The Evolution of Poxvirus Vaccines

Sánchez-Sampedro, Lucas; Perdiguero, Beatriz; Mejías-Pérez, Ernesto; García-Arriaza, Juan; Pilato, Mauro Di; Esteban, Mariano

doi:10.3390/v7041726

Cited by 168 publications

(193 citation statements)

References 615 publications

(349 reference statements)

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“…Therefore, different countries and the WHO have increased their stockpile of smallpox vaccine over the years (4,5). However, the first-generation vaccines used to eradicate smallpox had rates of adverse effects that are not acceptable by current health care standards (6,7).…”

mentioning

confidence: 99%

Genomic Analysis, Phenotype, and Virulence of the Historical Brazilian Smallpox Vaccine Strain IOC: Implications for the Origins and Evolutionary Relationships of Vaccinia Virus

Medaglia

Moussatché

Nitsche

et al. 2015

J Virol

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Smallpox was declared eradicated in 1980 after an intensive vaccination program using different strains of vaccinia virus (VACV; Poxviridae). VACV strain IOC (VACV-IOC) was the seed strain of the smallpox vaccine manufactured by the major vaccine producer in Brazil during the smallpox eradication program. However, little is known about the biological and immunological features as well as the phylogenetic relationships of this first-generation vaccine. In this work, we present a comprehensive characterization of two clones of VACV-IOC. Both clones had low virulence in infected mice and induced a protective immune response against a lethal infection comparable to the response of the licensed vaccine ACAM2000 and the parental strain VACV-IOC. Full-genome sequencing revealed the presence of several fragmented virulence genes that probably are nonfunctional, e.g., F1L, B13R, C10L, K3L, and C3L. Most notably, phylogenetic inference supported by the structural analysis of the genome ends provides evidence of a novel, independent cluster in VACV phylogeny formed by VACV-IOC, the Brazilian field strains Cantagalo (CTGV) and Serro 2 viruses, and horsepox virus, a VACV-like virus supposedly related to an ancestor of the VACV lineage. Our data strongly support the hypothesis that CTGV-like viruses represent feral VACV that evolved in parallel with VACV-IOC after splitting from a most recent common ancestor, probably an ancient smallpox vaccine strain related to horsepox virus. Our data, together with an interesting historical investigation, revisit the origins of VACV and propose new evolutionary relationships between ancient and extant VACV strains, mainly horsepox virus, VACV-IOC/CTGV-like viruses, and Dryvax strain. IMPORTANCEFirst-generation vaccines used to eradicate smallpox had rates of adverse effects that are not acceptable by current health care standards. Moreover, these vaccines are genetically heterogeneous and consist of a pool of quasispecies of VACV. Therefore, the search for new-generation smallpox vaccines that combine low pathogenicity, immune protection, and genetic homogeneity is extremely important. In addition, the phylogenetic relationships and origins of VACV strains are quite nebulous. We show the characterization of two clones of VACV-IOC, a unique smallpox vaccine strain that contributed to smallpox eradication in Brazil. The immunogenicity and reduced virulence make the IOC clones good options for alternative second-generation smallpox vaccines. More importantly, this study reveals the phylogenetic relationship between VACV-IOC, feral VACV established in nature, and the ancestor-like horsepox virus. Our data expand the discussion on the origins and evolutionary connections of VACV lineages. S mallpox, caused by variola virus (genus Orthopoxvirus, family Poxviridae), accounted for millions of deaths throughout human history. The disease was declared eradicated in 1980 after a worldwide program implemented by the WHO involving strict surveillance and intensive vaccination using vaccinia vi...

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mentioning

confidence: 99%

Genomic Analysis, Phenotype, and Virulence of the Historical Brazilian Smallpox Vaccine Strain IOC: Implications for the Origins and Evolutionary Relationships of Vaccinia Virus

Medaglia

Moussatché

Nitsche

et al. 2015

J Virol

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“…Thus, multiple research laboratories are now modifying VACV to develop vectors that retain immunogenicity and have improved safety profiles (73). One strategy used by researchers is to alter the expression of the immune evasion genes of a VACV-based vector (5) in an effort to retain VACV immunogenicity and improve safety. We show here that vΔK1L infection in mouse ear pinnae has decreased pathogenicity but no loss in its ability to activate an acquired immune response or protect against a lethal VACV challenge.…”

Section: Discussionmentioning

confidence: 99%

“…The continued study of VACV remains important because there are reports of VACV infections in animals and humans (2)(3)(4). Moreover, VACV derivatives are now being used as vectors for vaccines against other infectious diseases and as oncolytic virotherapy (5).…”

Section: Abstract K1l Poxvirus Vaccines Vaccinia Virus Viral Pathmentioning

confidence: 99%

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Cruz

Han

Roy

et al. 2017

J Virol

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All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-B antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-B in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8 ϩ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity. IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-B activation among its other antagonistic functions.A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.

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“…The most common virus vector to be applied experimentally is the orthopoxvirus vaccinia, successfully used in the vaccination campaign to eradicate smallpox. 35 The observation that a 9000-base-pair segment of the vaccinia virus genome could be deleted without affecting either its infectivity or its ability to replicate led to the development of recombinant vaccinia viruses with inserted foreign genes. Indeed, it has been shown that up to 25,000 base pairs of foreign DNA can be inserted into the virus, which offers the potential for inserting several genes into a single vector to produce a multicomponent vaccine.…”

Section: Virus Vectors: Most Virus Vector Studies Have Concentrated Omentioning

confidence: 99%

Recent Advances in Vaccine Technologies

Francis¹

2018

Veterinary Clinics of North America: Small Animal Practice

126

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This brief review discusses some recent advances in vaccine technologies with particular reference to their application within veterinary medicine. It highlights some of the key inactivated/killed approaches to vaccination, including natural split-product and subunit vaccines, recombinant subunit and protein vaccines, and peptide vaccines. It also covers live/attenuated vaccine strategies, including modified live marker/differentiating infected from vaccinated animals vaccines, live vector vaccines, and nucleic acid vaccines.

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The Evolution of Poxvirus Vaccines

Cited by 168 publications

References 615 publications

Genomic Analysis, Phenotype, and Virulence of the Historical Brazilian Smallpox Vaccine Strain IOC: Implications for the Origins and Evolutionary Relationships of Vaccinia Virus

Genomic Analysis, Phenotype, and Virulence of the Historical Brazilian Smallpox Vaccine Strain IOC: Implications for the Origins and Evolutionary Relationships of Vaccinia Virus

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Recent Advances in Vaccine Technologies

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