Evaluation of 21st-Century Risks of Smallpox Vaccination and Policy Options

Lane, John; Goldstein, J.

doi:10.7326/0003-4819-138-6-200303180-00014

Cited by 66 publications

(61 citation statements)

References 35 publications

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“…Genetically modified viral vectors derived from VV have proved to be a versatile tool for gene therapy [18], and are currently applied as expression vectors for DC-based immunotherapy and vaccination against cancer and infectious diseases [19][20][21]. Although considered highly safe in humans, vaccination with VV strains can cause significant and fatal complications especially in immunocompromised hosts and young children [22]. VV possesses an enormously variable set of immune evasion mechanisms, including interactions with complement, cytokines and chemokines [23][24][25][26][27], potentially causing immunosuppression of the host.…”

Section: Introductionmentioning

confidence: 99%

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Humrich¹,

Thumann²,

Greiner³

et al. 2007

Eur J Immunol

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A crucial event for the induction of an anti-viral immune response is the coordinated, phenotype-dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signalregulated kinase-1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine-induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non-infected bystander DC, which depends on the activity of IFN-a. Although functional, these chemokine receptors are resistant to lipopolysaccharide-induced down-regulation. In addition, VV-infected and noninfected bystander DC fail to up-regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigenpresenting cells at multiple functional levels, revealing a potent viral strategy of immune escape.See accompanying commentary: http://dx

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Section: Introductionmentioning

confidence: 99%

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Humrich¹,

Thumann²,

Greiner³

et al. 2007

Eur J Immunol

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“…However, replication-competent poxvirus vectors pose serious health risks because of their welldocumented capacity to disseminate in immunosuppressed individuals (7,9,31,41,43). These risks have increased in recent years due to a rising proportion of the population living with immunosuppression resulting from human immunodeficiency virus (HIV) infection, organ transplantation, or cancer therapies.…”

mentioning

confidence: 99%

Role of Genes That Modulate Host Immune Responses in the Immunogenicity and Pathogenicity of Vaccinia Virus

Jackson

Ilyinskii²,

Philippon³

et al. 2005

J Virol

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Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.

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“…Although vaccination is now being offered to some healthcare workers and other "first responders," there are valid concerns about potential vaccine risks (3,9). Vaccination is not recommended for those with eczema and other exfoliative skin disorders or those with immunodeficiencies or for pregnant women.…”

mentioning

confidence: 99%

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

Keith

Wan

Ciesla

et al. 2004

Antimicrob Agents Chemother

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A new series of ether lipid esters of cidofovir (CDV) were evaluated against vaccinia and cowpox viruses. Activity was dependent on number of atoms in the alkyl or alkoxyalkyl chain, the linker moiety, and the presence of a double bond in the alkoxyalkyl chains linked to the phosphonate moiety of CDV.The threat of an intentional or unintentional spread of poxvirus infections to a vulnerable population has led to increased efforts to find safe, rapidly deployable treatments against such infections. Although vaccination is now being offered to some healthcare workers and other "first responders," there are valid concerns about potential vaccine risks (3, 9). Vaccination is not recommended for those with eczema and other exfoliative skin disorders or those with immunodeficiencies or for pregnant women. Therefore, the use of antiviral therapy in the event of a poxvirus outbreak or in the treatment of vaccination complications against smallpox virus (4) points to the continued need to examine available antiviral therapies as well as to develop new and more efficient treatment.Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5, 10, 12); however, these compounds are inactive when given orally.Previous in vitro studies have shown that multiple-log increases in antiviral activity against orthopoxvirus replication (8), as well as enhanced inhibition of cytomegalovirus and herpesvirus replication by these esters (2), were observed with hexadecyloxypropyl (HDP) and octadecyloxyethyl (ODE) derivatives of CDV and cCDV (HDP-CDV, HDP-cCDV, ODE-CDV, and ODE-cCDV) compared to the results seen with the parent compounds. HDP-CDV, ODE-CDV, and oleyloxypropyl-CDV (OLP-CDV) have oral bioavailabilities of 88 to 93% in mice (6) and have oral activity against vaccinia virus (VV) and cowpox virus (CV) infections in mice (11).In this study, the unmodified acyclic nucleoside phosphonates CDV and cCDV (along with a new series of analogs synthesized by esterification of these compounds with an alkyl chain with or without the propoxy-or ethoxy-linker moieties) were evaluated (using methodologies described previously) (7) for activity (plaque reduction assay) against VV and CV and for cytotoxicity (neutral red uptake assay) in human foreskin fibroblast (HFF) cells. To determine efficacy, briefly, HFF cells seeded in 6-well plates 2 days prior to use were infected with either VV or CV by the addition of 20 to 30 PFU per well. After a 1-h incubation period, various concentrations of drug were added to triplicate wells and plates were incubated at 37°C for 3 days. Toxicity was evaluated using HFF cells seeded in 96-well plates incubated with various concentrations of drug for 7 days at 37°C. After incubation, cell monolayers were stained with a 0.01% solution of neutral red. The compounds were synthesized as reported previously (8).As presented in Table 1, the most active ether lipid esters of CDV were OLE-CDV, ODBG-CDV, TDP-CDV, OLP-CDV, and ODP-...

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Evaluation of 21st-Century Risks of Smallpox Vaccination and Policy Options

Cited by 66 publications

References 35 publications

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Role of Genes That Modulate Host Immune Responses in the Immunogenicity and Pathogenicity of Vaccinia Virus

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

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