http://www.abayfor.de/cgi-bin1/webcon/abayfor/details/20/Projekte/num/462/2
Project ID: FORGEN II IS3
Begin: 01.07.1999
End: 30.06.2002
Abstract: Aim of the Project:
Development of new live vaccines consisting of the benevolent Escherichia coli strain DSM6601 and inactivated virulence genes of pathogenic bacteria. The resulting vaccines will be produced by our cooperation partner "Ardeypharm" GmbH.
The Project: Certain E. coli strains, pathogenic for humans, colonize farm animals without causing symptoms. These include enterohemorrhagic E. coli (EHEC) causing sometimes fatal disease also in Germany and enterotoxigenic E. coli responsible for diarrhea in travellers and children in third world countries. Both E. coli groups express adhesins and toxins, which constitute main virulence factors. The responsible genes will be molecularly cloned and mutagenized in order to loose virulence capacitiy but retain immunogenicity. The mutated genes will be expressed in E. coli strain DSM6601. The introduction of genes encoding an invasion system and/or the Listeria monocytogenes hemolysin will allow the vaccine strains to deliver the antigens into endosomes and/or the cytoplasm of host cells. This targeted delivery allows the induction of defined immune responses. Vaccination with the recombinant DSM6601 strains of e.g. cattle will block colonization of these animals by the corresponding bacterial pathogens. Additionally, the Mip antigen from Legionella pneumophila and Chlamydia will also be introduced into DSM6601 to generate vaccines against these intracellular pathogens. This project will not only produce new vaccines but will help to develop new strategies for vaccine design.
Fibromyalgia and Intestinal Infection: The Bacteriophages Connection ImmuneSupport.com
03-15-2002
By Theophil Hey, M.D.
Based on the scientific results of twelve years of continuous investigation we now regard as proven that a connection exists between Primary Fibromyalgia Syndrome (PFS) and evidence of bacteriophages (specific E. coli phages) found in the stool of patients.
The virology department of the Medical College in Hanover (MHH) used electron- microscopes to detect bacteriophages (viruses) in the stool of more than 80% of patients examined. By comparison, they were detected in only 12 - 13% of the control group. Scientifically speaking, this result is deemed to be of great scientific significance.
Explanation
Bacteriophages (viruses) infect their specific host cell (in this case the E. coli bacteria) and cause the E. coli bacteria to produce new viruses via the viral genes.
Up to 400 new viruses develop in this way inside the E. coli bacteria. After the E. coli bacteria has practically surrendered its cell contents for the production of the virus it then dies (lytic virus reproduction) and bursts. A virus “brood” results. A number of the released viruses find new, not yet infected E. coli bacteria, infects them and the whole process begins anew. Medically significant and the cause of the patients symptoms are the particles of the sheaths released during the process of E-coli lysis (the death of the bacteria) - the lipopolysaccharides with their active component Lipid A - which represent highly potent endotoxins.
This means that primary fibromyalgic syndrome (often found in combination with chronic fatigue syndrome and irritable colon) is to be assessed primarily as an infection of the intestine - specific bateriophages infect their specific host cells (in this case E coli) - secondly, through the release of endotoxins, as intoxication locally (reaction of the bowels) and in the blood circulation after absorption through the intestinal walls.
If no significant change in the bacterial colonisation of the bowels comes about, this process can result in the patient experiencing an alternating course of the disease lasting months and years. To minimise or even eliminate the symptoms we must attempt to keep the virus away from its host cell (E. coli), or, at least, to minimise it permanently.
1. Cleansing of the bowels:
Day 1: e.g., salinic purgatives
Day 2 - 6: colistin sulphate ( - Diarönt mono 4x2.000.000 I.U.) together with Nystatin (4x1.000.000 I.U.)
2. Symbiosis management: -Saccharomyces boulardii (possibly permanently), 250mg 2x1 before meals, e.g., Perocur forte -Lactobacillus acid. (e.g. Paidoflor 2x1 after meals) -Lactulose ( e.g. Bifiteral 1 measure mornings)
3. Prevention of new infection: no raw meat (everything boiled or well-done; boiled salamis, boiled ham; no fast-food) no fresh milk (not been pasteurized), no cheese made from fresh milk, no raw vegetables or salad which have been grown in natural or liquid manure.
A low E-coli count means: the viruses can only infect a small number of E. coli and so cause very few to die. Consequently low amounts of endotoxins (poisons) are released. On the other hand: mass colonisation of the bowels by E-coli bacteria at the same time as their specific bateriophages (viruses) are present can result in a massive release of poisons and exceedingly unpleasant symptoms.
We are ready at all times to help if you have further questions, but must point out that an immediate reply is not always possible.
The pathogenesis of the primary fibromyalgic syndrome
Association of primary fibromyalgic syndrome (PFS) with evidence of bacteriophages in the stool. T. Hey, General Practitioner; A. Breull; G.C.Fischer, Dept. of General Medicine; W. Verhagen, Dept. of Virology; Med. Hochschule Hannover
The symptoms of PFS have been the subject of studies by numerous authors in the past ten years; they have repeatedly been described in detail, questions have been asked as to possible causes, many possible associations discussed and more or less effective therapy methods recommended. PFS represents a daily new challenge for us doctors - everyday we are faced with patients suffering from the unpleasant symptoms. They come hoping for an explanation - and for relief from their complaint.
This was the reason for me to make use of all possibilities available to me in an investigation into the pathogenesis of the symptoms. It is well known that PFS is a follow-up diagnosis. BSG, blood count, RF, CRP, CK as well as internal, orthopaedic and x-ray diagnosis show no evidence of a pathological substrate. It is merely the tender-points (ACR model) which can be clinically confirmed by the examiner as being typically symptomatic.
No more was known about the complaint up to this time. There was no known cause for this illness. All attempted treatments were treatment of the symptoms using analgesics, anti-rheumatic agents, tri-cyclic anti-depressives and exhaustive clarification of the course of the illness involving a great amount of patient-time.
Patients in my survey were first subjected to the same diagnostic steps before the question of a virus genesis was broached. Antibody tests were carried out to search for Coxackie B viruses, Herpes simplex viruses, Varicella zoster viruses, Entero viruses, Adeno viruses as well as Epstein-Barr viruses but no evidence of an association with the complaint was to be found.
Attempts to breed the virus taken from the blood, urine, stool and pharyngeal wash on egg albumin also failed to produce any positive results. I consulted with the department for virology in the MHH, Hanover and they recommended as a last diagnostic possibility examination of the stool under electron microscopes. This diagnostic step brought evidence of vast numbers of bacteriophages in the stool of the first 5 patients!
This represented the first objectively demonstrable substrate above and beyond the clinical symptoms which was common to all patients. The question now was: Is it at all theoretically possible for bacteriophages to harm human body cells? Can other mechanisms - triggered by the presence of bacteriophages - strain the human organism? The bacteriophages detected were quite definitely T-phages - i.e., specific E-coli phages. Which means that they cannot harm the human cell.
When this virus has reached its specific host cell and infected it, there follows a multiplication of the virus - (lytic phase) or lysogenesis occurs, i.e., the phage genom is attached to the E-coli DNA and passed on with every splitting of the E-coli. Through factors as yet unknown to us this passive virus phase can change back into the vegetative - i.e., lytic - form and so pass into the afore-mentioned multiplication process again. The E-coli disintegrates during the process.
The sheath of the E-coli is made up of lipopolysaccharides - as are all gram-negative bacteria - including the pathogen Lipid-A, which can be defined as an endotoxin. This would mean that in this association the released endotoxins are directly to blame as human pathogenic.
Subsequently, 272 patients suffering from PFS were subjected to stool diagnosis within two years (group A). 4185 stool examinations taken from the virology dept of the MHH served as a control group. 63 patients (group B) were selected from the survey group A and from these at least three stool samples were taken at an acute stage of their illness; these were used to confirm a closer association of the illness with evidence of coli-phages.
Group D, consisting of 30 patients from our survey who quite clearly did not suffer from PFS symptoms, was used as our control group. The results showed that specific coli phages were evident in the 225 of the 272 patients belonging to group A (=82.7%).
In the control group from the medical school there was evidence of phage infestation in merely 520 of the 4,185 persons tested (=12.4%). This result is highly significant. In the selected group B there was even clearer evidence of phages - 98.4% = 62 out of 63 persons. Results from the survey control group D lay by 13.3%, similar to control group C from the medical school (12.4%).
At the same time the department of immunology in the MHH analysed the endotoxins (LPS and lipid A) and the specific anti-bodies in the serum of the patients in group B for LPS and Lipid A in IGM and IGG form. Evidence of endotoxins was found directly in the serum of only 7 of the 63 patients (=11.1%), but specific anti-bodies against LPS and Lipid A were found in significantly greater numbers than in a healthy control group of blood donors.
The cause of the illness and its typical alternating course must be a consequence of a lysis of E coli infected with phages occurring in the bowels and induced by bacteriophages; endotoxins are subsequently released in the bowels and absorbed via the bowel wall into the blood system. Evidence of specific endotoxins and their anti-bodies in the serum constitute proof of this conjecture.
This means that the course of the illness begins with alimentary intake of T-bacteriophages (directly or in E coli bacteria in the lytic or lysogenic phase), followed by their colonisation and reproduction in the bowels and finally the lysis of the E coli, the release of endotoxins and their absorption. The idea that the release of endotoxins in the bowels is induced by phages and that Lipid A is absorbed into the blood system has not yet been recognised as a pathogenic process. 10 picogramm lipid A per ml serum is regarded as highly toxic!
According to this investigation primary fibromyalgic syndrome must primarily be regarded as an infection (bacteriophage infect of E. coli) and secondly as an intoxication (endotoxin) which enables us to understand the diverse occurrences of this illness with its chronically alternating course.
Theophil Hey, M.D. Braustraße 3 31675 Bückeburg www.praxishey.de
Arthritis Rheum 2002 Jun;46(6):1671-82 Related Articles, Books, LinkOut
Escherichia coli heat-labile enterotoxin B subunit prevents autoimmune arthritis through induction of regulatory CD4+ T cells.
Luross JA, Heaton T, Hirst TR, Day MJ, Williams NA.
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
OBJECTIVE: The receptor-binding B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a highly stable, nontoxic protein that is capable of modulating immune responses. This study was conducted to determine whether mucosal administration of EtxB can block collagen-induced arthritis (CIA) and to investigate the mechanisms involved. METHODS: Clinical arthritis in DBA/1 mice was monitored following mucosal administration of EtxB on 4 occasions. The dependence of disease prevention on receptor binding by EtxB and the associated alterations to the immune response to type II collagen (CII) were assessed. Adoptive transfer experiments and lymph node cell cocultures were used to investigate the underlying mechanisms. RESULTS: Both intranasal and intragastric delivery of EtxB were effective in preventing CIA; a 1-microg dose of EtxB was protective after intranasal administration. A non-receptor-binding mutant of EtxB failed to prevent disease. Intranasal EtxB lowered both the incidence and severity of arthritis when given either at the time of disease induction or 25 days later. EtxB markedly reduced levels of anti-CII IgG2a antibodies and interferon-gamma (IFNgamma) production while not affecting levels of IgG1, interleukin-4 (IL-4), or IL-10. Disease protection could be transferred by CD4+ T cells from treated mice, an effect that was abrogated upon depletion of the CD25+ population. In addition, CD4+CD25+ T cells from treated mice were able to suppress anti-CII IFNgamma production by CII-primed lymph node cells. CONCLUSION: Mucosal administration of EtxB can be used to prevent or treat CIA. Modulation of the anti-CII immune response by EtxB is associated with a reduction in Th1 cell reactivity without a concomitant shift toward Th2. Instead, EtxB mediates its effects through enhancing the activity of a population of CD4+ regulatory T cells.
PMID: 12115200 [PubMed - indexed for MEDLINE]
Immunostimulant Patch Containing Heat-Labile Enterotoxin from Escherichia coli Enhances Immune Responses to Injected Influenza Virus Vaccine through Activation of Skin Dendritic Cells
Mimi Guebre-Xabier, Scott A. Hammond, Diane E. Epperson, Jianmei Yu, Larry Ellingsworth, and Gregory M. Glenn*
IOMAI Corporation, Gaithersburg, Maryland 20878
Received 29 October 2002/ Accepted 7 February 2003
Vaccine strategies, such as influenza virus vaccination of the elderly, are highly effective at preventing disease but provide protection for only the responding portion of the vaccinees. Adjuvants improve the magnitude and rates of responses, but their potency must be attenuated to minimize side effects. Topical delivery of strong adjuvants such as heat-labile enterotoxin from Escherichia coli (LT) induces potent immune responses. We hypothesized that LT delivered alone in an immunostimulating (LT-IS) patch placed on the skin at the site of injection could augment the immune response to injected vaccines. This was based on the observation that topically applied LT induces migration of activated antigen-presenting cells (APCs) from the skin to the proximal draining lymph node (DLN), and that APCs loaded with antigen by injection in the same anatomical region also migrate to the same DLN. We observed that when influenza virus vaccine is injected and an LT-IS patch is placed to target the same DLN, the influenza virus antibody response is enhanced. Similarly, influenza virus-specific T cells isolated from the lungs show increased levels of gamma interferon and interleukin-4 production. An LT-IS patch placed near an injected vaccine also leads to increased levels of hemagglutination inhibition titers, enhanced mucosal immunoglobulin A responses, and enhanced antigen presentation. Although the mechanisms by which an LT-IS patch exerts its enhancing effects need further study, the enhanced immune responses, ability to safely use potent adjuvants, and simplicity of LT-IS patch application address an important unmet need and provide a new immune enhancement strategy.
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* Corresponding author. Mailing address: IOMAI Corporation, 20 Firstfield Rd., Suite 250, Gaithersburg, MD 20878. Phone: (301) 556-4500. Fax: (301) 556-4501. E-mail: gglenn@iomai.com.
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Journal of Virology, May 2003, p. 5218-5225, Vol. 77, No. 9
0022-538X/03/$08.00+0 DOI: 10.1128/JVI.77.9.5218-5225.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&
list_uids=12763480&dopt=Abstract
Clin Immunol 2003 May;107(2):116-21 Related Articles,>Links
Influenza vaccination and Guillain Barre syndrome small star, filled.
Geier MR, Geier DA, Zahalsky AC.
The Genetic Centers of America, 14 Redgate Court, 20905, Silver Spring, MD,
USA
Acute and severe Guillain Barre Syndrome (GBS) cases reported following influenza vaccine to the Vaccine Adverse Events Reporting System (VAERS) database from 1991 through 1999 were examined. Endotoxin concentrations were measured using the Limulus amebocyte lysate assay in influenza vaccines. There were a total of 382 cases of GBS reported to the VAERS database following influenza vaccination (male/female ratio, 1.2). The median onset of GBS following influenza vaccine was 12 days (interquartile range, 7 days to 21 days). There was an increased risk of acute GBS (relative risk, 4.3; 95% confidence interval, 3.0 to 6.4) and severe GBS (relative risk, 8.5; 95% confidence interval, 3.7 to 18.9) in comparison to an adult tetanus-diphtheria (Td) vaccine control group. There were maximums in the incidence of GBS following influenza vaccine that occurred approximately every third year (1993, 1996, and 1998) and statistically significant variation in the incidence of GBS among different influenza manufacturers. Influenza vaccines contained from a 125- to a 1250-fold increase in endotoxin concentrations in comparison to an adult Td vaccine control and endotoxin concentrations varied up to 10-fold among different lots and manufacturers of influenza vaccine. The biologic mechanism for GBS following influenza vaccine may involve the synergistic effects of endotoxin and vaccine-induced autoimmunity. There were minimal potential reporting biases in the data reported to the VAERS database in this study. Patients should make an informed consent decision on whether to take this optional vaccine based upon its safety and efficacy and physicians should vigilantly report GBS following influenza vaccination to the VAERS in the United States so that continued evaluation of the safety of influenza vaccine may be undertaken.
PMID: 12763480 [PubMed - in process]
(You mean they use endotoxin to produce shock in rats?)
Effects of Hypothermia on Mortality and Inflammatory Responses to Endotoxin-Induced Shock in Rats
Takumi Taniguchi,1* Hiroko Kanakura,2 Yasuhiro Takemoto,2 and Ken Yamamoto2
Department of Emergency and Critical Care Medicine,1 Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medical Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan2
Received 6 December 2002/ Returned for modification 24 April 2003/ Accepted 13 June 2003
We studied the effects of hypothermia on mortality rate, concentrations of tumor necrosis factor alpha and interleukin 6 in plasma, and the end products of nitric oxide (NO) in endotoxemia. It was found that moderate and mild hypothermia improved the mortality rate and attenuated cytokine responses and the elevation of the end products of NO after endotoxin injection and that these beneficial effects were similar for moderate and mild hypothermia.
http://www.corixa.com/default.asp?pid=infect_detail&id=23
Product Detail
MPL® adjuvant, our flagship adjuvant, is a derivative of the lipid A molecule found in gram-negative bacteria, and has been observed to be a potent immunostimulant. Licenses for MPL adjuvant have been granted to several affiliates of GSK and to Wyeth for development in over 20 disease targets. Vaccines that incorporate MPL adjuvant have completed or are now in late-stage clinical trials to protect against infection from:
herpes virus
hepatitis B virus
human papilloma virus
malaria
Technical Description
MPL adjuvant is a proprietary form of monophosphoryl lipid A, a derivative of bacterial endotoxin, one of the most potent immunostimulants known. Prepared from a heptoseless mutant of Salmonella minnesota, MPL is chemically similar to lipid A but lacks an acid-labile phosphoryl group and a base-labile acyl group. MPL retains the beneficial biological activities of lipid A but with a safety profile suitable for evaluation in pediatric applications.
MPL may be a key component of vaccines using technologies such as recombinant and synthetic antigens. While vaccines incorporating these antigens are considered safer than previous attenuated or killed whole-cell vaccines, many of them are poorly immunogenic in the absence of a potent adjuvant. MPL has demonstrated utility with peptide, bacterial sub-unit and synthetic polysaccharide antigens. Vaccines for infectious diseases and allergy desensitization containing this microbially derived adjuvant have demonstrated that MPL is well tolerated in human clinical trials involving thousands of doses.
Clinical Experience with MPL
In GSK's clinical trial involving nonresponders and comparing Engerix-B with the new vaccine containing our MPL adjuvant, investigators measured seroconversion rates (protective antibody levels) one month after each of three vaccine doses; at zero, one and six months. After the first dose, 78% of the group given the new vaccine seroconverted versus 59% of the Engerix-B. After two doses, 96% versus 76% seroconverted. After the third and final treatment, 98% of patients receiving the vaccine containing MPL adjuvant seroconverted compared to only 81% of patients given Engerix-B.
In a multicenter study of healthy individuals, more than 98% of those vaccinated with Engerix-B containing MPL adjuvant achieved protective anti-hepatitis B antibody levels after just two doses, whereas three doses of the current Engerix-B product were required to obtain a similar level of protection.
Mechanism of Action
MPL activates cells of the monocyte/macrophage lineage and stimulates release of several cytokines, including IL-1, IL-12, TNFa and GM-CSF. Presumably through the action of these cytokines, lymphoid and antigen-presenting cells, including dendritic cells, are recruited to the local lymphoid organs where efficient immuno-enhancing cellular interactions can take place. These initial events mediated by MPL induce a strong TH1-type of cellular response characterized by increased production of IFN-g and IL-2. In turn, IFN-g promotes the production of complement fixing antibodies (i.e., IgG2a in the mouse), a hallmark of responses mediated by MPL.
MPL enhances immune responses to a variety of viral and bacterial antigen types, including peptides, proteins, polysaccharides and tumor cell lysates. Antigens successfully tested in preclinical studies include hepatitis B surface antigen, tetanus toxoid, trivalent split influenza, and a recombinant protein derived from the saliva-binding region of an adhesion protein of Streptococcus mutans. MPL produced striking results in studies with capsular polysaccharide antigens from organisms such as Hemophilus influenza b, several strains of pneumococcal bacteria and the Vi antigen from Salmonella typhi.
Clinical Trials
MPL adjuvants have completed Phase III clinical trials with GlaxoSmithKline hepatitis vaccines.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&
db=pubmed&dopt=Abstract&list_uids=15302111
Behav Brain Res. 2004 Sep 23;154(1):63-9.
Endotoxin exposure in early life alters the development of anxiety-like behaviour in the Fischer 344 rat.
Walker FR, March J, Hodgson DM.
Laboratory of Neuroimmunology, School of Behavioural Sciences, University ofNewcastle, Newcastle 2308, NSW, Australia.
Previous research in the rat has demonstrated that neonatal exposure to bacterial endotoxin alters the level of anxiety-like behaviour displayed in adulthood. Currently, however, little is known about the emergence and development of this type of behaviour. Given the ability of neonatal endotoxin exposure to alter neural substrates involved in regulating anxiety, we tested the hypothesis that it may also alter the developmental trajectory of anxiety-like behaviour in the rat.
Male Fischer 344 neonatal rats were treated with endotoxin (0.05mg/kg lipopolysaccharide from Salmonella enteriditis) or vehicle on postnatal days 3 and 5. Age related changes in anxiety-like behaviour were subsequently investigated using the elevated plus maze apparatus at three developmental time points; adolescence (43 days), adulthood (80 days) and senescence (400 days).
Neonatal endotoxin exposure was found to significantly increase circulating levels of corticosterone on postnatal days 3 and 5 at 4h postadministration ( [Formula: see text] ). Additionally, endotoxin exposure was found to markedly alter anxiety-like behaviour in adulthood and senescence ([Formula: see text] ).
Specifically, adult and senescent endotoxin treated animals displayed significantly more anxiety-like behaviour than vehicle treated controls. Interestingly no significant differences in anxiety-like behaviour were observed between treatment groups during adolescence. These findings highlight the importance of the early life microbial environment in the development of emotional behaviour and suggests that neonatal infection may be an important predictor of susceptibility to anxiety related disorders in adult life.
PMID: 15302111 [PubMed - in process]
http://www.nih.go.jp/JJID/57/58.pdf
Endotoxin Content in Haemophilus influenzae Type b Vaccine
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=
PubMed&list_uids=12704357&dopt=Abstract
J Allergy Clin Immunol. 2003 Apr;111(4):777-83. Related Articles, Links
Endotoxin content of standardized allergen vaccines.
Trivedi B, Valerio C, Slater JE.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md, USA.
BACKGROUND: Endotoxin is a ubiquitous and potent proinflammatory agent. Previous limited studies suggest that it is pres-ent in allergen vaccines and that this could affect the safety and efficacy of allergen immunotherapy. The endotoxin content of standardized allergen vaccines is unknown. OBJECTIVE: The purpose of this study was to quantify the amount of endotoxin contained in standardized allergen vaccines. METHODS: The endotoxin content of 14 allergen vaccines was measured by using the Limulus amebocyte lysate (LAL) gel-clot assay. To account for (1,3)-beta-d-glucan and protease interference, vaccines were selectively depleted of endotoxin and then retested with the gel-clot assay. Proteases were also heat-inactivated in selected vaccines. Fifty-eight lots of vaccines were tested, including at least two manufacturers per vaccine. RESULTS: The endotoxin content of the 58 vaccines ranged from undetectable to 34,000 EU/mL. Cat pelt (12,735 EU/mL; range, 5177 to 33,805) had significantly more endotoxin activity than cat hair (2883 EU/mL; range, 1 to 16,962), and Dermatophagoides farinae extracts (4619 EU/mL; range, 849 to 8485) had more than Dermatophagoides pteronyssinus (11 EU/mL; range, 1 to 34). Grass (160 EU/mL; range, 3 to 1561) and ragweed pollen (341 EU/mL; range, 8 to 1697) vaccines contained less endotoxin. (1,3)-beta-d-glucan interference was significant (>10%) only in three ragweed vaccines and two grass vaccines. Heat inactivation had no effect. There were considerable differences in endotoxin content of the same vaccines made by different manufacturers. CONCLUSIONS: The endotoxin content of standardized allergen vaccines is extremely variable. Interference by proteases and (1,3)-beta-d-glucans is minimal. The effects of the high levels of endotoxin in some vaccines on the immunomodulatory changes associated with allergen immunotherapy require further study.
PMID: 12704357 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=
PubMed&list_uids=11978151&dopt=Abstract
Ann Pharmacother. 2002 May;36(5):776-80. Related Articles, Links
Comment in:
Ann Pharmacother. 2002 Oct;36(10):1650; author reply 1650-1.
Clinical implications of endotoxin concentrations in vaccines.
Geier DA, Geier MR.
Genetic Centers of America, 14 Redgate Court, Silver Spring, MD 20905-5726, USA.
BACKGROUND: A previous study suggested that high concentrations of endotoxin may be present in whole-cell diphtheria/tetanus/pertussis (DTP) vaccine, and the scientific literature contains many studies examining the reactivity of whole-cell DTP vaccine. The medical and scientific communities have previously reported that the presence of endotoxin in commercial vaccines may have negative effects on vaccine recipients. OBJECTIVE: To determine the endotoxin concentrations in whole-cell DTP, acellular DTP(DTaP), and DT vaccines and determine the clinical experience with each vaccine. METHODS: To study the endotoxin concentrations in vaccines, the Limulus amebocyte lysate (LAL) assay was used. The vaccines analyzed with the LAL assay were whole-cell DTP vaccine lots manufactured by Connaught, Lederle, the Michigan and Massachusetts Departments of Health, and Wyeth; DTaP vaccine lots manufactured by Merieux and Takeda; and DT vaccine lots manufactured by Wyeth and Lederle. The incidence of adverse reactions following whole-cell DTP, DTaP, and DT vaccines were determined based on analysis of the Vaccine Adverse Events Reporting System (VAERS) database. RESULTS: The results of the LAL assay showed that whole-cell DTP vaccines contained considerably more endotoxin than either DTaP or DT vaccines. The VAERS showed that statistically significantly more adverse reactions were associated with whole-cell DTP vaccine than DTaP or DT vaccines. CONCLUSIONS: This analysis confirmed higher concentrations of endotoxin in whole-cell DTP vaccines compared with DTaP or DT vaccines. As high concentrations of endotoxin may be correlated with a higher incidence of adverse events, the switch from whole-cell DTP to DTaP for routine vaccinations in the US seems well justified.
PMID: 11978151 [PubMed - indexed for MEDLINE]
Project ID: FORGEN II IS3
Begin: 01.07.1999
End: 30.06.2002
Abstract: Aim of the Project:
Development of new live vaccines consisting of the benevolent Escherichia coli strain DSM6601 and inactivated virulence genes of pathogenic bacteria. The resulting vaccines will be produced by our cooperation partner "Ardeypharm" GmbH.
The Project: Certain E. coli strains, pathogenic for humans, colonize farm animals without causing symptoms. These include enterohemorrhagic E. coli (EHEC) causing sometimes fatal disease also in Germany and enterotoxigenic E. coli responsible for diarrhea in travellers and children in third world countries. Both E. coli groups express adhesins and toxins, which constitute main virulence factors. The responsible genes will be molecularly cloned and mutagenized in order to loose virulence capacitiy but retain immunogenicity. The mutated genes will be expressed in E. coli strain DSM6601. The introduction of genes encoding an invasion system and/or the Listeria monocytogenes hemolysin will allow the vaccine strains to deliver the antigens into endosomes and/or the cytoplasm of host cells. This targeted delivery allows the induction of defined immune responses. Vaccination with the recombinant DSM6601 strains of e.g. cattle will block colonization of these animals by the corresponding bacterial pathogens. Additionally, the Mip antigen from Legionella pneumophila and Chlamydia will also be introduced into DSM6601 to generate vaccines against these intracellular pathogens. This project will not only produce new vaccines but will help to develop new strategies for vaccine design.
Fibromyalgia and Intestinal Infection: The Bacteriophages Connection ImmuneSupport.com
03-15-2002
By Theophil Hey, M.D.
Based on the scientific results of twelve years of continuous investigation we now regard as proven that a connection exists between Primary Fibromyalgia Syndrome (PFS) and evidence of bacteriophages (specific E. coli phages) found in the stool of patients.
The virology department of the Medical College in Hanover (MHH) used electron- microscopes to detect bacteriophages (viruses) in the stool of more than 80% of patients examined. By comparison, they were detected in only 12 - 13% of the control group. Scientifically speaking, this result is deemed to be of great scientific significance.
Explanation
Bacteriophages (viruses) infect their specific host cell (in this case the E. coli bacteria) and cause the E. coli bacteria to produce new viruses via the viral genes.
Up to 400 new viruses develop in this way inside the E. coli bacteria. After the E. coli bacteria has practically surrendered its cell contents for the production of the virus it then dies (lytic virus reproduction) and bursts. A virus “brood” results. A number of the released viruses find new, not yet infected E. coli bacteria, infects them and the whole process begins anew. Medically significant and the cause of the patients symptoms are the particles of the sheaths released during the process of E-coli lysis (the death of the bacteria) - the lipopolysaccharides with their active component Lipid A - which represent highly potent endotoxins.
This means that primary fibromyalgic syndrome (often found in combination with chronic fatigue syndrome and irritable colon) is to be assessed primarily as an infection of the intestine - specific bateriophages infect their specific host cells (in this case E coli) - secondly, through the release of endotoxins, as intoxication locally (reaction of the bowels) and in the blood circulation after absorption through the intestinal walls.
If no significant change in the bacterial colonisation of the bowels comes about, this process can result in the patient experiencing an alternating course of the disease lasting months and years. To minimise or even eliminate the symptoms we must attempt to keep the virus away from its host cell (E. coli), or, at least, to minimise it permanently.
1. Cleansing of the bowels:
Day 1: e.g., salinic purgatives
Day 2 - 6: colistin sulphate ( - Diarönt mono 4x2.000.000 I.U.) together with Nystatin (4x1.000.000 I.U.)
2. Symbiosis management: -Saccharomyces boulardii (possibly permanently), 250mg 2x1 before meals, e.g., Perocur forte -Lactobacillus acid. (e.g. Paidoflor 2x1 after meals) -Lactulose ( e.g. Bifiteral 1 measure mornings)
3. Prevention of new infection: no raw meat (everything boiled or well-done; boiled salamis, boiled ham; no fast-food) no fresh milk (not been pasteurized), no cheese made from fresh milk, no raw vegetables or salad which have been grown in natural or liquid manure.
A low E-coli count means: the viruses can only infect a small number of E. coli and so cause very few to die. Consequently low amounts of endotoxins (poisons) are released. On the other hand: mass colonisation of the bowels by E-coli bacteria at the same time as their specific bateriophages (viruses) are present can result in a massive release of poisons and exceedingly unpleasant symptoms.
We are ready at all times to help if you have further questions, but must point out that an immediate reply is not always possible.
The pathogenesis of the primary fibromyalgic syndrome
Association of primary fibromyalgic syndrome (PFS) with evidence of bacteriophages in the stool. T. Hey, General Practitioner; A. Breull; G.C.Fischer, Dept. of General Medicine; W. Verhagen, Dept. of Virology; Med. Hochschule Hannover
The symptoms of PFS have been the subject of studies by numerous authors in the past ten years; they have repeatedly been described in detail, questions have been asked as to possible causes, many possible associations discussed and more or less effective therapy methods recommended. PFS represents a daily new challenge for us doctors - everyday we are faced with patients suffering from the unpleasant symptoms. They come hoping for an explanation - and for relief from their complaint.
This was the reason for me to make use of all possibilities available to me in an investigation into the pathogenesis of the symptoms. It is well known that PFS is a follow-up diagnosis. BSG, blood count, RF, CRP, CK as well as internal, orthopaedic and x-ray diagnosis show no evidence of a pathological substrate. It is merely the tender-points (ACR model) which can be clinically confirmed by the examiner as being typically symptomatic.
No more was known about the complaint up to this time. There was no known cause for this illness. All attempted treatments were treatment of the symptoms using analgesics, anti-rheumatic agents, tri-cyclic anti-depressives and exhaustive clarification of the course of the illness involving a great amount of patient-time.
Patients in my survey were first subjected to the same diagnostic steps before the question of a virus genesis was broached. Antibody tests were carried out to search for Coxackie B viruses, Herpes simplex viruses, Varicella zoster viruses, Entero viruses, Adeno viruses as well as Epstein-Barr viruses but no evidence of an association with the complaint was to be found.
Attempts to breed the virus taken from the blood, urine, stool and pharyngeal wash on egg albumin also failed to produce any positive results. I consulted with the department for virology in the MHH, Hanover and they recommended as a last diagnostic possibility examination of the stool under electron microscopes. This diagnostic step brought evidence of vast numbers of bacteriophages in the stool of the first 5 patients!
This represented the first objectively demonstrable substrate above and beyond the clinical symptoms which was common to all patients. The question now was: Is it at all theoretically possible for bacteriophages to harm human body cells? Can other mechanisms - triggered by the presence of bacteriophages - strain the human organism? The bacteriophages detected were quite definitely T-phages - i.e., specific E-coli phages. Which means that they cannot harm the human cell.
When this virus has reached its specific host cell and infected it, there follows a multiplication of the virus - (lytic phase) or lysogenesis occurs, i.e., the phage genom is attached to the E-coli DNA and passed on with every splitting of the E-coli. Through factors as yet unknown to us this passive virus phase can change back into the vegetative - i.e., lytic - form and so pass into the afore-mentioned multiplication process again. The E-coli disintegrates during the process.
The sheath of the E-coli is made up of lipopolysaccharides - as are all gram-negative bacteria - including the pathogen Lipid-A, which can be defined as an endotoxin. This would mean that in this association the released endotoxins are directly to blame as human pathogenic.
Subsequently, 272 patients suffering from PFS were subjected to stool diagnosis within two years (group A). 4185 stool examinations taken from the virology dept of the MHH served as a control group. 63 patients (group B) were selected from the survey group A and from these at least three stool samples were taken at an acute stage of their illness; these were used to confirm a closer association of the illness with evidence of coli-phages.
Group D, consisting of 30 patients from our survey who quite clearly did not suffer from PFS symptoms, was used as our control group. The results showed that specific coli phages were evident in the 225 of the 272 patients belonging to group A (=82.7%).
In the control group from the medical school there was evidence of phage infestation in merely 520 of the 4,185 persons tested (=12.4%). This result is highly significant. In the selected group B there was even clearer evidence of phages - 98.4% = 62 out of 63 persons. Results from the survey control group D lay by 13.3%, similar to control group C from the medical school (12.4%).
At the same time the department of immunology in the MHH analysed the endotoxins (LPS and lipid A) and the specific anti-bodies in the serum of the patients in group B for LPS and Lipid A in IGM and IGG form. Evidence of endotoxins was found directly in the serum of only 7 of the 63 patients (=11.1%), but specific anti-bodies against LPS and Lipid A were found in significantly greater numbers than in a healthy control group of blood donors.
The cause of the illness and its typical alternating course must be a consequence of a lysis of E coli infected with phages occurring in the bowels and induced by bacteriophages; endotoxins are subsequently released in the bowels and absorbed via the bowel wall into the blood system. Evidence of specific endotoxins and their anti-bodies in the serum constitute proof of this conjecture.
This means that the course of the illness begins with alimentary intake of T-bacteriophages (directly or in E coli bacteria in the lytic or lysogenic phase), followed by their colonisation and reproduction in the bowels and finally the lysis of the E coli, the release of endotoxins and their absorption. The idea that the release of endotoxins in the bowels is induced by phages and that Lipid A is absorbed into the blood system has not yet been recognised as a pathogenic process. 10 picogramm lipid A per ml serum is regarded as highly toxic!
According to this investigation primary fibromyalgic syndrome must primarily be regarded as an infection (bacteriophage infect of E. coli) and secondly as an intoxication (endotoxin) which enables us to understand the diverse occurrences of this illness with its chronically alternating course.
Theophil Hey, M.D. Braustraße 3 31675 Bückeburg www.praxishey.de
Arthritis Rheum 2002 Jun;46(6):1671-82 Related Articles, Books, LinkOut
Escherichia coli heat-labile enterotoxin B subunit prevents autoimmune arthritis through induction of regulatory CD4+ T cells.
Luross JA, Heaton T, Hirst TR, Day MJ, Williams NA.
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
OBJECTIVE: The receptor-binding B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a highly stable, nontoxic protein that is capable of modulating immune responses. This study was conducted to determine whether mucosal administration of EtxB can block collagen-induced arthritis (CIA) and to investigate the mechanisms involved. METHODS: Clinical arthritis in DBA/1 mice was monitored following mucosal administration of EtxB on 4 occasions. The dependence of disease prevention on receptor binding by EtxB and the associated alterations to the immune response to type II collagen (CII) were assessed. Adoptive transfer experiments and lymph node cell cocultures were used to investigate the underlying mechanisms. RESULTS: Both intranasal and intragastric delivery of EtxB were effective in preventing CIA; a 1-microg dose of EtxB was protective after intranasal administration. A non-receptor-binding mutant of EtxB failed to prevent disease. Intranasal EtxB lowered both the incidence and severity of arthritis when given either at the time of disease induction or 25 days later. EtxB markedly reduced levels of anti-CII IgG2a antibodies and interferon-gamma (IFNgamma) production while not affecting levels of IgG1, interleukin-4 (IL-4), or IL-10. Disease protection could be transferred by CD4+ T cells from treated mice, an effect that was abrogated upon depletion of the CD25+ population. In addition, CD4+CD25+ T cells from treated mice were able to suppress anti-CII IFNgamma production by CII-primed lymph node cells. CONCLUSION: Mucosal administration of EtxB can be used to prevent or treat CIA. Modulation of the anti-CII immune response by EtxB is associated with a reduction in Th1 cell reactivity without a concomitant shift toward Th2. Instead, EtxB mediates its effects through enhancing the activity of a population of CD4+ regulatory T cells.
PMID: 12115200 [PubMed - indexed for MEDLINE]
Immunostimulant Patch Containing Heat-Labile Enterotoxin from Escherichia coli Enhances Immune Responses to Injected Influenza Virus Vaccine through Activation of Skin Dendritic Cells
Mimi Guebre-Xabier, Scott A. Hammond, Diane E. Epperson, Jianmei Yu, Larry Ellingsworth, and Gregory M. Glenn*
IOMAI Corporation, Gaithersburg, Maryland 20878
Received 29 October 2002/ Accepted 7 February 2003
Vaccine strategies, such as influenza virus vaccination of the elderly, are highly effective at preventing disease but provide protection for only the responding portion of the vaccinees. Adjuvants improve the magnitude and rates of responses, but their potency must be attenuated to minimize side effects. Topical delivery of strong adjuvants such as heat-labile enterotoxin from Escherichia coli (LT) induces potent immune responses. We hypothesized that LT delivered alone in an immunostimulating (LT-IS) patch placed on the skin at the site of injection could augment the immune response to injected vaccines. This was based on the observation that topically applied LT induces migration of activated antigen-presenting cells (APCs) from the skin to the proximal draining lymph node (DLN), and that APCs loaded with antigen by injection in the same anatomical region also migrate to the same DLN. We observed that when influenza virus vaccine is injected and an LT-IS patch is placed to target the same DLN, the influenza virus antibody response is enhanced. Similarly, influenza virus-specific T cells isolated from the lungs show increased levels of gamma interferon and interleukin-4 production. An LT-IS patch placed near an injected vaccine also leads to increased levels of hemagglutination inhibition titers, enhanced mucosal immunoglobulin A responses, and enhanced antigen presentation. Although the mechanisms by which an LT-IS patch exerts its enhancing effects need further study, the enhanced immune responses, ability to safely use potent adjuvants, and simplicity of LT-IS patch application address an important unmet need and provide a new immune enhancement strategy.
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* Corresponding author. Mailing address: IOMAI Corporation, 20 Firstfield Rd., Suite 250, Gaithersburg, MD 20878. Phone: (301) 556-4500. Fax: (301) 556-4501. E-mail: gglenn@iomai.com.
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Journal of Virology, May 2003, p. 5218-5225, Vol. 77, No. 9
0022-538X/03/$08.00+0 DOI: 10.1128/JVI.77.9.5218-5225.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&
list_uids=12763480&dopt=Abstract
Clin Immunol 2003 May;107(2):116-21 Related Articles,>Links
Influenza vaccination and Guillain Barre syndrome small star, filled.
Geier MR, Geier DA, Zahalsky AC.
The Genetic Centers of America, 14 Redgate Court, 20905, Silver Spring, MD,
USA
Acute and severe Guillain Barre Syndrome (GBS) cases reported following influenza vaccine to the Vaccine Adverse Events Reporting System (VAERS) database from 1991 through 1999 were examined. Endotoxin concentrations were measured using the Limulus amebocyte lysate assay in influenza vaccines. There were a total of 382 cases of GBS reported to the VAERS database following influenza vaccination (male/female ratio, 1.2). The median onset of GBS following influenza vaccine was 12 days (interquartile range, 7 days to 21 days). There was an increased risk of acute GBS (relative risk, 4.3; 95% confidence interval, 3.0 to 6.4) and severe GBS (relative risk, 8.5; 95% confidence interval, 3.7 to 18.9) in comparison to an adult tetanus-diphtheria (Td) vaccine control group. There were maximums in the incidence of GBS following influenza vaccine that occurred approximately every third year (1993, 1996, and 1998) and statistically significant variation in the incidence of GBS among different influenza manufacturers. Influenza vaccines contained from a 125- to a 1250-fold increase in endotoxin concentrations in comparison to an adult Td vaccine control and endotoxin concentrations varied up to 10-fold among different lots and manufacturers of influenza vaccine. The biologic mechanism for GBS following influenza vaccine may involve the synergistic effects of endotoxin and vaccine-induced autoimmunity. There were minimal potential reporting biases in the data reported to the VAERS database in this study. Patients should make an informed consent decision on whether to take this optional vaccine based upon its safety and efficacy and physicians should vigilantly report GBS following influenza vaccination to the VAERS in the United States so that continued evaluation of the safety of influenza vaccine may be undertaken.
PMID: 12763480 [PubMed - in process]
(You mean they use endotoxin to produce shock in rats?)
Effects of Hypothermia on Mortality and Inflammatory Responses to Endotoxin-Induced Shock in Rats
Takumi Taniguchi,1* Hiroko Kanakura,2 Yasuhiro Takemoto,2 and Ken Yamamoto2
Department of Emergency and Critical Care Medicine,1 Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medical Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan2
Received 6 December 2002/ Returned for modification 24 April 2003/ Accepted 13 June 2003
We studied the effects of hypothermia on mortality rate, concentrations of tumor necrosis factor alpha and interleukin 6 in plasma, and the end products of nitric oxide (NO) in endotoxemia. It was found that moderate and mild hypothermia improved the mortality rate and attenuated cytokine responses and the elevation of the end products of NO after endotoxin injection and that these beneficial effects were similar for moderate and mild hypothermia.
http://www.corixa.com/default.asp?pid=infect_detail&id=23
Product Detail
MPL® adjuvant, our flagship adjuvant, is a derivative of the lipid A molecule found in gram-negative bacteria, and has been observed to be a potent immunostimulant. Licenses for MPL adjuvant have been granted to several affiliates of GSK and to Wyeth for development in over 20 disease targets. Vaccines that incorporate MPL adjuvant have completed or are now in late-stage clinical trials to protect against infection from:
herpes virus
hepatitis B virus
human papilloma virus
malaria
Technical Description
MPL adjuvant is a proprietary form of monophosphoryl lipid A, a derivative of bacterial endotoxin, one of the most potent immunostimulants known. Prepared from a heptoseless mutant of Salmonella minnesota, MPL is chemically similar to lipid A but lacks an acid-labile phosphoryl group and a base-labile acyl group. MPL retains the beneficial biological activities of lipid A but with a safety profile suitable for evaluation in pediatric applications.
MPL may be a key component of vaccines using technologies such as recombinant and synthetic antigens. While vaccines incorporating these antigens are considered safer than previous attenuated or killed whole-cell vaccines, many of them are poorly immunogenic in the absence of a potent adjuvant. MPL has demonstrated utility with peptide, bacterial sub-unit and synthetic polysaccharide antigens. Vaccines for infectious diseases and allergy desensitization containing this microbially derived adjuvant have demonstrated that MPL is well tolerated in human clinical trials involving thousands of doses.
Clinical Experience with MPL
In GSK's clinical trial involving nonresponders and comparing Engerix-B with the new vaccine containing our MPL adjuvant, investigators measured seroconversion rates (protective antibody levels) one month after each of three vaccine doses; at zero, one and six months. After the first dose, 78% of the group given the new vaccine seroconverted versus 59% of the Engerix-B. After two doses, 96% versus 76% seroconverted. After the third and final treatment, 98% of patients receiving the vaccine containing MPL adjuvant seroconverted compared to only 81% of patients given Engerix-B.
In a multicenter study of healthy individuals, more than 98% of those vaccinated with Engerix-B containing MPL adjuvant achieved protective anti-hepatitis B antibody levels after just two doses, whereas three doses of the current Engerix-B product were required to obtain a similar level of protection.
Mechanism of Action
MPL activates cells of the monocyte/macrophage lineage and stimulates release of several cytokines, including IL-1, IL-12, TNFa and GM-CSF. Presumably through the action of these cytokines, lymphoid and antigen-presenting cells, including dendritic cells, are recruited to the local lymphoid organs where efficient immuno-enhancing cellular interactions can take place. These initial events mediated by MPL induce a strong TH1-type of cellular response characterized by increased production of IFN-g and IL-2. In turn, IFN-g promotes the production of complement fixing antibodies (i.e., IgG2a in the mouse), a hallmark of responses mediated by MPL.
MPL enhances immune responses to a variety of viral and bacterial antigen types, including peptides, proteins, polysaccharides and tumor cell lysates. Antigens successfully tested in preclinical studies include hepatitis B surface antigen, tetanus toxoid, trivalent split influenza, and a recombinant protein derived from the saliva-binding region of an adhesion protein of Streptococcus mutans. MPL produced striking results in studies with capsular polysaccharide antigens from organisms such as Hemophilus influenza b, several strains of pneumococcal bacteria and the Vi antigen from Salmonella typhi.
Clinical Trials
MPL adjuvants have completed Phase III clinical trials with GlaxoSmithKline hepatitis vaccines.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&
db=pubmed&dopt=Abstract&list_uids=15302111
Behav Brain Res. 2004 Sep 23;154(1):63-9.
Endotoxin exposure in early life alters the development of anxiety-like behaviour in the Fischer 344 rat.
Walker FR, March J, Hodgson DM.
Laboratory of Neuroimmunology, School of Behavioural Sciences, University ofNewcastle, Newcastle 2308, NSW, Australia.
Previous research in the rat has demonstrated that neonatal exposure to bacterial endotoxin alters the level of anxiety-like behaviour displayed in adulthood. Currently, however, little is known about the emergence and development of this type of behaviour. Given the ability of neonatal endotoxin exposure to alter neural substrates involved in regulating anxiety, we tested the hypothesis that it may also alter the developmental trajectory of anxiety-like behaviour in the rat.
Male Fischer 344 neonatal rats were treated with endotoxin (0.05mg/kg lipopolysaccharide from Salmonella enteriditis) or vehicle on postnatal days 3 and 5. Age related changes in anxiety-like behaviour were subsequently investigated using the elevated plus maze apparatus at three developmental time points; adolescence (43 days), adulthood (80 days) and senescence (400 days).
Neonatal endotoxin exposure was found to significantly increase circulating levels of corticosterone on postnatal days 3 and 5 at 4h postadministration ( [Formula: see text] ). Additionally, endotoxin exposure was found to markedly alter anxiety-like behaviour in adulthood and senescence ([Formula: see text] ).
Specifically, adult and senescent endotoxin treated animals displayed significantly more anxiety-like behaviour than vehicle treated controls. Interestingly no significant differences in anxiety-like behaviour were observed between treatment groups during adolescence. These findings highlight the importance of the early life microbial environment in the development of emotional behaviour and suggests that neonatal infection may be an important predictor of susceptibility to anxiety related disorders in adult life.
PMID: 15302111 [PubMed - in process]
http://www.nih.go.jp/JJID/57/58.pdf
Endotoxin Content in Haemophilus influenzae Type b Vaccine
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=
PubMed&list_uids=12704357&dopt=Abstract
J Allergy Clin Immunol. 2003 Apr;111(4):777-83. Related Articles, Links
Endotoxin content of standardized allergen vaccines.
Trivedi B, Valerio C, Slater JE.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md, USA.
BACKGROUND: Endotoxin is a ubiquitous and potent proinflammatory agent. Previous limited studies suggest that it is pres-ent in allergen vaccines and that this could affect the safety and efficacy of allergen immunotherapy. The endotoxin content of standardized allergen vaccines is unknown. OBJECTIVE: The purpose of this study was to quantify the amount of endotoxin contained in standardized allergen vaccines. METHODS: The endotoxin content of 14 allergen vaccines was measured by using the Limulus amebocyte lysate (LAL) gel-clot assay. To account for (1,3)-beta-d-glucan and protease interference, vaccines were selectively depleted of endotoxin and then retested with the gel-clot assay. Proteases were also heat-inactivated in selected vaccines. Fifty-eight lots of vaccines were tested, including at least two manufacturers per vaccine. RESULTS: The endotoxin content of the 58 vaccines ranged from undetectable to 34,000 EU/mL. Cat pelt (12,735 EU/mL; range, 5177 to 33,805) had significantly more endotoxin activity than cat hair (2883 EU/mL; range, 1 to 16,962), and Dermatophagoides farinae extracts (4619 EU/mL; range, 849 to 8485) had more than Dermatophagoides pteronyssinus (11 EU/mL; range, 1 to 34). Grass (160 EU/mL; range, 3 to 1561) and ragweed pollen (341 EU/mL; range, 8 to 1697) vaccines contained less endotoxin. (1,3)-beta-d-glucan interference was significant (>10%) only in three ragweed vaccines and two grass vaccines. Heat inactivation had no effect. There were considerable differences in endotoxin content of the same vaccines made by different manufacturers. CONCLUSIONS: The endotoxin content of standardized allergen vaccines is extremely variable. Interference by proteases and (1,3)-beta-d-glucans is minimal. The effects of the high levels of endotoxin in some vaccines on the immunomodulatory changes associated with allergen immunotherapy require further study.
PMID: 12704357 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=
PubMed&list_uids=11978151&dopt=Abstract
Ann Pharmacother. 2002 May;36(5):776-80. Related Articles, Links
Comment in:
Ann Pharmacother. 2002 Oct;36(10):1650; author reply 1650-1.
Clinical implications of endotoxin concentrations in vaccines.
Geier DA, Geier MR.
Genetic Centers of America, 14 Redgate Court, Silver Spring, MD 20905-5726, USA.
BACKGROUND: A previous study suggested that high concentrations of endotoxin may be present in whole-cell diphtheria/tetanus/pertussis (DTP) vaccine, and the scientific literature contains many studies examining the reactivity of whole-cell DTP vaccine. The medical and scientific communities have previously reported that the presence of endotoxin in commercial vaccines may have negative effects on vaccine recipients. OBJECTIVE: To determine the endotoxin concentrations in whole-cell DTP, acellular DTP(DTaP), and DT vaccines and determine the clinical experience with each vaccine. METHODS: To study the endotoxin concentrations in vaccines, the Limulus amebocyte lysate (LAL) assay was used. The vaccines analyzed with the LAL assay were whole-cell DTP vaccine lots manufactured by Connaught, Lederle, the Michigan and Massachusetts Departments of Health, and Wyeth; DTaP vaccine lots manufactured by Merieux and Takeda; and DT vaccine lots manufactured by Wyeth and Lederle. The incidence of adverse reactions following whole-cell DTP, DTaP, and DT vaccines were determined based on analysis of the Vaccine Adverse Events Reporting System (VAERS) database. RESULTS: The results of the LAL assay showed that whole-cell DTP vaccines contained considerably more endotoxin than either DTaP or DT vaccines. The VAERS showed that statistically significantly more adverse reactions were associated with whole-cell DTP vaccine than DTaP or DT vaccines. CONCLUSIONS: This analysis confirmed higher concentrations of endotoxin in whole-cell DTP vaccines compared with DTaP or DT vaccines. As high concentrations of endotoxin may be correlated with a higher incidence of adverse events, the switch from whole-cell DTP to DTaP for routine vaccinations in the US seems well justified.
PMID: 11978151 [PubMed - indexed for MEDLINE]
