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http://www.umassmed.edu/news/news-archi ... e-disease/
MassBiologics at UMMS developing pre-exposure prophylaxis to prevent Lyme disease
New research to be presented at infectious disease conference IDWeek; Monoclonal antibodies reactive against a broad range of Borrelia species in studies
Worldwide, three main genospecies of the bacteria Borrelia are associated with Lyme disease in humans. B. burgdorferi is the main cause of Lyme disease in North America, while B. garinii and B. afzelii are the prevalent strains that cause the disease in Europe and Asia. To develop a human monoclonal antibody for pre-exposure prophylaxis of Lyme disease, Dr. Klempner, Yang Wang, MD, PhD, assistant professor of medicine, and colleagues created a panel of borreliacidal human monoclonal antibodies by immunizing mice that were transgenic for human immunoglobulin genes for a surface protein of B. burgdorferi. They tested more than 90 monoclonal antibodies and picked four for further investigation, based on how well they killed the bacteria. Two of the four were selected for further study in vivo—both prevented infection of mice when challenged with infected ticks.
These studies suggest that OspA-specific human monoclonal antibody could provide pre-exposure prophylaxis for Lyme disease worldwide caused by a broad range of Borrelia genospecies, since the antibody target appears ‘highly conserved’—common across most species of Borrelia.
Klempner said preclinical development is now under way to define the pharmacokinetics and refine the minimum dosage required to provide long-term protection from infection.
This version shines a whole new light on what is actually being proposed. I am by no stretch of the imagination an anti-vaxxer, but this development causes me to have considerable concern.
Messing with monoclonal antibody treatments in people is quite different than making the case in a mouse model. They are working on providing directed antibodies to OspA. While different than a vaccine which stimulates the immune system to make its own antibodies to an injected antigen this, in theory, will directly inject constructed antibodies against those same antigens. What else could those antibodies potentially form immune complexes or react with? ............
J Neuroimmunol. 2005 Feb;159(1-2):192-5. Epub 2004 Nov 26.
Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue.
Alaedini A1, Latov N.
Neurological sequela of chronic Lyme disease include encephalopathy, myelopathy and peripheral neuropathy. These have generally been attributed to either persistent infection or pathogen-induced autoimmunity. In this study, we investigated the presence of cross-reactive human neural epitopes that share amino acid sequences with Borrelia burgdorferi OspA protein. Sequence similarity analysis was carried out by searching known cDNA sequences from brain tissue. The cDNA database search yielded three sequences that were identical to sequences in OspA. Corresponding peptides were synthesized and antibodies were generated against them in rabbits. Antibodies against two of the homologous OspA peptides were found to react with neurons in human brain, spinal cord and dorsal root ganglia by immunohistochemistry.
Clin Vaccine Immunol. 2007 Nov;14(11):1437-41. Epub 2007 Sep 19.
Serum reactivity against Borrelia burgdorferi OspA in patients with rheumatoid arthritis.
Hsieh YF1, Liu HW, Hsu TC, Wei JC, Shih CM, Krause PJ, Tsay GJ.
Lyme arthritis and rheumatoid arthritis share common clinical features and synovial histology. It is unclear whether they also share similar pathogenesis. Previous studies have shown that the severity and duration of Lyme arthritis correlate directly with serum concentrations of antibody against outer surface protein A (OspA) of the causative pathogen Borrelia burgdorferi. We tested the sera of 68 subjects with rheumatoid arthritis, 147 subjects with other autoimmune diseases, and 44 healthy subjects who had never had Lyme disease, as well as sera of 16 patients who had Lyme disease, for reactivity against the B. burgdorferi OspA protein. The sera of about a quarter of the rheumatoid arthritis patients and a 10th of the autoimmune disease and Lyme disease patients reacted against OspA antigen. Of 50 rheumatoid arthritis patients who could be evaluated for disease severity, a 28-joint count disease activity score of >2.6 was noted for 11 of 15 (73%) patients whose sera reacted against OspA antigen and 13 of 35 (37%; P < 0.05) whose sera were nonreactive. Serum reactivity against OspA antigen is associated with the pathogenesis of rheumatoid arthritis.
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1303-8. Epub 2004 Jan 23.
An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.
Willett TA1, Meyer AL, Brown EL, Huber BT.
1Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111, USA.
The antigenic component of a common Lyme disease vaccine is recombinant outer surface protein A (rOspA) of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Coincidentally, patients with chronic, treatment-resistant Lyme arthritis develop an immune response against OspA, whereas those with acute Lyme disease usually do not. Treatment-resistant Lyme arthritis occurs in a subset of Lyme arthritis patients and is linked to HLA.DRB1*0401 (DR4) and related alleles. Recent work from our laboratory identified T cell crossreactivity between epitopes of OspA and lymphocyte function-associated antigen 1alpha(L) chain (LFA-1alpha(L)) in these patients. We generated a form of rOspA, FTK-OspA, in which the LFA-1alpha(L)/rOspA crossreactive T cell epitope was mutated to reduce the possible risk of autoimmunity in genetically susceptible individuals. FTK-OspA did not stimulate human or mouse DR4-restricted, WT-OspA-specific T cells, whereas it did stimulate antibody responses specific for WT-OspA that were similar to mice vaccinated WT-OspA. We show here that the protective efficacy of FTK-OspA is indistinguishable from that of WT-OspA in vaccination trials, as both C3H/HeJ and BALB/c FTK-OspA-vaccinated mice were protected from Bb infection. These data demonstrate that this rOspA-derived vaccine lacking the predicted cross-reactive T cell epitope, but retaining the capacity to elicit antibodies against infection, is effective in generating protective immunity.
J Peripher Nerv Syst. 2004 Sep;9(3):165-7.
Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi.
Latov N1, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH 3rd.
Neurological syndromes that follow vaccination or infection are often attributed to autoimmune mechanisms. We report six patients who developed neuropathy or cognitive impairment, within several days to 2 months, following vaccination with the OspA antigen of Borrelia burgdorferi. Two of the patients developed cognitive impairment, one chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy, one both cognitive impairment and CIDP, and one cognitive impairment and sensory axonal neuropathy. The patients with cognitive impairment had T2 hyperintense white matter lesions on magnetic resonance imaging. The similarity between the neurological sequelae observed in the OspA-vaccinated patients and those with chronic Lyme disease suggests a possible role for immune mechanisms in some of the manifestations of chronic Lyme disease that are resistant to antibiotic treatment.
Thyroid. 2006 Mar;16(3):225-36.
Human thyroid autoantigens and proteins of Yersinia and Borrelia share amino acid sequence homology that includes binding motifs to HLA-DR molecules and T-cell receptor.
Benvenga S1, Santarpia L, Trimarchi F, Guarneri F.
We previously reported that the spirochete Borrelia burgdorferi could trigger autoimmune thyroid diseases (AITD). Subsequently, we showed local amino acid sequence homology between all human thyroid autoantigens (human thyrotropin receptor [hTSH-R], human thyroglobulin [hTg], human thyroperoxidase [hTPO], human sodium iodide symporter [hNIS]) and Borrelia proteins (n = 6,606), and between hTSH-R and Yersinia enterocolitica (n = 1,153). We have now updated our search of homology with Borrelia (n = 11,198 proteins) and extended our search on Yersinia to the entire species (n = 40,964 proteins). We also searched the homologous human and microbial sequences for peptide-binding motifs of HLA-DR molecules, because a number of these class II major histocompatibility complex (MHC) molecules (DR3, DR4, DR5, DR8, and DR9) are associated with AITD. Significant homologies were found for only 16 Borrelia proteins (5 with hTSH-R, 2 with hTg, 3 with hTPO, and 6 with hNIS) and only 19 Yersinia proteins (4 with hTSH-R, 2 with hTg, 2 with hTPO, and 11 with hNIS). Noteworthy, segments of thyroid autoantigens homologous to these microbial proteins are known to be autoantigenic. Also, the hTSH-R homologous region of one Borrelia protein (OspA) contains an immunodominant epitope that others have found to be homologous to hLFA-1. This is of interest, as the hLFA-1/ICAM-1 ligand/receptor pair is aberrantly expressed in the follicular cells of thyroids affected by Hashimoto's thyroiditis. A computer-assisted search detected antigenic peptide binding motifs to the DR molecules implicated in AITD. In conclusion, our in silico data do not directly demonstrate that Borrelia and Yersinia proteins trigger AITD but suggest that a restricted number of them might have the potential to, at least in persons with certain HLA-DR alleles.
Monoclonal antibodies are used for treatments for other types of diseases and conditions, but they are not without risk or adverse side effects. I highly doubt enough research has been done to determine whether these could safely be used on a yearly basis in human beings. Maybe it will prove out, but I wouldn't hold my breath waiting and I won't be lining up to enter a clinical trial on this one.
Nat Rev Drug Discov. 2010 Apr;9(4):325-38. doi: 10.1038/nrd3003. Epub 2010 Mar 22.
The safety and side effects of monoclonal antibodies.
Hansel TT1, Kropshofer H, Singer T, Mitchell JA, George AJ.
Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. In March 2006, a life-threatening cytokine release syndrome occurred during a first-in-human study with TGN1412 (a CD28-specific superagonist mAb), resulting in a range of recommendations to improve the safety of initial human clinical studies with mAbs. Here, we review some of the adverse effects encountered with mAb therapies, and discuss advances in preclinical testing and antibody technology aimed at minimizing the risk of these events.
Suzuki M, Kato C, Kato A. Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. Journal of Toxicologic Pathology. 2015;28(3):133-139. doi:10.1293/tox.2015-0031.
Antibodies can swiftly provide therapeutics to target disease-related molecules discovered in genomic research. Antibody engineering techniques have been actively developed and these technological innovations have intensified the development of therapeutic antibodies. From the mid-1990’s, a series of therapeutic antibodies were launched that are now being used in clinic. The disease areas that therapeutic antibodies can target have subsequently expanded, and antibodies are currently utilized as pharmaceuticals for cancer, inflammatory disease, organ transplantation, cardiovascular disease, infection, respiratory disease, ophthalmologic disease, and so on. This paper briefly describes the modes of action of therapeutic antibodies. Several non-clinical study results of the pathological changes induced by therapeutic antibodies are also presented to aid the future assessment of the toxic potential of an antibody developed as a therapeutic.
Edited to add an additional reference.