Clonal vaccinia virus grown in cell culture as a new smallpox vaccine

109

107

The potential threat of smallpox as a bioweapon has led to the production and stockpiling of smallpox vaccine in some countries. Human monkeypox, a rare but important viral zoonosis endemic to central and western Africa, has recently emerged in the United States. Thus, even though smallpox has been eradicated, a vaccinia virus vaccine that can induce protective immunity against smallpox and monkeypox is still invaluable. The ability of the highly attenuated vaccinia virus vaccine strain LC16m8, with a mutation in the important immunogenic membrane protein B5R, to induce protective immunity against monkeypox in nonhuman primates was evaluated in comparison with the parental Lister strain. Monkeys were immunized with LC16m8 or Lister and then infected intranasally or subcutaneously with monkeypox virus strain Liberia or Zr-599, respectively. Immunized monkeys showed no symptoms of monkeypox in the intranasal-inoculation model, while nonimmunized controls showed typical symptoms. In the subcutaneous-inoculation model, monkeys immunized with LC16m8 showed no symptoms of monkeypox except for a mild ulcer at the site of monkeypox virus inoculation, and those immunized with Lister showed no symptoms of monkeypox, while nonimmunized controls showed lethal and typical symptoms. These results indicate that LC16m8 prevents lethal monkeypox in monkeys, and they suggest that LC16m8 may induce protective immunity against smallpox.

Section: Discussioncontrasting

confidence: 53%

LC16m8, a Highly Attenuated Vaccinia Virus Vaccine Lacking Expression of the Membrane Protein B5R, Protects Monkeys from Monkeypox

Saijo¹,

Ami²,

Suzaki³

et al. 2006

109

107

“…In addition, a vaccine regimen incorporating peptides may also be utilized in a prime-and-boost strategy to reduce side effects from the present vaccines, especially in immunocompromised individuals. Some recent studies have utilized attenuated viruses for this purpose, either alone or as part of a prime-boost regimen, in monkeys (19) and humans (61).…”

Section: Discussionmentioning

confidence: 99%

Protection against Lethal Vaccinia Virus Challenge in HLA-A2 Transgenic Mice by Immunization with a Single CD8⁺T-Cell Peptide Epitope of Vaccinia and Variola Viruses

Snyder

Belyakov

Dzutsev

et al. 2004

103

“…This is an ankyrin-Fbox-containing protein of unknown function and a homolog of the variola virus (Bangladesh) B18R gene. Moreover, in a previous study, a similar DVX_213-encoding strain, called CL3, was shown to be the most virulent clone among six different Dryvax-derived isolates (51). We wondered if DVX_213 might be a virulence factor and tested it by inserting a yellow fluorescent protein (YFP)-GTP cassette into the DVX_213 locus in DPP25.…”

Section: Figmentioning

confidence: 99%

Evolution of and Evolutionary Relationships between Extant Vaccinia Virus Strains

Qin

Favis

Famulski

et al. 2015

Although vaccinia virus (VACV) was once used as a vaccine to eradicate smallpox on a worldwide scale, the biological origins of VACV are uncertain, as are the historical relationships between the different strains once used as smallpox vaccines. Here, we sequenced additional VACV strains that either represent relatively pristine examples of old vaccines (e.g., Dryvax, Lister, and Tashkent) or have been subjected to additional laboratory passage (e.g., IHD-W and WR). These genome sequences were compared with those previously reported for other VACVs as well as other orthopoxviruses. These extant VACVs do not always cluster in simple phylogenetic trees that are aligned with the known historical relationships between these strains. Rather, the pattern of deletions suggests that all existing strains likely come from a complex stock of viruses that has been passaged, distributed, and randomly sampled over time, thus obscuring simple historical or geographic links. We examined surviving nonclonal vaccine stocks, like Dryvax, which continue to harbor larger and now rare variants, including one that we have designated "clone DPP25." DPP25 encodes genes not found in most VACV strains, including an ankyrin-F-box protein, a homolog of the variola virus (Bangladesh) B18R gene which we show can be deleted without affecting virulence in mice. We propose a simple common mechanism by which recombination of a larger and hypothetical DPP25-like ancestral strain, combined with selection for retention of critically important genes near the terminal inverted repeat boundaries (vaccinia virus growth factor gene and an interferon alpha/beta receptor homolog), could produce all known VACV variants. IMPORTANCE Smallpox was eradicated by using a combination of intensive disease surveillance and vaccination using vaccinia virus (VACV).Interestingly, little is known about the historical relationships between different strains of VACV and how these viruses may have evolved from a common ancestral strain. To understand these relationships, additional strains were sequenced and compared to existing strains of VACV as well as other orthopoxviruses by using whole-genome sequence alignments. Extant strains of VACV did not always cluster in simple phylogenetic trees based on known historical relationships between these strains. Based on these findings, it is possible that all existing strains of VACV are derived from a single complex stock of viruses that has been passaged, distributed, and sampled over time.