Smallpox Vaccine Safety Is Dependent on T Cells and Not B Cells

Gordon, Shari N.; Cecchinato, Valentina; Andresen, Vibeke; Heraud, Jean‐Michel; Hryniewicz, Anna; Parks, Robyn Washington; Venzon, David; Chung, Hye-Kyung; Karpova, Tatiana S.; McNally, James M.; Silvera, Peter; Reimann, Keith A.; Matsui, Hajime; Kanehara, Tomomi; Shinmura, Yasuhiko; Yokote, Hiroyuki; Franchini, Genoveffa

doi:10.1093/infdis/jiq162

Cited by 57 publications

(43 citation statements)

References 40 publications

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“…Nevertheless, they are key players in controlling primary infection (e.g., vaccination) (48,49). In this context, immunization with B141 and B388 efficiently stimulated the production of IFN-␥, TNF-␣, or IL-2 by CD4 ϩ and CD8 ϩ T cells in response to VACV.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…(14,15), and M. tuberculosis (16,17). A key role for TCD8 immunity has also been established for the safety of smallpox vaccination in nonhuman primates (18) and humans (19). Therefore, microbial T cell epitope-based vaccines can complement current efforts to develop safe and effective antibody-targeted subunit vaccines.…”

Section: Introductionmentioning

confidence: 99%

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Gilchuk¹,

Spencer²,

Conant³

et al. 2013

J. Clin. Invest.

141

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CD8 + T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection -information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.

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“…Studies only performed after the eradication of smallpox finally clarified the role of humoral and T cell responses to Vaccinia. It is the long-lived humoral responses that persist after exposure to Vaccinia that are responsible for protection against smallpox infection, but the T cell responses against Vaccinia antigens are required to curtail the spread of the Vaccinia virus itself [4]. The practice of pre-vaccination with an attenuated version of Vaccinia was used particularly in Germany [5].…”

Section: Introductionmentioning

confidence: 99%