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PubMed2003

Smallpox vaccination and bioterrorism with pox viruses.

Bioterrorist attacks occupy a special place amongst the innumerable potential types of terrorist attack, with the intentional release of pox viruses being especially feared in this connection. Apart from the variola virus, the agent responsible for smallpox in humans, the monkeypox virus and numerous other animal pox viruses pose potential risks for humans and animals. This risk scenario also includes recombinations between the various pox viruses, changes in hosts and genetically engineered manipulations of pox viruses. For over 200 years, the method of choice for combatting smallpox was via vaccination with a reproductive, original vaccinia virus. Worldwide eradication of smallpox at the end of the 1970s and the discontinuation of routine smallpox vaccination in 1980 can be credited to such vaccination. Unfortunately, these vaccinations were associated with a large number of postvaccinal impairments, sometimes resulting in death (e.g. postvaccinal encephalitis). The only way to restrict such postvaccinal complications was to carry out initial vaccination within the first 2 postnatal years. Initial vaccination at a later age led to such a sharp increase in the number of vaccines with complications that vaccination had to be discouraged. The dilemma of the smallpox vaccine stocks stems from the fact that a large portion of these stocks are produced with the same vaccinia strains as before. This is irresponsible, especially as the percentage of immune-suppressed persons in the population, for whom vaccination-related complications pose an especial threat, is increasing. One solution to the dilemma of the smallpox vaccine stocks is the MVA strain. It is harmless, protects humans and animals equally well against smallpox and can be applied parenterally.

Animals↗
PubMed1981

Characterization of antibodies to orthopoxviruses in human sera by radioimmunoassay.

Serological surveillance of suspected orthopoxvirus infections in man is important for confirming the success of the worldwide smallpox eradication programme. An adsorption radioimmunoassay (RIA) was used to differentiate sera from patients who were naturally infected with human monkeypox or variola virus, and individuals who were immunized with vaccinia virus. The antisera were adsorbed with uninfected chicken chorioallantoic membrane (CAM) and vaccinia-infected CAM before reacting in RIA with vaccinia, monkeypox, and variola antigens. Each serum group showed characteristic patterns of residual antibody activity which made it possible to identify antibody specificities.When 45 human sera were tested by this method, 71% were identified as having vaccinia, variola, or monkeypox adsorption characteristics, while the remaining 29% could not be identified. Of the identified sera, 9 were characteristic of vaccinia, 8 of variola, and 15 of monkeypox. Six of the 15 monkeypox sera were virologically confirmed monkeypox infections, 6 were suspected monkeypox infections but were not virologically confirmed, and 3 were of unknown aetiology.The adsorption RIA provides a method of identifying serologically the poxvirus responsible for infection long after the acute phase of illness.

Animals↗
PubMed1982

Surveillance of orthopoxvirus infections, and associated research, in the period after smallpox eradication.

In 1980, the World Health Assembly declared the global eradication of smallpox and recommended the universal discontinuation of smallpox vaccination; nevertheless, it recommended that surveillance and research on orthopoxvirus infections should continue. By early 1982, all except 8 countries in the world had stopped routine vaccination programmes and all except 1 no longer required an international certificate of smallpox vaccination for travellers. Since 1978, as a result of continuing active surveillance, 176 smallpox rumours have been investigated in 60 countries. Two of these concerned the two laboratory-associated cases that occurred in the United Kingdom in 1978; all the others were false alarms. Special surveillance programmes for human monkeypox have been developed in West and Central Africa. The number of laboratories retaining variola virus stocks has been reduced to four. Investigations to determine the identity and origin of the six known isolates of "whitepox" virus have continued. Research on mapping of variola DNA and on monoclonal antibodies against certain orthopoxvirus antigens is continuing. All these measures are aimed at ensuring that the achievement of smallpox eradication is permanent.

DNA, Viral↗
PubMedDate not supplied

[Results of examining wild monkeys for the presence of smallpox antibodies and smallpox group viruses].

The results of examinations of sera, blood and organs of different species of monkeys from some Asian and African countries for the presence of antibody to smallpox and viruses of the smallpox group. Significant titers of smallpox antibodies (antihemagglutinins virus-neutralizing and, in some cases, precipitating antibody) were found in a considerable number of monkeys shot near foci with human cases (Equatorial province of Zair Republic). In the same monkeys kidney tissues yielded 3 isolates of smallpox virus group two of which were indistinguishable in the laboratory tests from variola virus. On the basis of these data it is concluded that smallpox viruses circulate among wildlife monkeys in some areas of Equatorial Africa. Further studies along these lines are necessary.

Africa↗
PubMed2001

The vaccinia virus superoxide dismutase-like protein (A45R) is a virion component that is nonessential for virus replication.

A characterization of the A45R gene from vaccinia virus (VV) strain Western Reserve is presented. The open reading frame is predicted to encode a 125-amino-acid protein (M(r), of 13,600) with 39% amino acid identity to copper-zinc superoxide dismutase (Cu-Zn SOD). Sequencing of the A45R gene from other orthopoxviruses, here and by others, showed that the protein is highly conserved in all viruses sequenced, including 16 strains of VV, 2 strains of cowpox virus, camelpox virus, and 4 strains of variola virus. In all cases the protein lacks key residues involved in metal ion binding that are important for the catalytic activity. The A45R protein was expressed in Escherichia coli, purified, and tested for SOD activity, but neither enzymatic nor inhibitory SOD activity was detected. Additionally, no virus-encoded SOD activity was detected in infected cells or purified virions. A monoclonal antibody raised against the A45R protein expressed in E. coli identified the A45R gene product as a 13.5-kDa protein that is expressed late during VV infection. Confocal microscopy of VV-infected cells indicated that the A45R protein accumulated predominantly in cytoplasmic viral factories. Electron microscopy and biochemical analyses showed that the A45R protein is incorporated into the virion core. A deletion mutant lacking the majority of the A45R gene and a revertant virus in which the deleted gene was restored were constructed and characterized. The growth properties of the deletion mutant virus were indistinguishable from those of wild-type and revertant viruses in all cell lines tested, including macrophages. Additionally, the virulence and pathogenicity of the three viruses were also comparable in murine and rabbit models of infection. A45R is unusual in being the first VV core protein described that affects neither virus replication nor virulence.

Animals↗
PubMed2006

Enhanced antiproliferative effects of alkoxyalkyl esters of cidofovir in human cervical cancer cells in vitro.

Nearly all cervical cancers are associated with the high-risk subtypes of human papillomavirus (HPV) expressing the E6 and E7 oncoproteins. The E6 and E7 oncoproteins reduce cellular levels of the p53 and the retinoblastoma (pRb) tumor suppressors, respectively, and represent an important component of the malignant phenotype. Several groups have shown that treatment with cidofovir suppresses levels of E6 and E7, restoring cellular p53 and pRb levels, in turn slowing cell replication and increasing the susceptibility of the cancer cells to radiation and apoptosis. Recently, our group synthesized alkoxyalkyl esters of cidofovir, which were found to be >100 times more active than unmodified cidofovir in vitro against various double-stranded DNA viruses, including cytomegalovirus, herpes simplex virus, adenoviruses, cowpox, vaccinia, and variola viruses. We compared the activity of octadecyloxyethyl-cidofovir (ODE-CDV) and oleyloxyethyl-cidofovir (OLE-CDV) with that of unmodified cidofovir against both HPV-negative and HPV-positive cervical cancer cells. We compared the antiproliferation activity in CaSki, HeLa, and Me-180 cells, prototypical HPV-positive cell lines bearing the HPV-16, HPV-18, and HPV-68 high-risk subtypes, with the activity in C33A cells, a cervical cancer cell line lacking HPV, and in nonmalignant primary human foreskin fibroblast cells. OLE-CDV and ODE-CDV were several logs more potent than cidofovir in CaSki, Me-180, HeLa, and C33A cervical cancer cells as determined by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt proliferation assay. Cell cycle analysis indicates that the cidofovir analogues interfere with passage of dividing cells through the S phase. ODE-CDV and OLE-CDV were 500 to 17,000 times more active than cidofovir in inhibiting the growth of cervical cancer cells. ODE-CDV and OLE-CDV showed selectivity for cervical cancer cells versus nonmalignant human foreskin fibroblast cells and warrant further investigation as potential therapies for cervical cancer.

Antineoplastic Agents↗
PubMed2005

HLA-A*0201, HLA-A*1101, and HLA-B*0702 transgenic mice recognize numerous poxvirus determinants from a wide variety of viral gene products.

In virus models explored in detail in mice, CTL typically focus on a few immunodominant determinants. In this study we use a multipronged approach to understand the diversity of CTL responses to vaccinia virus, a prototypic poxvirus with a genome approximately 20-fold larger than that of the model RNA viruses typically studied in mice. Based on predictive computational algorithms for peptide binding to HLA supertypes, we synthesized a panel of 2889 peptides to begin to create an immunomic map of human CTL responses to poxviruses. Using this panel in conjunction with CTLs from vaccinia virus-infected HLA transgenic mice, we identified 14 HLA-A*0201-, 4 HLA-A*1101-, and 3 HLA-B*0702-restricted CD8(+) T cell determinants distributed over 20 distinct proteins. These peptides were capable of binding one or multiple A2, A3, and B7 supertype molecules with affinities typical of viral determinants. Surprisingly, many of the viral proteins recognized are predicted to be late gene products, in addition to the early intermediate gene products expected. Nearly all of the determinants identified have identical counterparts encoded by modified vaccinia virus Ankara as well as variola virus, the agent of smallpox. These findings have implications for the design of new smallpox vaccines and the understanding of immune responses to large DNA viruses in general.

Animals↗
PubMed2004

Zoonotic poxvirus infections in humans.

PURPOSE OF REVIEW: The 2003 USA monkeypox epidemic caused by imported African rodents, newly emergent poxvirus zoonoses in Brazil and the possible use of variola virus for biological warfare has led to renewed interest in poxviruses and anti-poxviral therapies. Increasing foreign travel and importation of exotic animal species increases the likelihood of poxvirus infections occurring outside their usual geographical range and diagnostic delay has important implications. The present review provides an overview of these rare zoonoses. RECENT FINDINGS: Three genera of Poxviridae are known to cause human zoonoses: orthopoxviruses, parapoxviruses and yatapoxvirus. Most cases are occupational, sporadic and have few cutaneous lesions with low morbidity. The exception is monkeypox, similar to smallpox, with significant morbidity and childhood mortality. Molecular characterization using polymerase chain reaction (PCR) amplification and other methods provides accurate phylogenetic identification and suggests that a cowpox-like virus is the probable ancestor of variola and other zoonotic poxviruses. DNA genomic sequencing of the Brazilian Cantagalo and Araçatuba viruses shows a close relationship to vaccinia virus. Poxviruses have potential in cancer immunotherapy and their ability to evade host-cell immune responses may provide a basis for new antipoxvirus therapies. Other agents, particularly nucleoside phosphonates such as cidofovir, show therapeutic action against poxviruses. SUMMARY: Human zoonotic poxvirus infections are rare but increasingly encountered outside their usual geographical range. The 2003 USA monkeypox outbreak emphasizes the importance of early accurate diagnosis, particularly because increasing numbers of immunosuppressed individuals increases the potential for severe or fatal infections. PCR methodology enables accurate phylogenetic typing and has identified new diseases, but rapid, reliable methods must be made available for clinicians. More research into therapeutic agents for the prevention and treatment of poxvirus infections is required.

Animals↗
PubMedDate not supplied

[The time scale in poxvirus evolution].

Unlike vertebrates and RNA-containing viruses, the objective estimate of molecular clock for DNA-containing viruses was so far absent. An extended central conservative genomic region of orthopoxviruses (about 102 kbp) and the sequence of DNA polymerase gene (about 3 kbp) of the viruses belonging to various genera from the family Poxviridae were analyzed. During this analysis, the known dating of variola virus (VARV) transfer from West Africa to South America (XVI century) and our own data on close phylogenetic relations between the modem West African and South American VARV isolates were used. As a result of this work, it was calculated for the first time that the rate of mutation accumulation in these DNA-containing viruses amounted to 0.9-1.2 x 10(-6) substitutions per site per year. The poxviruses started separating from the ancestor virus to form the modem genera approximately 500 thousand years ago; the ancestor of the genus Orthopoxvirus separated about 300 thousand years ago; and its division into the modem studied species took place approximately 14 thousand years ago.

DNA, Viral↗
PubMed2003

[Human cowpox/catpox infection. A potentially unrecognized disease].

HISTORY AND ADMISSION FINDINGS: A 36-year-old woman initially noticed a red spot, about pea-sized, with a central pimple over the right eyebrow and a swollen submandibular lymph node. A pressure-sensitive, 4 cm large, node developed out of this small spot, with a central, black, tightly-adhering crust bearing several varioliform vesicles around its edge. In addition to swelling of the right half of the face, the patient had a fever up to 39.5 degrees C, general malaise, nausea and vomiting. Various antibiotics were ineffective. The woman was hospitalized with a diagnosis of facial erysipelas. She owned a cat which had developed a purulent nodule on a forepaw a few days before onset of the patient's disease. LABORATORY TEST: ESR and CRP were moderately elevated, no leukocytosis and blood cultures were sterile. Wound smears showed colonization with Klebsiella pneumoniae and Enterobacter cloacae. DIAGNOSIS, TREATMENT AND COURSE: The patient's general condition improved under initially calculated antibiotic dosages, which was later adapted to the measured resistance. The black-crusted nodes became larger, however, and incision was performed on the 8 th day after hospitalization, under the suspicion of fluctuation. However, no pus was removed, but there was massive inflammatory infiltration of the soft tissue. Examination of samples of skin and part of the crust revealed orthopox virus (cowpox virus). Spontaneous healing followed within 3 weeks, leaving only a small scar. CONCLUSIONS: This was a cowpox virus in the sense of a zoonosis transmitted by the cat. In Germany, now that smallpox has been eradicated, the clinical presentation of infections with the orthopox virus, which are closely related to variola virus, are too little recognized. Atopic and immunocompromised patients are at risk of a cutaneous dissemination with a more severe course of the infectious illness; even a lethal outcome has been reported in Germany.

Adult↗
PubMed2004

The host response to smallpox: analysis of the gene expression program in peripheral blood cells in a nonhuman primate model.

Smallpox has played an unparalleled role in human history and remains a significant potential threat to public health. Despite the historical significance of this disease, we know little about the underlying pathophysiology or the virulence mechanisms of the causative agent, variola virus. To improve our understanding of variola pathogenesis and variola-host interactions, we examined the molecular and cellular features of hemorrhagic smallpox in cynomolgus macaques. We used cDNA microarrays to analyze host gene expression patterns in sequential blood samples from each of 22 infected animals. Variola infection elicited striking and temporally coordinated patterns of gene expression in peripheral blood. Of particular interest were features that appear to represent an IFN response, cell proliferation, immunoglobulin gene expression, viral dose-dependent gene expression patterns, and viral modulation of the host immune response. The virtual absence of a tumor necrosis factor alpha/NF-kappaB-activated transcriptional program in the face of an overwhelming systemic infection suggests that variola gene products may ablate this response. These results provide a detailed picture of the host transcriptional response during smallpox infection, and may help guide the development of diagnostic, therapeutic, and prophylactic strategies.

Animals↗
PubMed1973

Virus excretion in smallpox. 2. Excretion in the throats of household contacts.

Throat swabs of 34 of 328 family contacts of 52 smallpox cases, examined 4-8 days after the onset of the disease in the family, were positive for variola virus. The log titre of virus per swab ranged from 2 to 3.95. A higher proportion of unvaccinated than of vaccinated contacts excreted the virus. Only 4 of the virus-positive contacts developed clinical smallpox; this occurred 5-7 days after their swabs were examined. Excretion of virus in the throats of these contacts, a few of whom were in the incubation period of the disease, suggests the possibility that they could have spread the infection. This possibility, if kept in mind, may help in tracing the source of infection or in determining the incubation period in a few instances when difficulty is experienced.

Adolescent↗
PubMed2006

Obligatory requirement for antibody in recovery from a primary poxvirus infection.

To understand the correlates of protective immunity against primary variola virus infection in humans, we have used the well-characterized mousepox model. This is an excellent surrogate small-animal model for smallpox in which the disease is caused by infection with the closely related orthopoxvirus, ectromelia virus. Similarities between the two infections include virus replication and transmission, aspects of pathology, and development of pock lesions. Previous studies using ectromelia virus have established critical roles for cytokines and effector functions of CD8 T cells in the control of acute stages of poxvirus infection. Here, we have used mice deficient in B cells to demonstrate that B-cell function is also obligatory for complete virus clearance and recovery of the host. In the absence of B cells, virus persists and the host succumbs to infection, despite the generation of CD8 T-cell responses. Intriguingly, transfer of naive B cells or ectromelia virus-immune serum to B-cell-deficient mice with established infection allowed these animals to clear virus and fully recover. In contrast, transfer of ectromelia virus-immune CD8 T cells was ineffective. Our data show that mice deficient in CD8 T-cell function die early in infection, whereas those deficient in B cells or antibody production die much later, indicating that B-cell function becomes critical after the effector phase of the CD8 T-cell response to infection subsides. Strikingly, our results show that antibody prevents virus from seeding the skin and forming pock lesions, which are important for virus transmission between hosts.

Adoptive Transfer↗
PubMed2001

[Smallpox and smallpox virus--200 years since the first vaccination in Norway].

In December 1801, the first vaccination against smallpox in Norway took place. Vaccine material came from Denmark, England, Ireland, and other countries; it was also obtained from a few local cowpox cases. What mattered was the effect, not the origin. Several reports indicate that variola virus itself, the cause of smallpox, was also used for human vaccination after passages through cows and horses. A vaccine institute for production of vaccine in calves was established in Kristiania in 1891. Cowpox was once a rare disease in cattle, but a total of 70,985 bovine cases were reported between 1889 and 1928. The source of infection was thought to be humans vaccinated against smallpox. Pox-like diseases were also registered in horses, pigs, sheep, goats and dogs at that time. Compulsory vaccination continued in Norway until 1976; smallpox is now eradicated. During the last decades, however, cowpox virus infections have re-emerged among zoo animals, domestic cats and humans in Western Europe, with small wild rodents and shrews as wildlife reservoirs. Vaccinia virus is also met with new interest as a vector in recombinant vaccines. Given the fact that the human population no longer has immunity against orthopoxviruses and the new possible exposure through pets and wildlife, it may be appropriate to reflect on poxvirus history in Norway in the light of the present situation.

Animals↗
PubMed2005

An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection.

The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10(7) PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.

Amino Acid Sequence↗
PubMed1980

A study of the specificities of sequential antisera to variola and monkeypox viruses by radioimmunoassay.

The specificities of antisera during development of the humoral antibody response to poxvirus antigens were examined in monkeys injected with chimp-9 whitepox virus or monkeypox virus. Sera were obtained from 3 African green (vervet) monkeys inoculated with chimp-9 whitepox virus, 1 rhesus monkey inoculated with monkeypox virus, and 2 rhesus monkeys inoculated with soluble monkeypox viral antigen. The sequentially obtained sera from each animal were adsorbed with uninfected chicken chorioallantoic membranes (CAM) or vaccinia virus-infected CAM. The adsorbed sera were tested by radioimmunoassay to determine the specificity of the residual antibodies to vaccinia, variola, and monkeypox viruses. The adsorbed sera at different stages of the immune response showed increasing specificity with time after inoculation. Generally, antibodies in sera collected earlier than 21-27 days after immunization could not be identified after adsorption, but late sera could be identified unequivocally.

Epitopes↗
PubMed2002

Orthologs of the vaccinia A13L and A36R virion membrane protein genes display diversity in species of the genus Orthopoxvirus.

Alignment of vaccinia and variola virus genomes has highlighted some targets that display diversity. We have investigated the sequence diversity of two viral membrane protein genes from 36 different orthopoxvirus (OPV) strains to evaluate the suitability of these loci to differentiate between OPV species. Orthologs of the vaccinia virus Copenhagen A13L gene were all predicted to have functional genes that ranged between 201-213 bps in length. Whereas the N- and C-termini of each protein were relatively well conserved within the genus, a central proline-rich domain displayed characteristic species-specific amino acid motifs. Orthologs of the A36R gene displayed considerable sequence variation between species and strains. The majority of variation was localised to the last 100 bps of the gene. Multiple-alignment of these sequences identified the presence of gaps, insertions or frame-shift mutations among the samples examined. Nearly all strains of cowpox virus contained different nucleotide sequences at this locus. Phylogenetic analysis of the aligned sequences showed that variola and camelpox viruses shared a common ancestry with cowpox virus, whereas ectromelia viruses were divergent from all the other OPVs examined. Phylogeny generated with A13L sequences distributed the OPV species in a manner that correlated to their known properties.

Acinonyx↗