. Multiple Immunizations and Heterologous Infections Simultaneous or sequential infection or immunization with multiple vaccines or antigens can, through various mechanisms, influence the magnitude and/or quality of the immune response to individual antigens, either impeding or enhancing the immune response to one or the other, thereby affecting immune-mediated resolution of an infection and/or the development of protective immunity. There are several potential mechanisms by which this can occur, which vary with the nature of the antigen/agent and with the component of the immune response being evaluated or most important for providing protection. These include immune interference, T cell cross-reactivity, carrier-induced epitope suppression, and competition for antigen presentation (peptide competition for binding to MHC molecules or competition between T cells for the same antigen presenting cells). These mechanisms have been discussed in earlier reports from this committee (IOM, 2001a), and some have also been referred to in the preceding sections of this report. There is experimental animal evidence for each of these mechanisms in certain contexts. For the latter two mechanisms, there is also evidence from human studies that are relevant to the possible effects of multiple immunizations on risk for heterologous infections, which is briefly reviewed here. Carrier-Induced Epitope Suppression This process was first described in model systems, but has become clinically important in the context of conjugate vaccines. In such systems, the carrier is a protein antigen, to which is conjugated (covalently linked to create a single molecule) a non-protein antigen. In clinical practice, conjugation of a bacterial non-protein antigen to a protein carrier has been used to convert a

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction T cell-independent antigen (e.g., the type b capsular polysaccharide of Haemophilus influenzae or pneumococcal capsular polysaccharides) into a T cell-dependent antigen. Such conjugate vaccines are immunogenic in infants, inducing high-affinity IgG antibody and long-term immunological memory, whereas none of these features occurs when the polysaccharide alone is used as a vaccine. The basis for this is that the polysaccharide-protein conjugate will bind to and partially activate B cells that are specific for the polysaccharide, which internalize the conjugate, then process and present peptides from the protein component to CD4+ (helper) T cells specific for these peptides. This leads to activation of the T cells, that in turn help the B cells to produce high-affinity antibodies to the linked polysaccharide and mature into long-term memory B cells. In competition with these polysaccharide-specific B cells, are other B cells specific for the protein component of the conjugate. These B cells also present peptides to CD4+ T cells and in turn receive second signals allowing them to produce antibodies to the protein component of the conjugate vaccine. If the numbers of CD4+ T cells specific for the protein are limiting, then B cells specific for the polysaccharide component and B cells specific for the protein component of the conjugate are in competition with each other for limited numbers of CD4+ T cells capable of providing help (Insel, 1995). A variant of this can occur if multiple different carbohydrate antigens are conjugated to the same protein. In this case, the B cells specific for different carbohydrates may compete with each other for limited numbers of CD4- T cells. The latter situation may account in part for reduced responses seen when multivalent pneumococcal-tetanus toxoid conjugate vaccine was given along with H. influenzae type b-tetanus toxoid conjugate vaccine (Dagan et al., 1998). Competition for Antigen Presentation This describes a situation in which T cells responding to one antigen or infection compete with other T cells that are responding during the same time frame to other antigens or another infection, and one of the responses has a head start—it precedes the other by a few days or weeks. This gives the response to the earlier challenge a competitive advantage, such that it dominates and impedes the response to the delayed antigenic challenge or infection. Such competition is most readily observed in the context of strong CD8 T cell responses to viral infections (Chen, HD, 2001; Selin et al., 1998, 1999) or artificially manipulated immune responses (Kedl, 2000) in experimental animals. Bystander effects, including viral immune interference (see IOM, 2001a for more details) rather than competition for antigen presentation may affect responses to heterologous viral infections. An example of a heterologous effect in humans is the recent findings related to the timing of administration of MMR vaccine and varicella vaccine. If MMR and varicella vaccine are given at the same time or an interval of 30 or more days elapses between the administration of MMR and varicella vaccines, MMR and