Live Variola Virus Considerations for Continuing Research (2009) / Chapter Skim
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7 Development of Vaccines
7 Development of Vaccines
Pages 87-110
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From page 87... ...
However, the committee determined that live variola virus would not be required for the development of live vaccinia vaccines based on traditional vaccine strains but produced with modern tissue culture techniques, as safety and efficacy could be measured against the parental vaccine produced in animals. The committee concluded that research involving live variola virus would be required for the development of nonreplicating virus, live-attenuated virus, 87
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From page 88... ...
This chapter examines in turn the history and current status of smallpox vaccine development, the scientific pathway to development, salient regulatory requirements, and the need for live variola virus in this work. History of smallpox vaccine development Early attempts at preventing smallpox arose from the observations that people who survived the disease had lifetime protection against new exposures and that those who were exposed to variola virus via the cutaneous route had milder disease.
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From page 89... ...
DEVELOPMENT OF VACCINES 89 FIGURE 7-1 Cowpox pustule on the arm of Sarah Nelmes, from An Inquiry into the Causes and Effects of the Variolae Vaccinae by Edward Jenner (1749–1823) , engraved by Pearce, ca 1800 (colored engraving)
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From page 90... ...
U.S. Experience In the wake of the 2001 terrorist attacks in the United States and the deaths due to anthrax that occurred soon after, national security and public health officials began to debate the adoption of a smallpox vaccination program to prepare the country for an intentional release of variola virus (Fauci, 2002; Seiler et al., 2003)
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From page 91... ...
Although not subjected to any modern systematic scientific evaluation using live variola virus, the traditional vaccines set a benchmark against which all other smallpox vaccines must be measured because their efficacy has been established in the human population during natural outbreaks of smallpox. While the efficacy profile of first-generation vaccines is not completely known, the experience during eradication indicates a high level of effectiveness and infrequent serious adverse effects (IOM, 2005)
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From page 92... ...
: cloned virus process; reduced cultured vaccinia grown in Vero cells theoretical risk of virus adventitious agents compared with lymph derived vaccine; less neurovirulent in animal models Elstree-BN Lister Defined manufacturing (Bavarian-Nordic) process; reduced theoretical risk of adventitious agents compared with lymph derived vaccine Third Generation Replication- LC16m8 vaccine: derived Lister Experience in more than competent, from 53 serial passages 100,000 Japanese children highly attenuated in rabbit kidney cells; between 1973 and 1975; vaccinia virus temperature-sensitive, better safety profile than small-plaque phenotype traditional live vaccinia, due to mutation in the less neurovirulent in B5R gene animals but unproven clinical efficacy
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From page 93... ...
vaccinees in Germany in 1970s but unproven clinical efficacy NYVAC (Sanofi-Pasteur) : Copenhagen Theoretically improved attenuated by the safety profile, especially for deletion of 18 open those in whom live reading frames from a vaccinia is contraindicated plaque-cloned vaccinia isolate Subunit vaccines Recombinant proteins; Vaccinia Theoretically improved plasmid DNA viruses, safety profile different sources SOURCE: Adapted from Artenstein and Grabenstein, 2008.
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From page 94... ...
. Consequently, live variola virus itself was not central to the development of first-generation vaccines beyond the original observations of Jenner himself and his immediate followers.
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From page 95... ...
Live variola virus was not required for licensure of the second-generation ACAM2000 vaccine. VECTOR reports production of a recombinant and highly attenuated strain of vaccinia virus, b7, 5S2-S, by the insertion of a hepatitis B (HB)
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From page 96... ...
, variola virus was not endemic in West Germany at that time, and therefore no clinical data exist on MVA's effectiveness against smallpox. MVA has a good safety profile and has been evaluated extensively as a third-generation smallpox vaccine.
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From page 97... ...
. Live-attenuated virus vaccines that retain limited ability to replicate in human hosts offer another route to a safer smallpox vaccine that may be appropriate for use in those for whom second-generation vaccines pose too high a risk.
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From page 98... ...
Nonetheless, subunit vaccines based on up to three or four variola or vaccinia proteins have yielded promising results in the laboratory (Galmiche et al., 1999; Fogg et al., 2004) , providing in animal models protection close to that of traditional vaccines in the short term.
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From page 99... ...
. The FDA has stated that in vitro neutralization studies with live variola virus would be useful in efficacy trials of third-generation vaccines ( Merchlinsky, 2008; WHO, 2008)
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From page 100... ...
The inability of protein-based subunit vaccines to direct de novo protein synthesis in the vaccinee constitutes a major departure from the first- and second-generation vaccines. Consequently, notwithstanding the efficacy of a number of third-generation vaccine approaches in animal models using nonvariola orthopoxviruses, a degree of doubt remains with regard to their potential efficacy against variola virus.
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From page 101... ...
should be considered, since this would be the most likely route of human exposure. Although a path to licensure can be envisaged, the concerns raised in the previous section suggest that replacement of first- and second-generation vaccines with third-generation vaccines that do not produce lesions at the site of inoculation may be inadvisable for those segments of the population that have no contraindications for a traditional smallpox vaccine.
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From page 102... ...
The true efficacy of the first-generation vaccines was established through the experience of physicians and vaccinators and the success of the global eradication campaign, but there is little or no surviving evidence of evaluation in what could be considered a controlled clinical trial. Perhaps one of the most striking advances resulting from recent work on replacement smallpox vaccines is the number of animal models that have been developed and are ready for use to examine efficacy (see Chapter 4)
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From page 103... ...
(see Chapter 1) may be justified on the basis of less stringent evidence of efficacy and may not require the use of live variola virus.
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From page 104... ...
2009. Evaluation of smallpox vaccines using variola neutralization.
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From page 105... ...
2008. ACAM2000: A newly licensed cell culture-based live vaccinia smallpox vaccine.
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From page 106... ...
Modified vaccinia Ankara: Potential as an alternative smallpox vaccine. Clinical Infectious Diseases 38:1749–1753.
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From page 107... ...
2008. Monitoring the safety of a smallpox vaccination program in the United States: Report of the joint Smallpox Vaccine Safety Working Group of the advisory com mittee on immunization practices and the Armed Forces Epidemiological Board.
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From page 108... ...
2008. A review of the smallpox vaccine adverse events active surveillance system.
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From page 109... ...
2004. Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge.
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