Modified vaccinia virus Ankara for delivery of human tyrosinase as melanoma-associated antigen: induction of tyrosinase- and melanoma-specific human leukocyte antigen A*0201-restricted cytotoxic T cells in vitro and in vivo.
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Vaccination with tumor-associated antigens is a promising approach for cancer immunotherapy. Because the majority of these antigens are normal self antigens, they may require suitable delivery systems to promote their immunogenicity. A recombinant vector based on the modified vaccinia virus Ankara (MVA) was used for expression of human tyrosinase, a melanoma-specific differentiation antigen, and evaluated for its efficacy as an antitumor vaccine. Stable recombinant viruses (MVA-hTyr) were constructed that have deleted the selection marker lacZ and efficiently expressed human tyrosinase in primary human cells and cell lines. Tyrosinase-specific human CTLs were activated in vitro by MVA-hTyr-infected, HLA-A*0201-positive human dendritic cells. Importantly, an efficient tyrosinase- and melanoma-specific CTL response was induced in vitro using MVA-hTyr-infected autologous dendritic cells as activators for peripheral blood mononuclear cells derived from HLA-A*0201-positive melanoma patients despite prior vaccination against smallpox. Immunization of HLA-A*0201/Kb transgenic mice with MVA-hTyr induced A*0201-restricted CTLs specific for the human tyrosinase-derived peptide epitope 369-377. These in vivo primed CTLs were of sufficiently high avidity to recognize and lyse human melanoma cells, which present the endogenously processed tyrosinase peptide in the context of A*0201. Tyrosinase-specific CTL responses were significantly augmented by repeated vaccination with MVA-hTyr. These findings demonstrate that HLA-restricted CTLs specific for human tumor-associated antigens can be efficiently generated by immunization with recombinant MVA vaccines. The results are an essential basis for MVA-based vaccination trials in cancer patients. (+info)
Smallpox and its control in Canada.
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Edward Jenner's first treatise in 1798 described how he used cowpox material to provide immunity to the related smallpox virus. He sent this treatise and some cowpox material to his classmate John Clinch in Trinity, Nfld., who gave the first smallpox vaccinations in North America. Dissemination of the new technique, despite violent criticism, was rapid throughout Europe and the United States. Within a few years of its discovery, vaccination was instrumental in controlling smallpox epidemics among aboriginal people at remote trading posts of the Hudson's Bay Company. Arm-to-arm transfer at 8-day intervals was common through most of the 19th century. Vaccination and quarantine eliminated endemic smallpox throughout Canada by 1946. The last case, in Toronto in 1962, came from Brazil. (+info)
Experimental study of the role of inactivated vaccine in two-step vaccination against smallpox.
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In experiments on rabbits it was found that although administration of inactivated smallpox vaccine did not induce a demonstrable antibody response in the serum it enhanced the immune response to subsequent inoculation with live vaccine. The dose of inactivated vaccine corresponded to 8 x 10(7) PFU before inactivation (by (60)Co gamma-radiation); the dose of live vaccine was 1.2 x 10(5) PFU. When the interval between the two inoculations was 7-days, virus-neutralizing antibody appeared after 5 days and reached levels 2-4 times those obtained with live vaccine alone. With longer intervals (up to 60 days) the enhancement of the immune response was even greater. It seems likely that use of the two-step method may reduce the incidence of post-vaccination encephalitis and clinical studies to determine the optimum conditions for safety and efficacy are at present being undertaken. (+info)
Large-scale use of freeze-dried smallpox vaccine prepared in primary cultures of rabbit kidney cells.
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A lyophilized smallpox vaccine made from infected monolayer cultures of primary rabbit kidney cells was used together with a calf lymph vaccine in a field trial in Lombok, Indonesia, in 1973. About 60 000 children below 15 years of age were vaccinated: some 50 000 with the tissue culture vaccine and about 10 000 with calf lymph vaccine. Similar results were obtained with both vaccines in primary vaccinees and in revaccinees as regards the take rate, pock reactions, and serious secondary reactions. (+info)
An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine.
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The biological properties of poxvirus isolates from skin lesions on dairy cows and milkers during recent exanthem episodes in Cantagalo County, Rio de Janeiro State, Brazil, were more like vaccinia virus (VV) than cowpox virus. PCR amplification of the hemagglutinin (HA) gene substantiated the isolate classification as an Old World orthopoxvirus, and alignment of the HA sequences with those of other orthopoxviruses indicated that all the isolates represented a single strain of VV, which we have designated Cantagalo virus (CTGV). HA sequences of the Brazilian smallpox vaccine strain (VV-IOC), used over 20 years ago, and CTGV showed 98.2% identity; phylogeny inference of CTGV, VV-IOC, and 12 VV strains placed VV-IOC and CTGV together in a distinct clade. Viral DNA restriction patterns and protein profiles showed a few differences between VV-IOC and CTGV. Together, the data suggested that CTGV may have derived from VV-IOC by persisting in an indigenous animal(s), accumulating polymorphisms, and now emerging in cattle and milkers as CTGV. CTGV may represent the first case of long-term persistence of vaccinia in the New World. (+info)
Recent events and observations pertaining to smallpox virus destruction in 2002.
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To destroy all remaining stocks of variola virus on or before 31 December 2002 seems an even more compelling goal today than it did in 1999, when the 52d World Health Assembly authorized temporary retention of remaining stocks to facilitate the possible development of (1) a more attenuated, less reactogenic smallpox vaccine and (2) an antiviral drug that could be used in treatment of patients with smallpox. We believe the deadline established in 1999 should be adhered to, given the potential outcomes of present research. Although verification that every country will have destroyed its stock of virus is impossible, it is reasonable to assume that the risk of a smallpox virus release would be diminished were the World Health Assembly to call on each country to destroy its stocks of smallpox virus and to state that any person, laboratory, or country found to have virus after date x would be guilty of a crime against humanity. (+info)
Developing new smallpox vaccines.
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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. (+info)
Modeling potential responses to smallpox as a bioterrorist weapon.
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We constructed a mathematical model to describe the spread of smallpox after a deliberate release of the virus. Assuming 100 persons initially infected and 3 persons infected per infectious person, quarantine alone could stop disease transmission but would require a minimum daily removal rate of 50% of those with overt symptoms. Vaccination would stop the outbreak within 365 days after release only if disease transmission were reduced to <0.85 persons infected per infectious person. A combined vaccination and quarantine campaign could stop an outbreak if a daily quarantine rate of 25% were achieved and vaccination reduced smallpox transmission by > or = 33%. In such a scenario, approximately 4,200 cases would occur and 365 days would be needed to stop the outbreak. Historical data indicate that a median of 2,155 smallpox vaccine doses per case were given to stop outbreaks, implying that a stockpile of 40 million doses should be adequate. (+info)