The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Rama Akondy - One of the best experts on this subject based on the ideXlab platform.
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insights into human cd8 t cell memory using the yellow fever and Smallpox Vaccines
Immunology and Cell Biology, 2011Co-Authors: Rafi Ahmed, Rama AkondyAbstract:Live virus Vaccines provide a unique opportunity to study human CD8+ T-cell memory in the context of a controlled, primary acute viral infection. Yellow fever virus-17D and Dryvax are two such live-virus Vaccines that are highly efficacious, used worldwide and provide long-term immunity against yellow fever and Smallpox respectively. In this review, we describe the properties of virus-specific memory CD8+ T cells generated in Smallpox and yellow fever vaccinees. We address fundamental questions regarding magnitude, functional quality and longevity of the CD8+ T-cell response, which are otherwise challenging to address in humans. These findings provide insights into the attributes of the human immune system as well as provide a benchmark for the optimal quality of a CD8+ T-cell response that can be used to evaluate novel candidate Vaccines.
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Human Immune Memory to Yellow Fever and Smallpox Vaccination
Journal of Clinical Immunology, 2009Co-Authors: Jens Wrammert, Rama Akondy, Joe Miller, Rafi AhmedAbstract:Background Establishment of immunological memory is a hallmark of adaptive immune responses and the biological mechanism for the success of Vaccines. However, in humans, much of our knowledge about adaptive immune responses derives from studies of chronic viral infections. Objective Here, we summarize the work of our laboratory and others on B and T cell responses and the establishment and maintenance of immune memory after acute viral infections induced by vaccination with two of the most successful Vaccines to date, the yellow fever and the Smallpox Vaccines.
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human effector and memory cd8 t cell responses to Smallpox and yellow fever Vaccines
Immunity, 2008Co-Authors: Joseph D Miller, Robbert G Van Der Most, John Glidewell, Sophia Albott, Patryce L Mahar, Srilatha Edupuganti, Kaja Muralikrishna, David Masopust, Rama Akondy, Susan LalorAbstract:Summary To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8 + T cells responding to the live yellow fever virus and Smallpox Vaccines—two highly successful human Vaccines. Our results show that both Vaccines generated a brisk primary effector CD8 + T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8 + T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8 + T cells specific for persistent viruses. These results provide a benchmark for CD8 + T cell responses induced by two of the most effective Vaccines ever developed.
Michael Merchlinsky - One of the best experts on this subject based on the ideXlab platform.
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Smallpox Vaccines induce antibodies to the immunomodulatory secreted vaccinia virus complement control protein
Journal of General Virology, 2009Co-Authors: Joan E Adamo, Clement A. Meseda, Jerry P. Weir, Michael MerchlinskyAbstract:Vaccination with Dryvax elicits a broad humoral response against many viral proteins. Human vaccinia immune globulin was used to screen the secreted proteins from cells infected with Dryvax or the candidate Smallpox vaccine LC16m8 to determine whether the protective humoral response included antibodies against secreted viral proteins. Many proteins were detected, with the primary band corresponding to a band of 28 or 30 kDa in cells infected with Dryvax or LC16m8, respectively. This was identified as the vaccinia virus complement protein (VCP), which migrated more slowly in LC16m8-infected cells due to post-translational glycosylation. Vaccinia virus deleted in VCP, vVCPko, protected mice from a lethal intranasal challenge of vaccinia Western Reserve strain. Mice vaccinated with purified VCP demonstrated a strong humoral response, but were not protected against a moderate lethal challenge of vaccinia virus, suggesting that the humoral response against VCP is not critical for protection.
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comparative evaluation of the immune responses and protection engendered by lc16m8 and dryvax Smallpox Vaccines in a mouse model
Clinical and Vaccine Immunology, 2009Co-Authors: Clement A. Meseda, Anne E Mayer, Arunima Kumar, Alonzo D Garcia, Joseph Campbell, Paul Listrani, Jody Manischewitz, Lisa R King, Hana Golding, Michael MerchlinskyAbstract:The immune response elicited by LC16m8, a candidate Smallpox vaccine that was developed in Japan by cold selection during serial passage of the Lister vaccine virus in primary rabbit kidney cells, was compared to Dryvax in a mouse model. LC16m8 carries a mutation resulting in the truncation of the B5 protein, an important neutralizing target of the extracellular envelope form of vaccinia virus (EV). LC16m8 elicited a broad-spectrum immunoglobulin G (IgG) response that neutralized both EV and the intracellular mature form of vaccinia virus and provoked cell-mediated immune responses, including the activation of CD4 and CD8 cells, similarly to Dryvax. Mice inoculated with LC16m8 had detectable but low levels of anti-B5 IgG compared to Dryvax, but both Dryvax and LC16m8 sera neutralized vaccinia virus EV in vitro. A truncated B5 protein (8 kDa) was expressed abundantly in LC16m8-infected cells, and both murine immune sera and human vaccinia virus immunoglobulin recognized the truncated recombinant B5 protein in antigen-specific enzymelinked immunosorbent assays. At a high-dose intranasal challenge (100 or 250 50% lethal doses), LC16m8 and Dryvax conferred similar levels of protection against vaccinia virus strain WR postvaccination. Taken together, the results extend our current understanding of the protective immune responses elicited by LC16m8 and indicate that the relative efficacy in a mouse model rivals that of previously licensed Smallpox Vaccines.
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characterization and use of mammalian expressed vaccinia virus extracellular membrane proteins for quantification of the humoral immune response to Smallpox Vaccines
Clinical and Vaccine Immunology, 2007Co-Authors: Alonzo D Garcia, Clement A. Meseda, Michael Merchlinsky, Anne E Mayer, Arunima Kumar, Jerry P. WeirAbstract:The licensed Smallpox vaccine Dryvax is used as the standard in comparative immunogenicity and protection studies of new Smallpox vaccine candidates. Although the correlates of protection against Smallpox are unknown, recent studies have shown that a humoral response against the intracellular mature virion and extracellular enveloped virion (EV) forms of vaccinia virus is crucial for protection. Using a recombinant Semliki Forest virus (rSFV) vector system, we expressed a set of full-length EV proteins for the development of EV antigen-specific enzyme-linked immunosorbent assays (ELISAs) and the production of monospecific antisera. The EV-specific ELISAs were used to evaluate the EV humoral response elicited by Dryvax and the nonreplicating modified vaccinia virus Ankara (MVA) in mouse vaccination experiments comparing doses and routes of vaccination. Quantitatively similar titers of antibodies against EV antigens A33R, A56R, and B5R were measured in mice vaccinated with Dryvax and MVA when MVA was administered at a dose of 108 plaque-forming units. Further, a substantial increase in the EV-specific antibody response was induced in mice inoculated with MVA by using a prime-boost schedule. Finally, we investigated the abilities of the EV-expressing rSFV vectors to elicit the production of polyclonal monospecific antisera against the corresponding EV proteins in mice. The monospecific serum antibody levels against A33R, A56R, and B5R were measurably higher than the antibody levels induced by Dryvax. The resulting polyclonal antisera were used in Western blot analysis and immunofluorescence assays, indicating that rSFV particles are useful vectors for generating monospecific antisera.
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Mouse neurotoxicity test for vaccinia-based Smallpox Vaccines.
Vaccine, 2004Co-Authors: Steven A Rubin, Rolf E Taffs, Michael Merchlinsky, Kathryn M CarboneAbstract:The only US FDA licensed Smallpox vaccine, Dryvax, was associated with rare but serious neurological adverse events. After Smallpox was eradicated in the United States, mass vaccination ceased in 1971. As counter-bioterrorism/biowarfare measures, new Smallpox Vaccines are now being investigated. However, there are no established pre-clinical neurotoxicity assays with which to evaluate these new Vaccines prior to licensure. Here we report the development and initial characterization of a small animal neurotoxicity assay for vaccinia-based Smallpox Vaccines using Dryvax virus as a reference vaccine strain and the neuroadapted Western Reserve (WR) strain as a neurotoxic positive control. In neonatally inoculated mice, the WR strain produced significantly greater and more rapid onset of mortality than the Dryvax vaccine reference. Expression of virus antigen in neural cells and infectious virus replication in the brain was also significantly different between the two strains. In addition, the appearance of high titer virus antibody correlated with the clearance of virus from brain. With further validation, this assay incorporating a licensed vaccine reference standard and positive control strain may provide important pre-clinical neurotoxicity data on new vaccinia-based Smallpox vaccine strains.
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Developing new Smallpox Vaccines.
Emerging infectious diseases, 2001Co-Authors: Steven R. Rosenthal, Michael Merchlinsky, Cynthia Kleppinger, Karen L. GoldenthalAbstract:New stockpiles of Smallpox vaccine are required as a contingency for protecting civilian and military personnel against deliberate dissemination of Smallpox virus by terrorists or unfriendly governments. The Smallpox vaccine in the current stockpile consists of a live animal poxvirus (Vaccinia virus [VACV]) that was grown on the skin of calves. Because of potential issues with controlling this earlier manufacturing process, which included scraping VACV lesions from calfskin, new Vaccines are being developed and manufactured by using viral propagation on well-characterized cell substrates. We describe, from a regulatory perspective, the various strains of VACV, the adverse events associated with calf lymph-propagated Smallpox vaccine, the issues regarding selection and use of cell substrates for vaccine production, and the issues involved in demonstrating evidence of safety and efficacy.
Kevin L Karem - One of the best experts on this subject based on the ideXlab platform.
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unintentional transfer of vaccinia virus associated with Smallpox Vaccines acam2000 compared with dryvax
Human Vaccines & Immunotherapeutics, 2013Co-Authors: Danielle M Tack, Kevin L Karem, Jay R Montgomery, Limone C Collins, Marthe Bryantgenevier, Rosemary Tiernan, Maria Cano, Paige Lewis, Renata J M Engler, Inger K. DamonAbstract:Background: Routine vaccination against Smallpox (variola) ceased in the US in 1976. However, in 2002 limited coverage for military personnel and some healthcare workers was reinstituted. In March 2008, ACAM2000® replaced Dryvax® as the vaccine used in the United States against Smallpox. Unintentional transfer of vaccinia virus from a vaccination site by autoinoculation or contact transmission, can have significant public health implications. We summarize unintentional virus transfer AEs associated with ACAM2000® since March 2008 and compare with Dryvax®.Results: We identified 309 reports for ACAM2000® with skin or ocular involvement, of which 93 were autoinoculation cases and 20 were contact transmission cases. The rate for reported cases of autoinoculation was 20.6 per 100,000 vaccinations and for contact transmission was 4.4 per 100,000 vaccinations. Eighteen contact transmission cases could be attributed to contact during a sporting activity (45%) or intimate contact (45%). Of the 113 unintentional tr...
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humoral immunity to Smallpox Vaccines and monkeypox virus challenge proteomic assessment and clinical correlations
Journal of Virology, 2013Co-Authors: Michael B Townsend, Inger K. Damon, M S Keckler, Nishi Patel, David Huw Davies, Philip L Felgner, Kevin L KaremAbstract:Despite the eradication of Smallpox, orthopoxviruses (OPV) remain public health concerns. Efforts to develop new therapeutics and Vaccines for Smallpox continue through their evaluation in animal models despite limited understanding of the specific correlates of protective immunity. Recent monkeypox virus challenge studies have established the black-tailed prairie dog (Cynomys ludovicianus) as a model of human systemic OPV infections. In this study, we assess the induction of humoral immunity in humans and prairie dogs receiving Dryvax, Acam2000, or Imvamune vaccine and characterize the proteomic profile of immune recognition using enzyme-linked immunosorbent assays (ELISA), neutralization assays, and protein microarrays. We confirm anticipated similarities of antigenic protein targets of Smallpox vaccine-induced responses in humans and prairie dogs and identify several differences. Subsequent monkeypox virus intranasal infection of vaccinated prairie dogs resulted in a significant boost in humoral immunity characterized by a shift in reactivity of increased intensity to a broader range of OPV proteins. This work provides evidence of similarities between the vaccine responses in prairie dogs and humans that enhance the value of the prairie dog model system as an OPV vaccination model and offers novel findings that form a framework for examining the humoral immune response induced by systemic orthopoxvirus infection.
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analysis of variola and vaccinia virus neutralization assays for Smallpox Vaccines
Clinical and Vaccine Immunology, 2012Co-Authors: Christine M Hughes, Victoria A. Olson, Scott K. Smith, Sharon E. Frey, Robert C. Holman, Robert B Belshe, Lihan Yan, Frances K Newman, Whitni Davidson, Kevin L KaremAbstract:Possible Smallpox reemergence drives research for third-generation Vaccines that effectively neutralize variola virus. A comparison of neutralization assays using different substrates, variola and vaccinia (Dryvax and modified vaccinia Ankara [MVA]), showed significantly different 90% neutralization titers; Dryvax underestimated while MVA overestimated variola neutralization. Third-generation Vaccines may rely upon neutralization as a correlate of protection.
Rafi Ahmed - One of the best experts on this subject based on the ideXlab platform.
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insights into human cd8 t cell memory using the yellow fever and Smallpox Vaccines
Immunology and Cell Biology, 2011Co-Authors: Rafi Ahmed, Rama AkondyAbstract:Live virus Vaccines provide a unique opportunity to study human CD8+ T-cell memory in the context of a controlled, primary acute viral infection. Yellow fever virus-17D and Dryvax are two such live-virus Vaccines that are highly efficacious, used worldwide and provide long-term immunity against yellow fever and Smallpox respectively. In this review, we describe the properties of virus-specific memory CD8+ T cells generated in Smallpox and yellow fever vaccinees. We address fundamental questions regarding magnitude, functional quality and longevity of the CD8+ T-cell response, which are otherwise challenging to address in humans. These findings provide insights into the attributes of the human immune system as well as provide a benchmark for the optimal quality of a CD8+ T-cell response that can be used to evaluate novel candidate Vaccines.
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Human Immune Memory to Yellow Fever and Smallpox Vaccination
Journal of Clinical Immunology, 2009Co-Authors: Jens Wrammert, Rama Akondy, Joe Miller, Rafi AhmedAbstract:Background Establishment of immunological memory is a hallmark of adaptive immune responses and the biological mechanism for the success of Vaccines. However, in humans, much of our knowledge about adaptive immune responses derives from studies of chronic viral infections. Objective Here, we summarize the work of our laboratory and others on B and T cell responses and the establishment and maintenance of immune memory after acute viral infections induced by vaccination with two of the most successful Vaccines to date, the yellow fever and the Smallpox Vaccines.
Luis Mateo - One of the best experts on this subject based on the ideXlab platform.
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Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation Smallpox vaccine.
Vaccine, 2005Co-Authors: Jens Vollmar, Barbara Petzold, Amanda Handley, Nathaly Arndtz, Karl M. Eckl, T. Thomsen, Luis Mateo, Bernd Schlereth, Lynette King, Vanessa HülsemannAbstract:A Phase I trial was performed to investigate the safety and immunogenicity of the third generation Smallpox vaccine MVA-BN (IMVAMUNE), a highly attenuated clone derived from the Modified Vaccinia Virus Ankara strain 571, in naive and pre-immunized subjects. A total of 86 healthy subjects received the vaccine in five groups using different doses and routes of administration. All 38 subjects seroconverted in the groups receiving the highest dose (10(8) TCID50). All vaccinations were well tolerated with mainly mild or moderate pain at the injection site being the most frequent symptom. The results indicate that MVA-BN has the potential to be developed as an efficient and safe alternative to the conventional Smallpox Vaccines such as Lister-Elstree or Dryvax. Unique attributes render it a promising candidate for prophylactic mass immunization, even in subjects for whom conventional Smallpox Vaccines are contraindicated.
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modified vaccinia virus ankara protects macaques against respiratory challenge with monkeypox virus
Journal of Virology, 2005Co-Authors: Koert J Stittelaar, Geert Van Amerongen, Ivanela Kondova, Thijs Kuiken, Rob Van Lavieren, Frank Pistoor, H G M Niesters, Gerard J J Van Doornum, Ben A M Van Der Zeijst, Luis MateoAbstract:The use of classical Smallpox Vaccines based on vaccinia virus (VV) is associated with severe complications in both naive and immune individuals. Modified vaccinia virus Ankara (MVA), a highly attenuated replication-deficient strain of VV, has been proven to be safe in humans and immunocompromised animals, and its efficacy against Smallpox is currently being addressed. Here we directly compare the efficacies of MVA alone and in combination with classical VV-based Vaccines in a cynomolgus macaque monkeypox model. The MVA-based Smallpox vaccine protected macaques against a lethal respiratory challenge with monkeypox virus and is therefore an important candidate for the protection of humans against Smallpox.