Modified Vaccinia Virus Ankara Immunization Protects against Lethal Challenge with Recombinant Vaccinia Virus Expressing Murine Interleukin-4

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Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax. MVA was attenuated by extensive passage of vaccinia virus Ankara in chicken embryo fibroblasts. Several immunomodulatory genes and genes that influence host range are deleted or mutated, and replication is aborted in the late stage of infection in most nonavian cells. The effect of these mutations on immunogenicity is not well understood. Since the structural genes appear to be intact in MVA, it is hypothesized that critical targets for antibody neutralization have been retained. To test this, we probed microarrays of the Western Reserve (WR) proteome with sera from humans and macaques after MVA and Dryvax vaccination. As most protein sequences of MVA are 97 to 99% identical to those of other vaccinia virus strains, extensive binding cross-reactivity is expected, except for those deleted or truncated. Despite different hosts and immunization regimens, the MVA and Dryvax antibody profiles were broadly similar, with antibodies against membrane and core proteins being the best conserved. The responses to nonstructural proteins were less well conserved, although these are not expected to influence virus neutralization. The broadest antibody response was obtained for hyperimmune rabbits with WR, which is pathogenic in rabbits. These data indicate that, despite the mutations and deletions in MVA, its overall immunogenicity is broadly comparable to that of Dryvax, particularly at the level of antibodies to membrane proteins. The work supports other information suggesting that MVA may be a useful alternative to Dryvax.

mentioning

confidence: 99%

Antibody Profiling by Proteome Microarray Reveals the Immunogenicity of the Attenuated Smallpox Vaccine Modified Vaccinia Virus Ankara Is Comparable to That of Dryvax

Davies

Wyatt

Newman

et al. 2008

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127

“…Such concerns have led to the production and stockpiling of a modern version of the currently licensed vaccine as well as renewed efforts to develop or evaluate safer ones (18). The latter include attenuated live vaccinia virus (VACV) (6,12,22,32,44,50), DNA vaccines (19,20), and protein vaccines (15,16). There may also be a role for passive antibody to treat adverse effects of a live VACV vaccine or to provide immediate protection against smallpox in an emergency situation (8,51).…”

mentioning

confidence: 99%

Combinations of Polyclonal or Monoclonal Antibodies to Proteins of the Outer Membranes of the Two Infectious Forms of Vaccinia Virus Protect Mice against a Lethal Respiratory Challenge

Lustig

Fogg

Whitbeck

et al. 2005

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147

Previous studies demonstrated that antibodies to live vaccinia virus infection are needed for optimal protection against orthopoxvirus infection. The present report is the first to compare the protective abilities of individual and combinations of specific polyclonal and monoclonal antibodies that target proteins of the intracellular (IMV) and extracellular (EV) forms of vaccinia virus. The antibodies were directed to one IMV membrane protein, L1, and to two outer EV membrane proteins, A33 and B5. In vitro studies showed that the antibodies to L1 neutralized IMV and that the antibodies to A33 and B5 prevented the spread of EV in liquid medium. Prophylactic administration of individual antibodies to BALB/c mice partially protected them against disease following intranasal challenge with lethal doses of vaccinia virus. Combinations of antibodies, particularly anti-L1 and -A33 or -L1 and -B5, provided enhanced protection when administered 1 day before or 2 days after challenge. Furthermore, the protection was superior to that achieved with pooled immune gamma globulin from human volunteers inoculated with live vaccinia virus. In addition, single injections of anti-L1 plus anti-A33 antibodies greatly delayed the deaths of severe combined immunodeficiency mice challenged with vaccinia virus. These studies suggest that antibodies to two or three viral membrane proteins optimally derived from the outer membranes of IMV and EV, may be beneficial for prophylaxis or therapy of orthopoxvirus infections.

“…In developing vaccine candidates with greater safety profiles suitable for contemporary populations, many different approaches are under consideration and include the deletion of putative virulence genes from the genome of the current vaccine strain (23), DNA (25,38) or subunit vaccines that incorporate putative protective antigens of vaccinia virus (19,22), and the use of strains, such as MVA, that have been passaged in alternative hosts, resulting in attenuation and poor replicative capacity (9,16). There is considerable enthusiasm for moving forward with MVA for licensure at the present time (12,32,33,43). MVA has been used as a prevaccine in vaccine campaigns in the 1970s in Germany in more than 100,000 immunocompromised individuals or individuals with skin conditions, thus supporting the view that it can be administered to immunodeficient people without detrimental effects (31,42).…”

mentioning

confidence: 99%

Development of Smallpox Vaccine Candidates with Integrated Interleukin-15 That Demonstrate Superior Immunogenicity, Efficacy, and Safety in Mice

Perera¹,

Waldmann²,

Mosca³

et al. 2007

The potential use of variola virus, the etiological agent of smallpox, as a bioterror agent has heightened the interest in the reinitiation of smallpox vaccination. However, the currently licensed Dryvax vaccine, despite its documented efficacy in eradicating smallpox, is not optimal for the vaccination of contemporary populations with large numbers of individuals with immunodeficiencies because of severe adverse effects that can occur in such individuals. Therefore, the development of safer smallpox vaccines that can match the immunogenicity and efficacy of Dryvax for the vaccination of contemporary populations remains a priority. Using the Wyeth strain of vaccinia virus derived from the Dryvax vaccine, we generated a recombinant One of the greatest medical triumphs of the 20th century was the eradication of smallpox, a pestilence that had plagued mankind for thousands of years as attested by the presence of suggestive pock lesions in the mummified body of Rameses V, who died in 1160 BC (26). This monumental achievement within a span of 20 years that began as a WHO initiative in 1958 to control smallpox and then intensified in 1966 as a campaign to achieve eradication in 10 years was made possible by the relentless efforts of dedicated international teams of public health workers and epidemiologists and the availability of a highly efficacious live vaccine (18). During the smallpox eradication campaign, vaccine preparations were manufactured as infected calf lymph, a process that is now unacceptable in an era of bovine spongiform encephalopathy, from the American (Wyeth), British (Lister/Elstree), and Russian (EM63) strains of vaccinia virus with similar reactogenicities. Complications noted at the time included postvaccinal encephalitis, progressive vaccinia virus infection, especially in recipients with immunologic deficiencies, eczema vaccinatum in vaccinees or their contacts with skin eczema, and generalized vaccinia virus infection. These vaccine-associated complications were more pronounced in individuals with underlying immunodeficiencies who often contracted vaccinia by contact with a vaccinee (29,30). Toward the later stages of the eradication campaign, a derivative of vaccinia virus, modified vaccinia virus Ankara (MVA), which had undergone over 570 passages in chicken embryo fibroblasts, resulting in the loss of over 15% of its genomic content, including many of its hostrange-associated genes, was used as a prevaccine to reduce vaccine-associated complications in more than 100,000 people for whom the Dryvax vaccine was contraindicated due to preexisting immunodeficiencies or skin conditions (2, 31).Despite the certification of the Global Commission that smallpox had been eradicated in 1979 and the discontinuation of routine smallpox vaccination by all countries, military personnel in both the United States and Russia have continued smallpox vaccinations because of the many well-recognized attributes of variola virus that can be efficiently exploited in biological warfare (41). In more-recent times, t...