DOCSLIB.ORG

Safety of Intravenous Administration of a Canarypox Virus Encoding The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Safety of Intravenous Administration of a Canarypox Virus Encoding The Cancer Gene Therapy (2003) 10, 509–517 r 2003 Nature Publishing Group All rights reserved 0929-1903/03 $25.00 www.nature.com/cgt Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients Anand G Menon,1 Peter JK Kuppen,1 Sjoerd H van der Burg,2 Rienk Offringa,2 Marie Claude Bonnet,5 Bert IJ Harinck,1 Rob AEM Tollenaar,1 Anke Redeker,2 Hein Putter,4 Philippe Moingeon,5 Hans Morreau,3 Cornelis JM Melief,2 and Cornelis JH van de Velde1 1Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; 2Department of Immunohematology and Bloodbank, Leiden University Medical Center, Leiden, The Netherlands; 3Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; 4Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands; and 5Aventis Pasteur, Lyon, France. Overexpression of p53 occurs in more than 50% of colorectal cancers. Therefore, p53 represents an attractive target antigen for immunotherapy. We assessed the safety of a canarypox virus encoding the human wild-type p53 gene given intravenously to end- stage colorectal cancer patients in a three-step dose escalation study aimed at inducing p53 immune responses. Patients with metastatic disease of p53-overexpressing colorectal cancers were vaccinated three times at 3-week intervals, each time with 106.5 7.0 7.5 CCID50 (CCID50 ¼ cell culture infectious dose 50%; group 1, n ¼ 5), 10 CCID50 (group 2, n ¼ 5) or 10 CCID50 (group 3, n ¼ 6). Vital signs and the occurrence of adverse events were monitored and blood was analyzed for biochemical and hematological parameters as well as signs of auto-immune safety. In all, 16 patients were enrolled and 15 patients completed three vaccinations. No anaphylactic reaction or unwanted auto-immune reactions were observed. A total of 16 serious adverse events (SAEs) occurred: 10 in group 1, three in group 2 and three in group 3. All SAEs were tumor-related complications. There was no difference in the frequency of adverse events between the three groups, except for fever. Fever was the only vaccination-related adverse event consistently observed and was most frequent and outspoken in the group 3 patients. The majority was a grade 1 or 2 fever (93%) and grade 3 fever (7%) was observed in three patients of group 3. Some patients showed humoral and cellular responses against p53, following vaccinations. After having completed his initial treatment cycle, one patient (group 2) received a second treatment cycle 7.5 of three doses of 10 CCID50 and subsequently showed stable disease. All other patients showed progressive disease. We conclude that ALVAC-p53 can be administered intravenously to colorectal cancer patients without serious toxicity or pathological autoimmunity and can induce immune responses against p53. Cancer Gene Therapy (2003) 10, 509–517. doi:10.1038/sj.cgt.7700600 Keywords: colorectal cancer; P53; immunotherapy; canarypox virus umors are characterized by numerous changes in a antigens), viral antigens (e.g. HPV E6/E7), protein Tvariety of genes, resulting in altered products that can antigens (e.g. CEA, HER-2/neu, Ep-Cam) and mutated be unique targets for the immune system. Although the oncogene products (e.g. ras, p53, c-myc).1 majority are expressed on both tumor cells and normal The p53 gene is a tumor suppressor gene located on the cells, the expression of these tumor-associated antigens short arm of chromosome 17 that plays a pivotal role in (TAAs) has been found to differ significantly between ensuring genetic homeostasis.2 Mutations in the p53 gene normal cells and tumor cells, and thus may provide an are the most common genetic alteration in many tumors immunotherapeutic window. Potential targets include and result in the production of a defective protein with a carbohydrate antigens (e.g. gangliosides, blood groups significantly longer than normal half-life of p53.3 More than 50% of colorectal cancers demonstrate p53 over- expression, potentially allowing the tumor cells to be Received January 25, 2003. processed and the immunogenic epitopes to be presented Address correspondence and reprint requests to: Professor Dr CJH 4 van de Velde, Department of Surgery, K6-R, Leiden University to the immune system. Although p53 is an auto-antigen, it Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. has been demonstrated that humoral and cellular E-mail: [email protected] immune responses against p53 can be detected in cancer Safety of ALVAC-p53 in colorectal cancer AG Menon et al 510 patients.5–10 Enhancing these responses could result in ALVAC-p53 used in the present study, with doses up to effective antitumor responses, but also induce a hazar- 10 times the proportional human dose, revealed no dous reaction to normal cells that have lowexpression toxicity or auto-immune phenomena upon clinical or on levels of this auto-antigen. histopathological evaluation.14 The safety of ALVAC Vaccination against p53 can be performed using vector-based vaccines has been well established in various genetically modified viral vectors allowing high expression clinical trials where more than 1500 individuals, including of the transfected gene within antigen-presenting cells, cancer patients, have received ALVAC encoding a variety thereby eliciting strong immune response against p53. The of genes such as the rabies glycoprotein gene,15,16 HIV canarypox virus (ALVAC) is a well-characterized viral envelope genes,17,18 CEA19 and even multiple genes such vector capable of infecting a variety of human cells. This as CEA and B7.1.20 In this study, we show that repeated vector, which cannot replicate in non-avian species, can i.v. administration of ALVAC-p53 in end-stage colorectal nevertheless express inserted genes for up to a fewdays. cancer patients is well tolerated and does not induce This results in the induction of strong humoral and pathological auto-immunity, while stimulating p53-speci- cellular responses against these gene products.11 Hurpin fic immune responses. et al.12 compared subcutaneous, intramuscular, intrader- mal and intravenous (i.v.) administrations of ALVAC- p53 in mice and showed that only the i.v. vaccination Methods route was capable of inducing CTL responses against p53. Subsequent studies showed that i.v. vaccination of mice Patients with ALVAC-p53 resulted in long-term protection against Patients older than 18 years with histologically proven challenges with p53 overexpressing tumors. Although, colorectal cancer and evidence by imaging techniques of this does not resemble the clinical situation in which irresectable disease were eligible for inclusion. Patients tumors are already present, Roth et al.13 also showed that with metastatic disease that was untreatable by conven- established p53-overexpressing tumors were successfully tional therapies and patients with metastatic disease that eradicated with i.v. ALVAC-p53 administrations. was potentially treatable, but who refused conventional The use of viral vectors in humans is associated with therapy were also eligible. The study protocol was safety concerns for the patients and the environment, but approved by the local and national medical ethics as the canarypox virus is unable to replicate in committees as well as by the biological safety committee mammalian cells, these concerns do not apply to and the Dutch Ministry of Health and Environment ALVAC-based vaccines. Studies performed on rhesus before the study started. The inclusion and exclusion macaques that received i.v. injections of the same lot of criteria are summarized in Table 1. Table 1 Inclusion and exclusion criteria for participation in the ALVAC-p53 study Inclusion criteria Histologically proven colorectal cancer Evidence of irresectable or metastatic disease in patients untreatable by conventional therapies, or in patients who are treatable by conventional therapies, but who refuse these Immunohistochemically proven expression of p53 and MHC class I in at least 30% of tumor cells Serum CEA X10 mg/l Age over 18 years Negative pregnancy test (for women of child-bearing age) Use effective contraception during the trial and up to 3 months after the last injection (for men and women) WHO performance status of 0–1 Renal function and bilirubin levels within 1.5 Â the normal upper and lower levels, ASAT and ALAT within 3 Â the normal upper value and alkaline phospahatase within 5x the normal upper value Signed informed consent Exclusion criteria Auto-immune disease Symptomatic viral or other infections HIV seropositivity or refusal to hear the result of the HIV test Organ grafts Life expectancy of less than 3 months History of allergy: severe asthma or atopic eczema or known allergy to egg products or neomycin History of severe neurological, cardiovascular, renal, hepatic, endocrine, respiratory or bone marrow dysfunction Known family history of Li-Fraumeni syndrome Chemotherapy (with the exception of nitrosurea), or radiation therapy within 4 weeks preceding inclusion Immunotherapy, chemotherapy using nitrosurea, or hormonal therapy (other than contraception) within 6 weeks preceding inclusion History of treatment with extracted growth hormone Cancer Gene Therapy Safety of ALVAC-p53 in colorectal cancer AG Menon et al 511 Treatment and follow-up schedule toxicity tests, pyrogen assay identification, viral potency test and a particle count test. Patients were enrolled into three sequential groups of five individuals each and received three i.v. injections of ALVAC-p53 at 3-week intervals. At each of the three Statistical analyses injections, patients in group 1 received a tenth (106.5 The w2 test, Kruskal–Wallis test (CEA) and the ANOVA CCID50) of the total dose of ALVAC-p53, patients in (age and diagnosis metastases) tests were performed to 7.0 group 2 received a third (10 CCID50) of the total dose analyze the differences between clinical and tumor and patients in group 3 received the total dose (107.5 characteristics between groups 1 to 3.
Load more

Recommended publications
  • Evaluation of T-Cell and B-Cell Epitopes and Design of Multivalent Vaccines Against Htlv-1 Diseases
    EVALUATION OF T-CELL AND B-CELL EPITOPES AND DESIGN OF MULTIVALENT VACCINES AGAINST HTLV-1 DISEASES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Roshni Sundaram, M.S. * * * * * The Ohio State University 2003 Dissertation Committee: Approved by Professor Pravin T.P. Kaumaya, Adviser Professor Christopher M. Walker Adviser Professor Neil R. Baker Department of Microbiology Professor Marshall V. Williams ABSTRACT Human T-cell lymphotropic virus type I (HTLV-1) is a C type retrovirus that is the causative agent of an aggressive T-cell malignancy, adult T-cell leukemia/lymphoma (ATLL). The virus is also implicated in a number of inflammatory disorders, the most prominent among them being HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). HTLV-1, like many viruses that cause chronic infection, has adapted to persist in the face of an active immune response in infected individuals. The viral transactivator Tax is the primary target of the cellular immune response and humoral responses are mainly directed against the envelope protein. Vaccination against HTLV-1 is a feasible option as there is very little genetic and antigenic variability. Vaccination regimes against chronic viruses must be aimed at augmenting the immune response to a level that is sufficient to clear the virus. This requires that the vaccine delivers a potent stimulus to the immune system that closely resembles natural infection to activate both the humoral arm and the cellular arm. It is also clear that multicomponent vaccines may be more beneficial in terms of increasing the breadth of the immune response as well as being applicable in an outbred population.
    [Show full text]
  • Evolution of the PRD1-Adenovirus Lineage: a Viral Tree of Life Incongruent with the Cellular 3 Universal Tree of Life 4 5 Authors 6 Anthony C
    bioRxiv preprint doi: https://doi.org/10.1101/741942; this version posted August 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Title 2 Evolution of the PRD1-adenovirus lineage: a viral tree of life incongruent with the cellular 3 universal tree of life 4 5 Authors 6 Anthony C. Woo1,2*, Morgan Gaia1,2, Julien Guglielmini3, Violette Da Cunha1,2 and Patrick 7 Forterre1,2* 8 9 Affiliations 1 10 Unité de Biologie Moléculaire du Gène chez les Extrêmophiles (BMGE), Department of 11 Microbiology, Institut Pasteur, 25-28 Rue du Docteur Roux, 75015 Paris, France. 2 12 Department of Microbiology, CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 13 Institute for Integrative Biology of the Cell (I2BC), Bâtiment 21, Avenue de la Terrasse, 14 91190 Gif-sur-Yvette cedex, France. 3 15 HUB Bioinformatique et Biostatistique, C3BI, USR 3756 IP CNRS, Institut Pasteur, 25-28 16 Rue du Docteur Roux, 75015 Paris, France 17 *corresponding authors: 18 Anthony Woo: [email protected] 19 Patrick Forterre: [email protected] 20 21 Abstract 22 Double-stranded DNA viruses of the PRD1-adenovirus lineage are characterized by 23 homologous major capsid proteins containing one or two β-barrel domains known as the jelly 24 roll folds. Most of them also share homologous packaging ATPases of the FtsK/HerA 25 superfamily P-loop ATPases. Remarkably, members of this lineage infect hosts from the three 26 domains of life, suggesting that viruses from this lineage could be very ancient and share a 27 common ancestor.
    [Show full text]
  • A Brief Speculative History of Avipoxvirus in New Zealand
    A brief, speculative history of avipoxvirus in New Zealand Brett Gartrell, Laryssa Howe, Maurice Alley, Hye-Jeong Ha Intro to avipoxvirus (APV) • Global distribution • Reports in >280 bird species, 70 families, 20 orders globally • Economic losses in domestic poultry • Biodiversity losses in island ecosystems (Hawaii, Galapagos, Canary Islands) in conjunction with avian malaria (vaccinia virus, copyright E. Niles). APV infection characteristics • Excellent environmental stability • Need a break in the epithelium for infection to establish • Insect and mechanical vectors are main route of infection • Host specificity varies between strains APV molecular characteristics • Fowlpox virus is the type species of the Avipoxvirus genus • complete genomic sequences of Fowlpox virus and Canarypox virus • The two genomes are highly diverged, sharing only ca. 70% sequence identity • The 365-kbp genome of Canarypox virus is larger than that of Fowlpox virus (288 kbp) and shows significant differences in gene content APV phylogeny • Initially assigned strain/species status on host affected but confused by multi-host pathogenic strains • DNA sequences of the 4b core protein coding genomic region currently used. • Wide variation in genome has limited other pan-genus PCR primers • the vast majority of avian poxvirus isolates clustered into three major clades, represented by the Fowlpox virus (clade A), the Canarypox virus (clade B), and the Psittacinepox virus (clade C) APV phylogeny from NZ birds (HJ Ha PhD) Silvereye © P Sorrell Ha, H.J., Howe, L., Alley, M., Gartrell, B. 2011. The phylogenetic analysis of avipoxvirus in New Zealand. Veterinary Microbiology 150: 80–87 APV distribution in NZ Ha, H.J., Howe, L., Alley, M., Gartrell, B.
    [Show full text]
  • Genomic Characterisation of a Novel Avipoxvirus Isolated from an Endangered Yellow-Eyed Penguin (Megadyptes Antipodes)
    viruses Article Genomic Characterisation of a Novel Avipoxvirus Isolated from an Endangered Yellow-Eyed Penguin (Megadyptes antipodes) Subir Sarker 1,* , Ajani Athukorala 1, Timothy R. Bowden 2,† and David B. Boyle 2 1 Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia; [email protected] 2 CSIRO Livestock Industries, Australian Animal Health Laboratory, Geelong, VIC 3220, Australia; [email protected] (T.R.B.); [email protected] (D.B.B.) * Correspondence: [email protected]; Tel.: +61-3-9479-2317; Fax: +61-3-9479-1222 † Present address: CSIRO Australian Animal Health Laboratory, Australian Centre for Disease Preparedness, Geelong, VIC 3220, Australia. Abstract: Emerging viral diseases have become a significant concern due to their potential con- sequences for animal and environmental health. Over the past few decades, it has become clear that viruses emerging in wildlife may pose a major threat to vulnerable or endangered species. Diphtheritic stomatitis, likely to be caused by an avipoxvirus, has been recognised as a signifi- cant cause of mortality for the endangered yellow-eyed penguin (Megadyptes antipodes) in New Zealand. However, the avipoxvirus that infects yellow-eyed penguins has remained uncharacterised. Here, we report the complete genome of a novel avipoxvirus, penguinpox virus 2 (PEPV2), which was derived from a virus isolate obtained from a skin lesion of a yellow-eyed penguin. The PEPV2 genome is 349.8 kbp in length and contains 327 predicted genes; five of these genes were found to be unique, while a further two genes were absent compared to shearwaterpox virus 2 (SWPV2).
    [Show full text]
  • Avian Pox in Shearwaters on Lord Howe Island
    Association of Avian Veterinarians Australasian Committee Ltd. Annual Conference Proceedings Auckland New Zealand 2017. 25: 63-68. Avian Pox in Shearwaters on Lord Howe Island Subir Sarker1, Shubhagata Das2, Jennifer L. Lavers3, Ian Hutton4, Karla Helbig1, Chris Upton5, Jacob Imbery5, and Shane R. Raidal2 1. Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC, 3086 2. School of Animal and Veterinary Sciences, Charles Sturt University, NSW 2678 3. Institute for Marine and Antarctic Studies, University of Tasmania, TAS 7004 4. Lord Howe Island Museum, Lord Howe Island, NSW 2898 5. Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada. Abstract fungal infections are common and contribute to mortality (van Riper and Forrester, 2007). Until recently six avipox- Avipoxvirus infections occur in a wide range of bird spe- virus genomes were published; a pathogenic American cies worldwide. In Australia pox is common in the Aus- strain of Fowlpox virus (Afonso et al., 2000), an attenuat- tralian magpie (Cracticus tibicen), Currawongs (Strepera ed European strain of Fowlpox virus (Laidlaw and Skinner spp.) and Silvereyes (Zosterops lateralis) but very little , 2004), a virulent Canarypox virus (Tulman et al., 2004), a is known about the evolution of this family of viruses pathogenic South African strain of Pigeonpox virus, a Pen- or the disease ecology of avian poxviruses in seabirds. guinpox virus (Offerman et al., 2014) and a pathogenic Pox lesions have been seen in colonies of Shy Albatross Hungarian strain of Turkeypox virus (Banyai et al., 2015). (Thalassarche cauta) in Bass Strait but the epidemiology of pox in pelagic birds is not very well elucidated.
    [Show full text]
  • HIV VACCINE RESEARCH and DEVELOPMENT CD8 Group
    GLOSSARY OF KEY HIV VACCINE TERMS Immunogenicity – when attributed to a test vaccine, defines the • Since 2001, USAID has contributed $134 million to help discover an HIV vaccine. Currently, USAID is committing annual product’s ability to cause the body to produce antibodies or T-cells funding of $28 million through 2011 for HIV vaccine R&D. that may protect against an infection, disease, or foreign substance. • USAID provides support for all phases of HIV vaccine applied R&D, infrastructure, and capacity building for clinical trial Innate Immunity – a relatively nonspecific response that protects conduct, public communications, and policy analysis through a partnership with the International AIDS Vaccine Initiative. against a whole class or type of invaders but does not generate USAID does not support basic research. TECHNICAL ISSUE BRIEF immune memory (see adaptive immune response). Killer T-cells – a group of T-cells that is activated by helper T-cells • USAID plans involvement with the Global HIV/AIDS Vaccine Enterprise. PATHWAYS OF DISCOVERY: and has the ability to destroy cells infected by foreign invaders (such as viruses). Also known as cytotoxic T-cells, they may belong to the • USAID facilitates coordination between HIV vaccine clinical trial activities and HIV/AIDS prevention, care, and treatment HIV VACCINE RESEARCH AND DEVELOPMENT CD8 group. programs in developing countries. Lymphocytes – the diverse set of white blood cells (each with different functions) that are responsible for immune responses. virologists convenes twice a year to review the R&D portfolio activities. As the Global HIV/AIDS Vaccine Enterprise evolves Introduction There are two main types: B-cells (responsible for producing anti- under consideration by the organization.
    [Show full text]
  • A History of AIDS: Looking Back to See Ahead
    S94 Warner C. Greene Eur. J. Immunol. 2007. 37: S94–102 Breakthroughs in Immunology A history of AIDS: Looking back to see ahead Warner C. Greene Gladstone Institute of Virology and Immunology, University of California, Received 5/7/05 San Francisco, CA, USA Revised 22/8/07 Accepted 4/9/07 [DOI 10.1002/eji.200737441] Since breaking onto the scene 26 years ago, HIV has proven an indefatigable foe. Over 60 million people have been infected with this retrovirus, and 25 million have already died of AIDS. HIV infection is hitting the hardest in the developing world [1]. Tragically, Key words: 1600 babies continue to acquire HIV every day from their infected mothers. Over 12 AIDS Á Drug design/ million children have also been orphaned by AIDS, and this number will likely double by discovery Á Global 2010. With these sobering statistics as a backdrop, this feature traces the history of the pandemic Á HIV devastating HIV/AIDS pandemic and offers a view for what the future may hold. Á Infectious diseases Unfolding of a pandemic The appearance of AIDS in Haiti fueled speculation that the disease had originated there. Although not compell- ing, these theories stoked the fear and prejudice AIDS was first recognized in the summer of 1981 surrounding the disease. (Table 1). Young gay men began falling ill and dying of By late 1982, epidemiologic evidence indicated that opportunistic infections their immune systems should AIDS was an infectious disease transferred by bodily have fended off [2]. Those afflicted became emaciated fluids and by exposure to contaminated blood or blood and often developed dark purple lesions on their arms products [3].
    [Show full text]
  • Comparative Efficacy of Feline Leukemia Virus
    COMPARATIVE EFFICACY OF FELINE LEUKEMIA VIRUS INACTIVATED WHOLE VIRUS VACCINE AND CANARYPOX VIRUS-VECTORED VACCINE BY MODERN MOLECULAR ASSAYS AND CONVENTIONAL PARAMETERS M. Patel1, K. Carritt1, J. Lane1, H. Jayappa1, M. Stahl2. 1. Merck Animal Health, Elkhorn, NE. 2. Merck Animal Health, Summit, NJ. The purpose of this study was to compare the efficacy of two commercially available feline leukemia vaccines, Nobivac® Feline 2-FeLV (inactivated whole virus vaccine) and PureVax® Recombinant FeLV (live canarypox virus-vectored vaccine) following challenge with virulent feline leukemia virus. Cats were vaccinated subcutaneously at 8 and 11 weeks of age with Nobivac® Feline 2-FeLV vaccine (Group A, n =11) or PureVax® Recombinant FeLV vaccine (Group B, n=10), three weeks apart per manufacturer’s label. Group C (n=11) served as age-matched, unvaccinated controls. Three months after second vaccination, all cats were challenged with virulent FeLV- A/61E. Challenge outcome was monitored for 12 weeks post-challenge (PC) for the development of persistent viremia utilizing a commercial FeLV p27 ELISA. Circulating proviral DNA and plasma viral RNA loads were determined by quantitative PCR and real-time RT-PCR assay, respectively, from week 3 to 9 PC to determine whether FeLV vaccination would prevent nucleic acid persistence. Persistent viremia was observed in 0 of 11 (0%) of Group A cats, 5 of 10 (50%) of Group B cats and 10 of 11 (91%) of Group C cats. Cats in Group A were significantly protected from persistent viremia compared to Group B cats (P <0.013) and Group C cats (P <0.0001). No significant difference was found between Group B cats and Group C cats (P >0.063).
    [Show full text]
  • Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion
    Rockefeller University Digital Commons @ RU Publications Steinman Laboratory Archive 2000 Canarypox virus-induced maturation of dendritic cells is mediated by apoptotic cell death and tumor necrosis factor alpha secretion Ralf Ignatius Mary A. Marovich Erin Mahlhop Follow this and additional works at: https://digitalcommons.rockefeller.edu/steinman-publications JOURNAL OF VIROLOGY, Dec. 2000, p. 11329–11338 Vol. 74, No. 23 0022-538X/00/$04.00ϩ0 Copyright © 2000, American Society for Microbiology. All Rights Reserved. Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion RALF IGNATIUS,1† MARY MAROVICH,2 ERIN MEHLHOP,1 LORELEY VILLAMIDE,1 KARSTEN MAHNKE,1 WILLIAM I. COX,3 FRANK ISDELL,1 SARAH S. FRANKEL,2 JOHN R. MASCOLA,2 1 1 RALPH M. STEINMAN, AND MELISSA POPE * 1 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021 ; Downloaded from Division of Retrovirology, Walter Reed Army Institute of Research and Henry M. Jackson Foundation, Rockville, Maryland 208502; and Virogenetics Corporation, Rensselaer Technology Park, Troy, New York 121803 Received 23 August 2000/Accepted 1 September 2000 Recombinant avipox viruses are being widely evaluated as vaccines. To address how these viruses, which replicate poorly in mammalian cells, might be immunogenic, we studied how canarypox virus (ALVAC) interacts with primate antigen-presenting dendritic cells (DCs). When human and rhesus macaque monocyte- derived DCs were exposed to recombinant ALVAC, immature DCs were most susceptible to infection. However, http://jvi.asm.org/ many of the infected cells underwent apoptotic cell death, and dying infected cells were engulfed by uninfected DCs.
    [Show full text]
  • Differential Innate Immune Stimulation Elicited by Adenovirus and Poxvirus Vaccine Vectors
    Differential Innate Immune Stimulation Elicited by Adenovirus and Poxvirus Vaccine Vectors The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Teigler, Jeffrey Edward. 2014. Differential Innate Immune Stimulation Elicited by Adenovirus and Poxvirus Vaccine Vectors. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11745711 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Differential Innate Immune Stimulation Elicited by Adenovirus and Poxvirus Vaccine Vectors A dissertation presented by Jeffrey Edward Teigler To The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Virology Harvard University Cambridge, Massachusetts January 2014 © 2013 Jeffrey Edward Teigler All rights reserved. Dissertation Advisor: Dr. Dan H. Barouch Jeffrey Edward Teigler Differential Innate Immune Stimulation Elicited by Adenoviral and Poxviral Vaccine Vectors Abstract Vaccines are one of the most effective advances in medical science and continue to be developed for applications against infectious diseases, cancers, and autoimmunity. A common strategy for vaccine construction is the use of viral vectors derived from various virus families, with Adenoviruses (Ad) and Poxviruses (Pox) being extensively used. Studies utilizing viral vectors have shown a broad variety of vaccine-elicited immune response phenotypes. However, innate immune stimulation elicited by viral vectors and its possible role in shaping these vaccine-elicited adaptive immune responses remains unclear.
    [Show full text]
  • Recombinant Type 3 Vaccine Technology
    RECOMBINANT TYPE 3 VACCINE TECHNOLOGY RECOMBITEK KC2 is manufactured by Boehringer Ingelheim. All other RECOMBITEK vaccines are manufactured by Merial. Merial is now part of Boehringer Ingelheim. RECOMBITEK® and PUREVAX® are registered trademarks of Merial. ©2018 Merial, Inc., Duluth, GA. All rights reserved. PET-0510-BIO0618. VACCINE TECHNOLOGY TRADITIONAL VACCINE TECHNOLOGY • Vaccines were originally developed on an empirical basis, • A vector virus is a live virus that carries its own natural relying mostly on attenuation of pathogens (e.g., modified genes, plus the foreign immunity gene(s) of one or more live viral vaccines) or inactivation of pathogens (e.g., different virus(es). killed vaccines). • The vector virus used in RECOMBITEK® and PUREVAX® Type • Many current vaccines owe their success to their ability 3 Recombinant vaccines is a canarypox virus. to target pathogens that have low antigenic variability • Canarypox-vectored recombinant vaccines contain only and for which protection depends on antibody- a portion of the genetic material of a pathogen, not the mediated immunity. complete organism. Therefore, it is not possible for the • On the other hand, important cell-mediated immunity recombined canarypox to produce disease from the against intracellular pathogens is more difficult to obtain pathogen in the vaccinated animal. using inactivated pathogens as vaccines. • Live attenuated pathogen vaccines can elicit cell-mediated WHY CANARYPOX VIRUS? immunity, but may pose potential risks that cannot • Canarypox viruses have specific cytoplasmic requirements be overlooked. Although not often, these vaccines can for replication, which are not met by mammalian be virulent in susceptible hosts or experience reversal cytoplasm, therefore replication cannot occur in of attenuation.
    [Show full text]
  • Characterization of Canarypox-Like Viruses Infecting Endemic Birds in the Galaâ Pagos Islands
    Journal of Wildlife Diseases, 41(2), 2005, pp. 342±353 q Wildlife Disease Association 2005 CHARACTERIZATION OF CANARYPOX-LIKE VIRUSES INFECTING ENDEMIC BIRDS IN THE GALAÂ PAGOS ISLANDS Teresa Thiel,1 Noah K. Whiteman,1 Ana TirapeÂ,2,3 Maria Ines Baquero,2,4 Virna CedenÄo,2,3,4 Tim Walsh,5,6,7 Gustavo JimeÂnez UzcaÂtegui,6 and Patricia G. Parker1,5 1 Department of Biology, University of Missouri±St. Louis, Missouri 63121, USA 2 Laboratory of Fabricio Valverde, GalaÂpagos National Park, Isla Santa Cruz, GalaÂpagos, Ecuador 3 Concepto Azul, Guayaquil, Ecuador 4 Biotechnology Program, University of Guayaquil, Guayaquil, Ecuador 5 Charles Darwin Research Station, Puerto Ayora, Isla Santa Cruz, GalaÂpagos, Ecuador 6 Current address: Washington State University, Washington Animal Disease Diagnostic Laboratory, Pullman, Washington 99165-2037, USA 7 Corresponding author (email: [email protected]) ABSTRACT: The presence of avian pox in endemic birds in the GalaÂpagos Islands has led to concern that the health of these birds may be threatened by avipoxvirus introduction by domestic birds. We describe here a simple polymerase chain reaction±based method for identi®cation and discrimination of avipoxvirus strains similar to the fowlpox or canarypox viruses. This method, in conjunction with DNA sequencing of two polymerase chain reaction±ampli®ed loci totaling about 800 bp, was used to identify two avipoxvirus strains, Gal1 and Gal2, in pox lesions from yellow warblers (Dendroica petechia), ®nches (Geospiza spp.), and GalaÂpagos mockingbirds (Nesomimus parvulus) from the inhabited islands of Santa Cruz and Isabela. Both strains were found in all three passerine taxa, and sequences from both strains were less than 5% different from each other and from canarypox virus.
    [Show full text]