Expert Review of Vaccines
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Prospects for safe and effective vaccines against prion diseases Neil Andrew Mabbott To cite this article: Neil Andrew Mabbott (2015) Prospects for safe and effective vaccines against prion diseases, Expert Review of Vaccines, 14:1, 1-4 To link to this article: http://dx.doi.org/10.1586/14760584.2015.965691
Published online: 30 Sep 2014.
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Date: 11 September 2015, At: 20:00
Editorial
Prospects for safe and effective vaccines against prion diseases Expert Rev. Vaccines 14(1), 1–4 (2015)
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
Neil Andrew Mabbott The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK Tel.: +44 131 651 9100 Fax: +44 131 651 9105 [email protected]
Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrPSc) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt–Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved. Introducing the prion diseases
Prion diseases, or transmissible spongiform encephalopathies, are sub-acute, invariably fatal, neurodegenerative disorders affecting humans and animals. During prion disease, aggregations of PrPSc, an abnormally folded isoform of the host cellular prion protein (PrPC) accumulate in affected tissues. Prion infectivity copurifies with PrPSc and is considered to constitute the major component of the infectious agent. Cellular PrPC is a 30– 35 kDa glycoprotein linked to the cell surface via a glycophosphatidylinositol anchor. The globular domain of PrPC is rich in a-helical content, whereas during prion disease misfolded PrPSc lacks ahelices and has increased b-pleated sheet content. The accumulation of PrPSc in the CNS of prion-infected hosts coincides with neuronal loss, spongiosis and reactive glial responses. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy, chronic wasting disease in cervids and variant Creutzfeldt–Jakob disease (vCJD) in humans, are considered to be acquired peripherally such as by oral exposure. After exposure, the initial replication of prions within secondary lymphoid tissues is critical for their efficient transmission
to the CNS (termed neuroinvasion). Other prion diseases appear to arise spontaneously within the CNS (such as sporadic CJD), or are associated with mutations within the PRNP gene (which encodes PrPC). Since the emergence of vCJD in the UK human population (177 definite or probable cases, September 2014), much effort has been invested into developing an experimental vaccine against prions. Earlier studies showed that both passive (administration of anti-PrP antibodies) [1] and active immunization against PrP [2] were feasible approaches to attenuate experimental prion diseases. Many other potentially promising prophylactic and therapeutic experimental approaches have since been reported, but as outlined below, important issues remain to be resolved. Overcoming T-cell tolerance
A major hurdle that must be overcome in the development of an effective vaccine against prions is T-cell tolerance. Since PrPC is widely expressed, it is tolerated by the host preventing the development of cell-mediated and humoral immune responses to PrPC and prion disease-specific PrPSc. However, some anti-PrP antibodies may be generated toward the clinical phase of prion
KEYWORDS: prion disease • PrP • transmissible spongiform encephalopathy • vaccine
informahealthcare.com
10.1586/14760584.2015.965691
2015 Informa UK Ltd
ISSN 1476-0584
1
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
Editorial
Mabbott
disease [3]. In the absence of tolerance to PrP in PrP–/– (deficient) mice, PrP-specific antibodies are readily elicited. Studies have shown that cell-based immunotherapy can overcome host tolerance toward PrP in wild-type (PrP-expressing) hosts. PrP-sensitized CD4+ T cells from PrP–/– donors [4], or transgenic T cells with a PrP-specific T-cell receptor [5], can each impair prion disease pathogenesis when transferred into wild-type mice. In these examples, the transferred T cells did not induce PrP-specific antibody production by B cells, but instead appeared to mediate protection through secretion of IL-4. Antigen presentation to T cells via MHC-molecules on professional antigen-presenting cells such as dendritic cells is critical for the initial activation of naı¨ve T cells and induction of a specific immune response. Adoptive transfer of PrP peptide-loaded dendritic cells into wild-type mice induced the secretion of IL-4 and IFN-g by T cells, production of PrPspecific antibodies by B cells and increased survival time following peripheral exposure to prions [6]. These elegant approaches allow the cellular mechanisms which influence the induction of protective anti-PrP antibody responses to be studied, but are unlikely to be translated into clinical applications as they are currently too costly and technically challenging for widespread use. Much effort has been placed on the identification of novel epitopes or vaccine formulations, which may enhance the induction of high-affinity and protective anti-PrP antibody responses. Although many studies show tolerance to PrP can be broken in wild-type animals, specific-antibody titers have often been low, and effects on prion disease susceptibility limited. Despite these limitations, repeated injection (every 2 weeks) with PrP-absorbed Dynabeads induced a PrP-specific IgM response and prolonged survival time by approximately 11% after intraperitoneal prion exposure [7]. The use of DNA-based vaccines has also been tested, including immunization with cDNA encoding for heterologous (human) PrP fused to either a stimulatory T-cell epitope [8], or a targeting protein to enhance antigen uptake and presentation via MHC class I [9]. These procedures induce significant PrP-specific IgG in the serum but effects on prion pathogenesis are uncertain. An in silico approach has also been used to select a nonmammalian epitope with similar sequence to that recognized by the anti-PrP monoclonal antibody 6H4. Bacterial succinylarginine dihydrolase was identified, and when used to immunize mice it induced a PrP-specific antibody response and significantly delayed survival times (~7–10%) after intraperitoneal prion exposure [10]. Identification of prion-specific epitopes
To avoid the potential for autoimmune complications, the elicited immune response should be specific for disease-associated PrPSc, with negligible reactivity toward host PrPC. To date, three epitopes that are uniquely present within PrPSc have been identified: a YYR motif that is exposed upon PrPC misfolding; a YML motif in b-sheet 1 and another within the rigid loop linking b-sheet 2 to a-helix 2. When used individually or in a 2
multivalent format, vaccines based on these epitopes induce sustained PrPSc-specific antibody responses in sheep [11]. Whether they confer protection against prion infection remains to be determined. Crossing the blood–brain barrier
Over 10 years ago, it was demonstrated that passive immunization by administration of large quantities of anti-PrP monoclonal antibodies from shortly after intraperitoneal prion exposure significantly delayed disease pathogenesis and survival times. Although these studies suggest immunotherapeutic approaches are worth pursuing, the inability of large molecules such as immunoglobulins to cross the blood–brain barrier realistically limits their use to the early phase after prion exposure, prior to neuroinvasion. To address this issue, one study has shown that camelid single-domain PrP-specific antibodies can cross the blood–brain barrier [12]. Whether anti-PrP antibodies may attenuate prion disease within the CNS is uncertain. A separate study, using a brain-engraftable microglial cell line expressing an anti-PrP antibody single chain Fv fragment observed only marginal effects on disease pathogenesis [13]. Understanding the risks of autoimmunity to PrPC
The safety of any anti-prion vaccines must also be carefully considered. Immunization may plausibly exacerbate prion pathogenesis [14], since the replication of prions within B-cell follicles is important for efficient neuroinvasion. There has also been much controversy over whether anti-PrP antibodies cause autoimmunity or cell toxicity due to recognition of host PrPC [15–18]. A recent study sheds much light on this issue. By studying a panel of PrP-specific monoclonal antibodies, the authors showed that those which bound the a1 and a3 helices of the globular domain of PrPC induced rapid neurotoxicity [19]. These data provide valuable information on the screening of potentially neurotoxic anti-PrP antibodies. Systemic versus mucosal immunization
The route of immunization is likely to have a key bearing on efficacy. Many natural prion diseases in animals are considered to be acquired orally, such as the dietary transmission of bovine spongiform encephalopathy to humans via contaminated food. To date, experimental data suggest mucosal vaccination against prions appears to be effective and the most appropriate method for protection against orally acquired prion infections [20]. Although intramuscular vaccination induced a strong anti-PrP IgG response in mice which delayed survival time after intraperitoneal prion exposure, it did not offer protection to mule deer naturally (orally) exposed to chronic wasting disease prions [21]. In humans, the risk of accidental iatrogenic vCJD transmission via contaminated blood or blood products, tissues or contaminated surgical instruments is a current concern. In these instances, it is plausible that a strong mucosal (IgA-dominated) anti-PrP antibody response may offer little protection. Therefore, an ideal vaccine should induce both strong mucosal and systemic anti-PrP antibody responses. After peripheral Expert Rev. Vaccines 14(1), (2015)
Prospects for safe and effective vaccines against prion diseases
prion exposure neuroinvasion can occur within a matter of weeks. Thus, whatever the route of immunization, prophylactic vaccines must be able to prevent prions from establishing infection in the periphery and spreading to the CNS.
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
Will one vaccine protect against all prion disease strains?
Another important issue to consider is how effective candidate vaccines may be against novel or emerging prion strains? All attempts to date have used PrP as the immunogen. Prionspecific PrPSc is not a single entity, and is instead considered to represent a spectrum or repertoire of misfolded PrP species varying in biochemical, transmissibility and physicochemical properties. One can only speculate on the efficacy of these vaccines against prion diseases in which very little or no PrPSc is detected [22], or with apparently little peripheral involvement prior to neuroinvasion. However, an anti-PrP vaccine may have other potential benefits such as protection against Alzheimer’s disease neuropathogenesis, as amyloid-b protein-related synaptotoxicity in rats has been shown to be blocked by intravenous injection with anti-PrP monoclonal antibodies [23]. Conclusion
Many promising experimental anti-prion immunization approaches have been reported. Passive immunization attempts have been successful but multiple doses of large quantities of anti-PrP antibodies were required from around the time of exposure [1]. Passive immunization may be most effective when administered therapeutically immediately after a known prion exposure event to limit the establishment of disease in the secondary lymphoid tissues (e.g., after accidental iatrogenic exposure). Realistically, a cheap, safe and effective active immunization approach, which induces a high titre and long-lasting anti-PrP antibody response, is the ultimate goal. However, the
1.
2.
3.
4.
5.
White AR, Enever P, Tayebi M, et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 2003;422:80-3 Sigurdsson EM, Brown DR, Daniels M, et al. Immunization delays the onset of prion disease in mice. Am J Pathol 2002;161:13-17 Sassa Y, Kataoka N, Inoshima Y, Ishiguro N. Anti-PrP antibodies detected at terminal stage of prion-affected mouse. Cell Immunol 2010;263:212-18 Gourdain P, Gregoire S, Iken S, et al. Adoptive transfer of T lymphocytes sensitized against the prion protein attenuates prion invasion in scrapie-infected mice. J Immunol 2009;183:6619-28 Iken S, Bachy V, Gourdain P, et al. Th2-polarized PrP-specific transgenic T-cells
informahealthcare.com
lack of transfer of large immunoglobulin molecules across the blood–brain barrier limits the prophylactic and therapeutic efficacy of active vaccination to the early stages of prion disease in the periphery prior to neuroinvasion. As discussed above, an ideal vaccine will induce a protective systemic (IgG) and mucosal (IgA) response, be effective against multiple prion strains and recognize the spectrum of misfolded PrP species within PrPSc. Irrespective of whether a prophylactic or therapeutic approach is used, the anti-PrP antibodies must not bind PrPC and cause autoimmunity. Fortunately, significant progress has recently been made in identifying PrPSc-specific epitopes, and those which can mediate toxicity upon antibody binding [19]. Prion diseases are invariably fatal neurodegenerative disorders. However, fortunately in humans they are rare in incidence but the emergence of a novel prion strain such as vCJD can create significant uncertainty and have important health implications. New prion strains continue to be identified in livestock and their risks to other domestic animals and human health are uncertain. Therefore, one hopes that in the coming years the pharmaceutical industry can be engaged to help turn any promising, experimental anti-prion vaccine candidates into safe, effective and cheap formulations for widespread clinical use in humans and domestic animals. Financial & competing interests disclosure
This work was supported by Institute Strategic Programme grant (BB/ J004332/1) and project grant (BB/J014672/1 & BB/L007452/1) funding from the Biological and Biotechnological Research Council, as well as project grant funding from the European Commission (FP7 project no. 222887: PRIORITY). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript.
confer partial protection against murine scrapie. PLoS Pathog 2011;7(9):e1002216
References
Editorial
prime-protein boost strategy. Biomed Environ Sci 2011;24:523-9
6.
Bachy V, Ballerini C, Gourdain P, et al. Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie. J Gen Virol 2010;91:809-20
10.
Ishibashi D, Yamanaka H, Mori T, et al. Antigen mimicry-mediated anti-prion effects induced by bacterial enzyme succinylarginine dihydrolase in mice. Vaccine 2011;29:9321-8
7.
Tayebi M, Collinge J, Hawke S. Unswitched immunoglobulin M response prolongs mouse survival in prion disease. J Gen Virol 2009;90:777-82
11.
8.
Alexandrenne C, Wijkhuisen A, Dkhissi F, et al. Electrotransfer of cDNA coding for a heterologous prion protein generates autoantibodies against native murine prion protein in wild-type mice. DNA Cell Biol 2010;29:121-31
Maricinuik K, Maattanen P, Taschuk R, et al. Development of a multivalent, PrPSc-specific prion vaccine through rational optimization of three disease-specific epitopes. Vaccine 2014;32: 1988-97
12.
David MA, Jones DR, Tayebi M. Potential candidate camelid antibodies for the treatment of protein-misfolding diseases. J Neuroimmunol 2014;272:76-85
13.
Fujita K, Yamaguchi Y, Mori T, et al. Effects of a brain-engraftable microglial cell line expressing anti-prion scFv antibodies on survival times of mice infected with scrapie
9.
Han Y, Li Y, Song J, et al. Immune responses in wild-type mice against prion proteins induced using a DNA
3
Editorial
Mabbott
prions. Cell Mol Neurobiol 2011;31: 999-1008 Bremer J, Heikenwalder M, Haybaeck J, et al. Repetitive immunization enhances the susceptibility of mice to peripherally administered prions. PLoS One 2009;4: e7160
18.
15.
Solforosi L, Criado JR, McGavern DB, et al. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 2004;303:1514-16
19.
Sonati T, Reimann RR, Falsig J, et al. The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein. Nature 2013;501:102-6
16.
Klo¨hn P-C, Farmer M, Lineham J, et al. PrP antibodies do not trigger mouse hippocampal neuron apoptosis. Science 2012;335:52
20.
17.
Tayebi M, David M, Bate C, et al. Epitope-specific anti-prion antibodies upregulate apolipoprotein E and disrupt
Gon˜i F, Chablagoity JA, Prelli F, et al. High titres of mucosal and systemic anti-PrP antibodies abrogates oral prion infection in mucosal vaccinated mice. Neuroscience 2008;153:679-86
21.
Pilon JL, Rhyan JC, Wolfe LL, et al. Immunization with a synthetic peptide
14.
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
membrane cholesterol homeostasis. J Gen Virol 2010;91:3105-15
4
Xanthopoulos K, Lagoidaki R, Kontana A, et al. Immunization with recombinant prion protein leads to partial protection in a murine model of TSEs through a novel mechanism. PLoS One 2013;8:e59143
vaccine fails to protect mule deer (Odocoileus hemionus) from chronic wasting disease. J Wildlife Dis 2013;49: 694-8 22.
Dobie K, Barron R. Dissociation between transmissible spongiform encephalopathy (TSE) infectivity and proteinase K-resistant PrPSc levels in peripheral tissues from a murine transgenic model of TSE disease. J Virol 2013;87:5895-903
23.
Klyubin I, Nicoll AJ, Khalili-Shirazi A, et al. Peripheral administration of a humanized anti-PrP antibody blocks Alzheimer’s disease Ab synaptotoxicity. J Neurosci 2014;34:6140-5
Expert Rev. Vaccines 14(1), (2015)
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Prospects for safe and effective vaccines against prion diseases Neil Andrew Mabbott To cite this article: Neil Andrew Mabbott (2015) Prospects for safe and effective vaccines against prion diseases, Expert Review of Vaccines, 14:1, 1-4 To link to this article: http://dx.doi.org/10.1586/14760584.2015.965691
Published online: 30 Sep 2014.
Submit your article to this journal
Article views: 210
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierv20 Download by: [University of California, San Diego]
Date: 11 September 2015, At: 20:00
Editorial
Prospects for safe and effective vaccines against prion diseases Expert Rev. Vaccines 14(1), 1–4 (2015)
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
Neil Andrew Mabbott The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK Tel.: +44 131 651 9100 Fax: +44 131 651 9105 [email protected]
Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrPSc) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt–Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved. Introducing the prion diseases
Prion diseases, or transmissible spongiform encephalopathies, are sub-acute, invariably fatal, neurodegenerative disorders affecting humans and animals. During prion disease, aggregations of PrPSc, an abnormally folded isoform of the host cellular prion protein (PrPC) accumulate in affected tissues. Prion infectivity copurifies with PrPSc and is considered to constitute the major component of the infectious agent. Cellular PrPC is a 30– 35 kDa glycoprotein linked to the cell surface via a glycophosphatidylinositol anchor. The globular domain of PrPC is rich in a-helical content, whereas during prion disease misfolded PrPSc lacks ahelices and has increased b-pleated sheet content. The accumulation of PrPSc in the CNS of prion-infected hosts coincides with neuronal loss, spongiosis and reactive glial responses. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy, chronic wasting disease in cervids and variant Creutzfeldt–Jakob disease (vCJD) in humans, are considered to be acquired peripherally such as by oral exposure. After exposure, the initial replication of prions within secondary lymphoid tissues is critical for their efficient transmission
to the CNS (termed neuroinvasion). Other prion diseases appear to arise spontaneously within the CNS (such as sporadic CJD), or are associated with mutations within the PRNP gene (which encodes PrPC). Since the emergence of vCJD in the UK human population (177 definite or probable cases, September 2014), much effort has been invested into developing an experimental vaccine against prions. Earlier studies showed that both passive (administration of anti-PrP antibodies) [1] and active immunization against PrP [2] were feasible approaches to attenuate experimental prion diseases. Many other potentially promising prophylactic and therapeutic experimental approaches have since been reported, but as outlined below, important issues remain to be resolved. Overcoming T-cell tolerance
A major hurdle that must be overcome in the development of an effective vaccine against prions is T-cell tolerance. Since PrPC is widely expressed, it is tolerated by the host preventing the development of cell-mediated and humoral immune responses to PrPC and prion disease-specific PrPSc. However, some anti-PrP antibodies may be generated toward the clinical phase of prion
KEYWORDS: prion disease • PrP • transmissible spongiform encephalopathy • vaccine
informahealthcare.com
10.1586/14760584.2015.965691
2015 Informa UK Ltd
ISSN 1476-0584
1
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
Editorial
Mabbott
disease [3]. In the absence of tolerance to PrP in PrP–/– (deficient) mice, PrP-specific antibodies are readily elicited. Studies have shown that cell-based immunotherapy can overcome host tolerance toward PrP in wild-type (PrP-expressing) hosts. PrP-sensitized CD4+ T cells from PrP–/– donors [4], or transgenic T cells with a PrP-specific T-cell receptor [5], can each impair prion disease pathogenesis when transferred into wild-type mice. In these examples, the transferred T cells did not induce PrP-specific antibody production by B cells, but instead appeared to mediate protection through secretion of IL-4. Antigen presentation to T cells via MHC-molecules on professional antigen-presenting cells such as dendritic cells is critical for the initial activation of naı¨ve T cells and induction of a specific immune response. Adoptive transfer of PrP peptide-loaded dendritic cells into wild-type mice induced the secretion of IL-4 and IFN-g by T cells, production of PrPspecific antibodies by B cells and increased survival time following peripheral exposure to prions [6]. These elegant approaches allow the cellular mechanisms which influence the induction of protective anti-PrP antibody responses to be studied, but are unlikely to be translated into clinical applications as they are currently too costly and technically challenging for widespread use. Much effort has been placed on the identification of novel epitopes or vaccine formulations, which may enhance the induction of high-affinity and protective anti-PrP antibody responses. Although many studies show tolerance to PrP can be broken in wild-type animals, specific-antibody titers have often been low, and effects on prion disease susceptibility limited. Despite these limitations, repeated injection (every 2 weeks) with PrP-absorbed Dynabeads induced a PrP-specific IgM response and prolonged survival time by approximately 11% after intraperitoneal prion exposure [7]. The use of DNA-based vaccines has also been tested, including immunization with cDNA encoding for heterologous (human) PrP fused to either a stimulatory T-cell epitope [8], or a targeting protein to enhance antigen uptake and presentation via MHC class I [9]. These procedures induce significant PrP-specific IgG in the serum but effects on prion pathogenesis are uncertain. An in silico approach has also been used to select a nonmammalian epitope with similar sequence to that recognized by the anti-PrP monoclonal antibody 6H4. Bacterial succinylarginine dihydrolase was identified, and when used to immunize mice it induced a PrP-specific antibody response and significantly delayed survival times (~7–10%) after intraperitoneal prion exposure [10]. Identification of prion-specific epitopes
To avoid the potential for autoimmune complications, the elicited immune response should be specific for disease-associated PrPSc, with negligible reactivity toward host PrPC. To date, three epitopes that are uniquely present within PrPSc have been identified: a YYR motif that is exposed upon PrPC misfolding; a YML motif in b-sheet 1 and another within the rigid loop linking b-sheet 2 to a-helix 2. When used individually or in a 2
multivalent format, vaccines based on these epitopes induce sustained PrPSc-specific antibody responses in sheep [11]. Whether they confer protection against prion infection remains to be determined. Crossing the blood–brain barrier
Over 10 years ago, it was demonstrated that passive immunization by administration of large quantities of anti-PrP monoclonal antibodies from shortly after intraperitoneal prion exposure significantly delayed disease pathogenesis and survival times. Although these studies suggest immunotherapeutic approaches are worth pursuing, the inability of large molecules such as immunoglobulins to cross the blood–brain barrier realistically limits their use to the early phase after prion exposure, prior to neuroinvasion. To address this issue, one study has shown that camelid single-domain PrP-specific antibodies can cross the blood–brain barrier [12]. Whether anti-PrP antibodies may attenuate prion disease within the CNS is uncertain. A separate study, using a brain-engraftable microglial cell line expressing an anti-PrP antibody single chain Fv fragment observed only marginal effects on disease pathogenesis [13]. Understanding the risks of autoimmunity to PrPC
The safety of any anti-prion vaccines must also be carefully considered. Immunization may plausibly exacerbate prion pathogenesis [14], since the replication of prions within B-cell follicles is important for efficient neuroinvasion. There has also been much controversy over whether anti-PrP antibodies cause autoimmunity or cell toxicity due to recognition of host PrPC [15–18]. A recent study sheds much light on this issue. By studying a panel of PrP-specific monoclonal antibodies, the authors showed that those which bound the a1 and a3 helices of the globular domain of PrPC induced rapid neurotoxicity [19]. These data provide valuable information on the screening of potentially neurotoxic anti-PrP antibodies. Systemic versus mucosal immunization
The route of immunization is likely to have a key bearing on efficacy. Many natural prion diseases in animals are considered to be acquired orally, such as the dietary transmission of bovine spongiform encephalopathy to humans via contaminated food. To date, experimental data suggest mucosal vaccination against prions appears to be effective and the most appropriate method for protection against orally acquired prion infections [20]. Although intramuscular vaccination induced a strong anti-PrP IgG response in mice which delayed survival time after intraperitoneal prion exposure, it did not offer protection to mule deer naturally (orally) exposed to chronic wasting disease prions [21]. In humans, the risk of accidental iatrogenic vCJD transmission via contaminated blood or blood products, tissues or contaminated surgical instruments is a current concern. In these instances, it is plausible that a strong mucosal (IgA-dominated) anti-PrP antibody response may offer little protection. Therefore, an ideal vaccine should induce both strong mucosal and systemic anti-PrP antibody responses. After peripheral Expert Rev. Vaccines 14(1), (2015)
Prospects for safe and effective vaccines against prion diseases
prion exposure neuroinvasion can occur within a matter of weeks. Thus, whatever the route of immunization, prophylactic vaccines must be able to prevent prions from establishing infection in the periphery and spreading to the CNS.
Downloaded by [University of California, San Diego] at 20:00 11 September 2015
Will one vaccine protect against all prion disease strains?
Another important issue to consider is how effective candidate vaccines may be against novel or emerging prion strains? All attempts to date have used PrP as the immunogen. Prionspecific PrPSc is not a single entity, and is instead considered to represent a spectrum or repertoire of misfolded PrP species varying in biochemical, transmissibility and physicochemical properties. One can only speculate on the efficacy of these vaccines against prion diseases in which very little or no PrPSc is detected [22], or with apparently little peripheral involvement prior to neuroinvasion. However, an anti-PrP vaccine may have other potential benefits such as protection against Alzheimer’s disease neuropathogenesis, as amyloid-b protein-related synaptotoxicity in rats has been shown to be blocked by intravenous injection with anti-PrP monoclonal antibodies [23]. Conclusion
Many promising experimental anti-prion immunization approaches have been reported. Passive immunization attempts have been successful but multiple doses of large quantities of anti-PrP antibodies were required from around the time of exposure [1]. Passive immunization may be most effective when administered therapeutically immediately after a known prion exposure event to limit the establishment of disease in the secondary lymphoid tissues (e.g., after accidental iatrogenic exposure). Realistically, a cheap, safe and effective active immunization approach, which induces a high titre and long-lasting anti-PrP antibody response, is the ultimate goal. However, the
1.
2.
3.
4.
5.
White AR, Enever P, Tayebi M, et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 2003;422:80-3 Sigurdsson EM, Brown DR, Daniels M, et al. Immunization delays the onset of prion disease in mice. Am J Pathol 2002;161:13-17 Sassa Y, Kataoka N, Inoshima Y, Ishiguro N. Anti-PrP antibodies detected at terminal stage of prion-affected mouse. Cell Immunol 2010;263:212-18 Gourdain P, Gregoire S, Iken S, et al. Adoptive transfer of T lymphocytes sensitized against the prion protein attenuates prion invasion in scrapie-infected mice. J Immunol 2009;183:6619-28 Iken S, Bachy V, Gourdain P, et al. Th2-polarized PrP-specific transgenic T-cells
informahealthcare.com
lack of transfer of large immunoglobulin molecules across the blood–brain barrier limits the prophylactic and therapeutic efficacy of active vaccination to the early stages of prion disease in the periphery prior to neuroinvasion. As discussed above, an ideal vaccine will induce a protective systemic (IgG) and mucosal (IgA) response, be effective against multiple prion strains and recognize the spectrum of misfolded PrP species within PrPSc. Irrespective of whether a prophylactic or therapeutic approach is used, the anti-PrP antibodies must not bind PrPC and cause autoimmunity. Fortunately, significant progress has recently been made in identifying PrPSc-specific epitopes, and those which can mediate toxicity upon antibody binding [19]. Prion diseases are invariably fatal neurodegenerative disorders. However, fortunately in humans they are rare in incidence but the emergence of a novel prion strain such as vCJD can create significant uncertainty and have important health implications. New prion strains continue to be identified in livestock and their risks to other domestic animals and human health are uncertain. Therefore, one hopes that in the coming years the pharmaceutical industry can be engaged to help turn any promising, experimental anti-prion vaccine candidates into safe, effective and cheap formulations for widespread clinical use in humans and domestic animals. Financial & competing interests disclosure
This work was supported by Institute Strategic Programme grant (BB/ J004332/1) and project grant (BB/J014672/1 & BB/L007452/1) funding from the Biological and Biotechnological Research Council, as well as project grant funding from the European Commission (FP7 project no. 222887: PRIORITY). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript.
confer partial protection against murine scrapie. PLoS Pathog 2011;7(9):e1002216
References
Editorial
prime-protein boost strategy. Biomed Environ Sci 2011;24:523-9
6.
Bachy V, Ballerini C, Gourdain P, et al. Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie. J Gen Virol 2010;91:809-20
10.
Ishibashi D, Yamanaka H, Mori T, et al. Antigen mimicry-mediated anti-prion effects induced by bacterial enzyme succinylarginine dihydrolase in mice. Vaccine 2011;29:9321-8
7.
Tayebi M, Collinge J, Hawke S. Unswitched immunoglobulin M response prolongs mouse survival in prion disease. J Gen Virol 2009;90:777-82
11.
8.
Alexandrenne C, Wijkhuisen A, Dkhissi F, et al. Electrotransfer of cDNA coding for a heterologous prion protein generates autoantibodies against native murine prion protein in wild-type mice. DNA Cell Biol 2010;29:121-31
Maricinuik K, Maattanen P, Taschuk R, et al. Development of a multivalent, PrPSc-specific prion vaccine through rational optimization of three disease-specific epitopes. Vaccine 2014;32: 1988-97
12.
David MA, Jones DR, Tayebi M. Potential candidate camelid antibodies for the treatment of protein-misfolding diseases. J Neuroimmunol 2014;272:76-85
13.
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Expert Rev. Vaccines 14(1), (2015)
