1. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain
Abstracts
Background:
Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/ submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocytelineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA).
Methods:
On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used.
Results:
Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation.
Conclusion:
Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production. Keywords: Alum, Vaccine adverse effect, Vaccine adjuvant, Nanomaterial biodistribution, Nanomaterial neurodelivery, Macrophages, Macrophagic myofasciitis, CCL-2, Single nucleotide polymorphisms (SNPs)”
Link
http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-11-99
Citation
Khan, Zakir, Christophe Combadière, François-Jérôme Authier, Valérie Itier, François Lux, Christopher Exley, Meriem Mahrouf-Yorgov, Xavier Decrouy, Philippe Moretto, Olivier Tillement, Romain K. Gherardi, and Josette Cadusseau. "Slow CCL2-dependent Translocation of Biopersistent Particles from Muscle to Brain." BMC Medicine BMC Med 11.1 (2013)
Background:
Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/ submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocytelineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA).
Methods:
On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used.
Results:
Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation.
Conclusion:
Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production. Keywords: Alum, Vaccine adverse effect, Vaccine adjuvant, Nanomaterial biodistribution, Nanomaterial neurodelivery, Macrophages, Macrophagic myofasciitis, CCL-2, Single nucleotide polymorphisms (SNPs)”
Link
http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-11-99
Citation
Khan, Zakir, Christophe Combadière, François-Jérôme Authier, Valérie Itier, François Lux, Christopher Exley, Meriem Mahrouf-Yorgov, Xavier Decrouy, Philippe Moretto, Olivier Tillement, Romain K. Gherardi, and Josette Cadusseau. "Slow CCL2-dependent Translocation of Biopersistent Particles from Muscle to Brain." BMC Medicine BMC Med 11.1 (2013)
2. Self-Organized Criticality Theory of Autoimmunity
Abstracts
Background:
The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune ‘system’, to explain the cause of autoimmunity.
Methodology/Principal Findings:
Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8+ T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen crosspresentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).
Conclusions/Significance:
Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality
Link
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008382
Citation
Tsumiyama K, Miyazaki Y, Shiozawa S (2009) Self-Organized Criticality Theory of Autoimmunity. PLoS ONE 4(12): e8382. doi:10.1371/journal.pone.0008382
Background:
The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune ‘system’, to explain the cause of autoimmunity.
Methodology/Principal Findings:
Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8+ T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen crosspresentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).
Conclusions/Significance:
Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality
Link
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008382
Citation
Tsumiyama K, Miyazaki Y, Shiozawa S (2009) Self-Organized Criticality Theory of Autoimmunity. PLoS ONE 4(12): e8382. doi:10.1371/journal.pone.0008382
3. Predicting post-vaccination autoimmunity: Who might be at risk?
Abstracts
“Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded in improving public health. However, adverse effects, including autoimmune conditions may occur following vaccinations (autoimmune/inflammatory syndrome induced by adjuvants – ASIA syndrome). It has been postulated that autoimmunity could be triggered or enhanced by the vaccine immunogen contents, as well as by adjuvants, which are used to increase the immune reaction to the immunogen. Fortunately, vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the number of individuals developing post-vaccination ASIA. In this perspective we defined four groups of individuals who might be susceptible to develop vaccination-induced ASIA: patients with prior postvaccination autoimmune phenomena, patients with a medical history of autoimmunity, patients with a history of allergic reactions, and individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases; presence of autoantibodies; carrying certain genetic profiles, etc.).”
Link
https://www.ncbi.nlm.nih.gov/pubmed/25277820
Citation
Soriano, Alessandra, Gideon Nesher, and Yehuda Shoenfeld. "Predicting Post-vaccination Autoimmunity: Who Might Be at Risk?" Pharmacological Research 92 (2015): 18-22.
“Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded in improving public health. However, adverse effects, including autoimmune conditions may occur following vaccinations (autoimmune/inflammatory syndrome induced by adjuvants – ASIA syndrome). It has been postulated that autoimmunity could be triggered or enhanced by the vaccine immunogen contents, as well as by adjuvants, which are used to increase the immune reaction to the immunogen. Fortunately, vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the number of individuals developing post-vaccination ASIA. In this perspective we defined four groups of individuals who might be susceptible to develop vaccination-induced ASIA: patients with prior postvaccination autoimmune phenomena, patients with a medical history of autoimmunity, patients with a history of allergic reactions, and individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases; presence of autoantibodies; carrying certain genetic profiles, etc.).”
Link
https://www.ncbi.nlm.nih.gov/pubmed/25277820
Citation
Soriano, Alessandra, Gideon Nesher, and Yehuda Shoenfeld. "Predicting Post-vaccination Autoimmunity: Who Might Be at Risk?" Pharmacological Research 92 (2015): 18-22.
4. On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives
Abstracts
“Adjuvants are compounds incorporated into vaccines to enhance immunogenicity and the development of these molecules has become an expanding field of research in the last decades. Adding an adjuvant to a vaccine antigen leads to several advantages, including dose sparing and the induction of a more rapid, broader and strong immune response. Several of these molecules have been approved, including aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), virosomes and AS04. Adjuvants have recently been implicated in the new syndrome named “ASIA—Autoimmune/inflammatory Syndrome Induced by Adjuvants”, which describes an umbrella of clinical conditions including postvaccination adverse reactions. Recent studies implicate a web of mechanisms in the development of vaccine adjuvant-induced autoimmune diseases, in particular, in those associated with aluminium-based compounds. Fewer and unsystematised data are instead available about other adjuvants, despite recent evidence indicating that vaccines with different adjuvants may also cause specific autoimmune adverse reactions possible towards different pathogenic mechanisms. This topic is of importance as the specific mechanism of action of each single adjuvant may have different effects on the course of different diseases. Herein, we review the current evidence about the mechanism of action of currently employed adjuvants and discuss the mechanisms by which such components may trigger autoimmunity”
Link
http://www.sciencedirect.com/science/article/pii/S1568997215001226
Citation
Pellegrino, Paolo, Emilio Clementi, and Sonia Radice. "On Vaccine's Adjuvants and Autoimmunity: Current Evidence and Future Perspectives." Autoimmunity Reviews 14.10 (2015): 880-88.
“Adjuvants are compounds incorporated into vaccines to enhance immunogenicity and the development of these molecules has become an expanding field of research in the last decades. Adding an adjuvant to a vaccine antigen leads to several advantages, including dose sparing and the induction of a more rapid, broader and strong immune response. Several of these molecules have been approved, including aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), virosomes and AS04. Adjuvants have recently been implicated in the new syndrome named “ASIA—Autoimmune/inflammatory Syndrome Induced by Adjuvants”, which describes an umbrella of clinical conditions including postvaccination adverse reactions. Recent studies implicate a web of mechanisms in the development of vaccine adjuvant-induced autoimmune diseases, in particular, in those associated with aluminium-based compounds. Fewer and unsystematised data are instead available about other adjuvants, despite recent evidence indicating that vaccines with different adjuvants may also cause specific autoimmune adverse reactions possible towards different pathogenic mechanisms. This topic is of importance as the specific mechanism of action of each single adjuvant may have different effects on the course of different diseases. Herein, we review the current evidence about the mechanism of action of currently employed adjuvants and discuss the mechanisms by which such components may trigger autoimmunity”
Link
http://www.sciencedirect.com/science/article/pii/S1568997215001226
Citation
Pellegrino, Paolo, Emilio Clementi, and Sonia Radice. "On Vaccine's Adjuvants and Autoimmunity: Current Evidence and Future Perspectives." Autoimmunity Reviews 14.10 (2015): 880-88.
5. Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations
Abstracts
“Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as ‘‘small adults’’ with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., ‘‘ASIA’’), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in ‘‘ASIA’’ and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuroimmune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/22235057
Citation
Tomljenovic, L., and C. Shaw. "Mechanisms of Aluminum Adjuvant Toxicity and Autoimmunity in Pediatric Populations." Lupus 21.2 (2012): 223-30.
“Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as ‘‘small adults’’ with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., ‘‘ASIA’’), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in ‘‘ASIA’’ and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuroimmune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/22235057
Citation
Tomljenovic, L., and C. Shaw. "Mechanisms of Aluminum Adjuvant Toxicity and Autoimmunity in Pediatric Populations." Lupus 21.2 (2012): 223-30.
6. Exposure to Mercury and Aluminum in Early Life: Developmental Vulnerability as a Modifying Factor in Neurologic and Immunologic Effects
Abstracts
“Currently, ethylmercury (EtHg) and adjuvant-Al are the dominating interventional exposures encountered by fetuses, newborns, and infants due to immunization with Thimerosal-containing vaccines (TCVs). Despite their long use as active agents of medicines and fungicides, the safety levels of these substances have never been determined, either for animals or for adult humans—much less for fetuses, newborns, infants, and children. I reviewed the literature for papers reporting on outcomes associated with (a) multiple exposures and metabolism of EtHg and Al during early life; (b) physiological and metabolic characteristics of newborns, neonates, and infants relevant to xenobiotic exposure and effects; (c) neurobehavioral, immunological, and inflammatory reactions to Thimerosal and Al-adjuvants resulting from TCV exposure in infancy. Immunological and neurobehavioral effects of Thimerosal-EtHg and Al-adjuvants are not extraordinary; rather, these effects are easily detected in high and low income countries, with co-exposure to methylmercury (MeHg) or other neurotoxicants. Rigorous and replicable studies (in different animal species) have shown evidence of EtHg and Al toxicities. More research attention has been given to EtHg and findings have showed a solid link with neurotoxic effects in humans; however, the potential synergic effect of both toxic agents has not been properly studied. Therefore, early life exposure to both EtHg and Al deserves due consideration”
Link
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344667/
Citation
Dórea, José G. "Exposure to Mercury and Aluminum in Early Life: Developmental Vulnerability as a Modifying Factor in Neurologic and Immunologic Effects." International Journal of Environmental Research and Public Health 12.2 (2015): 1295-313.
“Currently, ethylmercury (EtHg) and adjuvant-Al are the dominating interventional exposures encountered by fetuses, newborns, and infants due to immunization with Thimerosal-containing vaccines (TCVs). Despite their long use as active agents of medicines and fungicides, the safety levels of these substances have never been determined, either for animals or for adult humans—much less for fetuses, newborns, infants, and children. I reviewed the literature for papers reporting on outcomes associated with (a) multiple exposures and metabolism of EtHg and Al during early life; (b) physiological and metabolic characteristics of newborns, neonates, and infants relevant to xenobiotic exposure and effects; (c) neurobehavioral, immunological, and inflammatory reactions to Thimerosal and Al-adjuvants resulting from TCV exposure in infancy. Immunological and neurobehavioral effects of Thimerosal-EtHg and Al-adjuvants are not extraordinary; rather, these effects are easily detected in high and low income countries, with co-exposure to methylmercury (MeHg) or other neurotoxicants. Rigorous and replicable studies (in different animal species) have shown evidence of EtHg and Al toxicities. More research attention has been given to EtHg and findings have showed a solid link with neurotoxic effects in humans; however, the potential synergic effect of both toxic agents has not been properly studied. Therefore, early life exposure to both EtHg and Al deserves due consideration”
Link
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344667/
Citation
Dórea, José G. "Exposure to Mercury and Aluminum in Early Life: Developmental Vulnerability as a Modifying Factor in Neurologic and Immunologic Effects." International Journal of Environmental Research and Public Health 12.2 (2015): 1295-313.
7. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep
Abstracts
“We describe a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination. The syndrome shows an acute phase that affects less than 0.5% of animals in a given herd, it appears 2-6 days after an adjuvant-containing inoculation and it is characterized by an acute neurological episode with low response to external stimuli and acute meningoencephalitis, most animals apparently recovering afterward. The chronic phase is seen in a higher proportion of flocks, it can follow the acute phase, and it is triggered by external stimuli, mostly low temperatures. The chronic phase begins with an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death. Gross lesions are related to a cachectic process with muscular atrophy, and microscopic lesions are mostly linked to a neurodegenerative process in both dorsal and ventral column of the gray matter of the spinal cord. Experimental reproduction of ovine ASIA in a small group of repeatedly vaccinated animals was successful. Detection of Al(III) in tissues indicated the presence of aluminum in the nervous tissue of experimental animals. The present report is the first description of a new sheep syndrome (ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can have devastating consequences as it happened after the compulsory vaccination against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of other similar diseases affecting both human and animals. A major research effort is needed in order to understand its complex pathogenesis.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/23579772
Citation
L, Luján et al. "Autoimmune/autoinflammatory Syndrome Induced by Adjuvants (ASIA Syndrome) in Commercial Sheep." Immunologic Research 56.2-3 (2013): 317-24
“We describe a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination. The syndrome shows an acute phase that affects less than 0.5% of animals in a given herd, it appears 2-6 days after an adjuvant-containing inoculation and it is characterized by an acute neurological episode with low response to external stimuli and acute meningoencephalitis, most animals apparently recovering afterward. The chronic phase is seen in a higher proportion of flocks, it can follow the acute phase, and it is triggered by external stimuli, mostly low temperatures. The chronic phase begins with an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death. Gross lesions are related to a cachectic process with muscular atrophy, and microscopic lesions are mostly linked to a neurodegenerative process in both dorsal and ventral column of the gray matter of the spinal cord. Experimental reproduction of ovine ASIA in a small group of repeatedly vaccinated animals was successful. Detection of Al(III) in tissues indicated the presence of aluminum in the nervous tissue of experimental animals. The present report is the first description of a new sheep syndrome (ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can have devastating consequences as it happened after the compulsory vaccination against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of other similar diseases affecting both human and animals. A major research effort is needed in order to understand its complex pathogenesis.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/23579772
Citation
L, Luján et al. "Autoimmune/autoinflammatory Syndrome Induced by Adjuvants (ASIA Syndrome) in Commercial Sheep." Immunologic Research 56.2-3 (2013): 317-24
8. Aluminum Vaccine Adjuvants: Are they Safe?
Abstracts
“Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science’s understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue”
Link
https://www.ncbi.nlm.nih.gov/pubmed/21568886
Citation
Tomljenovic, L., and C. A. Shaw. "Aluminum Vaccine Adjuvants: Are They Safe?" CMC Current Medicinal Chemistry 18.17 (2011): 2630-637.
“Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science’s understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue”
Link
https://www.ncbi.nlm.nih.gov/pubmed/21568886
Citation
Tomljenovic, L., and C. A. Shaw. "Aluminum Vaccine Adjuvants: Are They Safe?" CMC Current Medicinal Chemistry 18.17 (2011): 2630-637.
9. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity
Abstracts
“We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/23609067
Citation
Shaw, C. A., and L. Tomljenovic. "Aluminum in the Central Nervous System (CNS): Toxicity in Humans and Animals, Vaccine Adjuvants, and Autoimmunity." Immunologic Research 56.2-3 (2013): 304-16. Web.
“We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/23609067
Citation
Shaw, C. A., and L. Tomljenovic. "Aluminum in the Central Nervous System (CNS): Toxicity in Humans and Animals, Vaccine Adjuvants, and Autoimmunity." Immunologic Research 56.2-3 (2013): 304-16. Web.
10. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration
Abstracts
“Gulf War Syndrome is a multi-system disorder afflicting many veterans of Western armies in the 1990–1991 Gulf War. A number of those afflicted may show neurological deficits including various cognitive dysfunctions and motor neuron disease, the latter expression virtually indistinguishable from classical amyotrophic lateral sclerosis (ALS) except for the age of onset. This ALS “cluster” represents the second such ALS cluster described in the literature to date. Possible causes of GWS include several of the adjuvants in the anthrax vaccine and others. The most likely culprit appears to be aluminum hydroxide. In an initial series of experiments, we examined the potential toxicity of aluminum hydroxide in male, outbred CD-1 mice injected subcutaneously in two equivalent-tohuman doses. After sacrifice, spinal cord and motor cortex samples were examined by immunohistochemistry. Aluminum-treated mice showed significantly increased apoptosis of motor neurons and increases in reactive astrocytes and microglial proliferation within the spinal cord and cortex. Morin stain detected the presence of aluminum in the cytoplasm of motor neurons with some neurons also testing positive for the presence of hyper-phosphorylated tau protein, a pathological hallmark of various neurological diseases, including Alzheimer's disease and frontotemporal dementia. A second series of experiments was conducted on mice injected with six doses of aluminum hydroxide. Behavioural analyses in these mice revealed significant impairments in a number of motor functions as well as diminished spatial memory capacity. The demonstrated neurotoxicity of aluminum hydroxide and its relative ubiquity as an adjuvant suggest that greater scrutiny by the scientific community is warranted.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/19740540
Citation
Shaw, Christopher A., and Michael S. Petrik. "Aluminum Hydroxide Injections Lead to Motor Deficits and Motor Neuron Degeneration." Journal of Inorganic Biochemistry 103.11 (2009): 1555-562.
“Gulf War Syndrome is a multi-system disorder afflicting many veterans of Western armies in the 1990–1991 Gulf War. A number of those afflicted may show neurological deficits including various cognitive dysfunctions and motor neuron disease, the latter expression virtually indistinguishable from classical amyotrophic lateral sclerosis (ALS) except for the age of onset. This ALS “cluster” represents the second such ALS cluster described in the literature to date. Possible causes of GWS include several of the adjuvants in the anthrax vaccine and others. The most likely culprit appears to be aluminum hydroxide. In an initial series of experiments, we examined the potential toxicity of aluminum hydroxide in male, outbred CD-1 mice injected subcutaneously in two equivalent-tohuman doses. After sacrifice, spinal cord and motor cortex samples were examined by immunohistochemistry. Aluminum-treated mice showed significantly increased apoptosis of motor neurons and increases in reactive astrocytes and microglial proliferation within the spinal cord and cortex. Morin stain detected the presence of aluminum in the cytoplasm of motor neurons with some neurons also testing positive for the presence of hyper-phosphorylated tau protein, a pathological hallmark of various neurological diseases, including Alzheimer's disease and frontotemporal dementia. A second series of experiments was conducted on mice injected with six doses of aluminum hydroxide. Behavioural analyses in these mice revealed significant impairments in a number of motor functions as well as diminished spatial memory capacity. The demonstrated neurotoxicity of aluminum hydroxide and its relative ubiquity as an adjuvant suggest that greater scrutiny by the scientific community is warranted.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/19740540
Citation
Shaw, Christopher A., and Michael S. Petrik. "Aluminum Hydroxide Injections Lead to Motor Deficits and Motor Neuron Degeneration." Journal of Inorganic Biochemistry 103.11 (2009): 1555-562.
11. Aluminum Adjuvant Linked to Gulf War Illness Induces Motor Neuron Death in Mice
Abstracts
“Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine’s potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/17114826
Citation
Petrik, Michael S., Margaret C. Wong, Rena C. Tabata, Robert F. Garry, and Christopher A. Shaw. "Aluminum Adjuvant Linked to Gulf War Illness Induces Motor Neuron Death in Mice." NeuroMolecular Medicine 9.1 (2007): 83-100.
“Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine’s potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.”
Link
https://www.ncbi.nlm.nih.gov/pubmed/17114826
Citation
Petrik, Michael S., Margaret C. Wong, Rena C. Tabata, Robert F. Garry, and Christopher A. Shaw. "Aluminum Adjuvant Linked to Gulf War Illness Induces Motor Neuron Death in Mice." NeuroMolecular Medicine 9.1 (2007): 83-100.
