Adverse Effects of Vaccines Evidence and Causality (2012) / Chapter Skim
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3 Evaluating Biological Mechanisms of Adverse Events
3 Evaluating Biological Mechanisms of Adverse Events
Pages 57-102
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From page 57... ...
LATENCY BETWEEN ANTIGEN EXPOSURE AND PEAK ADAPTIVE IMMUNE RESPONSE Antigen exposure initiates an array of reactions involving the immune system, including the activation of white blood cells called lymphocytes that fight infection. After antigen exposure, two types of lymphocytes, B cells and T cells, differentiate into effector (e.g., antibody-producing B cells and cytotoxic and helper T cells)
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From page 58... ...
Activated B and T cells in turn release inflammatory mediators leading to the recruitment and activation of additional immune cells that further amplify the immune response through the release of inflammatory mediators. Regulatory cells and soluble immunoregulatory mediators (not discussed in this report)
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From page 59... ...
leading to the release of inflammatory mediators and enhancement of the immune response as described above. The review by Coffman et al.
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From page 60... ...
class switching (e.g., IgM to IgE) ; to support the activity of CD8+ T cells; to recruit and activate eosinophils, basophils, neutrophils, mast cells, and macrophages; and to down-regulate immune responses (Koretzky, 2008; Wan and Flavell, 2009)
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From page 61... ...
. These include, but are not limited to, opsonization, neutralization, complement activation, augmentation, and engagement of constant region (Fc)
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From page 62... ...
Complement Activation The complement system is comprised of more than 30 soluble or membrane-bound proteins. Complement activation, an outcome of a cascade of enzymatic reactions, leads to the generation of inflammatory mediators that play a role in host defense via three physiological processes (Dunkelberger and Song, 2010)
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From page 63... ...
The initiation of the classical pathway occurs when the complement component C1q, in complex with the complement components C1r and C1s, bind immune complexes (comprised of antigen bound by IgG or IgM antibodies)
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From page 64... ...
. Hypersensitivity Reactions Hypersensitivity reactions are immune-mediated reactions to substances, termed allergens, which do not generate adverse immune responses in the majority of the population.
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From page 65... ...
Complement-Mediated Hypersensitivity Definition of complement-mediated hypersensitivity A much less frequent cause of immediate hypersensitivity is due to complement-mediated hypersensitivity, which involves the activation of the complement pathway by dialysis membranes, for example. Complement activation generates the anaphylatoxins C3a and C5a which bind to complement receptors on the surface of mast cells, leading to the release of inflammatory mediators (Noone and Osguthorpe, 2003)
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From page 66... ...
Immune Complexes When present in adequate concentrations, antigen and antibody generate large complexes, termed immune complexes, which can lead to initiation of the inflammatory cascade through complement activation and engagement of Fc receptors, and to increased vascular permeability through the release of vasoactive factors upon activation of mast cells and neutrophils (Gao et al., 2006; Malbec and Daeron, 2007; Mayadas et al., 2009; Roubin and Benveniste, 1985; Volanakis, 1990)
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From page 67... ...
. Examples of Natural Infection, Vaccine, or Drug Exposure Thought to Cause a Clinical Condition or Disease That Is Due to Immune Complexes There are several conditions in which immune complex–mediated tissue damage occurs.
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From page 68... ...
The adverse events most suggestive of immune complex– mediated symptomatology are those associated with hepatitis B vaccine, as it is known that the antibodies raised to viral antigen in the course of the natural infection can form damage-inducing complexes. There are no data, however, documenting immune complexes containing hepatitis B surface antigen.
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From page 69... ...
. Although specific susceptibility genes have not been identified in most patients with febrile seizures, several susceptibility loci that are inherited in an autosomal dominant fashion in certain families have been identified (Audenaert et al., 2006; Hedera et al., 2006; Johnson et al., 1998; Kugler et al., 1998; Nabbout et al., 2002; Nakayama et al., 2000, 2002, 2004; Peiffer et al., 1999; Poduri et al., 2009; Wallace et al., 1996)
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From page 70... ...
and self-antigen leading to the development of tissue damage and clinical disease from antibodies and T cells directed initially against the exogenous agent that also react against self-antigen. Molecular mimicry as a mechanism that can cause pathologic damage and disease has been demonstrated in several animal models, most notably experimental allergic encephalomyelitis (EAE)
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From page 71... ...
An in vivo pathogenic autoimmune attack would also require the demonstration of local binding of antibody with activation of the complement cascade, activation of the appropriate co-stimulatory T cell signals and cytokines, and/or involvement of other pathogenic effector mechanisms in a biologically relevant tissue site. Examples of a Natural Infection, Vaccine, or Drug Exposure Thought to Cause a Clinical Condition or Disease That Is Due to Molecular Mimicry While molecular mimicry is a well-established mechanism in selected animal models, its relevance to human autoimmune disease remains in most cases to be convincingly proven.
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From page 72... ...
on Our List Thought to Be Due to Molecular Mimicry Some of the vaccine AEs under consideration by our committee share symptoms with human autoimmune diseases for which molecular mimicry has been hypothesized (i.e., arthritis, systemic lupus erythematosus, insulindependent diabetes mellitus, central and peripheral nervous system demyelinating diseases)
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From page 73... ...
Based on the literature reviewed, molecular mimicry was not confirmed to be a mechanism leading to the development of the adverse events postvaccination. Antigen Persistence During a typical immune response, the offending antigen is effectively removed or neutralized, which reduces the immune stimulation and ultimately results in a down-regulation of the immune response.
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From page 74... ...
A third example of infectious disease associated with antigen persistence is immune reconstitution inflammatory syndrome which is an escalating immune response to chronically persisting antigen in patients with human immunodeficiency virus (HIV) who are co-infected with mycobacteria, cytomegalovirus, Cryptococcus, herpes simplex virus, and so on.
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From page 75... ...
Examples include drug modifications of normal proteins, hapten-carrier complexes, and oxidative modification of normal cellular constituents. In bystander activation, there is a robust or exaggerated immune response to an exogenous agent that induces local tissue inflammation and stimulation of otherwise normal unaffected cells.
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From page 76... ...
VIRAL ACTIVITY Viral infections cause a host of symptoms in affected individuals. Some of these symptoms are attributable to direct or primary infection, persistent viral infection, and viral reactivation.
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From page 77... ...
Viral Reactivation Reactivation of infection can occur when the virus, following the acute infection, remains in a dormant or latent state somewhere in the body, where it can subsequently reemerge. Varicella zoster virus (VZV)
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From page 78... ...
The salient points in these examples are that the adverse effects observed are complications seen with natural infection and that the causal role of the vaccine virus was demonstrated by its isolation or identification by molecular techniques, typically from sites that are otherwise sterile. INJECTION-RELATED ADVERSE EVENTS One or more of the mechanisms described above could play a role in the development of many of the adverse events following vaccination reviewed by the committee.
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From page 79... ...
. In some CRPS patients, increased sympathetic nervous system activity is associated with increases in spontaneous pain and hyperalgesia (Bruehl, 2010)
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From page 80... ...
. The increase in stimulation of the sympathetic nervous system results in an increased heart rate and arterial pressure (Grubb, 2005)
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From page 81... ...
. COAGULATION AND HYPERCOAGULABLE STATES Injury to the vessel wall, regardless of the type of injury, leads to the stimulation or activation of endothelial cells and platelets, and to the generation of a thrombus or blood clot.
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From page 82... ...
. Not all individuals who suffer invasive disease have demonstrated recognized immune deficiencies, even when vaccine virus is recovered from the patient (Iyer et al.,
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From page 83... ...
But even when the triggering antigen such as egg or gelatin is known, it is not clear why some people develop anaphylaxis while the vast majority does not. Proposed mechanisms for other immune-mediated adverse responses are many, including molecular mimicry, development of immune complexes, inappropriate cytokine responses, antigen persistence, and epitope spreading, as described above.
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From page 84... ...
also suggest a role for an altered immune response. As noted above, much work remains to be done to elucidate and to develop strategies to document the immunologic mechanisms that lead to adverse effects in individual patients.
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From page 85... ...
Nervous system development is under genetic control, and is incompletely understood, but it is clearly a highly complex process in which interactions with the environment beginning in the womb may modify the developmental process. Factors that may modify brain development include maternal, fetal, and infant nutrition; infection; toxins; vascular insults; direct trauma; and aspects of the social environment, in addition to mutations in critical genes regulating development.
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From page 86... ...
Animal models have been most helpful in understanding disease processes affecting the brain, particularly when these are expressed as structural or motor changes, or as seizures. Advances in molecular genetics have allowed genes to be knocked out completely, temporarily knocked down, or to create milder phenotypes (hypomorphs)
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From page 87... ...
Several lines of evidence, including functional and structural imaging studies (Anagnostou and Taylor, 2011) and neuropathology have pointed to abnormal patterns of neural connectivity as characteristic of autism spectrum disorders (Schipul et al., 2011; Wass, 2011)
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From page 88... ...
Several murine models of genetic disorders have autistic features, and although such models can never reproduce the complete human phenotype, they have added further evidence that disruption of the function of genes participating in brain development may lead to autism spectrum disorders (Ey et al., 2011)
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From page 89... ...
as well as specific chromosomal and single-gene defects, including a variety of metabolic disorders and inflammatory or infectious antecedants. CONTRIBUTION OF ANIMAL MODELS Laboratory animals have been studied for decades as a means to understand both normal physiology and pathogenesis of diseases.
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From page 90... ...
Studies of the immune response to microbial agents include vaccine studies that are also subject to the concerns discussed above. One frequent difference between vaccine studies in animals and humans is that vaccine studies in laboratory animals may include adjuvants that are not used in humans.
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From page 91... ...
The techniques used to show replication of measles virus in the labyrinth represent an advantage of animal models, as discussed above; techniques to show replication of measles virus in the labyrinth will not be performed on living human patients. With animal models, it is possible to study whether particular genetic deficiencies or preexisting conditions attenuate, augment, or alter the immune response to infectious agents or microbial antigen, or whether the microbial or antigenic challenge exacerbates the preexisting condition or reveals otherwise unappreciated consequences of the genetic deficiency.
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From page 92... ...
2006. Genes and loci involved in febrile seizures and related epilepsy syndromes.
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From page 93... ...
2010. Complement and its role in innate and adaptive immune responses.
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From page 94... ...
2006. Molecular mimicry, bystander activation, or viral persistence: Infections and autoimmune disease.
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2002. The effect of high salt concentration on detection of serum immune complexes and autoantibodies to C1q in patients with systemic lupus erythematosus.
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1998. Hereditary febrile seizures: Phenotype and evidence for a chromosome 19p locus.
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2005. Molecular mimicry, microbial infection, and autoimmune disease: Evolution of the concept.
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2009. A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.
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2003. Acute motor axonal neuropathy rabbit model: Immune attack on nerve root axons.
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2004. Febrile seizures: An update.
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From page 101... ...
1997. Detection and preliminary characteriza tion of circulating immune complexes in patients with Lyme disease.
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