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From page 23...
... In this report, the committee examines the hypothesis that receipt of multiple immunizations, as recommended by public health authorities, adversely affects the developing immune system.
From page 24...
... . The scientific assessment has two components: an examination of the epidemiological and clinical evidence regarding a possible causal relationship
From page 25...
... , are summarized in Appendix B To evaluate the hypothesis on multiple immunizations and immune system dysfunction, the committee collected information from several sources.
From page 26...
... 26 _ c3 , a} c: ~ ~:L3 i LO 1_ , c3 ~ LLI LLI 0 ~ ¢ ova U 0 0 t ° ~ Car)
From page 27...
... does or does not cause the adverse event in question. The weight of the available clinical and epidemiological evidence determines whether it is possible to shift from that neutral position to a finding for causality ("the evidence favors acceptance of a causal relationship")
From page 28...
... and others (IOM, 1991, 1994) as an assessment of the "biological plausibility" of a causal relationship.
From page 29...
... It is then left with the task of examining proposed or conceivable biological mechanisms that might be operating if an epidemiologically sound association could be shown between vaccine exposure and an adverse event. Identification of sound mechanisms could influence the development of an appropriate research agenda and give support for policymakers, as decisions frequently must be made in situations of incomplete information regarding causality.
From page 30...
... Thus the committee finds that for the purpose of its reports, the lack of clarity in the phrase "biological plausibility" warrants the adoption of new terminology and a new approach to its discussion of biological data. The committee will review evidence regarding "biological mechanisms" that might be consistent with the proposed relationship between a vaccine exposure and given adverse events.
From page 31...
... In general, the committee cannot rely heavily on unpublished data in making its scientific assessments (regarding either causality or biological mechanisms) because they have not been subjected to a rigorous peer review process, and therefore must be interpreted with caution.
From page 32...
... Furthermore, the immunization schedule seems likely to expand in the next decade, with more vaccines for infants and children being developed or considered. The increase in the number of vaccines and vaccine doses given to children has led to concerns among some about possible adverse effects of individual vaccines or of the aggregate vaccine exposure.
From page 33...
... These concerns have gained prominence due to a generic consideration of biological mechanisms and due to studies, mostly ecological analyses, that are occasionally salient in the lay and scientific literature. The committee considered two possible pathways to adverse outcomes: stimulation of harmful immune responses or suppression of beneficial immune responses.
From page 35...
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From page 36...
... . The committee also considered neurological disorders for which the injury is known to be caused by the immune response, including MS and Guillain-Barre syndrome, but did not include these in its causality considerations due to the paucity of epidemiological/clinical information that addresses the possible role of multiple immunizations rather than individual vaccines.
From page 37...
... During their development and at all stages of their subsequent existence, T and B lymphocytes are "educated" by their environment. Initially, their antigen receptors have no intrinsic bias that is, they are as likely to recognize antigens from the individual (self antigens)
From page 38...
... In some rare disorders, single-gene defects are uniformly associated with the development of autoimmunity.2 However, the vast majority of human autoimmune diseases appear to be complex traits in which multiple genetic factors determine disease susceptibility and environmental factors determine whether disease develops (Ermann and Fathmann, 2001, Robles and Eisenbarth, 2001, Wanstrat and Wakeland, 2001~. Familiar examples of such diseases include type la diabetes mellitus, systemic lupus erythematosus (SLE)
From page 39...
... Atopy or allergy refers to diseases resulting from IgE-associated immune responses to innocuous environmental substances, such as certain foods or pollens. Allergic individuals have a hereditary predisposition to mount IgE responses when they encounter such substances, which are referred to as allergens, and they develop "atopic" (allergic)
From page 40...
... Second, the DTwP vaccine the whole-cell pertussis (wP) vaccine generally given in combination with diphtheria (D)
From page 41...
... pertussis vaccines some of which may not be antigenic and others of which contain multiple epitopes to which the immune system responds. The calculations also do not address the effects of changes in the presence or absence of contaminating proteins.
From page 42...
... This is consistent with the theoretical estimates presented to the committee, which suggest that the capacity of the infant's immune system is at least 1000 times greater than that maximally required to respond to vaccines (Kollman, 2001, Offit et al., 2002~. It is the judgment of several scientific groups, including the Immunization Safety Review Committee, that the antigen load of the recommended childhood immunization schedule has decreased, not increased, in the last 20 years or so and that the infant immune system has an adequate capacity to respond to that number of antigens.
From page 43...
... Epidemiological literature in support of the hygiene hypothesis includes findings of a negative correlation between risk for allergic diseases and a host of factors that would increase a child's exposure to bacteria and other infectious agents. These risk factors include, for example, the number of older siblings, the presence of pets, infections through the fecaloral route, and rural living.
From page 44...
... Patients become severely ill during the first few days of illness, but atypical measles is self-limited and resolves in 7-14 days (Brodsky, 1972~.There was only one report of a possible fatality among cases seen in the 1960s following use of the inactivated measles vaccine (Read et al., 1999~. Children with atypical measles were found to lack the antibody to the measles virus F protein, which is responsible for the virus's hemolytic and cell fusion properties (Annunziato et al., 1982, Redd et al., 1999~.
From page 45...
... However, upon exposure to wild-type RSV, they developed more severe infections than unvaccinated children did (CDC, 2000a, IOM, 1985~. Thus, the experimental RSV vaccine was never used clinically.
From page 46...
... The etiology of type la diabetes and other autoimmune diseases is multifactorial, involving genetics and environmental exposures. Genetic susceptibility, arising from combinations of multiple genetic factors, appears to be a necessary but not sufficient risk factor for the disease.
From page 47...
... Early exposure to certain viral infections also has shown protective effects (Ilk et al., 2001, Openshaw and Hewitt, 2000) , but some
From page 48...
... 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.
From page 49...
... 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.
From page 50...
... The authors concluded that there was no increase in the risk for invasive bacterial infection following receipt of DTwP vaccine, especially during the early postimmunization period. Interpretation of the study is limited by the lack of an unvaccinated comparison group.
From page 51...
... 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)
From page 52...
... 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.
From page 53...
... 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)
From page 54...
... . 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)
From page 55...
... 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.
From page 56...
... 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.
From page 57...
... 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.
From page 58...
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From page 59...
... also facilitates their recruitment to the target tissue. Bystander effects are almost certainly essential for molecular mimicry to succeed in overcoming normal regulatory mechanisms (see Figure 3~.
From page 60...
... 60 as x .s ~ .
From page 62...
... Rates of exposure to DT or DTP vaccine were assessed from yearly vaccination reports of child health care centers. Estimates of pertussis vaccine exposure among children born in 1980 or 1981 were based on reports of vaccine doses released.
From page 63...
... No associations were observed for children age 6 to 7 years. The authors concluded that DTP vaccines are not risk factors for allergic disease at the population level.
From page 65...
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From page 67...
... elevated odds ratios could be due to selection bias, exposure misclassification or multiple comparisons. United States.
From page 68...
... Information was obtained from medical records and a regional child health database on vaccines received (i.e., diphtheria-tetanus-whole-cell pertussis/diphtheria-tetanus, polio, and measles) and diagnoses of allergic diseases such as hay fever and asthma.
From page 69...
... examined the relationship between immunization and allergic disease in infants. Data on vaccines received, asthma, and allergic diseases were collected for 1,265 children born in 1977 and participating in a New Zealand health study.
From page 70...
... Although they used a logistic regression model for analysis, which would ordinarily generate odds ratios (and attendant Is) for the risk of asthma due to various immunizations, they appeared (not described)
From page 71...
... The authors concluded that there was no evidence supporting an increase in allergic disease after pertussis immunization of the magnitude reported in some other studies, and if there was any increased risk, they thought it was most likely to be associated with the acellular pertussis vaccines. However, limitations included wide confidence intervals restriction to symptom development before 2.5 years of age, the unclear and nonstandard statistical approach, and the focus only on the pertussis component of the immunization schedule.
From page 72...
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From page 73...
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From page 75...
... The ecological study indicated a protective DPT effect, and the only randomized study indicated minimal or no effect of pertussis vaccines, with a non-significant reduction in risk from the whole-cell vaccine. Given the design weaknesses in the observational studies, with effect sizes and modest degrees of statistical significance that are not robust to probable biases, and a randomized trial study that does not support the risk factor most frequently implicated in the observational studies, the committee concludes that the epidemiological and clinical evidence is inadequate to accept or reject a causal relationship between multiple immunization and an increased risk of allergic disease, particularly asthma.
From page 76...
... The evidence regarding the possibility that these mechanisms actually contribute to autoimmune diseases is discussed in a later section. Molecular mimicry.
From page 77...
... MULTIPLE IMMUNIZATIONS Relative accentuation of The responses env~ronnner~tal ark O;3'a car 77 1 The and other beneficial / responses 1 r / ~ 1 tAote{:lllar 1+ 1~1~ 1 ~ 1 in_ Key; ~=~ Eon Over-riding or inadequacy of normal ~mmunoregulam~y ~nechanisrns .
From page 78...
... infection and capable of enhancing autoimmune reactions. These nonspecific immune responses are usually self-limited, however, and resolve as the infection is cleared.
From page 79...
... Bystander effects are almost certainly essential for molecular mimicry to succeed in overcoming normal regulatory mechanisms (see Figure 3~. Through a process referred to as epitope spreading, the initial activation by an infection of cross-reactive T cells that react to a single self-antigen may play a critical role in facilitating, in a bystander-like manner, the activation of T cells that recognize other self antigens.
From page 80...
... 6 For historical reasons this process is called allergic rather than autoimmune encephalomyelitis. But the injury in this disease is mediated by Thl T cells, not Th2 T cells and IgE antibodies, which are the mediators of allergic diseases.
From page 81...
... Arguably the strongest evidence for true persistent autoimmunity induced by a specific infectious agent in humans is chronic Lyme disease arthritis. In this disease, there is clear evidence of genetic predisposition (linked to HLA type)
From page 82...
... The evidence that more than one infectious agent can trigger the onset of reactive arthritis and demyelinating neurological diseases is consistent with the notion that bystander effects may be a common feature of infection-induced autoimmune injury. Also, the evidence that a given T cell may be able to recognize multiple peptide-MHC complexes (Marrack et al.
From page 83...
... MULTIPLE IMMUNIZATIONS 83 TABLE 5 Putative Examples of Molecular Mimicry in Human Autoimmune Disorders with Proposed Cross-Reactive Autoantigens and Infection-Derived Antigens Organ/ Infection/ Cross Lyme arthritis Joints/LFA-1 Borrelia T cells burgdorferil Osp A Rheumatoid Joints/Hsp60 Mycobacteria/ T cells arthritis Hsp65 Multiple Brain/Myelin Papillomavirus/ T cells sclerosis basic protein L2 TypeIdiabetes PancreaticI3- CoxsackieB/ T cells cells/GAD P2-C Stiff man GABA-ergic hCMV/DNA T cells syndrome neurons/GAD binding protein Primary biliary Bile duct/pyrdeH E.coli/PDC-E2 T cells cirrhosis complex Rheumatoid Joints/DRBl* 04 E.colilDNAJI T cells/Antibody arthritis 01 EBV/gp 1 10 Multiple Brain/Myelin EBV/capsid T cells/Antibody sclerosis basic protein Myocarditis Heart/myosin Chlamydia/60kD T cells/Antibody protein Rheumatic fever Heart/cardiac Streptococci/ Antibody myosin/heart M protein b valves/kidney/ CNS Chagas disease Heart/3-1 adren- Trypanosoma Antibody ergic receptor cruzi/ribosomal protein Myasthenia Muscle/ Herpes Antibody gravis acetylcholine simplex/gpD receptor Guillain-Barre Peripheral nerve Campylobacter Antibody syndrome gangliosides jejuni LPS Source: Adapted from Marrack et al., 2001; Wucherpfennig, 2001
From page 84...
... That factors related to infection and immunization can affect immune responses raises the theoretical possibility that changes to vaccine formulations or the vaccine schedule might also alter the potential for vaccines to induce, facilitate, or amplify immune-mediated injury or autoimmunity. Theoretically, concomitant or sequential administration of multiple vaccines could have several possible effects, alone or in combination.
From page 85...
... It remains theoretically possible that molecular mimicry occurs in response to other vaccines but that the extent of the immune response induced has been insufficient to induce clinically evident disease. If this were the case, the addition of new vaccines that also induced cross-reactive immune responses might initiate injury and epitope spreading sufficient to result in clinically manifest autoimmunity.
From page 86...
... infant immunization schedule could possibly influence an individual's risk of autoimmunity, the committee concludes that these mechanisms are only theoretical. Bystander effects.
From page 87...
... Thus the bystander effects of vaccines on the systemic immune responses, which in theory might induce autoimmunity, are less robust than those resulting from wildtype infection. Coadministration of vaccines.
From page 88...
... 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)
From page 89...
... 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.
From page 90...
... 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.
From page 91...
... 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.
From page 92...
... , and conversely Thl 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 Thl, but by inducing the production of immunoregulatory cytokines (including IL-10 and TGF-~)
From page 93...
... A balanced immune response fosters the development of protective immune responses against pathogenic microbes, while preventing both a deleterious Thl 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.
From page 94...
... 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 effecter T and B cell responses.
From page 95...
... 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.
From page 96...
... 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 Thl-Th2 balance, a loss of immunoregulatory mechanisms that block untoward immune responses to environmental antigens, or both, could result in an increase in allergy.
From page 97...
... 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 immunemediated resolution of an infection and/or the development of protective immunity.
From page 98...
... Bystander effects, including viral immune interference (see IOM, 2001 a for more details) rather than competition for antigen presentation may affect responses to heterologous viral infections.
From page 99...
... infant immunization schedule could possibly influence an individual's risk for heterologous infections. SIGNIFICANCE ASSESSMENT The charge to the Immunization Safety Review committee includes consideration of the public health response to the immunization safety concerns it examines.
From page 100...
... Also discussed are indications of public concern about the safety of multiple immunizations and ideas that have been put forward about alternative approaches to the formulation of immunization policy. Disease Burden Autoimmune Disorders: Type I Diabetes As noted, diseases of autoimmunity affect 3 to 5 percent of the U.S.
From page 101...
... A serious allergic disease, asthma was estimated to have affected 14.6 million adults in 2000 (CDC, 2001b) and about 4 million children in 1998 (CDC, 2001a)
From page 102...
... , and in October 1999, the rotavirus vaccine was withdrawn from the childhood immunization schedule because of its association with increased reports of intussusception.8 Most recently, the threat of bioterrorism has led to discussion of vaccines against smallpox and anthrax, focusing attention on the benefits as well as the risks of using those vaccines. Without direct evidence, however, it is hard to know what effect such events have on beliefs and perceptions regarding vaccine safety, including any concerns regarding administration of multiple vaccines.
From page 103...
... But a better understanding of how such concerns affect decisions about immunization will also be needed. Considering Alternative Approaches to Immunization Policy The increasing number of vaccines in the childhood immunization schedule and the anticipated addition of still more vaccines is raising questions not only about the safety of multiple immunizations but also about the adequacy of the current approach to immunization policy-making, which emphasizes national recommendations and state mandates for universal immunization.
From page 104...
... acknowledged the challenges of reaching consensus regarding immunization policies with their broader approach to these issues, but they argued that more explicit attention to a wider range of conflicting views and values is needed to maintain public trust in immunization and other public health programs. Conclusions The committee's assessment of the significance of concerns about possible immune system dysfunctions as a result of multiple immunizations took several factors into account: the burden of the possible adverse outcomes of autoimmune diseases such as type 1 diabetes and allergic diseases such as asthma, indications of the extent of the concern about multiple immunizations, and views regarding the framework for immunization policy-making.
From page 105...
... The generalizability of the epidemiological evidence and the causality assessments to every possible type of exposure to multiple immunizations and every type of immune dysfunction is not clear. In addition, the burden of autoimmune and allergic diseases is great.
From page 106...
... By issuing the recommendation listed above, the committee does not intend to signal concern about health consequences of the multiple immunizations in the recommended childhood immunization schedule. In fact, the committee does not recommend a policy review by the CDC's Advisory Committee on Immunization Practices (ACIP)
From page 107...
... However, one of the challenges in addressing concerns about multiple immunizations is identification of appropriate and adequately sized study populations, allergy or autoimmune diseases have complex risk factors and potentially long intervals between vaccine exposure and diagnosis. Several vaccine-related data resources already exist, including the Vaccine Adverse Event Reporting System (VAERS)
From page 108...
... For allergic disorders, the clinical history of allergic diseases should be collected in follow-up evaluations, and the feasibility of specific tests for atopy considered. Studies of the normal development of the immune system in conjunction with surrogate markers of autoimmune and allergic disease and a cohort analysis of autoimmune and allergic disease could be carried out not only in the United States but in infants in a less developed country.
From page 109...
... Such data might also be useful in vaccine-related studies in high-risk cohorts, such as those in the DAISY study. The committee recommends exploring surrogates for type I diabetes and clinical history of allergic diseases in existing cohort studies of variations in the immunization schedule.
From page 110...
... But a review of the possible biological mechanisms for any adverse effects of multiple immunization on immune function suggests that the infant immune system is inherently capable of handling the numbers of antigens presented during routine immunization. A review of the clinical and epidemiological literature favors rejection of a causal relationship between multiple immunizations and risk of infection and type 1 diabetes.
From page 111...
... MULTIPLE IMMUNIZATIONS TABLE 6 Biological Mechanisms for the Possible Role of Immunizations in Increasing the Risk of Immune Dysfunction 111 Adverse Health Outcome Autoimmune disease Mechanism Molecular mimicry Bystander effect Loss of protection induced by homologous infection Via the hygiene hypothesis Collective mechanistic possibilities Committee Conclusion About the Weight of the Biological Evidence Theoretical only Weak Allergic disease Bystander effect Via the hygiene hypothesis Collective mechanistic Weak possibilities Heterologous Infections Carrier-induced epitope suppression Competition for antigen presentation Theoretical only Theoretical only Weak Weak Theoretical only
From page 113...
... MULTIPLE IMMUNIZATIONS 113 ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: 1e commr rem =nc us -elf t path n-e-~ -is wee <~ evlf enCe orb Jv$1a-n-c -Earl ace ..
From page 114...
... 114 IMMUNIZATION SAFETY RE VIE W - - -, ~om.ml~ee. o anv curmntIv Icensec vaccines on t ~e Oasis o concerns ~ The committee eco-m-m-end-s~ expel ..............................................................................................................................................................
From page 115...
... 1997. Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines.
From page 116...
... 1991. Apparent decreased risk of invasive bacterial disease after heterologous childhood immunization.
From page 117...
... 1995. The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCG-vaccination.
From page 118...
... 1992. No increased risk for invasive bacterial infection found following diphtheria-tetanus-pertussis immunization.
From page 119...
... 1996. A controlled trial of a twocomponent acellular, a f~ve-component acellular, and a whole-cell pertussis vaccine.
From page 120...
... 2001. Allergy and allergic diseases.
From page 121...
... 1998. Regulation of immune responses by TGF-beta.
From page 122...
... 1997. Randomized controlled trial of two-component, three-component, and f~ve- component acellular pertussis vaccines compared with whole-cell pertussis vaccine.
From page 123...
... 2001. Heterogeneity in diphtheria-tetanus-acellular pertussis vaccine specif~c cellular immunity during infancy: Relationship to variations in the kinetics of postnatal maturation of systemic Thl function.
From page 124...
... 1998. Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children.
From page 125...
... 1998. Molecular mimicry by herpes simplex virus-type 1: Autoimmune disease after viral infection.


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