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1

Vaccinia Virus Vaccines: Past, Present and Future  

PubMed Central

Vaccinia virus (VACV) has been used more extensively for human immunization than any other vaccine. For almost two centuries, VACV was employed to provide cross-protection against variola virus, the causative agent of smallpox, until the disease was eradicated in the late 1970s. Since that time, continued research on VACV has produced a number of modified vaccines with improved safety profiles. Attenuation has been achieved through several strategies, including sequential passage in an alternative host, deletion of specific genes or genetic engineering of viral genes encoding immunomodulatory proteins. Some highly attenuated third- and fourth-generation VACV vaccines are now being considered for stockpiling against a possible re-introduction of smallpox through bioterrorism. Researchers have also taken advantage of the ability of the VACV genome to accommodate additional genetic material to produce novel vaccines against a wide variety of infectious agents, including a recombinant VACV encoding the rabies virus glycoprotein that is administered orally to wild animals. This review provides an in-depth examination of these successive generations of VACV vaccines, focusing on how the understanding of poxviral replication and viral gene function permits the deliberate modification of VACV immunogenicity and virulence. PMID:19563829

Jacobs, Bertram L.; Langland, Jeffrey O.; Kibler, Karen V.; Denzler, Karen L.; White, Stacy D.; Holechek, Susan A.; Wong, Shukmei; Huynh, Trung; Baskin, Carole R.

2009-01-01

2

VACCINATION OF VAMPIRE BATS USING RECOMBINANT VACCINIA-RABIES VIRUS  

Microsoft Academic Search

Adult vampire bats (Desmodus rotundus) were vaccinated by intramuscular, scarifi- cation, oral, or aerosol routes (n58 in each group) using a vaccinia-rabies glycoprotein recom- binant virus. Sera were obtained before and 30 days after vaccination. All animals were then challenged intramuscularly with a lethal dose of rabies virus. Neutralizing antirabies antibodies were measured by rapid fluorescent focus inhibition test (RFFIT).

Alvaro Aguilar-Setien; Yolanda Leon Campos; Emiliano Tesoro Cruz; Bernard Brochier; Paul-Pierre Pastoret

2002-01-01

3

Human CD4+ T Cell Epitopes from Vaccinia Virus Induced by Vaccination or Infection  

PubMed Central

Despite the importance of vaccinia virus in basic and applied immunology, our knowledge of the human immune response directed against this virus is very limited. CD4+ T cell responses are an important component of immunity induced by current vaccinia-based vaccines, and likely will be required for new subunit vaccine approaches, but to date vaccinia-specific CD4+ T cell responses have been poorly characterized, and CD4+ T cell epitopes have been reported only recently. Classical approaches used to identify T cell epitopes are not practical for large genomes like vaccinia. We developed and validated a highly efficient computational approach that combines prediction of class II MHC-peptide binding activity with prediction of antigen processing and presentation. Using this approach and screening only 36 peptides, we identified 25 epitopes recognized by T cells from vaccinia-immune individuals. Although the predictions were made for HLA-DR1, eight of the peptides were recognized by donors of multiple haplotypes. T cell responses were observed in samples of peripheral blood obtained many years after primary vaccination, and were amplified after booster immunization. Peptides recognized by multiple donors are highly conserved across the poxvirus family, including variola, the causative agent of smallpox, and may be useful in development of a new generation of smallpox vaccines and in the analysis of the immune response elicited to vaccinia virus. Moreover, the epitope identification approach developed here should find application to other large-genome pathogens. PMID:17937498

Calvo-Calle, J. Mauricio; Strug, Iwona; Nastke, Maria-Dorothea; Baker, Stephen P; Stern, Lawrence J

2007-01-01

4

Construction of Live Vaccines Using Genetically Engineered Poxviruses: Biological Activity of Vaccinia Virus Recombinants Expressing the Hepatitis B Virus Surface Antigen and the Herpes Simplex Virus Glycoprotein D  

Microsoft Academic Search

Potential live vaccines using recombinant vaccinia viruses have been constructed for both hepatitis B and herpes simplex. These recombinant vaccinia viruses express cloned genes of the hepatitis B virus surface antigen (HBsAg) or the glycoprotein D from herpes simplex virus (HSV-gD). The HBsAg synthesized in vitro under the regulation of vaccinia virus is secreted from infected cells as a particle

Enzo Paoletti; Bernard R. Lipinskas; Carol Samsonoff; Susan Mercer; Dennis Panicali

1984-01-01

5

Recombinant Vaccinia Virus: Immunization against Multiple Pathogens  

NASA Astrophysics Data System (ADS)

The coding sequences for the hepatitis B virus surface antigen, the herpes simplex virus glycoprotein D, and the influenza virus hemagglutinin were inserted into a single vaccinia virus genome. Rabbits inoculated intravenously or intradermally with this polyvalent vaccinia virus recombinant produced antibodies reactive to all three authentic foreign antigens. In addition, the feasibility of multiple rounds of vaccination with recombinant vaccinia virus was demonstrated.

Perkus, Marion E.; Piccini, Antonia; Lipinskas, Bernard R.; Paoletti, Enzo

1985-09-01

6

Vaccinia viruses: vaccines against smallpox and vectors against infectious diseases and tumors  

PubMed Central

Less than 200 years after its introduction, widespread use of vaccinia virus (VACV) as a smallpox vaccine has eradicated variola virus. Along with the remarkable success of the vaccination program, frequent and sometimes severe adverse reactions to VACV were encountered. After eradication, VACV has been reserved for select populations who might be at significant risk for orthopoxvirus infections. Events over the past decade have renewed concerns over the potential use of variola virus as a biological weapon. Accordingly, interest in VACV and attenuated derivatives has increased, both as vaccines against smallpox and as vectors for other vaccines. This article will focus on new developments in the field of orthopoxvirus immunization and will highlight recent advances in the use of vaccinia viruses as vectors for infectious diseases and malignancies. PMID:21854314

Walsh, Stephen R; Dolin, Raphael

2011-01-01

7

Host range, growth property, and virulence of the smallpox vaccine: Vaccinia virus Tian Tan strain  

SciTech Connect

Vaccinia Tian Tan (VTT) was used as a vaccine against smallpox in China for millions of people before 1980, yet the biological characteristics of the virus remain unclear. We have characterized VTT with respect to its host cell range, growth properties in vitro, and virulence in vivo. We found that 11 of the 12 mammalian cell lines studied are permissive to VTT infection whereas one, CHO-K1, is non-permissive. Using electron microscopy and sequence analysis, we found that the restriction of VTT replication in CHO-K1 is at a step before viral maturation probably due to the loss of the V025 gene. Moreover, VTT is significantly less virulent than vaccinia WR but remains neurovirulent in mice and causes significant body weight loss after intranasal inoculation. Our data demonstrate the need for further attenuation of VTT to serve either as a safer smallpox vaccine or as a live vaccine vector for other pathogens.

Fang Qing [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Yang Lin [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Zhu Weijun [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Liu Li [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Wang Haibo [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Yu Wenbo [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Xiao Genfu [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Tien Po [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Zhang Linqi [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China); Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016 (United States); AIDS Research Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (China); Chen Zhiwei [Modern Virology Research Center and AIDS Center, National Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei 430072 (China) and Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016 (United States)]. E-mail: zchen@adarc.org

2005-05-10

8

Reemergence of Vaccinia Virus during Zoonotic Outbreak, Pará State, Brazil  

PubMed Central

In 2010, vaccinia virus caused an outbreak of bovine vaccinia that affected dairy cattle and rural workers in Pará State, Brazil. Genetic analyses identified the virus as distinct from BeAn58058 vaccinia virus (identified in 1960s) and from smallpox vaccine virus strains. These findings suggest spread of autochthonous group 1 vaccinia virus in this region. PMID:24274374

de Assis, Felipe L.; Vinhote, Wagner M.; Barbosa, José D.; de Oliveira, Cairo H.S.; de Oliveira, Carlos M.G.; Campos, Karinny F.; Silva, Natália S.; Trindade, Giliane de Souza

2013-01-01

9

Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response  

PubMed Central

Vaccinia virus protein A33 (A33VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33VACV and A33CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104–120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope’s critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox. PMID:23842430

2013-01-01

10

Improved protection conferred by vaccination with a recombinant vaccinia virus that incorporates a foreign antigen into the extracellular enveloped virion.  

PubMed

Recombinant poxviruses have shown promise as vaccine vectors. We hypothesized that improved cellular immune responses could be developed to a foreign antigen by incorporating it as part of the extracellular enveloped virion (EEV). We therefore constructed a recombinant vaccinia virus that replaced the cytoplasmic domain of the B5R protein with a test antigen, HIV-1 Gag. Mice immunized with the virus expressing Gag fused to B5R had significantly better primary CD4 T-cell responses than recombinant virus expressing HIV-Gag from the TK-locus. The CD8 T-cell responses were less different between the two groups. Importantly, although we saw differences in the immune response to the test antigen, the vaccinia virus-specific immune responses were similar with both constructs. When groups of vaccinated mice were challenged 30 days later with a recombinant Listeria monocytogenes that expresses HIV-Gag, mice inoculated with the virus that expresses the B5R-Gag fusion protein had lower colony counts of Listeria in the liver and spleen than mice vaccinated with the standard recombinant. Thus, vaccinia virus expressing foreign antigen incorporated into EEV may be a better vaccine strategy than standard recombinant vaccinia virus. PMID:15110531

Kwak, Heesun; Mustafa, Waleed; Speirs, Kendra; Abdool, Asha J; Paterson, Yvonne; Isaacs, Stuart N

2004-05-01

11

A vaccinia virus renaissance: new vaccine and immunotherapeutic uses after smallpox eradication.  

PubMed

In 1796, Edward Jenner introduced the concept of vaccination with cowpox virus, an Orthopoxvirus within the family Poxviridae that elicits cross protective immunity against related orthopoxviruses, including smallpox virus (variola virus). Over time, vaccinia virus (VACV) replaced cowpox virus as the smallpox vaccine, and vaccination efforts eventually led to the successful global eradication of smallpox in 1979. VACV has many characteristics that make it an excellent vaccine and that were crucial for the successful eradication of smallpox, including (1) its exceptional thermal stability (a very important but uncommon characteristic in live vaccines), (2) its ability to elicit strong humoral and cell-mediated immune responses, (3) the fact that it is easy to propagate, and (4) that it is not oncogenic, given that VACV replication occurs exclusively within the host cell cytoplasm and there is no evidence that the viral genome integrates into the host genome. Since the eradication of smallpox, VACV has experienced a renaissance of interest as a viral vector for the development of recombinant vaccines, immunotherapies, and oncolytic therapies, as well as the development of next-generation smallpox vaccines. This revival is mainly due to the successful use and extensive characterization of VACV as a vaccine during the smallpox eradication campaign, along with the ability to genetically manipulate its large dsDNA genome while retaining infectivity and immunogenicity, its wide mammalian host range, and its natural tropism for tumor cells that allows its use as an oncolytic vector. This review provides an overview of new uses of VACV that are currently being explored for the development of vaccines, immunotherapeutics, and oncolytic virotherapies. PMID:22777090

Verardi, Paulo H; Titong, Allison; Hagen, Caitlin J

2012-07-01

12

A vaccinia virus renaissance  

PubMed Central

In 1796, Edward Jenner introduced the concept of vaccination with cowpox virus, an Orthopoxvirus within the family Poxviridae that elicits cross protective immunity against related orthopoxviruses, including smallpox virus (variola virus). Over time, vaccinia virus (VACV) replaced cowpox virus as the smallpox vaccine, and vaccination efforts eventually led to the successful global eradication of smallpox in 1979. VACV has many characteristics that make it an excellent vaccine and that were crucial for the successful eradication of smallpox, including (1) its exceptional thermal stability (a very important but uncommon characteristic in live vaccines), (2) its ability to elicit strong humoral and cell-mediated immune responses, (3) the fact that it is easy to propagate, and (4) that it is not oncogenic, given that VACV replication occurs exclusively within the host cell cytoplasm and there is no evidence that the viral genome integrates into the host genome. Since the eradication of smallpox, VACV has experienced a renaissance of interest as a viral vector for the development of recombinant vaccines, immunotherapies, and oncolytic therapies, as well as the development of next-generation smallpox vaccines. This revival is mainly due to the successful use and extensive characterization of VACV as a vaccine during the smallpox eradication campaign, along with the ability to genetically manipulate its large dsDNA genome while retaining infectivity and immunogenicity, its wide mammalian host range, and its natural tropism for tumor cells that allows its use as an oncolytic vector. This review provides an overview of new uses of VACV that are currently being explored for the development of vaccines, immunotherapeutics, and oncolytic virotherapies. PMID:22777090

Verardi, Paulo H.; Titong, Allison; Hagen, Caitlin J.

2012-01-01

13

Immune and histopathological responses in animals vaccinated with recombinant vaccinia viruses that express individual genes of human respiratory syncytial virus.  

PubMed Central

Previous reports have established that vaccinia virus (VV) recombinants expressing G, F, or N protein of respiratory syncytial (RS) virus protect small animals against intranasal challenge with live RS virus. This work demonstrates that a variety of parameters affect the protection induced by recombinant viruses. The route of vaccination, the subtype of challenge virus, and the species used influenced the antibody titers and extent of protection. During these studies, observations were also made on the subclass of antibody generated, and pulmonary histopathological changes induced by challenge after vaccination were noted. The effect of route of inoculation on host response was examined by vaccinating mice intranasally, intraperitoneally, or by scarification with a recombinant VV expressing the RS virus G glycoprotein. Intranasal vaccination induced 25-fold-higher titers of antibody to RS virus in the lung than the intraperitoneal route did, but both routes resulted in complete suppression of virus replication after intranasal challenge 21 days after vaccination. Scarification was a less effective method of vaccination. The antibody induced by recombinant VV in mice was mostly immunoglobulin G2a (IgG2a) with some IgG2b. No antibody to RS virus was detected in the IgA, IgM, IgG1, or IgG3 subclass irrespective of the vaccination route. The G and F glycoproteins were shown to elicit similar subclasses of antibody. However, animals vaccinated with the G and F vectors differed strikingly in their response to challenge by heterologous virus. Mice or cotton rats vaccinated with recombinant VV carrying the G gene of RS virus were protected against challenge only with homologous subtype A virus. Vaccination with a recombinant VV expressing the F glycoprotein induced protection against both homologous and heterologous subtype B virus challenge. The protection induced in mice was greater than that detected in cotton rats, indicating that the host may also affect immunity. Finally, this report describes histological examination of mouse lungs after vaccination and challenge. Vaccinated mice that were subsequently challenged had significantly greater lung lesion scores than unvaccinated challenged mice. The lesions were primarily peribronchiolar and perivascular infiltrations of polymorphonuclear cells and lymphocytes. Further work will establish whether these pulmonary changes are a desirable immune response to virus invasion or a potential immunopathogenic hazard. The results have important implications for planning a strategy of vaccination against RS virus and emphasize potential dangers that may attend the use of recombinant VV as vaccines. PMID:3316707

Stott, E J; Taylor, G; Ball, L A; Anderson, K; Young, K K; King, A M; Wertz, G W

1987-01-01

14

DNA\\/MVA HIV1\\/AIDS vaccine elicits long-lived vaccinia virus-specific immunity and confers protection against a lethal monkeypox challenge  

Microsoft Academic Search

Modified vaccinia Ankara (MVA) is being tested in humans as an alternative to the current smallpox vaccine Dryvax. Here, we compare the magnitude and longevity of protective immune responses elicited by a DNA\\/MVA HIV-1 vaccine with those elicited by Dryvax using a monkeypox virus\\/macaque model. The DNA\\/MVA vaccine elicited similar levels of vaccinia virus (VV)-specific antibody and 5–10-fold lower levels

Pragati Nigam; Patricia L. Earl; Jeffrey L. Americo; Sunita Sharma; Linda S. Wyatt; Yvette Edghill-Spano; Lakshmi S. Chennareddi; Peter Silvera; Bernard Moss; Harriet L. Robinson; Rama Rao Amara

2007-01-01

15

Infectious vaccinia virus recombinants that express hepatitis B virus surface antigen  

NASA Astrophysics Data System (ADS)

Potential live vaccines against hepatitis B virus have been produced. The coding sequence for hepatitis B virus surface antigen (HBsAg) has been inserted into the vaccinia virus genome under control of vaccinia virus early promoters. Cells infected with these vaccinia virus recombinants synthesize and excrete HBsAg and vaccinated rabbits rapidly produce antibodies to HBsAg.

Smith, Geoffrey L.; Mackett, Michael; Moss, Bernard

1983-04-01

16

Modified vaccinia virus ankara (MVA) as production platform for vaccines against influenza and other viral respiratory diseases.  

PubMed

Respiratory viruses infections caused by influenza viruses, human parainfluenza virus (hPIV), respiratory syncytial virus (RSV) and coronaviruses are an eminent threat for public health. Currently, there are no licensed vaccines available for hPIV, RSV and coronaviruses, and the available seasonal influenza vaccines have considerable limitations. With regard to pandemic preparedness, it is important that procedures are in place to respond rapidly and produce tailor made vaccines against these respiratory viruses on short notice. Moreover, especially for influenza there is great need for the development of a universal vaccine that induces broad protective immunity against influenza viruses of various subtypes. Modified Vaccinia Virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform. MVA can encode one or more foreign antigens and thus functions as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. However, there are some practical and regulatory issues that need to be addressed in order to develop MVA-based vaccines on short notice at the verge of a pandemic. In this review, we discuss promising novel influenza virus vaccine targets and the use of MVA for vaccine development against various respiratory viruses. PMID:25036462

Altenburg, Arwen F; Kreijtz, Joost H C M; de Vries, Rory D; Song, Fei; Fux, Robert; Rimmelzwaan, Guus F; Sutter, Gerd; Volz, Asisa

2014-07-01

17

Construction of Live Vaccines by Using Genetically Engineered Poxviruses: Biological Activity of Recombinant Vaccinia Virus Expressing Influenza Virus Hemagglutinin  

Microsoft Academic Search

Recombinant vaccinia viruses containing the cloned hemagglutinin (HA) gene from influenza virus were constructed. The biological activity of these poxvirus vectors was demonstrated both in vitro and in vivo. Expression of HA in cells infected with recombinant vaccinia was detected by using specific anti-HA antiserum and 125I-labeled protein A, showing that HA synthesized under the regulation of vaccinia virus was

Dennis Panicali; Stephen W. Davis; Randall L. Weinberg; Enzo Paoletti

1983-01-01

18

Genomic Analysis of the Vaccinia Virus Strain Variants Found in Dryvax Vaccine?†  

PubMed Central

Smallpox was eradicated using variant forms of vaccinia virus-based vaccines. One of these was Dryvax, a calf lymph vaccine derived from the New York City Board of Health strain. We used genome-sequencing technology to examine the genetic diversity of the population of viruses present in a sample of Dryvax. These studies show that the conserved cores of these viruses exhibit a lower level of sequence variation than do the telomeres. However, even though the ends of orthopoxviruses are more genetically plastic than the cores, there are still many telomeric genes that are conserved as intact open reading frames in the 11 genomes that we, and 4 genomes that others, have sequenced. Most of these genes likely modulate inflammation. Our sequencing also detected an evolving pattern of mutation, with some genes being highly fragmented by randomly assorting mutations (e.g., M1L), while other genes are intact in most viruses but have been disrupted in individual strains (e.g., I4L in strain DPP17). Over 85% of insertion and deletion mutations are associated with repeats, and a rare new isolate bearing a large deletion in the right telomere was identified. All of these strains cluster in dendrograms consistent with their origin but which also surprisingly incorporate horsepox virus. However, these viruses also exhibit a “patchy” pattern of polymorphic sites characteristic of recombinants. There is more genetic diversity detected within a vial of Dryvax than between variola virus major and minor strains, and our study highlights how propagation methods affect the genetics of orthopoxvirus populations. PMID:21976639

Qin, Li; Upton, Chris; Hazes, Bart; Evans, David H.

2011-01-01

19

Effect of the Deletion of Genes Encoding Proteins of the Extracellular Virion Form of Vaccinia Virus on Vaccine Immunogenicity and Protective Effectiveness in the Mouse Model  

PubMed Central

Antibodies to both infectious forms of vaccinia virus, the mature virion (MV) and the enveloped virion (EV), as well as cell-mediated immune response appear to be important for protection against smallpox. EV virus particles, although more labile and less numerous than MV, are important for dissemination and spread of virus in infected hosts and thus important in virus pathogenesis. The importance of the EV A33 and B5 proteins for vaccine induced immunity and protection in a murine intranasal challenge model was evaluated by deletion of both the A33R and B5R genes in a vaccine-derived strain of vaccinia virus. Deletion of either A33R or B5R resulted in viruses with a small plaque phenotype and reduced virus yields, as reported previously, whereas deletion of both EV protein-encoding genes resulted in a virus that formed small infection foci that were detectable and quantifiable only by immunostaining and an even more dramatic decrease in total virus yield in cell culture. Deletion of B5R, either as a single gene knockout or in the double EV gene knockout virus, resulted in a loss of EV neutralizing activity, but all EV gene knockout viruses still induced a robust neutralizing activity against the vaccinia MV form of the virus. The effect of elimination of A33 and/or B5 on the protection afforded by vaccination was evaluated by intranasal challenge with a lethal dose of either vaccinia virus WR or IHD-J, a strain of vaccinia virus that produces relatively higher amounts of EV virus. The results from multiple experiments, using a range of vaccination doses and virus challenge doses, and using mortality, morbidity, and virus dissemination as endpoints, indicate that the absence of A33 and B5 have little effect on the ability of a vaccinia vaccine virus to provide protection against a lethal intranasal challenge in a mouse model. PMID:23785523

Meseda, Clement A.; Campbell, Joseph; Kumar, Arunima; Garcia, Alonzo D.; Merchlinsky, Michael; Weir, Jerry P.

2013-01-01

20

Genomic Sequence and Virulence of Clonal Isolates of Vaccinia Virus Tiantan, the Chinese Smallpox Vaccine Strain  

PubMed Central

Despite the worldwide eradication of smallpox in 1979, the potential bioterrorism threat from variola virus and the ongoing use of vaccinia virus (VACV) as a vector for vaccine development argue for continued research on VACV. In China, the VACV Tiantan strain (TT) was used in the smallpox eradication campaign. Its progeny strain is currently being used to develop a human immunodeficiency virus (HIV) vaccine. Here we sequenced the full genomes of five TT clones isolated by plaque purification from the TT (752-1) viral stock. Phylogenetic analysis with other commonly used VACV strains showed that TT (752-1) and its clones clustered and exhibited higher sequence diversity than that found in Dryvax clones. The ?190 kbp genomes of TT appeared to encode 273 open reading frames (ORFs). ORFs located in the middle of the genome were more conserved than those located at the two termini, where many virulence and immunomodulation associated genes reside. Several patterns of nucleotide changes including point mutations, insertions and deletions were identified. The polymorphisms in seven virulence-associated proteins and six immunomodulation-related proteins were analyzed. We also investigated the neuro- and skin- virulence of TT clones in mice and rabbits, respectively. The TT clones exhibited significantly less virulence than the New York City Board of Health (NYCBH) strain, as evidenced by less extensive weight loss and morbidity in mice as well as produced smaller skin lesions and lower incidence of putrescence in rabbits. The complete genome sequences, ORF annotations, and phenotypic diversity yielded from this study aid our understanding of the Chinese historic TT strain and are useful for HIV vaccine projects employing TT as a vector. PMID:23593246

Zhang, Qicheng; Tian, Meijuan; Feng, Yi; Zhao, Kai; Xu, Jing; Liu, Ying; Shao, Yiming

2013-01-01

21

Protective Properties of Vaccinia Virus-Based Vaccines: Skin Scarification Promotes a Nonspecific Immune Response That Protects against Orthopoxvirus Disease  

PubMed Central

ABSTRACT The process of vaccination introduced by Jenner generated immunity against smallpox and ultimately led to the eradication of the disease. Procedurally, in modern times, the virus is introduced into patients via a process called scarification, performed with a bifurcated needle containing a small amount of virus. What was unappreciated was the role that scarification itself plays in generating protective immunity. In rabbits, protection from lethal disease is induced by intradermal injection of vaccinia virus, whereas a protective response occurs within the first 2 min after scarification with or without virus, suggesting that the scarification process itself is a major contributor to immunoprotection. IMPORTANCE These results show the importance of local nonspecific immunity in controlling poxvirus infections and indicate that the process of scarification should be critically considered during the development of vaccination protocols for other infectious agents. PMID:24760885

Rice, Amanda D.; Adams, Mathew M.; Lindsey, Scott F.; Swetnam, Daniele M.; Manning, Brandi R.; Smith, Andrew J.; Burrage, Andrew M.; Wallace, Greg; MacNeill, Amy L.

2014-01-01

22

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

Microsoft Academic Search

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

Masayuki Saijo; Yasushi Ami; Yuriko Suzaki; Noriyo Nagata; Naoko Iwata; Hideki Hasegawa; Momoko Ogata; Shuetsu Fukushi; Tetsuya Mizutani; T. Sata; Takeshi Kurata; Ichiro Kurane; Shigeru Morikawa

2006-01-01

23

Induction of Antibody Responses to African Horse Sickness Virus (AHSV) in Ponies after Vaccination with Recombinant Modified Vaccinia Ankara (MVA)  

PubMed Central

Background African horse sickness virus (AHSV) causes a non-contagious, infectious disease in equids, with mortality rates that can exceed 90% in susceptible horse populations. AHSV vaccines play a crucial role in the control of the disease; however, there are concerns over the use of polyvalent live attenuated vaccines particularly in areas where AHSV is not endemic. Therefore, it is important to consider alternative approaches for AHSV vaccine development. We have carried out a pilot study to investigate the ability of recombinant modified vaccinia Ankara (MVA) vaccines expressing VP2, VP7 or NS3 genes of AHSV to stimulate immune responses against AHSV antigens in the horse. Methodology/Principal Findings VP2, VP7 and NS3 genes from AHSV-4/Madrid87 were cloned into the vaccinia transfer vector pSC11 and recombinant MVA viruses generated. Antigen expression or transcription of the AHSV genes from cells infected with the recombinant viruses was confirmed. Pairs of ponies were vaccinated with MVAVP2, MVAVP7 or MVANS3 and both MVA vector and AHSV antigen-specific antibody responses were analysed. Vaccination with MVAVP2 induced a strong AHSV neutralising antibody response (VN titre up to a value of 2). MVAVP7 also induced AHSV antigen–specific responses, detected by western blotting. NS3 specific antibody responses were not detected. Conclusions This pilot study demonstrates the immunogenicity of recombinant MVA vectored AHSV vaccines, in particular MVAVP2, and indicates that further work to investigate whether these vaccines would confer protection from lethal AHSV challenge in the horse is justifiable. PMID:19543394

Maan, Sushila; Rao, Shujing; Mertens, Peter; Blacklaws, Barbara; Davis-Poynter, Nick; Wood, James; Castillo-Olivares, Javier

2009-01-01

24

Protective Immunity in Macaques Vaccinated with a Modified Vaccinia Virus Ankara-Based Measles Virus Vaccine in the Presence of Passively Acquired Antibodies  

PubMed Central

Recombinant modified vaccinia virus Ankara (MVA), encoding the measles virus (MV) fusion (F) and hemagglutinin (H) (MVA-FH) glycoproteins, was evaluated in an MV vaccination-challenge model with macaques. Animals were vaccinated twice in the absence or presence of passively transferred MV-neutralizing macaque antibodies and challenged 1 year later intratracheally with wild-type MV. After the second vaccination with MVA-FH, all the animals developed MV-neutralizing antibodies and MV-specific T-cell responses. Although MVA-FH was slightly less effective in inducing MV-neutralizing antibodies in the absence of passively transferred antibodies than the currently used live attenuated vaccine, it proved to be more effective in the presence of such antibodies. All vaccinated animals were effectively protected from the challenge infection. These data suggest that MVA-FH should be further tested as an alternative to the current vaccine for infants with maternally acquired MV-neutralizing antibodies and for adults with waning vaccine-induced immunity. PMID:10756037

Stittelaar, Koert J.; Wyatt, Linda S.; de Swart, Rik L.; Vos, Helma W.; Groen, Jan; van Amerongen, Geert; van Binnendijk, Robert S.; Rozenblatt, Shmuel; Moss, Bernard; Osterhaus, Albert D. M. E.

2000-01-01

25

Protection of Mice from Fatal Measles Encephalitis by Vaccination with Vaccinia Virus Recombinants Encoding Either the Hemagglutinin or the Fusion Protein  

NASA Astrophysics Data System (ADS)

Vaccinia virus recombinants encoding the hemagglutinin or fusion protein of measles virus have been constructed. Infection of cell cultures with the recombinants led to the synthesis of authentic measles proteins as judged by their electrophoretic mobility, recognition by antibodies, glycosylation, proteolytic cleavage, and presentation on the cell surface. Mice vaccinated with a single dose of the recombinant encoding the hemagglutinin protein developed antibodies capable of both inhibiting hemagglutination activity and neutralizing measles virus, whereas animals vaccinated with the recombinant encoding the fusion protein developed measles neutralizing antibodies. Mice vaccinated with either of the recombinants resisted a normally lethal intracerebral inoculation of a cell-associated measles virus subacute sclerosing panencephalitis strain.

Drillien, Robert; Spehner, Daniele; Kirn, Andre; Giraudon, Pascale; Buckland, Robin; Wild, Fabian; Lecocq, Jean-Pierre

1988-02-01

26

Immunogenicity and Safety of Defective Vaccinia Virus Lister: Comparison with Modified Vaccinia Virus Ankara  

PubMed Central

Potent and safe vaccinia virus vectors inducing cell-mediated immunity are needed for clinical use. Replicating vaccinia viruses generally induce strong cell-mediated immunity; however, they may have severe adverse effects. As a vector for clinical use, we assessed the defective vaccinia virus system, in which deletion of an essential gene blocks viral replication, resulting in an infectious virus that does not multiply in the host. The vaccinia virus Lister/Elstree strain, used during worldwide smallpox eradication, was chosen as the parental virus. The immunogenicity and safety of the defective vaccinia virus Lister were evaluated without and with the inserted human p53 gene as a model and compared to parallel constructs based on modified vaccinia virus Ankara (MVA), the present “gold standard” of recombinant vaccinia viruses in clinical development. The defective viruses induced an efficient Th1-type immune response. Antibody and cytotoxic-T-cell responses were comparable to those induced by MVA. Safety of the defective Lister constructs could be demonstrated in vitro in cell culture as well as in vivo in immunodeficient SCID mice. Similar to MVA, the defective viruses were tolerated at doses four orders of magnitude higher than those of the wild-type Lister strain. While current nonreplicating vectors are produced mainly in primary chicken cells, defective vaccinia virus is produced in a permanent safety-tested cell line. Vaccines based on this system have the additional advantage of enhanced product safety. Therefore, a vector system was made which promises to be a valuable tool not only for immunotherapy for diseases such as cancer, human immunodeficiency virus infection, or malaria but also as a basis for a safer smallpox vaccine. PMID:12097585

Ober, B. T.; Brühl, P.; Schmidt, M.; Wieser, V.; Gritschenberger, W.; Coulibaly, S.; Savidis-Dacho, H.; Gerencer, M.; Falkner, F. G.

2002-01-01

27

Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults  

PubMed Central

A randomized, double-blind, placebo-controlled phase I trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of 3 doses of DNA vaccine (Advax) plus 1 dose of recombinant modified vaccinia virus Ankara (MVA) (TBC-M4) or 3 doses of TBC-M4 alone (groups A and B, respectively). Both vaccine regimens were found to be safe and well tolerated. Gamma interferon (IFN-?) enzyme-linked immunosorbent spot (ELISPOT) assay responses were detected in 1/10 (10%) individuals in group A after three Advax primes and in 9/9 individuals (100%) after the MVA boost. In group B, IFN-? ELISPOT responses were detected in 6/12 (50%) and 7/11 (64%) individuals after the second and third MVA vaccinations, respectively. Responses to all vaccine components, but predominantly to Env, were seen. The breadth and magnitude of the T cell response and viral inhibition were greater in group A than in group B, indicating that the quality of the T-cell response was enhanced by the DNA prime. Intracellular cytokine staining indicated that the T-cell responses were polyfunctional but were skewed toward Env with a CD4+ phenotype. At 2 weeks after the last vaccination, HIV-specific antibody responses were detected in all (100%) group B and 1/11 (9.1%) group A vaccinees. Vaccinia virus-specific responses were detected in all (100%) group B and 2/11 (18.2%) group A vaccinees. In conclusion, HIV-specific T-cell responses were seen in the majority of volunteers in groups A and B but with a trend toward greater quality of the T-cell response in group A. Antibody responses were better in group B than in group A. PMID:23345581

Hayes, Peter; Gilmour, Jill; von Lieven, Andrea; Gill, Dilbinder; Clark, Lorna; Kopycinski, Jakub; Cheeseman, Hannah; Chung, Amy; Alter, Galit; Dally, Len; Zachariah, Devika; Lombardo, Angela; Ackland, James; Sayeed, Eddy; Jackson, Akil; Boffito, Marta; Gazzard, Brian; Fast, Patricia E.; Laufer, Dagna

2013-01-01

28

Deletion of Major Nonessential Genomic Regions in the Vaccinia Virus Lister Strain Enhances Attenuation without Altering Vaccine Efficacy in Mice?  

PubMed Central

The vaccinia virus (VACV) Lister strain was one of the vaccine strains that enabled smallpox eradication. Although the strain is most often harmless, there have been numerous incidents of mild to life-threatening accidents with this strain and others. In an attempt to further attenuate the Lister strain, we investigated the role of 5 genomic regions known to be deleted in the modified VACV Ankara (MVA) genome in virulence in immunodeficient mice, immunogenicity in immunocompetent mice, and vaccine efficacy in a cowpox virus challenge model. Lister mutants were constructed so as to delete each of the 5 regions or various combinations of these regions. All of the mutants replicated efficiently in tissue culture except region I mutants, which multiplied more poorly in human cells than the parental strain. Mutants with single deletions were not attenuated or only moderately so in athymic nude mice. Mutants with multiple deletions were more highly attenuated than those with single deletions. Deleting regions II, III, and V together resulted in total attenuation for nude mice and partial attenuation for SCID mice. In immunocompetent mice, the Lister deletion mutants induced VACV specific humoral responses equivalent to those of the parental strain but in some cases lower cell-mediated immune responses. All of the highly attenuated mutants protected mice from a severe cowpox virus challenge at low vaccine doses. The data suggest that several of the Lister mutants combining multiple deletions could be used in smallpox vaccination or as live virus vectors at doses equivalent to those used for the traditional vaccine while displaying increased safety. PMID:21367889

Dimier, Julie; Ferrier-Rembert, Audrey; Pradeau-Aubreton, Karine; Hebben, Matthias; Spehner, Danièle; Favier, Anne-Laure; Gratier, Danielle; Garin, Daniel; Crance, Jean-Marc; Drillien, Robert

2011-01-01

29

A Human Multi-Epitope Recombinant Vaccinia Virus as a Universal T Cell Vaccine Candidate against Influenza Virus  

Microsoft Academic Search

There is a need to develop a universal vaccine against influenza virus infection to avoid developing new formulations of a seasonal vaccine each year. Many of the vaccine strategies for a universal vaccine target strain-conserved influenza virus proteins, such as the matrix, polymerase, and nucleoproteins, rather than the surface hemagglutinin and neuraminidase proteins. In addition, non-disease-causing viral vectors are a

Alan G. Goodman; Paul P. Heinen; Susana Guerra; Aneesh Vijayan; Carlos Oscar S. Sorzano; Carmen E. Gomez; Mariano Esteban; Eliane Namie Miyaji

2011-01-01

30

Vaccination of horses with a recombinant modified vaccinia Ankara virus (MVA) expressing African horse sickness (AHS) virus major capsid protein VP2 provides complete clinical protection against challenge  

PubMed Central

African horse sickness virus (AHSV) is an arthropod-borne pathogen that infects all species of equidae and causes high mortality in horses. Previously, a recombinant modified vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 was shown to induce virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR ?/?) against virulent AHSV challenge. This study builds on the previous work, examining the protective efficacy of MVA-VP2 vaccination in the natural host of AHSV infection. A study group of 4 horses was vaccinated twice with a recombinant MVA virus expressing the major capsid protein (VP2) of AHSV serotype 9. Vaccinated animals and a control group of unvaccinated horses were then challenged with a virulent strain of AHSV-9. The vaccinated animals were completely protected against clinical disease and also against viraemia as measured by standard end-point dilution assays. In contrast, all control horses presented viraemia after challenge and succumbed to the infection. These results demonstrate the potential of recombinant MVA viruses expressing the outer capsid VP2 of AHSV as a protective vaccine against AHSV infection in the field. PMID:24837765

Alberca, Berta; Bachanek-Bankowska, Katarzyna; Cabana, Marta; Calvo-Pinilla, Eva; Viaplana, Elisenda; Frost, Lorraine; Gubbins, Simon; Urniza, Alicia; Mertens, Peter; Castillo-Olivares, Javier

2014-01-01

31

Oral vaccination of the fox against rabies using a live recombinant vaccinia virus  

Microsoft Academic Search

Rabies, a viral disease affecting all warm-blooded animals, is prevalent in most parts of the world1, where it propagates amongst wild animals, particularly the fox and dog. The public health and economic consequences of infection in man and livestock are well known. Attempts to control the disease by vaccinating wild carnivores with inactivated or attenuated rabies virus remain controversial, and

J. Blancou; M. P. Kieny; R. Lathe; J. P. Lecocq; P. P. Pastore; J. P. Soulebot; P. Desmettre

1986-01-01

32

Expression of rabies virus glycoprotein from a recombinant vaccinia virus  

Microsoft Academic Search

Rabies is one of the oldest diseases known to man, but its successful control has remained elusive. Although effective vaccines of tissue culture origin against rabies do exist1, such preparations are expensive. Live vaccinia virus (VV) recombinants expressing influenza or hepatitis B antigens have recently been used to immunize against these diseases2-4. We have now used this approach to produce

M. P. Kieny; R. Lathe; R. Drillien; D. Spehner; S. Skory; D. Schmitt; T. Wiktor; H. Koprowski; J. P. Lecocq

1984-01-01

33

Immunogenicities of intravenous and intramuscular administrations of modified vaccinia virus Ankara-based multi-CTL epitope vaccine for human immunodeficiency virus type 1 in mice.  

PubMed

A vaccine against human immunodeficiency virus (HIV) is still awaited. Although the correlates of protection remain elusive, it is likely that CD8+ T cells play an important role in the control of this infection. To firmly establish the importance of these cells in protective immunity, a means of efficient elicitation of CD8+ T cell responses in the absence of antibody is needed and, when available, might represent a crucial step towards a protective vaccine. Here, a novel vaccine candidate was constructed as a multi-cytotoxic T lymphocyte (CTL) epitope gene delivered and expressed using modified vaccinia virus Ankara (MVA). The immunogen consists of 20 human, one murine and three rhesus macaque epitopes. The non-human epitopes were included so that the vaccine can be tested for immunogenicity and optimal vaccination doses, routes and regimes in experimental animals. Mice were immunized intravenously (i.v.) or intramuscularly (i.m.) using a single dose of 10(6) p.f.u. of the recombinant MVA and the induction of CTL was assessed. It was demonstrated that both administration routes induced specific CTL responses and that the i.v. route was moderately more immunogenic than the i.m. route. The frequencies of ex vivo splenocytes producing interferon-y upon MHC class I-restricted peptide stimulation were determined using an ELISPOT assay. Also, the correct processing and presentation of some HLA-restricted epitopes in human cells was confirmed. PMID:9460927

Hanke, T; Blanchard, T J; Schneider, J; Ogg, G S; Tan, R; Becker, M; Gilbert, S C; Hill, A V; Smith, G L; McMichael, A

1998-01-01

34

Antibody Profiling by Proteome Microarray Reveals the Immunogenicity of the Attenuated Smallpox Vaccine Modified Vaccinia Virus Ankara Is Comparable to That of Dryvax? †  

PubMed Central

Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax. MVA was attenuated by extensive passage of vaccinia virus Ankara in chicken embryo fibroblasts. Several immunomodulatory genes and genes that influence host range are deleted or mutated, and replication is aborted in the late stage of infection in most nonavian cells. The effect of these mutations on immunogenicity is not well understood. Since the structural genes appear to be intact in MVA, it is hypothesized that critical targets for antibody neutralization have been retained. To test this, we probed microarrays of the Western Reserve (WR) proteome with sera from humans and macaques after MVA and Dryvax vaccination. As most protein sequences of MVA are 97 to 99% identical to those of other vaccinia virus strains, extensive binding cross-reactivity is expected, except for those deleted or truncated. Despite different hosts and immunization regimens, the MVA and Dryvax antibody profiles were broadly similar, with antibodies against membrane and core proteins being the best conserved. The responses to nonstructural proteins were less well conserved, although these are not expected to influence virus neutralization. The broadest antibody response was obtained for hyperimmune rabbits with WR, which is pathogenic in rabbits. These data indicate that, despite the mutations and deletions in MVA, its overall immunogenicity is broadly comparable to that of Dryvax, particularly at the level of antibodies to membrane proteins. The work supports other information suggesting that MVA may be a useful alternative to Dryvax. PMID:17977963

Davies, D. Huw; Wyatt, Linda S.; Newman, Frances K.; Earl, Patricia L.; Chun, Sookhee; Hernandez, Jenny E.; Molina, Douglas M.; Hirst, Siddiqua; Moss, Bernard; Frey, Sharon E.; Felgner, Philip L.

2008-01-01

35

Modified Vaccinia Virus Ankara Protects Macaques against Respiratory Challenge with Monkeypox Virus  

Microsoft Academic Search

The use of classical smallpox vaccines based on vaccinia virus (VV) is associated with severe complications in both naive and immune individuals. Modified vaccinia virus Ankara (MVA), a highly attenuated replication- deficient strain of VV, has been proven to be safe in humans and immunocompromised animals, and its efficacy against smallpox is currently being addressed. Here we directly compare the

Koert J. Stittelaar; Geert van Amerongen; Ivanela Kondova; Thijs Kuiken; Rob F. van Lavieren; Frank H. M. Pistoor; Hubert G. M. Niesters; Gerard van Doornum; Ben A. M. van der Zeijst; Luis Mateo; Paul J. Chaplin; Albert D. M. E. Osterhaus

2005-01-01

36

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

PubMed Central

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. PMID:16698998

Saijo, Masayuki; Ami, Yasushi; Suzaki, Yuriko; Nagata, Noriyo; Iwata, Naoko; Hasegawa, Hideki; Ogata, Momoko; Fukushi, Shuetsu; Mizutani, Tetsuya; Sata, Tetsutaro; Kurata, Takeshi; Kurane, Ichiro; Morikawa, Shigeru

2006-01-01

37

Modified Vaccinia Virus Ankara Induces Toll-Like Receptor-Independent Type I Interferon Responses  

Microsoft Academic Search

Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus strain undergoing clinical evaluation as a replication-deficient vaccine vector against various infections and tumor diseases. To analyze the basis of its high immunogenicity, we investigated the mechanism of how MVA induces type I interferon (IFN) responses. MVA stimulation of bone marrow-derived dendritic cells (DC) showed that plasmacytoid DC were

Zoe Waibler; Martina Anzaghe; Holger Ludwig; Shizuo Akira; Siegfried Weiss; Gerd Sutter; Ulrich Kalinke

2007-01-01

38

The combination of marker gene swapping and fluorescence-activated cell sorting improves the efficiency of recombinant modified vaccinia virus Ankara vaccine production for human use.  

PubMed

Modified vaccinia virus Ankara (MVA) is employed as a human vaccine vector for the high expression of heterologous genes and the lack of replication in mammalian cells. This study demonstrates that cells infected by recombinant viruses can be obtained by fluorescence-activated cell sorting. Recombinant viruses are generated by a swapping event between a red fluorescent protein gene in the acceptor virus and a plasmid cassette coding for both a green fluorescent marker and a transgene. To prevent the carry-over of parental virus, due to superinfection of the cells harbouring recombinant viruses, the sorting is performed on cells infected at low m.o.i. in the presence of a reversible inhibitor of viral particle release. Terminal dilution cloning is then used to isolate both green and marker-free recombinant viruses, which can be identified by whole-plate fluoroimaging. The differential visualization of all the viral types involved allows a stepwise monitoring of all recombinations and leads to a straightforward and efficient flow cytometry-based cell sorting purification protocol. As an example of the efficacy of this sorting procedure, the construction of rMVA's coding for the rat nuclear protein HMGB1 and H5N1 influenza A virus hemagglutinin is reported. The entire recombinant MVA production process is carried out in serum-free media employing primary chicken embryo fibroblasts (CEF), which are certified for the preparation of human vaccines. This rMVA production method is faster, simpler and more reliable than any other available procedure for obtaining safe vaccine stocks for human use. PMID:19778556

Di Lullo, Giulia; Soprana, Elisa; Panigada, Maddalena; Palini, Alessio; Agresti, Alessandra; Comunian, Claudio; Milani, Adelaide; Capua, Ilaria; Erfle, Volker; Siccardi, Antonio G

2010-02-01

39

Elimination of fox rabies from Belgium using a recombinant vaccinia-rabies vaccine: an update  

Microsoft Academic Search

To improve both safety and stability of the vaccines used in the field to vaccinate foxes against rabies by the oral route, a recombinant vaccinia virus, expressing the glycoprotein of rabies virus (VVTGgRAB) has been developed. VVTGgRAB innocuity was verified in target species and in domestic animals as well as in numerous wild animal species that could compete with the

B. Brochier; F. Costy; P.-P. Pastoret

1995-01-01

40

Vaccinia Virus Infection in Monkeys, Brazilian Amazon  

PubMed Central

To detect orthopoxvirus in the Brazilian Amazon, we conducted a serosurvey of 344 wild animals. Neutralizing antibodies against orthopoxvirus were detected by plaque-reduction neutralizing tests in 84 serum samples. Amplicons from 6 monkey samples were sequenced. These amplicons identified vaccinia virus genetically similar to strains from bovine vaccinia outbreaks in Brazil. PMID:20507750

Abrahão, Jônatas S.; Silva-Fernandes, André T.; Lima, Larissa S.; Campos, Rafael K.; Guedes, Maria I.M.C.; Cota, Marcela M.G.; Assis, Felipe L.; Borges, Iara A.; Souza-Júnior, Milton F.; Lobato, Zélia I.P.; Bonjardim, Cláudio A.; Ferreira, Paulo C.P.; Trindade, Giliane S.

2010-01-01

41

Fighting Cancer with Vaccinia Virus: Teaching New Tricks to an Old Dog  

Microsoft Academic Search

Vaccinia virus has played a huge part in human beings' victory over smallpox. With smallpox being eradicated and large-scale vaccination stopped worldwide, vaccinia has assumed a new role in our fight against another serious threat to human health: cancer. Recent advances in molecular biology, virology, immunology, and cancer genetics have led to the design of novel cancer therapeutics based on

Yuqiao Shen; John Nemunaitis

2005-01-01

42

Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development  

Microsoft Academic Search

Summal~ There is considerable interest in designing an effective vaccine to the ubiquitous Epstein-Barr virus (EBV). An important role for EBV-specific cytotoxic T lymphocytes (CTLs) in eliminating virus-infected cells is well established. Limited studies using a small number of immune donors have defined target epitopes within the latent antigens of EBV. The present study provides an extensive analysis of the

R. Khanna; S. t L. Burrows; M. G. Kuri; C. A. Jacob; I. S. Misko; T. B. Scul; E. Kieff; D. J. Moss

1992-01-01

43

Nucleotide sequence of 21.8 kbp of variola major virus strain Harvey and comparison with vaccinia virus.  

PubMed

A 21.8 kbp region of the genome of variola major virus (strain Harvey), a virus that caused haemorrhagic-type smallpox, has been sequenced and shown to possess 96% nucleotide identity to the corresponding region of vaccinia virus, the smallpox vaccine. Overall the gene arrangement in the two viruses is highly similar and individual open reading frames (ORFs) display a high degree of amino acid identity, for instance 26 of the 32 variola virus ORFs have > or = 90% identity with their vaccinia virus counterparts. A remarkable difference is the disruption of seven vaccinia virus ORFs into small fragments in variola virus. These include the variola virus homologue of vaccinia virus SalF2R, which encodes a protein related to C-type animal lectins, and SalF7L, which encodes an active 3 beta-hydroxysteroid dehydrogenase enzyme that contributes to vaccinia virus virulence. Upstream of the variola virus haemagglutinin gene there is a deletion of 1910 bp so that the equivalent of vaccinia virus gene SalF17R is truncated, and SalF16R, which shows amino acid similarity to the tumour necrosis factor receptor, is absent. The region sequenced includes the genes for thymidylate kinase and DNA ligase both of which are active in vaccinia virus and are highly conserved in variola virus. Other conserved ORFs with interesting homologies are those encoding profilin, superoxide dismutase and part of guanylate kinase. Two vaccinia virus genes encoding glycoproteins of the outer envelope of extracellular enveloped virus are also conserved in variola virus and this homology is likely to have contributed to the immunological protection which vaccinia virus evoked against smallpox. Lastly, there are multiple instances in which short oligonucleotide direct repeats flank a region absent from either variola or vaccinia virus. PMID:1331292

Aguado, B; Selmes, I P; Smith, G L

1992-11-01

44

A Modified Vaccinia Ankara Virus (MVA) Vaccine Expressing African Horse Sickness Virus (AHSV) VP2 Protects Against AHSV Challenge in an IFNAR ?/? Mouse Model  

PubMed Central

African horse sickness (AHS) is a lethal viral disease of equids, which is transmitted by Culicoides midges that become infected after biting a viraemic host. The use of live attenuated vaccines has been vital for the control of this disease in endemic regions. However, there are safety concerns over their use in non-endemic countries. Research efforts over the last two decades have therefore focused on developing alternative vaccines based on recombinant baculovirus or live viral vectors expressing structural components of the AHS virion. However, ethical and financial considerations, relating to the use of infected horses in high biosecurity installations, have made progress very slow. We have therefore assessed the potential of an experimental mouse-model for AHSV infection for vaccine and immunology research. We initially characterised AHSV infection in this model, then tested the protective efficacy of a recombinant vaccine based on modified vaccinia Ankara expressing AHS-4 VP2 (MVA-VP2). PMID:21298069

Castillo-Olivares, Javier; Calvo-Pinilla, Eva; Casanova, Isabel; Bachanek-Bankowska, Katarzyna; Chiam, Rachael; Maan, Sushila; Nieto, Jose Maria; Ortego, Javier; Mertens, Peter Paul Clement

2011-01-01

45

Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara.  

PubMed

Heterologous prime-boost immunization strategies can evoke powerful T cell immune responses and may be of value in developing an improved tuberculosis vaccine. We show that recombinant modified vaccinia virus Ankara, expressing Mycobacterium tuberculosis Ag 85A (M.85A), strongly boosts bacille Calmette-Guérin (BCG)-induced Ag 85A specific CD4(+) and CD8(+) T cell responses in mice. A comparison of intranasal (i.n.) and parenteral immunization of BCG showed that while both routes elicited comparable T cell responses in the spleen, only i.n. delivery elicited specific T cell responses in the lung lymph nodes, and these responses were further boosted by i.n. delivery of M.85A. Following aerosol challenge with M. tuberculosis, i.n. boosting of BCG with either BCG or M.85A afforded unprecedented levels of protection in both the lungs (2.5 log) and spleens (1.5 log) compared with naive controls. Protection in the lung correlated with the induction of Ag 85A-specific, IFN-gamma-secreting T cells in lung lymph nodes. These findings support further evaluation of mucosally targeted prime-boost vaccination approaches for tuberculosis. PMID:12874255

Goonetilleke, Nilu P; McShane, Helen; Hannan, Carolyn M; Anderson, Richard J; Brookes, Roger H; Hill, Adrian V S

2003-08-01

46

Human vaccinia infection after contact with a raccoon rabies vaccine bait - Pennsylvania, 2009.  

PubMed

Since 2003, the U.S. Department of Agriculture's Wildlife Services has coordinated a multistate oral rabies vaccination (ORV) program for wildlife in a 15-state zone extending from Maine to Alabama and in Texas. The program seeks to enhance local control and prevent the spread of epizootic rabies among raccoons and, in Texas, among gray foxes and coyotes. The program uses baits containing liquid vaccinia-rabies glycoprotein (V-RG) recombinant virus vaccine. Because contact with ruptured baits can produce vaccinia virus infection in certain persons, surveillance for human and domestic animal contact with the baits is conducted, relying largely on reports from persons who find baits and call telephone numbers printed on them. In August 2009, during the autumn baiting campaign in western Pennsylvania, a woman aged 35 years who was taking immunosuppressive medication for inflammatory bowel disease contacted the Pennsylvania Department of Health (PADOH) after handling a ruptured bait, which had leaked liquid rabies vaccine onto a patch of abraded skin on her right hand. The patient subsequently developed vaccinia virus infection and was treated with human vaccinia immune globulin intravenous (VIGIV) and an investigational antiviral agent. This report describes this case, which was the second case of human vaccinia infection related to the ORV program. Public health agencies should educate the public, and particularly pet owners, regarding potential hazards associated with handling wildlife rabies vaccine baits and should provide guidance for persons exposed to this vaccine. PMID:19893480

2009-11-01

47

Effective Induction of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Macaques by Using a Multiepitope Gene and DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccination Regimen  

PubMed Central

DNA and modified vaccinia virus Ankara (MVA) are vaccine vehicles suitable and safe for use in humans. Here, by using a multicytotoxic T-lymphocyte (CTL) epitope gene and a DNA prime-MVA boost vaccination regimen, high levels of CTLs specific for a single simian immunodeficiency virus (SIV) gag-derived epitope were elicited in rhesus macaques. These vaccine-induced CTLs were capable of killing SIV-infected cells in vitro. Fluorescence-activated cell sorter analysis using soluble tetrameric major histocompatibility complex-peptide complexes showed that the vaccinated animals had 1 to 5% circulating CD8+ lymphocytes specific for the vaccine epitope, frequencies comparable to those in SIV-infected monkeys. Upon intrarectal challenge with pathogenic SIVmac251, no evidence for protection was observed in at least two of the three vaccinated animals. This study does not attempt to define correlates of protective immunity nor design a protective vaccine against immunodeficiency viruses, but it demonstrates clearly that the DNA prime-MVA boost regimen is an effective protocol for induction of CTLs in macaques. It also shows that powerful tools for studying the role of CTLs in the control of SIV and human immunodeficiency virus infections are now available: epitope-based vaccines, a protocol for an effective induction of CTLs in primates, and a simple and sensitive method for quantitation of epitope-specific T cells. The advantages of the DNA prime-MVA boost regimen as well as the correlations of tetramer staining of peripheral blood lymphocytes with CTL killing in vitro and postchallenge control of viremia are discussed. PMID:10438842

Hanke, Tomas; Samuel, Rachel V.; Blanchard, Tom J.; Neumann, Veronica C.; Allen, Todd M.; Boyson, Jon E.; Sharpe, Sally A.; Cook, Nicola; Smith, Geoffrey L.; Watkins, David I.; Cranage, Martin P.; McMichael, Andrew J.

1999-01-01

48

Vaccinia recombinant virus expressing the rabies virus glycoprotein: safety and efficacy trials in Canadian wildlife.  

PubMed

Twenty-six meadow voles (Microtus pennsylvanicus), ten woodchucks (Marmota monax), thirteen grey squirrels (Sciurus carolinensis), thirteen ring-billed gulls (Larus delawarensis), six red-tailed hawks (Buteo jamaicensis) and eight great horned owls (Bubo virginianus) received vaccinia virus recombinant expressing the rabies virus glycoprotein (V-RG) by direct instillation into the oral cavity. Each of ten coyotes (Canis latrans) received the virus in two vaccine-laden baits. Several voles and most of the gulls died from diseases unrelated to vaccination during the observation period, but all other animals remained healthy and survived. These deaths from causes other than vaccination and the absence of any lesions suggestive of vaccinia infection indicate that it is unlikely that any animal suffered or died as a result of V-RG administration. In addition several animals showed an unexpected high level of rabies neutralizing antibodies. PMID:2249183

Artois, M; Charlton, K M; Tolson, N D; Casey, G A; Knowles, M K; Campbell, J B

1990-10-01

49

Vaccinia recombinant virus expressing the rabies virus glycoprotein: safety and efficacy trials in Canadian wildlife.  

PubMed Central

Twenty-six meadow voles (Microtus pennsylvanicus), ten woodchucks (Marmota monax), thirteen grey squirrels (Sciurus carolinensis), thirteen ring-billed gulls (Larus delawarensis), six red-tailed hawks (Buteo jamaicensis) and eight great horned owls (Bubo virginianus) received vaccinia virus recombinant expressing the rabies virus glycoprotein (V-RG) by direct instillation into the oral cavity. Each of ten coyotes (Canis latrans) received the virus in two vaccine-laden baits. Several voles and most of the gulls died from diseases unrelated to vaccination during the observation period, but all other animals remained healthy and survived. These deaths from causes other than vaccination and the absence of any lesions suggestive of vaccinia infection indicate that it is unlikely that any animal suffered or died as a result of V-RG administration. In addition several animals showed an unexpected high level of rabies neutralizing antibodies. PMID:2249183

Artois, M; Charlton, K M; Tolson, N D; Casey, G A; Knowles, M K; Campbell, J B

1990-01-01

50

Vaccine Efficacy against Malaria by the Combination of Porcine Parvovirus-Like Particles and Vaccinia Virus Vectors Expressing CS of Plasmodium  

PubMed Central

With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8+ T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8+ T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria. PMID:22529915

Rodríguez, Dolores; González-Aseguinolaza, Gloria; Rodríguez, Juan R.; Vijayan, Aneesh; Gherardi, Magdalena; Rueda, Paloma; Casal, J. Ignacio; Esteban, Mariano

2012-01-01

51

Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors.  

PubMed

Successful immunotherapy of established tumors depends on overcoming the suppressive influence of the local tumor microenvironment. The direct injection of vaccinia virus expressing the B7.1 (CD80) costimulatory molecule into melanoma lesions resulted in local and systemic immunity with associated clinical responses. Therefore, we sought to evaluate the effects of a vaccinia virus expressing three costimulatory molecules, B7.1, ICAM-1, and LFA-3 (rV-TRICOM), in patients with metastatic melanoma. A standard dose escalation phase I clinical trial was performed. Thirteen patients were enrolled and 12 were available for follow-up. Local vaccination was feasible, with only low-grade injection site reactions associated with mild fatigue and myalgia reported. There was one occurrence of grade 1 vitiligo. Overall there was a 30.7% objective clinical response, with one patient achieving a complete response for more than 22 months. An inverse association was detected between anti-vaccinia antibody and anti-vaccinia T cell responses. Patients who failed to respond to vaccination but received high-dose interleukin-2 had a trend toward improved survival. Collectively, these results confirm the safety profile and feasibility of direct injection of vaccinia virus expressing multiple costimulatory molecules in patients with established tumors. Further clinical investigation is needed to better define the role of antigen, adjuvant cytokines, costimulation, and cross-presentation in the host immune response to local vaccination with vaccinia viruses expressing immunomodulatory molecules. PMID:16454657

Kaufman, Howard L; Cohen, Seth; Cheung, Ken; DeRaffele, Gail; Mitcham, Josephine; Moroziewicz, Dorota; Schlom, Jeffrey; Hesdorffer, Charles

2006-02-01

52

Interaction between Rabies Infection and Oral Administration of Vaccinia-Rabies Recombinant Virus to Foxes (Vulpes vulpes)  

Microsoft Academic Search

SUMMARY We have investigated the influence of anti-rabies vaccination on the onset of the disease as well as the delay of death in foxes previously infected with rabies virus. A live vaccinia recombinant virus expressing the rabies virus glycoprotein (VVTGgRAB) was used as vaccine. Foxes were divided into six experimental groups of four animals. On day 0, each fox was

B. M. Brochier; J. Blancou; M. F. A. Aubert; M. P. Kieny; P. Desmettre; P.-P. Pastoret

1989-01-01

53

Comparison of the susceptibility of the red fox ( Vulpes vulpes) to a vaccinia-rabies recombinant virus and to cowpox virus  

Microsoft Academic Search

Sylvatic rabies can be efficiently controlled by vaccination of foxes with a vaccinia-rabies recombinant virus. However, the risk of recombination between the engineered vaccine virus and other orthopoxviruses endemic in wildlife, such as cowpox virus, still needs to be investigated. In this study, foxes inoculated orally and intradermally with cowpox virus were found to be not very susceptible to cowpox

D. Boulanger; B. Brochier; A. Crouch; M. Bennett; R. M. Gaskell; D. Baxby; P.-P. Pastoret

1995-01-01

54

A Single Immunization With Modified Vaccinia Virus Ankara-Based Influenza Virus H7 Vaccine Affords Protection in the Influenza A(H7N9) Pneumonia Ferret Model.  

PubMed

Since the first reports in early 2013, >440 human cases of infection with avian influenza A(H7N9) have been reported including 122 fatalities. After the isolation of the first A(H7N9) viruses, the nucleotide sequences became publically available. Based on the coding sequence of the influenza virus A/Shanghai/2/2013 hemagglutinin gene, a codon-optimized gene was synthesized and cloned into a recombinant modified vaccinia virus Ankara (MVA). This MVA-H7-Sh2 viral vector was used to immunize ferrets and proved to be immunogenic, even after a single immunization. Subsequently, ferrets were challenged with influenza virus A/Anhui/1/2013 via the intratracheal route. Unprotected animals that were mock vaccinated or received empty vector developed interstitial pneumonia characterized by a marked alveolitis, accompanied by loss of appetite, weight loss, and heavy breathing. In contrast, animals vaccinated with MVA-H7-Sh2 were protected from severe disease. PMID:25246535

Kreijtz, Joost H C M; Wiersma, Lidewij C M; De Gruyter, Heidi L M; Vogelzang-van Trierum, Stella E; van Amerongen, Geert; Stittelaar, Koert J; Fouchier, Ron A M; Osterhaus, Albert D M E; Sutter, Gerd; Rimmelzwaan, Guus F

2015-03-01

55

Expression in recombinant vaccinia virus of the equine herpesvirus 1 gene encoding glycoprotein gp13 and protection of immunized animals.  

PubMed Central

The equine herpesvirus 1 (EHV-1) gene encoding glycoprotein 13 (gp13) was cloned into the hemagglutinin (HA) locus of vaccinia virus (Copenhagen strain). Expression of the gp13 gene was driven by the early/late vaccinia virus H6 promoter. Metabolically radiolabeled polypeptides of approximately 47 and 44 kilodaltons and 90 kilodaltons (glycosylated form) were precipitated with both polyclonal and gp13-specific monoclonal antibodies. Presentation of gp13 on the cytoplasmic membrane of cells infected with the recombinant gp13 vaccinia virus was demonstrated by immunofluorescence of unfixed cells. Inoculation of the recombinant gp13 vaccinia virus into guinea pigs induced neutralizing antibodies to both EHV-1 and vaccinia virus. Hamsters vaccinated with the recombinant gp13 vaccinia virus survived a lethal challenge with the hamster-adapted Kentucky strain of EHV-1. These results indicate that expression in vaccinia virus vectors of EHV-1 gp13, the glycoprotein homolog of herpes simplex virus gC-1 and gC-2, pseudorabies virus gIII, and the varicella-zoster virus gpV may provide useful vaccine candidates for equine herpesvirus infections. Images PMID:2550665

Guo, P X; Goebel, S; Davis, S; Perkus, M E; Languet, B; Desmettre, P; Allen, G; Paoletti, E

1989-01-01

56

Immunological Memory after Exposure to Variola Virus, Monkeypox Virus, and Vaccinia Virus  

PubMed Central

We compared cellular and humoral immunity to vaccinia virus (VV) in individuals exposed to 3 different orthopoxviruses: 154 individuals previously vaccinated with VV, 7 individuals with a history of monkeypox virus infection, and 8 individuals with a history of variola virus infection. Among individuals vaccinated >20 years prior, 9 (14%) of 66 individuals demonstrated VV-specific interferon (IFN)-? enzyme-linked immunospot (ELISPOT) assay responses; 21 (50%) of 42 had lymphoproliferative (LP) responses, and 29 (97%) of 30 had VV-specific neutralizing antibodies. One year after monkeypox virus infection, 6 of 7 individuals had IFN-? ELISPOT responses, all had VV-specific LP responses, and 3 of 7 had VV-specific neutralizing antibodies. Of 8 individuals with a history of variola virus infection, 1 had a VV-specific IFN-? ELISPOT response, 4 had LP responses against whole VV, 7 had LP responses against heat-denatured vaccinia antigen, and 7 had VV-specific neutralizing antibodies. Survivors of variola virus infection demonstrated VV-specific CD4 memory cell responses and neutralizing antibodies >40 years after infection. PMID:17357051

Sivapalasingam, Sumathi; Kennedy, Jeffrey S.; Borkowsky, William; Valentine, Fred; Zhan, Ming-Xia; Pazoles, Pamela; Paolino, Anna; Ennis, Francis A.; Steigbigel, Neal H.

2007-01-01

57

Safety and Tolerability of Conserved Region Vaccines Vectored by Plasmid DNA, Simian Adenovirus and Modified Vaccinia Virus Ankara Administered to Human Immunodeficiency Virus Type 1-Uninfected Adults in a Randomized, Single-Blind Phase I Trial  

PubMed Central

Trial Design HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee) adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported. Methods Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination. Results Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1) and predominantly transient (<48 hours). Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range) of 633 (231-1533) post-vaccination, which is of no safety concern. Conclusions These data demonstrate safety and good tolerability of the pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines and together with their high immunogenicity support their further development towards efficacy studies. Trial Registration ClinicalTrials.gov NCT01151319 PMID:25007091

Hayton, Emma-Jo; Rose, Annie; Ibrahimsa, Umar; Del Sorbo, Mariarosaria; Capone, Stefania; Crook, Alison; Black, Antony P.; Dorrell, Lucy; Hanke, Tomáš

2014-01-01

58

RATIOS OF VACCINIA VIRUS PARTICLES TO VIRUS INFECTIOUS UNITS  

PubMed Central

Total virus particle counts, infectivity titrations and the ratios between particles and infective units have been determined for vaccinia virus infected tissues. Growth curves of vaccinia in the chorioallantoic membrane are characterized by relatively low ratios from 1 to 4 days after inoculation and a marked rise in the ratio at more prolonged intervals. Ratio determinations of vaccinia virus passages in the egg, rabbit skin, and guinea pig skin have been made to study the phenomenon of adaptation in different hosts. The embryonated egg chorioallantoic membrane shows no variation in the ratio of particles to infectious units during passage and it is concluded that this host is completely susceptible to vaccinia. During adaptive passages on the skin of rabbits and guinea pigs relatively large amounts of non-infective virus appear as indicated by a rise in the particle-infectivity ratios. The extent of ratio increase appears related to the general resistance of the host to the virus. Finally, treatment of crude tissue extracts with sonic vibration is described as an aid in dispersing the virus particles for quantitative particle counts. PMID:14429524

Overman, John R.; Sharp, D. Gordon

1959-01-01

59

Vaccinia Virus Requires Glutamine but Not Glucose for Efficient Replication  

PubMed Central

ABSTRACT Viruses require host cell metabolism to provide the necessary energy and biosynthetic precursors for successful viral replication. Vaccinia virus (VACV) is a member of the Poxviridae family, and its use as a vaccine enabled the eradication of variola virus, the etiologic agent of smallpox. A global metabolic screen of VACV-infected primary human foreskin fibroblasts suggested that glutamine metabolism is altered during infection. Glutamine and glucose represent the two main carbon sources for mammalian cells. Depriving VACV-infected cells of exogenous glutamine led to a substantial decrease in infectious virus production, whereas starving infected cells of exogenous glucose had no significant impact on replication. Viral yield in glutamine-deprived cells or in cells treated with an inhibitor of glutaminolysis, the pathway of glutamine catabolism, could be rescued by the addition of multiple tricarboxylic acid (TCA) cycle intermediates. Thus, VACV infection induces a metabolic alteration to fully rely on glutamine to anaplerotically maintain the TCA cycle. VACV protein synthesis, but not viral transcription, was decreased in glutamine-deprived cells, which corresponded with a dramatic reduction in all VACV morphogenetic intermediates. This study reveals the unique carbon utilization program implemented during poxvirus infection and provides a potential metabolic pathway to target viral replication. IMPORTANCE Viruses are dependent on the metabolic machinery of the host cell to supply the energy and molecular building blocks needed for critical processes including genome replication, viral protein synthesis, and membrane production. This study investigates how vaccinia virus (VACV) infection alters global cellular metabolism, providing the first metabolomic analysis for a member of the poxvirus family. Unlike most viruses examined to date, VACV does not activate glycolysis, and exogenous glucose is not required for maximal virus production. Instead, VACV requires exogenous glutamine for efficient replication, and inhibition of glutamine metabolism effectively blocks VACV protein synthesis. This study defines a major metabolic perturbation essential for the replication of a poxvirus and may lead to the discovery of novel antiviral therapies based on metabolic inhibitors. PMID:24501408

Fontaine, Krystal A.; Camarda, Roman

2014-01-01

60

Recombinant vaccinia viruses expressing GP46/M-2 protect against Leishmania infection.  

PubMed Central

Leishmania is a genus of parasitic protozoa capable of causing a spectrum of human diseases. The GP46/M-2 membrane glycoprotein has been demonstrated in a murine model system to elicit a protective immune response against infection with Leishmania amazonensis; in highly susceptible BALB/c mice, immunization leads to significant protection against infection. In the present study, for induction of long-term immunological effects, two recombinant vaccinia viruses, derived from the wild type and attenuated variant 48-7 and expressing the GP46/M-2 protein, were constructed; to ensure safety, we used the attenuated vaccinia virus mutant (48-7) as a live vector. Susceptible BALB/c mice immunized with either GP46/M-2-recombinant vaccinia virus were significantly protected against infection with L. amazonensis; 45 to 76% of the animals were completely protected (sterile) against a challenge inoculum of 10(3) infective organisms. The protectively immunized animals demonstrated T- and B-cell-dependent immunological responses; both lymphokine responses as well as antibody responses and long-term memory are indicative of T-cell activation. This first report of the use of a recombinant vaccinia virus to induce protection against a Leishmania infection indicates that recombinant vaccinia viruses should be of value in the design of a safe and effective vaccine against this parasitic disease. Images PMID:8335366

McMahon-Pratt, D; Rodriguez, D; Rodriguez, J R; Zhang, Y; Manson, K; Bergman, C; Rivas, L; Rodriguez, J F; Lohman, K L; Ruddle, N H

1993-01-01

61

Oral vaccination of raccoons ( Procyon lotor) with genetically modified rabies virus vaccines  

Microsoft Academic Search

Oral vaccination is an important tool currently in use to control the spread of rabies in wildlife populations in various programs around the world. Oral rabies vaccination (ORV) of raccoons represents the largest targeted program to control wildlife rabies in the United States. Currently, the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG) is the only licensed oral rabies vaccine in the

Jesse D. Blanton; Joshua Self; Michael Niezgoda; Marie-Luise Faber; Bernhard Dietzschold; Charles Rupprecht

2007-01-01

62

Vaccinia Virus Recombinant Expressing Herpes Simplex Virus Type 1 Glycoprotein D Prevents Latent Herpes in Mice  

NASA Astrophysics Data System (ADS)

In humans, herpes simplex virus causes a primary infection and then often a latent ganglionic infection that persists for life. Because these latent infections can recur periodically, vaccines are needed that can protect against both primary and latent herpes simplex infections. Infectious vaccinia virus recombinants that contain the herpes simplex virus type 1 (HSV-1) glycoprotein D gene under control of defined early or late vaccinia virus promoters were constructed. Tissue culture cells infected with these recombinant viruses synthesized a glycosylated protein that had the same mass (60,000 daltons) as the glycoprotein D produced by HSV-1. Immunization of mice with one of these recombinant viruses by intradermal, subcutaneous, or intraperitoneal routes resulted in the production of antibodies that neutralized HSV-1 and protected the mice against subsequent lethal challenge with HSV-1 or HSV-2. Immunization with the recombinant virus also protected the majority of the mice against the development of a latent HSV-1 infection of the trigeminal ganglia. This is the first demonstration that a genetically engineered vaccine can prevent the development of latency.

Cremer, Kenneth J.; Mackett, Michael; Wohlenberg, Charles; Notkins, Abner Louis; Moss, Bernard

1985-05-01

63

Combination therapy of vaccinia virus infection with human anti-H3 and anti-B5 monoclonal antibodies in a small animal model  

PubMed Central

Vaccinia virus possesses two immunologically distinct virion forms in vivo—mature virion (MV, IMV) and extracellular virion (EV, EEV). Here we show that combination therapy with two fully human mAbs against an immunodominant MV antigen, H3 (H3L), and an EV antigen, B5 (B5R), provides significantly better protection against vaccinia infection in a small animal model of progressive vaccinia (SCID mice infected with VACVNYCBOH vaccine strain) than a single human monoclonal or human vaccinia immune globulin (VIG), the currently licensed therapeutic for side effects of smallpox vaccination. PMID:20587859

McCausland, Megan M.; Benhnia, Mohammed Rafii-El-Idrissi; Crickard, Lindsay; Laudenslager, John; Granger, Steven W.; Tahara, Tomoyuki; Kubo, Ralph; Koriazova, Lilia; Kato, Shinichiro; Crotty, Shane

2010-01-01

64

Methodology for the Efficient Generation of Fluorescently Tagged Vaccinia Virus Proteins  

PubMed Central

Tagging of viral proteins with fluorescent proteins has proven an indispensable approach to furthering our understanding of virus-host interactions. Vaccinia virus (VACV), the live vaccine used in the eradication of smallpox, is particularly amenable to fluorescent live-cell microscopy owing to its large virion size and the ease with which it can be engineered at the genome level. We report here an optimized protocol for generating recombinant viruses. The minimal requirements for targeted homologous recombination during vaccinia replication were determined, which allows the simplification of construct generation. This enabled the alliance of transient dominant selection (TDS) with a fluorescent reporter and metabolic selection to provide a rapid and modular approach to fluorescently label viral proteins. By streamlining the generation of fluorescent recombinant viruses, we are able to facilitate downstream applications such as advanced imaging analysis of many aspects of the virus-host interplay that occurs during virus replication. PMID:24473272

Lynn, Helena; Yamamoto, Yui; Horsington, Jacquelyn; Newsome, Timothy P.

2014-01-01

65

Nonreplicating Vaccinia Virus Vectors Expressing the H5 Influenza Virus Hemagglutinin Produced in Modified Vero Cells Induce Robust Protection?  

PubMed Central

The timely development of safe and effective vaccines against avian influenza virus of the H5N1 subtype will be of the utmost importance in the event of a pandemic. Our aim was first to develop a safe live vaccine which induces both humoral and cell-mediated immune responses against human H5N1 influenza viruses and second, since the supply of embryonated eggs for traditional influenza vaccine production may be endangered in a pandemic, an egg-independent production procedure based on a permanent cell line. In the present article, the generation of a complementing Vero cell line suitable for the production of safe poxviral vaccines is described. This cell line was used to produce a replication-deficient vaccinia virus vector H5N1 live vaccine, dVV-HA5, expressing the hemagglutinin of a virulent clade 1 H5N1 strain. This experimental vaccine was compared with a formalin-inactivated whole-virus vaccine based on the same clade and with different replicating poxvirus-vectored vaccines. Mice were immunized to assess protective immunity after high-dose challenge with the highly virulent A/Vietnam/1203/2004(H5N1) strain. A single dose of the defective live vaccine induced complete protection from lethal homologous virus challenge and also full cross-protection against clade 0 and 2 challenge viruses. Neutralizing antibody levels were comparable to those induced by the inactivated vaccine. Unlike the whole-virus vaccine, the dVV-HA5 vaccine induced substantial amounts of gamma interferon-secreting CD8 T cells. Thus, the nonreplicating recombinant vaccinia virus vectors are promising vaccine candidates that induce a broad immune response and can be produced in an egg-independent and adjuvant-independent manner in a proven vector system. PMID:19279103

Mayrhofer, Josef; Coulibaly, Sogue; Hessel, Annett; Holzer, Georg W.; Schwendinger, Michael; Brühl, Peter; Gerencer, Marijan; Crowe, Brian A.; Shuo, Shen; Hong, Wanjing; Tan, Yee Joo; Dietrich, Barbara; Sabarth, Nicolas; Savidis-Dacho, Helga; Kistner, Otfried; Barrett, P. Noel; Falkner, Falko G.

2009-01-01

66

Expression of CCL20 and Granulocyte-Macrophage Colony-Stimulating Factor, but Not Flt3-L, from Modified Vaccinia Virus Ankara Enhances Antiviral Cellular and Humoral Immune Responses  

Microsoft Academic Search

While modified vaccinia virus Ankara (MVA) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases, its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts. In light of recent data demonstrating that vaccinia viruses, including MVA, preferentially infect antigen-presenting cells (APCs) that play crucial roles in

R. Chavan; K. A. Marfatia; I. C. An; D. A. Garber; M. B. Feinberg

2006-01-01

67

Development of a highly efficacious vaccinia-based dual vaccine against smallpox and anthrax, two important bioterror entities.  

PubMed

Bioterrorism poses a daunting challenge to global security and public health in the 21st century. Variola major virus, the etiological agent of smallpox, and Bacillus anthracis, the bacterial pathogen responsible for anthrax, remain at the apex of potential pathogens that could be used in a bioterror attack to inflict mass casualties. Although licensed vaccines are available for both smallpox and anthrax, because of inadequacies associated with each of these vaccines, serious concerns remain as to the deployability of these vaccines, especially in the aftermath of a bioterror attack involving these pathogens. We have developed a single vaccine (Wyeth/IL-15/PA) using the licensed Wyeth smallpox vaccine strain that is efficacious against both smallpox and anthrax due to the integration of immune-enhancing cytokine IL-15 and the protective antigen (PA) of B. anthracis into the Wyeth vaccinia virus. Integration of IL-15 renders Wyeth vaccinia avirulent in immunodeficient mice and enhances anti-vaccinia immune responses. Wyeth/IL-15/PA conferred sterile protection against a lethal challenge of B. anthracis Ames strain spores in rabbits. A single dose of Wyeth/IL-15/PA protected 33% of the vaccinated A/J mice against a lethal spore challenge 72 h later whereas a single dose of licensed anthrax vaccine protected only 10%. Our dual vaccine Wyeth/IL-15/PA remedies the inadequacies associated with the licensed vaccines, and the inherent ability of Wyeth vaccinia virus to be lyophilized without loss of potency makes it cold-chain independent, thus simplifying the logistics of storage, stockpiling, and field delivery in the event of a bioterror attack involving smallpox or anthrax. PMID:20921397

Merkel, Tod J; Perera, Pin-Yu; Kelly, Vanessa K; Verma, Anita; Llewellyn, Zara N; Waldmann, Thomas A; Mosca, Joseph D; Perera, Liyanage P

2010-10-19

68

Use of a Recombinant Vaccinia Virus Expressing Interferon Gamma for Post-Exposure Protection against Vaccinia and Ectromelia Viruses  

PubMed Central

Post-exposure vaccination with vaccinia virus (VACV) has been suggested to be effective in minimizing death if administered within four days of smallpox exposure. While there is anecdotal evidence for efficacy of post-exposure vaccination this has not been definitively studied in humans. In this study, we analyzed post-exposure prophylaxis using several attenuated recombinant VACV in a mouse model. A recombinant VACV expressing murine interferon gamma (IFN-?) was most effective for post-exposure protection of mice infected with VACV and ectromelia virus (ECTV). Untreated animals infected with VACV exhibited severe weight loss and morbidity leading to 100% mortality by 8 to 10 days post-infection. Animals treated one day post-infection had milder symptoms, decreased weight loss and morbidity, and 100% survival. Treatment on days 2 or 3 post-infection resulted in 40% and 20% survival, respectively. Similar results were seen in ECTV-infected mice. Despite the differences in survival rates in the VACV model, the viral load was similar in both treated and untreated mice while treated mice displayed a high level of IFN-? in the serum. These results suggest that protection provided by IFN-? expressed by VACV may be mediated by its immunoregulatory activities rather than its antiviral effects. These results highlight the importance of IFN-? as a modulator of the immune response for post-exposure prophylaxis and could be used potentially as another post-exposure prophylaxis tool to prevent morbidity following infection with smallpox and other orthopoxviruses. PMID:24147092

Holechek, Susan A.; Denzler, Karen L.; Heck, Michael C.; Schriewer, Jill; Buller, R. Mark; Legrand, Fatema A.; Verardi, Paulo H.; Jones, Leslie A.; Yilma, Tilahun; Jacobs, Bertram L.

2013-01-01

69

Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice  

Microsoft Academic Search

The spike protein (S), a membrane component of severe acute respiratory syndrome coronavirus (SARS-CoV) is anticipated to be an important component of candidate vaccines. We constructed recombinant forms of the highly attenuated modified vaccinia virus Ankara (MVA) containing the gene encoding full-length SARS-CoV S with and without a C-terminal epitope tag called MVA\\/S-HA and MVA\\/S, respectively. Cells infected with MVA\\/Sor

Himani Bisht; Anjeanette Roberts; Leatrice Vogel; Alexander Bukreyev; Peter L. Collins; Brian R. Murphy; Kanta Subbarao; Bernard Moss

2004-01-01

70

Vaccinia Virus Induces Programmed Necrosis in Ovarian Cancer Cells  

PubMed Central

The mechanisms by which oncolytic vaccinia virus induces tumor cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalization and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular adenosine triphosphate, altered mitochondrial metabolism, and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a receptor interacting protein (RIP1)/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-?, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events. PMID:23985697

Whilding, Lynsey M; Archibald, Kyra M; Kulbe, Hagen; Balkwill, Frances R; Öberg, Daniel; McNeish, Iain A

2013-01-01

71

Disabling complement regulatory activities of vaccinia virus complement control protein reduces vaccinia virus pathogenicity  

PubMed Central

Poxviruses encode a repertoire of immunomodulatory proteins to thwart the host immune system. One among this array is a homolog of the host complement regulatory proteins that is conserved in various poxviruses including vaccinia (VACV) and variola. The vaccinia virus complement control protein (VCP), which inhibits complement by decaying the classical pathway C3-convertase (decay-accelerating activity), and by supporting inactivation of C3b and C4b by serine protease factor I (cofactor activity), was shown to play a role in viral pathogenesis. However, the role its individual complement regulatory activities impart in pathogenesis, have not yet been elucidated. Here, we have generated monoclonal antibodies (mAbs) that block the VCP functions and utilized them to evaluate the relative contribution of complement regulatory activities of VCP in viral pathogenesis by employing a rabbit intradermal model for VACV infection. Targeting VCP by mAbs that inhibited the decay-accelerating activity as well as cofactor activity of VCP or primarily the cofactor activity of VCP, by injecting them at the site of infection, significantly reduced VACV lesion size. This reduction however was not pronounced when VCP was targeted by a mAb that inhibited only the decay-accelerating activity. Further, the reduction in lesion size by mAbs was reversed when host complement was depleted by injecting cobra venom factor. Thus, our results suggest that targeting VCP by antibodies reduces VACV pathogenicity and that principally the cofactor activity of VCP appears to contribute to the virulence. PMID:21803094

Bernet, John; Ahmad, Muzammil; Mullick, Jayati; Panse, Yogesh; Singh, Akhilesh K.; Parab, Pradeep B.; Sahu, Arvind

2011-01-01

72

Potential effect of prior raccoonpox virus infection in raccoons on vaccinia-based rabies immunization  

PubMed Central

Background The USDA, Wildlife Services cooperative oral rabies vaccination (ORV) program uses a live vaccinia virus-vectored (genus Orthopoxvirus) vaccine, Raboral V-RG® (V-RG), to vaccinate specific wildlife species against rabies virus in several regions of the U.S. Several naturally occurring orthopoxviruses have been found in North America, including one isolated from asymptomatic raccoons (Procyon lotor). The effect of naturally occurring antibodies to orthopoxviruses on successful V-RG vaccination in raccoons is the focus of this study. Results Overall, raccoons pre-immunized (n = 10) with a recombinant raccoonpox virus vaccine (RCN-F1) responded to vaccination with V-RG with lower rabies virus neutralizing antibody (VNA) titers than those which were not pre-immunized (n = 10) and some failed to seroconvert for rabies VNA to detectable levels. Conclusion These results suggest that the success of some ORV campaigns may be hindered where raccoonpox virus or possibly other orthopoxvirus antibodies are common in wildlife species targeted for ORV. If these areas are identified, different vaccination strategies may be warranted. PMID:18834520

Root, J Jeffrey; McLean, Robert G; Slate, Dennis; MacCarthy, Kathleen A; Osorio, Jorge E

2008-01-01

73

Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8  

Microsoft Academic Search

A highly attenuated LC16m8 (m8) smallpox vaccine has been licensed in Japan because of its extremely low neurovirulence profile, which is comparable to that of replication incompetent strains of vaccinia virus. From 1973 to 1975, m8 was administrated to >100,000 infants where it induced levels of immunity similar to that of the originating Lister strain, without any serious side effects.

Minoru Kidokoro; Masato Tashiro; Hisatoshi Shida

2005-01-01

74

GMCSF-armed vaccinia virus induces an antitumor immune response.  

PubMed

Oncolytic Western Reserve strain vaccinia virus selective for epidermal growth factor receptor pathway mutations and tumor-associated hypermetabolism was armed with human granulocyte-macrophage colony-stimulating factor (GMCSF) and a tdTomato fluorophore. As the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we used immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semipermissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene-carrying viruses was similar to unarmed virus. The hGMCSF-encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific antitumor immunity was also shown by ex vivo co-culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF-virus-treated tumors. These findings help clarify the mechanism of action of GMCSF-armed vaccinia viruses undergoing clinical trials. PMID:25042001

Parviainen, Suvi; Ahonen, Marko; Diaconu, Iulia; Kipar, Anja; Siurala, Mikko; Vähä-Koskela, Markus; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli

2015-03-01

75

Hydroxyurea-resistant vaccinia virus: overproduction of ribonucleotide reductase  

SciTech Connect

Repeated passage of vaccinia virus in increasing concentrations of hydroxyurea followed by plaque purification resulted in the isolation of variants capable of growth in 5 mM hydroxyurea, a drug concentration which inhibited the reproduction of wild-type vaccinia virus 1000-fold. Analyses of viral protein synthesis by using (/sup 35/S)methionine pulse-labeling at intervals throughout the infection cycle revealed that all isolates overproduced a 34,000-molecular-weight (MW) early polypeptide. Measurement of ribonucleoside-diphosphate reductase activity after infection indicated that 4- to 10-fold more activity was induced by hydroxyurea-resistant viruses than by the wild-type virus. A two-step partial purification resulted in a substantial enrichment for the 34,000-MW protein from extracts of wild-type and hydroxyurea-resistant-virus-infected, but not mock-infected, cells. In the presence of the drug, the isolates incorporated (/sup 3/H)thymidine into DNA earlier and a rate substantially greater than that of the wild type, although the onset of DNA synthesis was delayed in both cases. The drug resistance trait was markedly unstable in all isolates. In the absence of selective pressure, plaque-purified isolated readily segregated progeny that displayed a wide range of resistance phenotypes. The results of this study indicate that vaccinia virus encodes a subunit of ribonucleotide reductase which is 34,000-MW early protein whose overproduction confers hydroxyurea resistance on reproducing viruses.

Slabaugh, M.B.; Mathews, C.K.

1986-11-01

76

Comparison of the replication characteristics of vaccinia virus strains Guang 9 and Tian Tan in vivo and in vitro.  

PubMed

Vaccinia virus is widely used as a vector in the development of recombinant vaccines. Vaccinia virus strain Guang 9 (VG9), which was derived from vaccinia virus strain Tian Tan (VTT) by successive plaque-cloning purification, was more attenuated than VTT. In this study, the host cell range and the growth and replication of VG9 were compared with those of VTT. The results showed that both VG9 and VTT could infect permissive cells (Vero, TK-143 and CEF) and semipermissive cells PK (15) and induced a visible cytopathic effect (CPE). Both strains could infect nonpermissive CHO-K1 cells but neither was able to reproduce. The replicative ability of VG9 was a little lower than that of VTT. Additionally, recombinant vaccinia viruses containing a firefly luciferase gene (VG9-L and VTT-L) were constructed, and their expression in vitro and replication and spread in vivo were compared. The expression ability of VG9-L was lower than that of VTT-L. Whole-animal imaging data indicated that VG9-L could reproduce quickly and express the exogenous protein at the site of inoculation, regardless of whether the intramuscular, intracutaneous, subcutaneous or celiac inoculation route was used. VG9-L was better in its ability to express a foreign protein than VTT-L, but the time during which expression occurred was shorter. There was no dissemination of virus in mice inoculated with either strain. In summary, this study demonstrates the possibility of using VG9 for the production of smallpox vaccines or the construction of recombinant vaccinia virus vaccines. PMID:24838849

Zhu, Rong; Liu, Qiang; Huang, Weijin; Yu, Yongxin; Wang, Youchun

2014-10-01

77

Smallpox vaccine–induced antibodies are necessary and sufficient for protection against monkeypox virus  

Microsoft Academic Search

Vaccination with live vaccinia virus affords long-lasting protection against variola virus, the agent of smallpox. Its mode of protection in humans, however, has not been clearly defined. Here we report that vaccinia-specific B-cell responses are essential for protection of macaques from monkeypox virus, a variola virus ortholog. Antibody-mediated depletion of B cells, but not CD4+ or CD8+ T cells, abrogated

Yvette Edghill-Smith; Hana Golding; Jody Manischewitz; Lisa R King; Dorothy Scott; Mike Bray; Aysegul Nalca; Jay W Hooper; Chris A Whitehouse; Joern E Schmitz; Keith A Reimann; Genoveffa Franchini

2005-01-01

78

Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection  

Microsoft Academic Search

There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of

Koert J. Stittelaar; Johan Neyts; Lieve Naesens; Geert van Amerongen; Rob F. van Lavieren; Antonin Holý; Erik de Clercq; Edwin Fries; Chantal Maas; Paul G. H. Mulder; Ben A. M. van der Zeijst; Albert D. M. E. Osterhaus

2006-01-01

79

A pilot study comparing the development of EIAV Env-specific antibodies induced by DNA/recombinant vaccinia-vectored vaccines and an attenuated Chinese EIAV vaccine.  

PubMed

Data from successful attenuated lentiviral vaccine studies indicate that fully mature Env-specific antibodies characterized by high titer, high avidity, and the predominant recognition of conformational epitopes are associated with protective efficacy. Although vaccination with a DNA prime/recombinant vaccinia-vectored vaccine boost strategy has been found to be effective in some trials with non-human primate/simian/human immunodeficiency virus (SHIV) models, it remains unclear whether this vaccination strategy could elicit mature equine infectious anemia virus (EIAV) Env-specific antibodies, thus protecting vaccinated horses against EIAV infection. Therefore, in this pilot study we vaccinated horses using a strategy based on DNA prime/recombinant Tiantan vaccinia (rTTV)-vectored vaccines encoding EIAV env and gag genes, and observed the development of Env-specific antibodies, neutralizing antibodies, and p26-specific antibodies. Vaccination with DNA induced low titer, low avidity, and the predominant recognition of linear epitopes by Env-specific antibodies, which was enhanced by boosting vaccinations with rTTV vaccines. However, the maturation levels of Env-specific antibodies induced by the DNA/rTTV vaccines were significantly lower than those induced by the attenuated vaccine EIAV(FDDV). Additionally, DNA/rTTV vaccines did not elicit broadly neutralizing antibodies. After challenge with a virulent EIAV strain, all of the vaccinees and control horses died from EIAV disease. These data indicate that the regimen of DNA prime/rTTV vaccine boost did not induce mature Env-specific antibodies, which might have contributed to immune protection failure. PMID:23171359

Meng, Qinglai; Lin, Yuezhi; Ma, Jian; Ma, Yan; Zhao, Liping; Li, Shenwei; Yang, Kai; Zhou, Jianhua; Shen, Rongxian; Zhang, Xiaoyan; Shao, Yiming

2012-12-01

80

Attenuated vaccinia virus-circumsporozoite protein recombinants confer protection against rodent malaria.  

PubMed Central

NYVAC-based vaccinia virus recombinants expressing the circumsporozoite protein (CSP) were evaluated in the Plasmodium berghei rodent malaria model system. Immunization of mice with a NYVAC-based CSP recombinant elicited a high level of protection (60 to 100%). Protection did not correlate with CS repeat-specific antibody responses and was abrogated by in vivo CD8+ T-cell depletion. Protection was not enhanced by modification of the subcellular localization of CSP. These results suggest the potential of poxvirus-based vectors for the development of vaccine candidates for human malaria. PMID:8613376

Lanar, D E; Tine, J A; de Taisne, C; Seguin, M C; Cox, W I; Winslow, J P; Ware, L A; Kauffman, E B; Gordon, D; Ballou, W R; Paoletti, E; Sadoff, J C

1996-01-01

81

Evaluation of modified vaccinia virus Ankara expressing VP2 protein of infectious bursal disease virus as an immunogen in chickens  

PubMed Central

A recombinant modified vaccinia Ankara (MVA) virus expressing mature viral protein 2 (VP2) of the infectious bursal disease virus (IBDV) was constructed to develop MVA-based vaccines for poultry. We demonstrated that this recombinant virus was able to induce a specific immune response by observing the production of anti-IBDV-seroneutralizing antibodies in specific pathogen-free chickens. Besides, as the epitopes of VP2 responsible to induce IBDV-neutralizing antibodies are discontinuous, our results suggest that VP2 protein expressed from MVA-VP2 maintained the correct conformational structure. To our knowledge, this is the first report on the usefulness of MVA-based vectors for developing recombinant vaccines for poultry. PMID:22705743

Zajac, María Paula Del Médico; Taboga, Oscar Alberto; Calamante, Gabriela

2012-01-01

82

Murine Alveolar Macrophages Limit Replication of Vaccinia Virus  

PubMed Central

Because of concerns about zoonotic transmission of monkeypox to humans and the bioterrorism threat posed by Orthopoxviruses, there is renewed interest in probing cellular and molecular mechanisms of host defense to these pathogens. In particular, it is essential to understand viral-host interactions in the respiratory tract, which is the route of infection for smallpox and a likely route of transmission for monkeypox. In this study, we analyze functions of alveolar macrophages in poxvirus infection, using a recombinant vaccinia virus expressing firefly luciferase to quantify infection in mice and cell culture. Depletion of alveolar macrophages with liposomal clodronate worsens the overall severity of infection in mice, including greater replication and systemic dissemination of vaccinia as determined by bioluminescence imaging. Absence of alveolar macrophages increases total numbers of granulocytes and granulocytes/monocyte progenitor cells in the lung during vaccinia infection, indicating that protective effects of alveolar macrophages may be mediated in part by reducing the host inflammation. Alveolar macrophages also limit vaccinia infection in respiratory epithelium, as shown by a co-culture model of cell lines derived from alveolar macrophages and lung epithelium. Collectively, these data demonstrate that alveolar macrophages are key determinants of host defense against local and systemic infection with poxviruses. PMID:17331554

Rivera, Rachel; Hutchens, Martha; Luker, Kathryn E.; Sonstein, Joanne; Curtis, Jeffrey L.; Luker, Gary D.

2007-01-01

83

Chasing Jenner's Vaccine: Revisiting Cowpox Virus Classification  

PubMed Central

Cowpox virus (CPXV) is described as the source of the first vaccine used to prevent the onset and spread of an infectious disease. It is one of the earliest described members of the genus Orthopoxvirus, which includes the viruses that cause smallpox and monkeypox in humans. Both the historic and current literature describe “cowpox” as a disease with a single etiologic agent. Genotypic data presented herein indicate that CPXV is not a single species, but a composite of several (up to 5) species that can infect cows, humans, and other animals. The practice of naming agents after the host in which the resultant disease manifests obfuscates the true taxonomic relationships of “cowpox” isolates. These data support the elevation of as many as four new species within the traditional “cowpox” group and suggest that both wild and modern vaccine strains of Vaccinia virus are most closely related to CPXV of continental Europe rather than the United Kingdom, the homeland of the vaccine. PMID:21858000

Carroll, Darin S.; Emerson, Ginny L.; Li, Yu; Sammons, Scott; Olson, Victoria; Frace, Michael; Nakazawa, Yoshinori; Czerny, Claus Peter; Tryland, Morten; Kolodziejek, Jolanta; Nowotny, Norbert; Olsen-Rasmussen, Melissa; Khristova, Marina; Govil, Dhwani; Karem, Kevin; Damon, Inger K.; Meyer, Hermann

2011-01-01

84

IL-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires CD4+ T cells for heterosubtypic protection  

PubMed Central

Current influenza vaccines are ineffective against novel viruses and the source or the strain of the next outbreak of influenza is unpredictable; therefore, establishing universal immunity by vaccination to limit the impact of influenza remains a high priority. To meet this challenge, a novel vaccine has been developed using the immunogenic live vaccinia virus as a vaccine vector, expressing multiple H5N1 viral proteins (HA, NA, M1, M2, and NP) together with IL-15 as a molecular adjuvant. Previously, this vaccine demonstrated robust sterile cross-clade protection in mice against H5 influenza viruses, and herein its use has been extended to mediate heterosubtypic immunity toward viruses from both group 1 and 2 HA lineages. The vaccine protected mice against lethal challenge by increasing survival and significantly reducing lung viral loads against the most recent human H7N9, seasonal H3N2, pandemic-2009 H1N1, and highly pathogenic H7N7 influenza A viruses. Influenza-specific antibodies elicited by the vaccine failed to neutralize heterologous viruses and were unable to confer protection by passive transfer. Importantly, heterologous influenza-specific CD4+ and CD8+ T-cell responses that were elicited by the vaccine were effectively recalled and amplified following viral challenge in the lungs and periphery. Selective depletion of T-cell subsets in the immunized mice revealed an important role for CD4+ T cells in heterosubtypic protection, despite low sequence conservation among known MHC-II restricted epitopes across different influenza viruses. This study illustrates the potential utility of our multivalent Wyeth/IL-15/5Flu as a universal influenza vaccine with a correlate of protective immunity that is independent of neutralizing antibodies. PMID:24706798

Valkenburg, Sophie A.; Li, Olive T. W.; Mak, Polly W. Y.; Mok, Chris K. P.; Nicholls, John M.; Guan, Yi; Waldmann, Thomas A.; Peiris, J. S. Malik; Perera, Liyanage P.; Poon, Leo L. M.

2014-01-01

85

[Expression of the glow worm luciferase gene in mammalian cells using vectors based on vaccinia viruses].  

PubMed

The transient expression of the two reporter genes, the genes for luciferase and bacterial beta-galactosidase, were used for comparative estimation of vaccinia viral promoters and for characterizing of the constructed plasmids. The recombinant clones of vaccinia virus expressing simultaneously and with high efficiency the luciferase and beta-galactosidase were used for studying the reproduction of vaccinia virus in mammalian cells. The advantages of the luciferase gene in using it as a reporter gene are discussed. PMID:1903177

Krauzova, V I; Kopylova-Sviridova, T N; Timiriasova, T M; Fodor, I I

1991-02-01

86

killed-virus influenza vaccine Polio vaccine  

E-print Network

killed-virus influenza vaccine Polio vaccine FluMist Thomas Francis, Jr. National Institutes of Health live-virus influenza vaccine Hunein Maassab Jonas Salk Type-A virus trivalent cold that Maassab's innovative, trivalent, cold- adapted influenza vaccine, FluMist, which uses live but weakened

Shyy, Wei

87

Marker gene swapping facilitates recombinant Modified Vaccinia Virus Ankara production by host-range selection.  

PubMed

Modified Vaccinia Virus Ankara (MVA) is employed widely as an experimental and human vaccine vector for its lack of replication in mammalian cells and high expression of heterologous genes. Recombinant MVA technology can be improved greatly by combining transient host-range selection (based on the restoration in MVA of the deleted vaccinia gene K1L) with the differential expression of fluorescent proteins. Recombinant virus results from swapping a red protein gene (in the acceptor virus) with a cassette of the transfer plasmid comprising the transgene and the green marker K1Lgfp (a chimeric gene comprising K1L and EGFP). Recombinant selection is performed in the selective host RK13. Finally, in the non-selective host BHK-21, a single crossover between identical flanking regions excises the marker gene. The three types of viruses involved (red parental, green intermediate and colourless final recombinant) are visualized differentially by fluorescence microscopy or fluoro-imaging of terminal dilution microcultures, leading to a straightforward and efficient purification protocol. This method (Red-to-Green gene swapping) reduces greatly the time needed to obtain marker-free recombinant MVA and increases the reliability of the construction process. PMID:19038289

Di Lullo, Giulia; Soprana, Elisa; Panigada, Maddalena; Palini, Alessio; Erfle, Volker; Staib, Caroline; Sutter, Gerd; Siccardi, Antonio G

2009-03-01

88

Field use of a vaccinia-rabies recombinant vaccine for the control of sylvatic rabies in Europe and North America.  

PubMed

During recent years, most research on the control of sylvatic rabies has concentrated on developing methods of oral vaccination of wild rabies vectors. To improve both the safety and the stability of the vaccine used, a recombinant vaccinia virus, which expresses the immunising glycoprotein of rabies virus (VRG), has been developed and tested extensively in the laboratory as well as in the field. From 1989 to 1995, approximately 8.5 million VRG vaccine doses were dispersed in Western Europe to vaccinate red foxes (Vulpes vulpes), and in the United States of America (USA) to vaccinate raccoons (Procyon lotor) and coyotes (Canis latrans). In Europe, the use of VRG has led to the elimination of sylvatic rabies from large areas of land, which have consequently been freed from the need for vaccination. Nevertheless, despite very good examples of cross-border cooperation, reinfections have occurred in some regions, due to the difficulty of co-ordinating vaccination plans among neighbouring countries. In the USA, preliminary data from field trails indicate a significant reduction in the incidence of rabies in vaccinated areas. PMID:9025144

Brochier, B; Aubert, M F; Pastoret, P P; Masson, E; Schon, J; Lombard, M; Chappuis, G; Languet, B; Desmettre, P

1996-09-01

89

Resolution of poxvirus telomeres: processing of vaccinia virus concatemer junctions by conservative strand exchange.  

PubMed Central

The replication of vaccinia virus proceeds through concatemeric intermediates which are resolved into unit-length DNA. In vaccinia virus-infected cells, plasmids containing the vaccinia virus DNA junction fragment that connects concatemers are resolved into linear minichromosomes of vector DNA flanked by hairpin loops. Resolution requires two copies of a specific nucleotide sequence conserved among poxviruses and found proximal to the hairpin loop. This study demonstrates that orientation of each sequence with respect to the other as well as to the axis of symmetry is critical for resolution, the processing of plasmids containing heterologous pairs of resolution sites is influenced by mismatched nucleotides between the sites, and the vaccinia virus hairpin in the linear minichromosome is a heteroduplex composed of DNA from each strand of the concatemer junction. A model incorporating site-specific recombination and orientated branch migration is proposed to account for resolution of the vaccinia virus concatemer junction. Images PMID:2352329

Merchlinsky, M

1990-01-01

90

Co-expressing GP5 and M proteins under different promoters in recombinant modified vaccinia virus ankara (rMVA)-based vaccine vector enhanced the humoral and cellular immune responses of porcine reproductive and respiratory syndrome virus (PRRSV)  

Microsoft Academic Search

The porcine reproductive and respiratory syndrome virus (PRRSV) has three major structural proteins which designated as GP5,\\u000a M, and N. Protein GP5 and M have been considered very important to arouse the humoral and cellular immune responses against\\u000a PRRSV infection and proposed to be the excellent candidate proteins in the design of PRRS bioengineering vaccine. There were\\u000a some attempts on

Qisheng Zheng; Desheng Chen; Peng Li; Zhixiang Bi; Ruibing Cao; Bin Zhou; Puyan Chen

2007-01-01

91

Casein kinase 2 regulates vaccinia virus actin tail formation.  

PubMed

Casein kinase 2 (CK2) is a pleiotropic serine/threonine kinase that regulates numerous cellular processes and is essential to the infectious cycle of several viruses. Here we investigated the potential role of CK2 in vaccinia virus (VACV) infection. We used the CK2 inhibitor TBB and found that CK2 inactivation impaired VACV dissemination and actin tail formation. We used RNAi and confirmed that CK2 depletion impaired VACV actin tail formation. Furthermore, we designed a recombinant virus that allowed us to specifically detect cell-associated enveloped viruses (CEVs) at the plasma membrane and demonstrated that CK2 inactivation does not affect CEV formation. Finally, we showed that CK2 depletion impaired the recruitment of Src to CEVs. We discuss the possibility that CK2 may stimulate the A36-dependent recruitment of Src through A36 phosphorylation. PMID:22209233

Alvarez, Diego E; Agaisse, Hervé

2012-02-20

92

Prime-Boost Immunization Schedules Based on Influenza Virus and Vaccinia Virus Vectors Potentiate Cellular Immune Responses against Human Immunodeficiency Virus Env Protein Systemically and in the Genitorectal Draining Lymph Nodes  

Microsoft Academic Search

Vaccines that elicit systemic and mucosal immune responses should be the choice to control human immunodeficiency virus (HIV) infections. We have previously shown that prime-boost immunizations with influenza virus Env and vaccinia virus (VV) WR Env recombinants induced an enhanced systemic CD8 T-cell response against HIV-1 Env antigen. In this report, we analyzed in BALB\\/c mice after priming with influenza

M. Magdalena Gherardi; JoseLuis Najera; Eva Perez-Jimenez; Susana Guerra; A. Garcia-Sastre; Mariano Esteban

2003-01-01

93

Efficacy and safety of a modified vaccinia Ankara (MVA) vectored plague vaccine in mice  

PubMed Central

The efficacy and safety of plague vaccines based on the modified vaccinia Ankara (MVA) viral vector was evaluated. MVA recombinants were constructed expressing Yersinia pestis antigens under the translational control of the encephalomyocarditis virus (EMCV) internal ribosomal entry site (IRES) and/or fused to the tissue plasminogen activator (tPA) secretory signal. A MVA/Y. pestis recombinant that expressed a truncated version of the low-calcium response V antigen (MVA/IRES/tPA/V307), conferred significant protection (87.5%–100%) against intranasal or intraperitoneal challenge with CO92 (encapsulated) or Java 9 (non-encapsulated) strains of Y pestis, respectively. In contrast, a MVA/Y. pestis recombinant that expressed the full-length V antigen provided only 37.5% protection against challenge with CO92 or Java 9 strains, respectively. Interestingly, a MVA/Y. pestis recombinant that expressed the capsular protein (F1) did not elicit significant antibody titers but still conferred 50% and 25% protection against CO92 or Java 9 challenge, respectively. The MVA/Y. pestis recombinant viruses did not demonstrate any mortality or morbidity in SCID mice. Based on their safety and efficacy in mice, these MVA/Y. pestis recombinants are candidates for further development as biodefense and public health vaccines. PMID:20638759

Brewoo, Joseph N.; Powell, Tim D.; Stinchcomb, Dan T.; Osorio, Jorge E.

2010-01-01

94

Determinants of vaccinia virus early gene transcription termination.  

PubMed

Vaccinia virus early gene transcription requires the vaccinia termination factor, VTF, nucleoside triphosphate phosphohydrolase I, NPH I, ATP, the virion RNA polymerase, and the motif, UUUUUNU, in the nascent RNA, found within 30 to 50 bases from the poly A addition site, in vivo. In this study, the relationships among the vaccinia early gene transcription termination efficiency, termination motif specificity, and the elongation rate were investigated. A low transcription elongation rate maximizes termination efficiency and minimizes specificity for the UUUUUNU motif. Positioning the termination motif over a 63 base area upstream from the RNA polymerase allowed efficient transcript release, demonstrating a remarkable plasticity in the transcription termination complex. Efficient transcript release was observed during ongoing transcription, independent of VTF or UUUUUNU, but requiring both NPH I and either ATP or dATP. This argues for a two step model: the specifying step, requiring both VTF and UUUUUNU, and the energy-dependent step employing NPH I and ATP. Evaluation of NPH I mutants for the ability to stimulate transcription elongation demonstrated that ATPase activity and a stable interaction between NPH I and the Rap94 subunit of the viral RNA polymerase are required. These observations demonstrate that NPH I is a component of the elongating RNA polymerase, which is catalytically active during transcription elongation. PMID:18433825

Piacente, Sarah; Christen, Linda; Dickerman, Benjamin; Mohamed, Mohamed R; Niles, Edward G

2008-06-20

95

Generation of an attenuated Tiantan vaccinia virus by deletion of the ribonucleotide reductase large subunit.  

PubMed

Attenuation of the virulence of vaccinia Tiantan virus (VTT) underlies the strategy adopted for mass vaccination campaigns. This strategy provides advantages of safety and efficacy over traditional vaccines and is aimed at minimization of adverse health effects. In this study, a mutant form of the virus, MVTT was derived from VTT by deletion of the ribonucleotide reductase large subunit (R1) (TI4L). Compared to wild-type parental (VTT) and revertant (VTT-rev) viruses, virulence of the mutant MVTT was reduced by 100-fold based on body weight reduction and by 3,200-fold based on determination of the intracranial 50% lethal infectious dose. However, the immunogenicity of MVTT was equivalent to that of the parental VTT. We also demonstrated that the TI4L gene is not required for efficient replication. These data support the conclusion that MVTT can be used as a replicating virus vector or as a platform for the development of vaccines against infectious diseases and for cancer therapy. PMID:24677065

Kan, Shifu; Jia, Peng; Sun, Lili; Hu, Ningning; Li, Chang; Lu, Huijun; Tian, Mingyao; Qi, Yanxin; Jin, Ningyi; Li, Xiao

2014-09-01

96

Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vaccinia-immune individuals.  

PubMed

Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax in vaccinia-naïve and vaccinia-immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax challenge at 3 months. Two or more doses of MVA prior to Dryvax reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax vaccinia-specific CD8(+) T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. PMID:17126963

Parrino, Janie; McCurdy, Lewis H; Larkin, Brenda D; Gordon, Ingelise J; Rucker, Steven E; Enama, Mary E; Koup, Richard A; Roederer, Mario; Bailer, Robert T; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S

2007-02-01

97

Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants  

PubMed Central

Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production. PMID:23928462

Melamed, Sharon; Wyatt, Linda S.; Kastenmayer, Robin J.; Moss, Bernard

2013-01-01

98

The development and use of a vaccinia-rabies recombinant oral vaccine for the control of wildlife rabies; a link between Jenner and Pasteur.  

PubMed Central

To improve both safety and stability of the oral vaccines used in the field to vaccinate foxes against rabies, a recombinant vaccinia virus, which expresses the immunizing G protein of rabies virus has been developed by inserting the cDNA which codes for the immunogenic glycoprotein of rabies virus into the thymidine kinase (TK) gene of the Copenhagen strain of vaccinia virus. The efficacy of this vaccine was tested by the oral route, primarily in foxes. The immunity conferred, a minimum of 12 months in cubs and 18 months in adult animals, corresponds to the duration of the protection required for vaccination of foxes in the field. Innocuity was tested in foxes, domestic animals, and in numerous European wild animal species that could compete with the red fox for the vaccine bait. No clinical signs or lesions were observed in any of the vaccinated animals during a minimum of 28 days post vaccination. Moreover, no transmission of immunizing doses of the recombinant occurred between foxes or other species tested. To study the stability of the vaccine strain, baits containing the vaccine were placed in the field. Despite considerable variations of environmental temperatures, the vaccine remained stable for at least one month. Because bait is taken within one month, it can be assumed that most animals taking the baits are effectively vaccinated. To test the field efficacy of the recombinant vaccine, large-scale campaigns of fox vaccination were set up in a 2200 km2 region of southern Belgium, were rabies was prevalent. A dramatic decrease in the incidence of rabies was noted after the campaigns. The recombinant is presently used to control wildlife rabies in the field both in several European countries and in the United States. PMID:8666066

Pastoret, P. P.; Brochier, B.

1996-01-01

99

Genome Scale Patterns of Recombination between Coinfecting Vaccinia Viruses  

PubMed Central

ABSTRACT Recombination plays a critical role in virus evolution. It helps avoid genetic decline and creates novel phenotypes. This promotes survival, and genome sequencing suggests that recombination has facilitated the evolution of human pathogens, including orthopoxviruses such as variola virus. Recombination can also be used to map genes, but although recombinant poxviruses are easily produced in culture, classical attempts to map the vaccinia virus (VACV) genome this way met with little success. We have sequenced recombinants formed when VACV strains TianTan and Dryvax are crossed under different conditions. These were a single round of growth in coinfected cells, five rounds of sequential passage, or recombinants obtained using leporipoxvirus-mediated DNA reactivation. Our studies showed that recombinants contain a patchwork of DNA, with the number of exchanges increasing with passage. Further passage also selected for TianTan DNA and correlated with increased plaque size. The recombinants produced through a single round of coinfection contain a disproportionate number of short conversion tracks (<1 kbp) and exhibited 1 exchange per 12 kbp, close to the ?1 per 8 kbp in the literature. One by-product of this study was that rare mutations were also detected; VACV replication produces ?1 × 10?8 mutation per nucleotide copied per cycle of replication and ?1 large (21 kbp) deletion per 70 rounds of passage. Viruses produced using DNA reactivation appeared no different from recombinants produced using ordinary methods. An attractive feature of this approach is that when it is combined with selection for a particular phenotype, it provides a way of mapping and dissecting more complex virus traits. IMPORTANCE When two closely related viruses coinfect the same cell, they can swap genetic information through a process called recombination. Recombination produces new viruses bearing different combinations of genes, and it plays an important role in virus evolution. Poxviruses are a family of viruses that includes variola (or smallpox) virus, and although poxviruses are known to recombine, no one has previously mapped the patterns of DNAs exchanged between viruses. We coinfected cells with two different vaccinia poxviruses, isolated the progeny, and sequenced them. We show that poxvirus recombination is a very accurate process that assembles viruses containing DNA copied from both parents. In a single round of infection, DNA is swapped back and forth ?18 times per genome to make recombinant viruses that are a mosaic of the two parental DNAs. This mixes many different genes in complex combinations and illustrates how recombination can produce viruses with greatly altered disease potential. PMID:24574414

Qin, Li

2014-01-01

100

Spread of vaccinia virus through shaving during military training, Joint Base San Antonio-Lackland, TX, June 2014.  

PubMed

Although naturally occurring smallpox virus was officially declared eradicated in 1980, concern for biological warfare prompted the U.S. Government in 2002 to recommend smallpox vaccination for select individuals. Vaccinia, the smallpox vaccine virus, is administered into the skin, typically on the upper arm, where the virus remains viable and infectious until the scab falls off and the epidermis is fully intact - typically 2-4 weeks. Adverse events following smallpox vaccination may occur in the vaccinee, in individuals who have contact with the vaccinee (i.e., secondary transmission), or in individuals who have contact with the vaccinee's contact (i.e., tertiary transmission). In June 2014 at Joint Base San Antonio-Lackland, TX, two cases of inadvertent inoculation of vaccinia and one case of a non-viral reaction following vaccination occurred in the security forces training squadron. This includes the first reported case of shaving as the likely source of autoinoculation after contact transmission. This paper describes the diagnosis and treatment of these cases, the outbreak investigation, and steps taken to prevent future transmission. PMID:25162496

Webber, Bryant J; Montgomery, Jay R; Markelz, Ana E; Allen, Kahtonna C; Hunninghake, John C; Ritchie, Simon A; Pawlak, Mary T; Johnston, Lindsay A; Oliver, Tiffany A; Winterton, Brad S

2014-08-01

101

Vaccinia virus A34 glycoprotein determines the protein composition of the extracellular virus envelope.  

PubMed

The outer envelope of the extracellular form of vaccinia virus contains five virus-encoded proteins, F13, A33, A34, A56, and B5, that, with the exception of A56, are implicated in virus egress or infectivity. A34, a type II transmembrane glycoprotein, is involved in the induction of actin tails, the release of enveloped virus from the surfaces of infected cells, and the disruption of the virus envelope after ligand binding prior to virus entry. To investigate interactions between A34 and other envelope proteins, a recombinant vaccinia virus (vA34R(HA)) expressing an epitope-tagged version of A34 (A34(HA)) was constructed by appending an epitope from influenza virus hemagglutinin to the C terminus of A34. Complexes of A34(HA) with B5 and A36, but not with A33 or F13, were detected in vA34R(HA)-infected cells. A series of vaccinia viruses expressing mutated versions of the B5 protein was used to investigate the domain(s) of B5 required for interaction with A34. Both the cytoplasmic and the transmembrane domains of B5 were dispensable for binding to A34. Most of the extracellular domain of B5, which contains four short consensus repeats homologous to complement control proteins, was sufficient for A34 interaction, indicating that both proteins interact through their ectodomains. Immunofluorescence experiments on cells infected with A34-deficient virus indicated that A34 is required for efficient targeting of B5, A36, and A33 into wrapped virions. Consistent with this observation, the envelope of A34-deficient virus contained normal amounts of F13 but decreased amounts of A33 and B5 with respect to the parental WR virus. These results point to A34 as a major determinant in the protein composition of the vaccinia virus envelope. PMID:18094186

Perdiguero, Beatriz; Lorenzo, María M; Blasco, Rafael

2008-03-01

102

Immunotherapeutic Potential of Oncolytic Vaccinia Virus  

PubMed Central

The concept of oncolytic viral therapy was based on the hypothesis that engineering tumor-selectivity into the replication potential of viruses would permit direct destruction of tumor cells as a result of viral-mediated lysis, resulting in amplification of the therapy exclusively within the tumor environment. The immune response raised by the virus was not only considered to be necessary for the safety of the approach, but also something of a hindrance to optimal therapeutic activity and repeat dosing. However, the pre-clinical and subsequent clinical success of several oncolytic viruses expressing selected cytokines has demonstrated the potential for harnessing the immune response as an additional and beneficial mechanism of therapeutic activity within the platform. Over the last few years, a variety of novel approaches have been incorporated to try to enhance this immunotherapeutic activity. Several innovative and subtle approaches have moved far beyond the expression of a single cytokine transgene, with the hope of optimizing anti-tumor immunity while having minimal detrimental impact on viral oncolytic activity. PMID:24987615

Thorne, Steve H.

2014-01-01

103

Vaccinia virus strain differences in cell attachment and entry  

SciTech Connect

Vaccinia virus (VACV) strain WR can enter cells by a low pH endosomal pathway or direct fusion with the plasma membrane at neutral pH. Here, we compared attachment and entry of five VACV strains in six cell lines and discovered two major patterns. Only WR exhibited pH 5-enhanced rate of entry following neutral pH adsorption to cells, which correlated with sensitivity to bafilomycin A1, an inhibitor of endosomal acidification. Entry of IHD-J, Copenhagen and Elstree strains were neither accelerated by pH 5 treatment nor prevented by bafilomycin A1. Entry of the Wyeth strain, although not augmented by pH 5, was inhibited by bafilomycin A1. WR and Wyeth were both relatively resistant to the negative effects of heparin on entry, whereas the other strains were extremely sensitive due to inhibition of cell binding. The relative sensitivities of individual vaccinia virus strains to heparin correlated inversely with their abilities to bind to and enter glycosaminoglycan-deficient sog9 cells but not other cell lines tested. These results suggested that that IHD-J, Copenhagen and Elstree have a more limited ability than WR and Wyeth to use the low pH endosomal pathway and are more dependent on binding to glycosaminoglycans for cell attachment.

Bengali, Zain; Townsley, Alan C. [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Bethesda, MD 20892-3210 (United States); Moss, Bernard, E-mail: bmoss@nih.go [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Bethesda, MD 20892-3210 (United States)

2009-06-20

104

Expression of Herpes Simplex Virus 1 Glycoprotein B by a Recombinant Vaccinia Virus and Protection of Mice against Lethal Herpes Simplex Virus 1 Infection  

NASA Astrophysics Data System (ADS)

The herpes simplex virus 1 (HSV-1) strain F gene encoding glycoprotein gB was isolated and modified at the 5' end by in vitro oligonucleotide-directed mutagenesis. The modified gB gene was inserted into the vaccinia virus genome and expressed under the control of a vaccinia virus promoter. The mature gB glycoprotein produced by the vaccinia virus recombinant was glycosylated, was expressed at the cell surface, and was indistinguishable from authentic HSV-1 gB in terms of electrophoretic mobility. Mice immunized intradermally with the recombinant vaccinia virus produced gB-specific neutralizing antibodies and were resistant to a lethal HSV-1 challenge.

Cantin, Edouard M.; Eberle, Richard; Baldick, Joseph L.; Moss, Bernard; Willey, Dru E.; Notkins, Abner L.; Openshaw, Harry

1987-08-01

105

Immune modulation in primary vaccinia virus zoonotic human infections.  

PubMed

In 2010, the WHO celebrated the 30th anniversary of the smallpox eradication. Ironically, infections caused by viruses related to smallpox are being increasingly reported worldwide, including Monkeypox, Cowpox, and Vaccinia virus (VACV). Little is known about the human immunological responses elicited during acute infections caused by orthopoxviruses. We have followed VACV zoonotic outbreaks taking place in Brazil and analyzed cellular immune responses in patients acutely infected by VACV. Results indicated that these patients show a biased immune modulation when compared to noninfected controls. Amounts of B cells are low and less activated in infected patients. Although present, T CD4(+) cells are also less activated when compared to noninfected individuals, and so are monocytes/macrophages. Similar results were obtained when Balb/C mice were experimentally infected with a VACV sample isolated during the zoonotic outbreaks. Taking together, the data suggest that zoonotic VACVs modulate specific immune cell compartments during an acute infection in humans. PMID:22229039

Silva Gomes, Juliana Assis; de Araújo, Fernanda Fortes; de Souza Trindade, Giliane; Quinan, Bárbara Resende; Drumond, Betânia Paiva; Ferreira, Jaqueline Maria Siqueira; Mota, Bruno Eduardo Fernandes; Nogueira, Maurício Lacerda; Kroon, Erna Geessien; Santos Abrahão, Jônatas; Côrrea-Oliveira, Rodrigo; da Fonseca, Flávio Guimarães

2012-01-01

106

Group 1 Vaccinia virus Zoonotic Outbreak in Maranhão State, Brazil  

PubMed Central

In Brazil, several exanthematic autochthone Vaccinia virus (VACV) outbreaks affecting dairy cattle and rural workers have been reported since 1999. Although outbreaks had been first described in the Brazilian Southeast, VACV outbreaks were notified in all Brazilian regions in < 10 years. However, in this context, VACV outbreaks had not been described in some Brazilian States, likely because of a lack of notification, or yet unknown epidemiological reasons. Here, we describe the first VACV outbreak in Maranhão State, northeastern Brazil. The virus isolated from this outbreak showed several biological and molecular features that resemble other Group 1 Brazilian VACV, including a deletion signature in the A56R gene. This study raises new questions about diversity and epidemiology of Brazilian VACV. PMID:24166043

Oliveira, Danilo Bretas; Assis, Felipe Lopes; Ferreira, Paulo Cesar Peregrino; Bonjardim, Cláudio Antônio; Trindade, Giliane de Souza; Kroon, Erna Geessien; Abrahão, Jônatas Santos

2013-01-01

107

Rabbitpox virus and vaccinia virus infection of rabbits as a model for human smallpox.  

PubMed

The threat of smallpox release and use as a bioweapon has encouraged the search for new vaccines and antiviral drugs, as well as development of new small-animal models in which their efficacy can be determined. Here, we reinvestigate a rabbit model in which the intradermal infection of rabbits with very low doses of either rabbitpox virus (RPV) or vaccinia virus Western Reserve (VV-WR) recapitulates many of the clinical features of human smallpox. Following intradermal inoculation with RPV, rabbits develop systemic disease characterized by extensive viremia, numerous secondary lesions on the skin and mucocutaneous tissues, severe respiratory disease, death by 9 days postinfection, and, importantly, natural aerosol transmission between animals. Contrary to previous reports, intradermal infection with VV-WR also resulted in a very similar lethal systemic disease in rabbits, again with natural aerosol transmission between animals. When sentinel and index animals were cohoused, transmission rates approached 100% with either virus, with sentinel animals exhibiting a similar, severe disease. Lower rates of transmission were observed when index and sentinel animals were housed in separate cages. Sentinel animals infected with RPV with one exception succumbed to the disease. However, the majority of VV-WR-infected sentinel animals, while becoming seriously ill, survived. Finally, we tested the efficacy of the drug 1-O-hexadecyloxypropyl-cidofovir in the RPV/rabbit model and found that an oral dose of 5 mg/kg twice a day for 5 days beginning 1 day before infection was able to completely protect rabbits from lethal disease. PMID:17686856

Adams, Mathew M; Rice, Amanda D; Moyer, R W

2007-10-01

108

Host Cell Nuclear Proteins Are Recruited to Cytoplasmic Vaccinia Virus Replication Complexes  

PubMed Central

The initiation and termination of vaccinia virus postreplicative transcription have been reported to require cellular proteins, some of which are believed to be nuclear proteins. Vaccinia virus replicates in the cytoplasmic compartment of the cell, raising questions as to whether vaccinia virus has access to nuclear proteins. This was addressed here by following the fate of several nuclear proteins after infection of cells with vaccinia virus. The nuclear transcription factors YY1, SP1, and TATA binding protein were found to colocalize with virus replication complexes in the cytoplasm of infected cells. In addition, the nuclear proteins RNA polymerase II, TAFIIp32, and histone deacetylase 8, but not the structural protein lamin B, also were found in the cytoplasm of the cell. The association of YY1 with replication complexes was dependent on DNA replication and required only the DNA binding domain of the protein, indicating that DNA binding alone may be responsible for the association of nuclear transcription factors with viral replication complexes in the cytoplasm. The cytoplasmic localization of YY1 was resistant to the nuclear export inhibitor leptomycin B. Evidence is presented indicating that nuclear import and export pathways were not adversely affected by vaccinia virus infection. These observations indicate that vaccinia virus replication complexes have ready access to nuclear proteins by allowing leakage from the nucleus. PMID:16188987

Oh, Jaewook; Broyles, Steven S.

2005-01-01

109

The lipid raft-associated protein CD98 is required for vaccinia virus endocytosis.  

PubMed

Mature vaccinia virus (vaccinia MV) infects a broad range of animals in vivo and cell cultures in vitro; however, the cellular receptors that determine vaccinia MV tropism and entry pathways are poorly characterized. Here, we performed quantitative proteomic analyses of lipid raft-associated proteins upon vaccinia MV entry into HeLa cells. We found that a type II membrane glycoprotein, CD98, is enriched in lipid rafts upon vaccinia MV infection compared to mock-infected HeLa cells. The knockdown of CD98 expression in HeLa cells significantly reduced vaccinia MV entry. Furthermore, CD98 knockout (KO) mouse embryonic fibroblasts (MEFs) also exhibited reduced vaccinia MV infectivity without affecting MV attachment to cells, suggesting a role for CD98 in the postbinding step of virus entry. Further characterization with inhibitors and dominant negative proteins that block different endocytic pathways revealed that vaccinia MV entry into MEFs occurs through a clathrin-independent, caveolin-independent, dynamin-dependent, fluid-phase endocytic pathway, implying that CD98 plays a specific role in the vaccinia MV endocytic pathway. Infections of wild-type and CD98 KO MEF cells with different strains of vaccinia MV provided further evidence that CD98 plays a specific role in MV endocytosis but not in plasma membrane fusion. Finally, different CD98-C69 chimeric proteins were expressed in CD98 KO MEFs, but none were able to reconstitute MV infectivity, suggesting that the overall structure of the CD98 protein is required for vaccinia MV endocytosis. PMID:22345471

Schroeder, Nina; Chung, Che-Sheng; Chen, Chein-Hung; Liao, Chung-Lin; Chang, Wen

2012-05-01

110

Primary Human Macrophages Serve as Vehicles for Vaccinia Virus Replication and Dissemination  

PubMed Central

ABSTRACT Human monocytic and professional antigen-presenting cells have been reported only to exhibit abortive infections with vaccinia virus (VACV). We found that monocyte-derived macrophages (MDMs), including granulocyte macrophage colony-stimulating factor (GM-CSF)-polarized M1 and macrophage colony-stimulating factor (M-CSF)-polarized M2, but not human AB serum-derived cells, were permissive to VACV replication. The titers of infectious virions in both cell-free supernatants and cellular lysates of infected M1 and M2 markedly increased in a time-dependent manner. The majority of virions produced in permissive MDMs were extracellular enveloped virions (EEV), a secreted form of VACV associated with long-range virus dissemination, and were mainly found in the culture supernatant. Infected MDMs formed VACV factories, actin tails, virion-associated branching structures, and cell linkages, indicating that MDMs are able to initiate de novo synthesis of viral DNA and promote virus release. VACV replication was sensitive to inhibitors against the Akt and Erk1/2 pathways that can be activated by VACV infection and M-CSF stimulation. Classical activation of MDMs by lipopolysaccharide (LPS) plus gamma interferon (IFN-?) stimulation caused no effect on VACV replication, while alternative activation of MDMs by interleukin-10 (IL-10) or LPS-plus-IL-1? treatment significantly decreased VACV production. The IL-10-mediated suppression of VACV replication was largely due to Stat3 activation, as a Stat3 inhibitor restored virus production to levels observed without IL-10 stimulation. In conclusion, our data demonstrate that primary human macrophages are permissive to VACV replication. After infection, these cells produce EEV for long-range dissemination and also form structures associated with virions which may contribute to cell-cell spread. IMPORTANCE Our results provide critical information to the burgeoning fields of cancer-killing (oncolytic) virus therapy with vaccinia virus (VACV). One type of macrophage (M2) is considered a common presence in tumors and is associated with poor prognosis. Our results demonstrate a preference for VACV replication in M2 macrophages and could assist in designing treatments and engineering poxviruses with special considerations for their effect on M2 macrophage-containing tumors. Additionally, this work highlights the importance of macrophages in the field of vaccine development using poxviruses as vectors. The understanding of the dynamics of poxvirus-infected foci is central in understanding the effectiveness of the immune response to poxvirus-mediated vaccine vectors. Monocytic cells have been found to be an important part of VACV skin lesions in mice in controlling the infection as well as mediating virus transport out of infected foci. PMID:24696488

Byrd, Daniel; Shepherd, Nicole; Lan, Jie; Hu, Ningjie; Amet, Tohti; Yang, Kai; Desai, Mona

2014-01-01

111

Replication-Deficient Vaccinia Virus Encoding Bacteriophage T7 RNA Polymerase for Transient Gene Expression in Mammalian Cells  

Microsoft Academic Search

The vaccinia virus\\/bacteriophage T7 hybrid transient expression system employs a recombinant vaccinia virus that encodes the T7 RNA polymerase gene, a plasmid vector with a gene of interest regulated by a T7 promoter, and any cell line suitable for infection and transfection. Although high expression in a majority of cells is achieved. the severe cytopathic effects of vaccinia virus and

Linda S. Wyatt; Bernard Moss; Shmuel Rozenblatt

1995-01-01

112

Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma  

PubMed Central

Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose–escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-?. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma. PMID:15937544

Kaufman, Howard L.; DeRaffele, Gail; Mitcham, Josephine; Moroziewicz, Dorota; Cohen, Seth M.; Hurst-Wicker, Karl S.; Cheung, Ken; Lee, David S.; Divito, Joseph; Voulo, Magalese; Donovan, Julie; Dolan, Kate; Manson, Kelledy; Panicali, Dennis; Wang, Ena; Hörig, Heidi; Marincola, Francesco M.

2005-01-01

113

42 CFR 102.21 - Smallpox (Vaccinia) Vaccine Injury Table.  

Code of Federal Regulations, 2011 CFR

...unexpected and extreme response at the vaccination or inoculation site that results...is the initial skin lesion at the vaccination or inoculation site that generally occurs with smallpox vaccinations or inoculations. Minor...

2011-10-01

114

42 CFR 102.21 - Smallpox (Vaccinia) Vaccine Injury Table.  

Code of Federal Regulations, 2012 CFR

...unexpected and extreme response at the vaccination or inoculation site that results...is the initial skin lesion at the vaccination or inoculation site that generally occurs with smallpox vaccinations or inoculations. Minor...

2012-10-01

115

42 CFR 102.21 - Smallpox (Vaccinia) Vaccine Injury Table.  

Code of Federal Regulations, 2013 CFR

...unexpected and extreme response at the vaccination or inoculation site that results...is the initial skin lesion at the vaccination or inoculation site that generally occurs with smallpox vaccinations or inoculations. Minor...

2013-10-01

116

42 CFR 102.21 - Smallpox (Vaccinia) Vaccine Injury Table.  

Code of Federal Regulations, 2014 CFR

...unexpected and extreme response at the vaccination or inoculation site that results...is the initial skin lesion at the vaccination or inoculation site that generally occurs with smallpox vaccinations or inoculations. Minor...

2014-10-01

117

Virus-Vectored Influenza Virus Vaccines  

PubMed Central

Despite the availability of an inactivated vaccine that has been licensed for >50 years, the influenza virus continues to cause morbidity and mortality worldwide. Constant evolution of circulating influenza virus strains and the emergence of new strains diminishes the effectiveness of annual vaccines that rely on a match with circulating influenza strains. Thus, there is a continued need for new, efficacious vaccines conferring cross-clade protection to avoid the need for biannual reformulation of seasonal influenza vaccines. Recombinant virus-vectored vaccines are an appealing alternative to classical inactivated vaccines because virus vectors enable native expression of influenza antigens, even from virulent influenza viruses, while expressed in the context of the vector that can improve immunogenicity. In addition, a vectored vaccine often enables delivery of the vaccine to sites of inductive immunity such as the respiratory tract enabling protection from influenza virus infection. Moreover, the ability to readily manipulate virus vectors to produce novel influenza vaccines may provide the quickest path toward a universal vaccine protecting against all influenza viruses. This review will discuss experimental virus-vectored vaccines for use in humans, comparing them to licensed vaccines and the hurdles faced for licensure of these next-generation influenza virus vaccines. PMID:25105278

Tripp, Ralph A.; Tompkins, S. Mark

2014-01-01

118

Multiple viral ligands naturally presented by different class I molecules in transporter antigen processing-deficient vaccinia virus-infected cells.  

PubMed

The transporter associated with antigen processing (TAP) delivers the viral proteolytic products generated by the proteasome in the cytosol to the endoplasmic reticulum lumen that are subsequently recognized by cytotoxic T lymphocytes (CTLs). However, several viral epitopes have been identified in TAP-deficient models. Using mass spectrometry to analyze complex human leukocyte antigen (HLA)-bound peptide pools isolated from large numbers of TAP-deficient vaccinia virus-infected cells, we identified 11 ligands naturally presented by four different HLA-A, HLA-B, and HLA-C class I molecules. Two of these ligands were presented by two different HLA class I alleles, and, as a result, 13 different HLA-peptide complexes were formed simultaneously in the same vaccinia virus-infected cells. In addition to the high-affinity ligands, one low-affinity peptide restricted by each of the HLA-A, HLA-B, and HLA-C class I molecules was identified. Both high- and low-affinity ligands generated long-term memory CTL responses to vaccinia virus in an HLA-A2-transgenic mouse model. The processing and presentation of two vaccinia virus-encoded HLA-A2-restricted antigens took place via proteasomal and nonproteasomal pathways, which were blocked in infected cells with chemical inhibitors specific for different subsets of metalloproteinases. These data have implications for the study of the effectiveness of early empirical vaccination with cowpox virus against smallpox disease. PMID:22031944

Lorente, Elena; Infantes, Susana; Barnea, Eilon; Beer, Ilan; García, Ruth; Lasala, Fátima; Jiménez, Mercedes; Vilches, Carlos; Lemonnier, François A; Admon, Arie; López, Daniel

2012-01-01

119

Interaction between vaccinia virus extracellular virus envelope A33 and B5 glycoproteins.  

PubMed

The extracellular form of vaccinia virus acquires its outer envelope by wrapping with cytoplasmic membranes that contain at least seven virus-encoded proteins, of which four are glycoproteins. We searched for interactions between the vaccinia virus A33 glycoprotein and proteins A34, A36, B5, F12, and F13. First, when myc epitope-tagged A33 was expressed in combination with other envelope proteins, A33 colocalized with B5 and A36, suggesting that direct A33-B5 and A33-A36 interactions occur in the absence of infection. A recombinant vaccinia virus (vA33Rmyc) was constructed by introduction of the myc-tagged A33 version (A33myc) into A33-deficient vaccinia virus. A33myc partially restored plaque formation and colocalized with enveloped virions in infected cells. Coimmunoprecipitation experiments with extracts of vA33Rmyc-infected cells confirmed the existence of a physical association of A33 with A36 and B5. Of these, the A33-B5 interaction is a novel finding, whereas the interaction between A33 and A36 has been previously characterized. A collection of vaccinia viruses expressing mutated versions of the B5 protein was used to investigate the domain(s) of B5 required for interaction with A33. Both the cytoplasmic domain and most of the extracellular domain, but not the transmembrane domain, of the B5 protein were dispensable for binding to A33. Mutations in the extracellular portions of B5 and A33 that enhance extracellular virus release did not affect the interaction between the two. In contrast, substituting the B5 transmembrane domain with that of the vesicular stomatitis virus G glycoprotein prevented the association with A33. Immunofluorescence experiments on virus mutants indicated that B5 is required for efficient targeting of A33 into enveloped virions. These results point to the transmembrane domain of B5 as the major determinant of the A33-B5 interaction and demonstrate that protein-protein interactions are crucial in determining the composition of the virus envelope. PMID:16912323

Perdiguero, Beatriz; Blasco, Rafael

2006-09-01

120

Evaluation of the efficacy of modified vaccinia Ankara (MVA)/IMVAMUNE® against aerosolized rabbitpox virus in a rabbit model  

PubMed Central

Infection of rabbits with aerosolized rabbitpox virus (RPXV) produces a disease similar to monkeypox and smallpox in humans and provides a valuable, informative model system to test medical countermeasures against orthopoxviruses. Due to the eradication of smallpox, the evaluation of the efficacy of new-generation smallpox vaccines depends on relevant well-developed animal studies for vaccine licensure. In this study, we tested the efficacy of IMVAMUNE® [Modified Vaccinia Virus Ankara-Bavarian Nordic (MVA-BN®)] for protecting rabbits against aerosolized RPXV. Rabbits were vaccinated with either phosphate-buffered saline (PBS), Dryvax®, a single low dose of IMVAMUNE®, a single high dose of IMVAMUNE®, or twice with a high dose of IMVAMUNE®. Aerosol challenge with a lethal dose of RPXV was performed 4 weeks after the last vaccination. All PBS control animals succumbed to the disease or were euthanized because of the disease within 7 days postexposure. The rabbits vaccinated with Dryvax®, a low dose of IMVAMUNE®, or a single high dose of IMVAMUNE® showed minimal to moderate clinical signs of the disease, but all survived the challenge. The only clinical sign displayed by rabbits that had been vaccinated twice with a high dose of IMVAMUNE® was mild transient anorexia in just two out of eight rabbits. This study shows that IMVAMUNE® can be a very effective vaccine against aerosolized RPXV. PMID:19632316

Garza, Nicole L.; Hatkin, Josh M.; Livingston, Virginia; Nichols, Donald K.; Chaplin, Paul J.; Volkmann, Ariane; Fisher, Diana; Nalca, Aysegul

2009-01-01

121

Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity.  

PubMed Central

Soluble receptors for gamma interferon (IFN-gamma) are secreted from cells infected by 17 orthopoxviruses, including vaccinia, cowpox, rabbitpox, buffalopox, elephantpox, and camelpox viruses, representing three species (vaccinia, cowpox, and campelpox viruses). The B8R open reading frame of vaccinia virus strain Western Reserve, which has sequence similarity to the extracellular binding domain of cellular IFN-gamma receptors (IFN-gamma Rs), is shown to encode an IFN-gamma binding activity by expression in recombinant baculovirus. The soluble virus IFN-gamma Rs bind IFN-gamma and, by preventing its interaction with the cellular receptor, interfere with the antiviral effects induced by this cytokine. Interestingly, in contrast to cellular IFN-gamma Rs, which are highly species specific, the vaccinia, cowpox, and camelpox virus IFN-gamma Rs bind and inhibit the biological activity of human, bovine, and rat IFN-gamma but not mouse IFN-gamma. This unique broad species specificity of the IFN-gamma R would aid virus replication in different species and suggests that vaccinia, cowpox, and camelpox viruses may have evolved in several species, possibly including humans but excluding mice. Last, the conservation of an IFN-gamma R in orthopoxviruses emphasizes the importance of IFN-gamma in defense against poxvirus infections. PMID:7609027

Alcamí, A; Smith, G L

1995-01-01

122

Safety, Immunogenicity, and Efficacy of Prime-Boost Immunization with Recombinant Poxvirus FP9 and Modified Vaccinia Virus Ankara Encoding the Full-Length Plasmodium falciparum Circumsporozoite Protein  

PubMed Central

Heterologous prime-boost immunization with DNA and various recombinant poxviruses encoding malaria antigens is capable of inducing strong cell-mediated immune responses and partial protection in human sporozoite challenges. Here we report a series of trials assessing recombinant fowlpox virus and modified vaccinia virus Ankara encoding the Plasmodium falciparum circumsporozoite protein in various prime-boost combinations, doses, and application routes. For the first time, these vaccines were administered intramuscularly and at doses of up to 5 × 108 PFU. Vaccines containing this antigen proved safe and induced modest immune responses but showed no evidence of efficacy in a sporozoite challenge. PMID:16622207

Walther, Michael; Thompson, Fiona M.; Dunachie, Susanna; Keating, Sheila; Todryk, Stephen; Berthoud, Tamara; Andrews, Laura; Andersen, Rikke F.; Moore, Anne; Gilbert, Sarah C.; Poulton, Ian; Dubovsky, Filip; Tierney, Eveline; Correa, Simon; Huntcooke, Angela; Butcher, Geoffrey; Williams, Jack; Sinden, Robert E.; Hill, Adrian V. S.

2006-01-01

123

Enhanced efficacy of cidofovir combined with vaccinia immune globulin in treating progressive cutaneous vaccinia virus infections in immunosuppressed hairless mice.  

PubMed

The treatment of progressive vaccinia in individuals has involved antiviral drugs, such as cidofovir (CDV), brincidofovir, and/or tecovirimat, combined with vaccinia immune globulin (VIG). VIG is costly, and its supply is limited, so sparing the use of VIG during treatment is an important objective. VIG sparing was modeled in immunosuppressed mice by maximizing the treatment benefits of CDV combined with VIG to determine the effective treatments that delayed the time to death, reduced cutaneous lesion severity, and/or decreased tissue viral titers. SKH-1 hairless mice immunosuppressed with cyclophosphamide and hairless SCID mice (SHO strain) were infected cutaneously with vaccinia virus. Monotherapy, dual combinations (CDV plus VIG), or triple therapy (topical CDV, parenteral CDV, and VIG) were initiated 2 days postinfection and were given every 3 to 4 days through day 11. The efficacy assessment included survival rate, cutaneous lesion severity, and viral titers. Delays in the time to death and the reduction in lesion severity occurred in the following order of efficacy: triple therapy had greater efficacy than double combinations (CDV plus VIG or topical plus parenteral CDV), which had greater efficacy than VIG alone. Parenteral administration of CDV or VIG was necessary to suppress virus titers in internal organs (liver, lung, and spleen). The skin viral titers were significantly reduced by triple therapy only. The greatest efficacy was achieved by triple therapy. In humans, this regimen should translate to a faster cure rate, thus sparing the amount of VIG used for treatment. PMID:25385098

Smee, Donald F; Dagley, Ashley; Downs, Brittney; Hagloch, Joseph; Tarbet, E Bart

2015-01-01

124

Cowpox virus but not Vaccinia virus induces secretion of CXCL1, IL-8 and IL-6 and chemotaxis of monocytes in vitro.  

PubMed

Orthopoxviruses are large DNA viruses which can cause disease in numerous host species. Today, after eradication of Variola virus and the end of vaccination against smallpox, zoonotic Orthopoxvirus infections are emerging as potential threat to human health. The most common causes of zoonotic Orthopoxvirus infections are Cowpox virus in Europe, Monkeypox virus in Africa and Vaccinia virus in South America. Although all three viruses are genetically and antigenically closely related, the human diseases caused by each virus differ considerably. This observation may reflect different capabilities of these viruses to modulate the hosts' immune response. Therefore, we aimed at characterizing the specific cytokine response induced by Orthopoxvirus infection in vitro. We analysed the gene expression of nine human pro-inflammatory cytokines and chemokines in response to infection of HeLa cells and could identify an upregulation of cytokine gene expression following Cowpox virus and Monkeypox virus infection but not following Vaccinia virus infection. This was verified by a strong induction of especially IL-6, IL-8 and CXCL1 secretion into the cell culture supernatant following Cowpox virus infection. We could further show that supernatants derived from Cowpox virus-infected cells exhibit an increased chemotactic activity towards monocytic and macrophage-like cells. On the one hand, increased cytokine secretion by Cowpox virus-infected cells and subsequent monocyte/macrophage recruitment may contribute to host defence and facilitate clearance of the infection. On the other hand, given the assumed important role of circulating macrophages in viral spread, this may also point towards a mechanism facilitating delivery of the virus to further tissues in vivo. PMID:23207068

Bourquain, Daniel; Nitsche, Andreas

2013-01-01

125

A study of the vaccinia virus interferon-c receptor and its contribution to virus virulence  

Microsoft Academic Search

Vaccinia virus (VV) strain Western Reserve gene B8R encodes a 43 kDa glycoprotein that is secreted from infected cells early in infection as a homodimer. This protein has amino acid similarity with the extracellular domain of cellular IFN-c receptor (IFN-cR) and binds and inhibits IFN-c from a wide range of species. Here we demonstrate that the B8R protein also inhibits

Julian A. Symons; David C. Tscharke; Nicola Priceç; Geoffrey L. Smith

126

Antibodies, viruses and vaccines  

Microsoft Academic Search

Neutralizing antibodies are crucial for vaccine-mediated protection against viral diseases. They probably act, in most cases, by blunting the infection, which is then resolved by cellular immunity. The protective effects of neutralizing antibodies can be achieved not only by neutralization of free virus particles, but also by several activities directed against infected cells. In certain instances, non-neutralizing antibodies contribute to

Dennis R. Burton

2002-01-01

127

Safety, Immunogenicity and Efficacy of Modified Vaccinia Ankara (MVA) Against Dryvax® Challenge in Vaccinia-Naïve and Vaccinia-Immune Individuals  

PubMed Central

Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax® in vaccinia-naïve and immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax® challenge at 3 months. Two or more doses of MVA prior to Dryvax® reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax® vaccinia-specific CD8+ T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax® vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. PMID:17126963

Parrino, Janie; McCurdy, Lewis H.; Larkin, Brenda D.; Gordon, Ingelise J.; Rucker, Steven E.; Enama, Mary E.; Koup, Richard A.; Roederer, Mario; Bailer, Robert T.; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S.

2007-01-01

128

Coated microneedle arrays for transcutaneous delivery of live virus vaccines.  

PubMed

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8(+) T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices. PMID:22245683

Vrdoljak, Anto; McGrath, Marie G; Carey, John B; Draper, Simon J; Hill, Adrian V S; O'Mahony, Conor; Crean, Abina M; Moore, Anne C

2012-04-10

129

Systemically administered DNA and fowlpox recombinants expressing four vaccinia virus genes although immunogenic do not protect mice against the highly pathogenic IHD-J vaccinia strain.  

PubMed

The first-generation smallpox vaccine was based on live vaccinia virus (VV) and it successfully eradicated the disease worldwide. Therefore, it was not administered any more after 1980, as smallpox no longer existed as a natural infection. However, emerging threats by terrorist organisations has prompted new programmes for second-generation vaccine development based on attenuated VV strains, which have been shown to cause rare but serious adverse events in immunocompromised patients. Considering the closely related animal poxviruses that might also be used as bioweapons, and the increasing number of unvaccinated young people and AIDS-affected immunocompromised subjects, a safer and more effective smallpox vaccine is still required. New avipoxvirus-based vectors should improve the safety of conventional vaccines, and protect from newly emerging zoonotic orthopoxvirus diseases and from the threat of deliberate release of variola or monkeypox virus in a bioterrorist attack. In this study, DNA and fowlpox recombinants expressing the L1R, A27L, A33R and B5R genes were constructed and evaluated in a pre-clinical trial in mouse, following six prime/boost immunisation regimens, to compare their immunogenicity and protective efficacy against a challenge with the lethal VV IHD-J strain. Although higher numbers of VV-specific IFN?-producing T lymphocytes were observed in the protected mice, the cytotoxic T-lymphocyte response and the presence of neutralising antibodies did not always correlate with protection. In spite of previous successful results in mice, rabbits and monkeys, where SIV/HIV transgenes were expressed by the fowlpox vector, the immune response elicited by these recombinants was low, and most of the mice were not protected. PMID:24050999

Bissa, Massimiliano; Pacchioni, Sole Maria; Zanotto, Carlo; De Giuli Morghen, Carlo; Illiano, Elena; Granucci, Francesca; Zanoni, Ivan; Broggi, Achille; Radaelli, Antonia

2013-12-26

130

Animal Movement and Establishment of Vaccinia Virus Cantagalo Strain in Amazon Biome, Brazil  

PubMed Central

To understand the emergence of vaccinia virus Cantagalo strain in the Amazon biome of Brazil, during 2008–2010 we conducted a molecular and epidemiologic survey of poxvirus outbreaks. Data indicate that animal movement was the major cause of virus dissemination within Rondônia State, leading to the establishment and spread of this pathogen. PMID:21470472

Quixabeira-Santos, Jociane Cristina; Medaglia, Maria Luiza G.; Pescador, Caroline A.

2011-01-01

131

Protein interactions among the vaccinia virus late transcription factors.  

PubMed

The viral proteins A1L, A2L, G8R, and H5R positively modulate vaccinia virus late gene expression. Host-encoded proteins hnRNP A2 and RBM3 may also interact with these viral factors to influence late gene expression. In these studies, a yeast two-hybrid screen and in vitro pulldown and crosslinking experiments were used to investigate protein--protein interactions among these factors. These studies confirmed a previous observation that G8R interacts with itself and A1L. However, self-interactions of A1L and H5R, and interactions between A2L and G8R, A2L and H5R, and H5R and G8R were also observed. In addition, the proteins hnRNP A2 and RBM3 both showed some interaction with A2L. Illustration of these interactions is a step toward understanding the architecture of the late gene transcription complex as it occurs in poxviruses. PMID:15518812

Dellis, Stephanie; Strickland, Kyle C; McCrary, William J; Patel, Ashwin; Stocum, Eileen; Wright, Cynthia F

2004-11-24

132

Novel avian influenza virus vaccines  

Microsoft Academic Search

Summary Current vaccines against avian influenza (AI) virus infections are primarily based on classical inactivated whole-virus preparations. Although administration of these vaccines can protect poultry from clinical disease, sterile immunity is not achieved under field conditions, allowing for undetected virus spread and evolution under immune cover. Therefore, there is an urgent need for a robust and reliable system of differentiation

W. Fuchs; A. Römer-Oberdörfer; J. Veits; T. C. Mettenleiter

2009-01-01

133

Rationalizing the development of live attenuated virus vaccines  

PubMed Central

Since the first demonstration of the protective effects of vaccinia inoculation, vaccination has been one of the medicine’s greatest successes. The design of vaccines against viral disease has evolved considerably over the last 50 years. Classically attenuated viruses, those created by passaging a virus in cultured cells, have proven to be an effective means for preventing many viral diseases, including smallpox, polio, measles, mumps, and yellow fever. However, empiric attenuation is not a reliable approach for all viruses and there are a number of safety issues associated with the use of live, attenuated viruses (LAVs). While inactivated viruses and subunit vaccines alleviate many of these concerns, they have generally been less efficacious than their LAV counterparts. Advances in molecular virology have provided new ways of controlling viral replication and virulence, renewing interest in LAV vaccines. These rationally attenuated viruses may lead to a new generation of safer, more widely applicable LAV vaccines. Here, we review several new approaches to viral attenuation and vaccine design, including deleterious gene mutation, altered replication fidelity, codon deoptimization, and control by microRNAs or zinc finger nucleases. While each of these approaches has garnered significant attention in recent months, they are still in their infancy and require further in vitro and animal testing before progressing to clinical trials. PMID:20531338

Lauring, Adam S.; Jones, Jeremy O.; Andino, Raul

2010-01-01

134

Unpolarized Release of Vaccinia Virus and HIV Antigen by Colchicine Treatment Enhances Intranasal HIV Antigen Expression and Mucosal Humoral Responses  

PubMed Central

The induction of a strong mucosal immune response is essential to building successful HIV vaccines. Highly attenuated recombinant HIV vaccinia virus can be administered mucosally, but even high doses of immunization have been found unable to induce strong mucosal antibody responses. In order to solve this problem, we studied the interactions of recombinant HIV vaccinia virus Tiantan strain (rVTT-gagpol) in mucosal epithelial cells (specifically Caco-2 cell layers) and in BALB/c mice. We evaluated the impact of this virus on HIV antigen delivery and specific immune responses. The results demonstrated that rVTT-gagpol was able to infect Caco-2 cell layers and both the nasal and lung epithelia in BALB/c mice. The progeny viruses and expressed p24 were released mainly from apical surfaces. In BALB/c mice, the infection was limited to the respiratory system and was not observed in the blood. This showed that polarized distribution limited antigen delivery into the whole body and thus limited immune response. To see if this could be improved upon, we stimulated unpolarized budding of the virus and HIV antigens by treating both Caco-2 cells and BALB/c mice with colchicine. We found that, in BALB/c mice, the degree of infection and antigen expression in the epithelia went up. As a result, specific immune responses increased correspondingly. Together, these data suggest that polarized budding limits antigen delivery and immune responses, but unpolarized distribution can increase antigen expression and delivery and thus enhance specific immune responses. This conclusion can be used to optimize mucosal HIV vaccine strategies. PMID:21935396

Zhang, Yan; Yang, Jingyi; Bao, Rong; Chen, Yaoqing; Zhou, Dihan; He, Benxia; Zhong, Maohua; Li, Yaoming; Liu, Fang; Li, Qiaoli; Yang, Yi; Han, Chen; Sun, Ying; Cao, Yuan; Yan, Huimin

2011-01-01

135

High, Broad, Polyfunctional, and Durable T Cell Immune Responses Induced in Mice by a Novel Hepatitis C Virus (HCV) Vaccine Candidate (MVA-HCV) Based on Modified Vaccinia Virus Ankara Expressing the Nearly Full-Length HCV Genome  

PubMed Central

A major goal in the control of hepatitis C infection is the development of a vaccine. Here, we have developed a novel HCV vaccine candidate based on the highly attenuated poxvirus vector MVA (referred to as MVA-HCV) expressing the nearly full-length (7.9-kbp) HCV sequence, with the aim to target almost all of the T and B cell determinants described for HCV. In infected cells, MVA-HCV produces a polyprotein that is subsequently processed into the structural and nonstructural HCV proteins, triggering the cytoplasmic accumulation of dense membrane aggregates. In both C57BL/6 and transgenic HLA-A2-vaccinated mice, MVA-HCV induced high, broad, polyfunctional, and long-lasting HCV-specific T cell immune responses. The vaccine-induced T cell response was mainly mediated by CD8 T cells; however, although lower in magnitude, the CD4+ T cells were highly polyfunctional. In homologous protocol (MVA-HCV/MVA-HCV) the main CD8+ T cell target was p7+NS2, whereas in heterologous combination (DNA-HCV/MVA-HCV) the main target was NS3. Antigenic responses were also detected against other HCV proteins (Core, E1-E2, and NS4), but the magnitude of the responses was dependent on the protocol used. The majority of the HCV-induced CD8+ T cells were triple or quadruple cytokine producers. The MVA-HCV vaccine induced memory CD8+ T cell responses with an effector memory phenotype. Overall, our data showed that MVA-HCV induced broad, highly polyfunctional, and durable T cell responses of a magnitude and quality that might be associated with protective immunity and open the path for future considerations of MVA-HCV as a prophylactic and/or therapeutic vaccine candidate against HCV. PMID:23596307

Gómez, Carmen E.; Perdiguero, Beatriz; Cepeda, María Victoria; Mingorance, Lidia; García-Arriaza, Juan; Vandermeeren, Andrea; Sorzano, Carlos Óscar S.

2013-01-01

136

Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara  

PubMed Central

Malaria is a major global health problem for which an effective vaccine is required urgently. Prime-boost vaccination regimes involving plasmid DNA and recombinant modified vaccinia virus Ankara-encoding liver-stage malaria antigens have been shown to be powerfully immunogenic for T cells and capable of inducing partial protection against experimental malaria challenge in humans, manifested as a delay in time to patent parasitemia. Here, we report that substitution of plasmid DNA as the priming vector with a specific attenuated recombinant fowlpox virus, FP9, vaccine in such prime-boost regimes can elicit complete sterile protection that can last for 20 months. Protection at 20 months was associated with persisting memory but not effector T cell responses. The protective efficacy of various immunization regimes correlated with the magnitude of induced immune responses, supporting the strategy of maximizing durable T cell immunogenicity to develop more effective liver-stage vaccines against Plasmodium falciparum malaria. PMID:15781866

Webster, Daniel P.; Dunachie, Susanna; Vuola, Jenni M.; Berthoud, Tamara; Keating, Sheila; Laidlaw, Stephen M.; McConkey, Samuel J.; Poulton, Ian; Andrews, Laura; Andersen, Rikke F.; Bejon, Philip; Butcher, Geoff; Sinden, Robert; Skinner, Michael A.; Gilbert, Sarah C.; Hill, Adrian V. S.

2005-01-01

137

Prevention of vertical transmission of Neospora caninum in BALB\\/c mice by recombinant vaccinia virus carrying NcSRS2 gene  

Microsoft Academic Search

Neosporacaninum infection is the major cause of bovine abortion. To develop a vaccine against N.caninum infection, recombinant vaccinia viruses carrying NcSRS2 and NcSAG1 genes (vv\\/Nc-p43 and vv\\/Nc-p36, respectively) were constructed and were tested in a mouse model. Vaccination of dams with vv\\/Nc-p43 appeared to confer effective protection against vertical transmission to offspring, though that with vv\\/Nc-p36 only provided partial protection.

Yoshifumi Nishikawa; Xuenan Xuan; Hideyuki Nagasawa; Ikuo Igarashi; Kozo Fujisaki; Haruki Otsuka; Takeshi Mikami

2001-01-01

138

Highly attenuated modified vaccinia virus Ankara replicates in baby hamster kidney cells, a potential host for virus propagation, but not in various human transformed and primary cells.  

PubMed

Although desirable for safety reasons, the host range restrictions of modified vaccinia virus Ankara (MVA) make it less applicable for general use. Propagation in primary chicken embryo fibroblasts (CEF) requires particular cell culture experience and has no pre-established record of tissue culture reproducibility. We investigated a variety of established cell lines for productive virus growth and recombinant gene expression. Baby hamster kidney cells (BHK), a well-characterized, easily maintained cell line, supported MVA growth and as proficient expression of the E. coli lacZ reporter gene as the highly efficient CEF, whereas other cell lines were non-permissive or allowed only very limited MVA replication. Importantly, no virus production occurred in patient-derived infected primary human cells. These results emphasize the safety and now improved accessibility of MVA for the development of expression vectors and live recombinant vaccines. PMID:9472619

Drexler, I; Heller, K; Wahren, B; Erfle, V; Sutter, G

1998-02-01

139

Oral vaccination of raccoons (Procyon lotor) with genetically modified rabies virus vaccines  

PubMed Central

Oral vaccination is an important tool currently in use to control the spread of rabies in wildlife populations in various programs around the world. Oral rabies vaccination (ORV) of raccoons represents the largest targeted program to control wildlife rabies in the United States. Currently, the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG) is the only licensed oral rabies vaccine in the US. In the current study, captive raccoons were used to evaluate two previously described constructs of a rabies virus vaccine developed by reverse genetics (SPBNGAS and SPBNGAS-GAS) for immunogenicity and efficacy compared to the V-RG vaccine. Four of five control animals succumbed to rabies virus after severe challenge, while three of five animals vaccinated orally with SPBNGAS succumbed. No mortality was observed for animals administered SPBNGAS-GAS or the V-RG vaccine. The results of this preliminary study suggest that SPBNGAS-GAS provides comparable efficacy to V-RG. Additional studies will be needed to determine the duration of immunity and optimal dosage of SPBNGAS-GAS and to examine its efficacy in other reservoir species. PMID:17826874

Blanton, Jesse D.; Self, Joshua; Niezgoda, Michael; Faber, Marie-Luise; Dietzschold, Bernhard; Rupprecht, Charles

2007-01-01

140

Blockade of Chemokine Activity by a Soluble Chemokine Binding Protein from Vaccinia Virus1  

Microsoft Academic Search

Chemokines direct migration of immune cells into sites of inflammation and infection. Chemokine receptors are seven-trans- membrane domain proteins that, in contrast to other cytokine receptors, cannot be easily engineered as soluble chemokine inhibitors. Poxviruses encode several soluble cytokine receptors to evade immune surveillance, providing new strategies for immune modulation. Here we show that vaccinia virus and other orthopoxviruses (cowpox

Antonio Alcami; Julian A. Symons; Paul D. Collins; Timothy J. Williams; Geoffrey L. Smith

141

One-step selection of Vaccinia virus-binding DNA aptamers by MonoLEX  

PubMed Central

Background As a new class of therapeutic and diagnostic reagents, more than fifteen years ago RNA and DNA aptamers were identified as binding molecules to numerous small compounds, proteins and rarely even to complete pathogen particles. Most aptamers were isolated from complex libraries of synthetic nucleic acids by a process termed SELEX based on several selection and amplification steps. Here we report the application of a new one-step selection method (MonoLEX) to acquire high-affinity DNA aptamers binding Vaccinia virus used as a model organism for complex target structures. Results The selection against complete Vaccinia virus particles resulted in a 64-base DNA aptamer specifically binding to orthopoxviruses as validated by dot blot analysis, Surface Plasmon Resonance, Fluorescence Correlation Spectroscopy and real-time PCR, following an aptamer blotting assay. The same oligonucleotide showed the ability to inhibit in vitro infection of Vaccinia virus and other orthopoxviruses in a concentration-dependent manner. Conclusion The MonoLEX method is a straightforward procedure as demonstrated here for the identification of a high-affinity DNA aptamer binding Vaccinia virus. MonoLEX comprises a single affinity chromatography step, followed by subsequent physical segmentation of the affinity resin and a single final PCR amplification step of bound aptamers. Therefore, this procedure improves the selection of high affinity aptamers by reducing the competition between aptamers of different affinities during the PCR step, indicating an advantage for the single-round MonoLEX method. PMID:17697378

Nitsche, Andreas; Kurth, Andreas; Dunkhorst, Anna; Pänke, Oliver; Sielaff, Hendrik; Junge, Wolfgang; Muth, Doreen; Scheller, Frieder; Stöcklein, Walter; Dahmen, Claudia; Pauli, Georg; Kage, Andreas

2007-01-01

142

A Loss of Function Analysis of Host Factors Influencing Vaccinia virus Replication by RNA Interference  

PubMed Central

Vaccinia virus (VACV) is a large, cytoplasmic, double-stranded DNA virus that requires complex interactions with host proteins in order to replicate. To explore these interactions a functional high throughput small interfering RNA (siRNA) screen targeting 6719 druggable cellular genes was undertaken to identify host factors (HF) influencing the replication and spread of an eGFP-tagged VACV. The experimental design incorporated a low multiplicity of infection, thereby enhancing detection of cellular proteins involved in cell-to-cell spread of VACV. The screen revealed 153 pro- and 149 anti-viral HFs that strongly influenced VACV replication. These HFs were investigated further by comparisons with transcriptional profiling data sets and HFs identified in RNAi screens of other viruses. In addition, functional and pathway analysis of the entire screen was carried out to highlight cellular mechanisms involved in VACV replication. This revealed, as anticipated, that many pro-viral HFs are involved in translation of mRNA and, unexpectedly, suggested that a range of proteins involved in cellular transcriptional processes and several DNA repair pathways possess anti-viral activity. Multiple components of the AMPK complex were found to act as pro-viral HFs, while several septins, a group of highly conserved GTP binding proteins with a role in sequestering intracellular bacteria, were identified as strong anti-viral VACV HFs. This screen has identified novel and previously unexplored roles for cellular factors in poxvirus replication. This advancement in our understanding of the VACV life cycle provides a reliable knowledge base for the improvement of poxvirus-based vaccine vectors and development of anti-viral theraputics. PMID:24901222

Gonzalez, Orland; Haga, Ismar R.; Pechenick Jowers, Tali; Reynolds, Danielle K.; Wildenhain, Jan; Tekotte, Hille; Auer, Manfred; Tyers, Mike; Ghazal, Peter; Zimmer, Ralf; Haas, Jürgen

2014-01-01

143

A loss of function analysis of host factors influencing Vaccinia virus replication by RNA interference.  

PubMed

Vaccinia virus (VACV) is a large, cytoplasmic, double-stranded DNA virus that requires complex interactions with host proteins in order to replicate. To explore these interactions a functional high throughput small interfering RNA (siRNA) screen targeting 6719 druggable cellular genes was undertaken to identify host factors (HF) influencing the replication and spread of an eGFP-tagged VACV. The experimental design incorporated a low multiplicity of infection, thereby enhancing detection of cellular proteins involved in cell-to-cell spread of VACV. The screen revealed 153 pro- and 149 anti-viral HFs that strongly influenced VACV replication. These HFs were investigated further by comparisons with transcriptional profiling data sets and HFs identified in RNAi screens of other viruses. In addition, functional and pathway analysis of the entire screen was carried out to highlight cellular mechanisms involved in VACV replication. This revealed, as anticipated, that many pro-viral HFs are involved in translation of mRNA and, unexpectedly, suggested that a range of proteins involved in cellular transcriptional processes and several DNA repair pathways possess anti-viral activity. Multiple components of the AMPK complex were found to act as pro-viral HFs, while several septins, a group of highly conserved GTP binding proteins with a role in sequestering intracellular bacteria, were identified as strong anti-viral VACV HFs. This screen has identified novel and previously unexplored roles for cellular factors in poxvirus replication. This advancement in our understanding of the VACV life cycle provides a reliable knowledge base for the improvement of poxvirus-based vaccine vectors and development of anti-viral theraputics. PMID:24901222

Beard, Philippa M; Griffiths, Samantha J; Gonzalez, Orland; Haga, Ismar R; Pechenick Jowers, Tali; Reynolds, Danielle K; Wildenhain, Jan; Tekotte, Hille; Auer, Manfred; Tyers, Mike; Ghazal, Peter; Zimmer, Ralf; Haas, Jürgen

2014-01-01

144

An Overview of the Vaccinia Virus Infectome: a Survey of the Proteins of the Poxvirus-Infected Cell  

PubMed Central

We have quantitatively profiled the proteins of vaccinia virus-infected HEK293T cells early and late during vaccinia virus infection. Proteins corresponding to 4,326 accessions were identified, the products of 3,798 genes. One hundred thirty-six of the proteins were vaccinia virus-encoded (?64% of the known vaccinia virus proteome). The remaining accessions were from the host cell. A total of 3,403 of the 4,326 accessions could be confidently quantitated at the precursor peptide level. Although vaccinia virus gene products spanned the entire abundance dynamic range of the cellular proteome, nearly all of the proteome dynamics observed as a result of infection were manifest in the virus gene products with very little plasticity in the host cell proteome. The vaccinia virus gene products could be grouped into four kinetic classes (i.e., four combinations of pre- and postreplicative expression). These protein kinetic classes reflected, almost entirely, the corresponding gene classes within the recently characterized vaccinia virus transcriptome map. The few cellular gene products that showed notable changes in abundance upon vaccinia virus infection were concentrated largely in just a few functional groups. After all of the quantitated cellular gene products were assigned to Gene Ontology (GO)-specific groups, quantitation values for a number of these GO-specific groups were significantly skewed toward over- or underabundance with respect to the global distribution of quantitation values. Quantitative analysis of host cell functions reflected several known facets of virus infection, along with some novel observations. PMID:22090131

Chou, Wayne; Ngo, Tuan

2012-01-01

145

Modulation of the Myxoma Virus Plaque Phenotype by Vaccinia Virus Protein F11  

PubMed Central

Vaccinia virus (VACV) produces large plaques consisting of a rapidly expanding ring of infected cells surrounding a lytic core, whereas myxoma virus (MYXV) produces small plaques that resemble a focus of transformed cells. This is odd, because bioinformatics suggests that MYXV carries homologs of nearly all of the genes regulating Orthopoxvirus attachment, entry, and exit. So why does MYXV produce foci? One notable difference is that MYXV-infected cells produce few of the actin microfilaments that promote VACV exit and spread. This suggested that although MYXV carries homologs of the required genes (A33R, A34R, A36R, and B5R), they are dysfunctional. To test this, we produced MYXV recombinants expressing these genes, but we could not enhance actin projectile formation even in cells expressing all four VACV proteins. Another notable difference between these viruses is that MYXV lacks a homolog of the F11L gene. F11 inhibits the RhoA-mDia signaling that maintains the integrity of the cortical actin layer. We constructed an MYXV strain encoding F11L and observed that, unlike wild-type MYXV, the recombinant virus disrupted actin stress fibers and produced plaques up to 4-fold larger than those of controls, and these plaques expanded ?6-fold faster. These viruses also grew to higher titers in multistep growth conditions, produced higher levels of actin projectiles, and promoted infected cell movement, although neither process was to the extent of that observed in VACV-infected cells. Thus, one reason for why MYXV produces small plaques is that it cannot spread via actin filaments, although the reason for this deficiency remains obscure. A second reason is that leporipoxviruses lack vaccinia's capacity to disrupt cortical actin. PMID:22514354

Irwin, Chad R.

2012-01-01

146

Genetic strain modification of a live rabies virus vaccine widely used in Europe for wildlife oral vaccination.  

PubMed

In Europe, the main reservoir and vector of rabies has been the red fox (Vulpes vulpes). Oral immunization of foxes with live vaccines, using attenuated rabies strains (SAD B19, SAD Bern), apathogenic mutants of an attenuated strain (SAG2) and the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG), has been shown to be the most effective method for the control and elimination of rabies. Among all vaccines currently used for wildlife oral vaccination, one vaccine (marketed as SAD Bern strain) has been widely used in Europe since 1992 with the distribution of 17million of baits in 2011. Because of the potential environmental safety risk of a live virus which could revert to virulence, the full genome sequencing of this vaccine was undertaken and the sequence was characterized and compared with those of referenced rabies viruses. The vaccine showed higher similarity to the strains belonging to the SAD B19 vaccine virus strains than to the SAD Bern vaccines. This study is the first one reporting on virus strain identity changes in this attenuated vaccine. PMID:23899697

Cliquet, Florence; Robardet, Emmanuelle; Picard Meyer, Evelyne

2013-10-01

147

A Pandemic Influenza H1N1 Live Vaccine Based on Modified Vaccinia Ankara Is Highly Immunogenic and Protects Mice in Active and Passive Immunizations  

PubMed Central

Background The development of novel influenza vaccines inducing a broad immune response is an important objective. The aim of this study was to evaluate live vaccines which induce both strong humoral and cell-mediated immune responses against the novel human pandemic H1N1 influenza virus, and to show protection in a lethal animal challenge model. Methodology/Principal Findings For this purpose, the hemagglutinin (HA) and neuraminidase (NA) genes of the influenza A/California/07/2009 (H1N1) strain (CA/07) were inserted into the replication-deficient modified vaccinia Ankara (MVA) virus - a safe poxviral live vector – resulting in MVA-H1-Ca and MVA-N1-Ca vectors. These live vaccines, together with an inactivated whole virus vaccine, were assessed in a lung infection model using immune competent Balb/c mice, and in a lethal challenge model using severe combined immunodeficient (SCID) mice after passive serum transfer from immunized mice. Balb/c mice vaccinated with the MVA-H1-Ca virus or the inactivated vaccine were fully protected from lung infection after challenge with the influenza H1N1 wild-type strain, while the neuraminidase virus MVA-N1-Ca induced only partial protection. The live vaccines were already protective after a single dose and induced substantial amounts of neutralizing antibodies and of interferon-?-secreting (IFN-?) CD4- and CD8 T-cells in lungs and spleens. In the lungs, a rapid increase of HA-specific CD4- and CD8 T cells was observed in vaccinated mice shortly after challenge with influenza swine flu virus, which probably contributes to the strong inhibition of pulmonary viral replication observed. In addition, passive transfer of antisera raised in MVA-H1-Ca vaccinated immune-competent mice protected SCID mice from lethal challenge with the CA/07 wild-type virus. Conclusions/Significance The non-replicating MVA-based H1N1 live vaccines induce a broad protective immune response and are promising vaccine candidates for pandemic influenza. PMID:20808939

Hessel, Annett; Schwendinger, Michael; Fritz, Daniela; Coulibaly, Sogue; Holzer, Georg W.; Sabarth, Nicolas; Kistner, Otfried; Wodal, Walter; Kerschbaum, Astrid; Savidis-Dacho, Helga; Crowe, Brian A.; Kreil, Thomas R.; Barrett, P. Noel; Falkner, Falko G.

2010-01-01

148

New vaccines against influenza virus  

PubMed Central

Vaccination is one of the most effective and cost-benefit interventions that prevent the mortality and reduce morbidity from infectious pathogens. However, the licensed influenza vaccine induces strain-specific immunity and must be updated annually based on predicted strains that will circulate in the upcoming season. Influenza virus still causes significant health problems worldwide due to the low vaccine efficacy from unexpected outbreaks of next epidemic strains or the emergence of pandemic viruses. Current influenza vaccines are based on immunity to the hemagglutinin antigen that is highly variable among different influenza viruses circulating in humans and animals. Several scientific advances have been endeavored to develop universal vaccines that will induce broad protection. Universal vaccines have been focused on regions of viral proteins that are highly conserved across different virus subtypes. The strategies of universal vaccines include the matrix 2 protein, the hemagglutinin HA2 stalk domain, and T cell-based multivalent antigens. Supplemented and/or adjuvanted vaccination in combination with universal target antigenic vaccines would have much promise. This review summarizes encouraging scientific advances in the field with a focus on novel vaccine designs. PMID:24427759

Lee, Young-Tae; Kim, Ki-Hye; Ko, Eun-Ju; Lee, Yu-Na; Kim, Min-Chul; Kwon, Young-Man; Tang, Yinghua; Cho, Min-Kyoung; Lee, Youn-Jeong

2014-01-01

149

Attenuated NYCBH vaccinia virus deleted for the E3L gene confers partial protection against lethal monkeypox virus disease in cynomolgus macaques.  

PubMed

The New York City Board of Health (NYCBH) vaccinia virus is the currently licensed vaccine for use in the US against smallpox. The vaccine under investigation in this study has been attenuated by deletion of the innate immune evasion gene, E3L, and shown to be protective in homologous virus mouse challenge and heterologous virus mouse and rabbit challenge models. In this study we compared NYCBH deleted for the E3L gene (NYCBH?E3L) to NYCBH for the ability to induce phosphorylation of proinflammatory signaling proteins and the ability to protect cynomolgus macaques from heterologous challenge with monkeypox virus (MPXV). NYCBH?E3L induced phosphorylation of PKR and eIF2? as well as p38, SAPK/JNK, and IRF3 which can lead to induction of proinflammatory gene transcription. Vaccination of macaques with two doses of NYCBH?E3L resulted in negligible pock formation at the site of scarification in comparison to vaccination using a single dose of NYCBH, but still elicited neutralizing antibodies and protected 75% of the animals from mortality after challenge with MPXV. However, NYCBH?E3L-vaccinated animals developed a high number of secondary skin lesions and blood viral load similar to that seen in unvaccinated controls. The NYCBH?E3L-vaccinated animals that survived MPXV challenge were able to show resolution of blood viral load, a decrease in number of skin lesions, and an improved clinical score by three weeks post challenge. These results suggest that although the highly attenuated NYCBH?E3L allows proinflammatory signal transduction to occur, it does not provide full protection against monkeypox challenge. PMID:22001879

Denzler, Karen L; Babas, Tahar; Rippeon, Amy; Huynh, Trung; Fukushima, Nobuko; Rhodes, Lowrey; Silvera, Peter M; Jacobs, Bertram L

2011-12-01

150

Computer Bytes, Viruses and Vaccines.  

ERIC Educational Resources Information Center

Presents a history of computer viruses, explains various types of viruses and how they affect software or computer operating systems, and describes examples of specific viruses. Available vaccines are explained, and precautions for protecting programs and disks are given. (nine references) (LRW)

Palmore, Teddy B.

1989-01-01

151

Vaccination with Venezuelan Equine Encephalitis Replicons Encoding Cowpox Virus Structural Proteins Protects Mice from Intranasal Cowpox Virus Challenge  

PubMed Central

An anti-poxvirus vaccine based on replicon particles of Venezuelan equine encephalitis virus (VRP) is being developed. The cowpox virus genes encoding structural proteins corresponding to vaccinia virus proteins A33, B5, and A27 were each expressed from VRP. High serum IgG titers against these proteins were generated in BALB/c mice vaccinated with each of these VRP. VRP induced both IgG1 and IgG2a with a strong predominance of IgG2a production. The response is long-lasting, as evidenced by the retention of high anti-B5 serum IgG titers through at least 50 weeks after priming immunization. Mice vaccinated with B5-, A33- or A27-VRP individually or together survived intranasal challenge with cowpox virus, with the multivalent vaccine formulation providing more effective protection from weight loss and clinical signs of illness than the monovalent vaccines. These results demonstrate that VRP may provide an effective alternative to vaccinia virus vaccines against poxvirus infection. PMID:17292434

Thornburg, Natalie J.; Ray, Caroline A.; Collier, Martha L.; Liao, Hua-Xin; Pickup, David J.; Johnston, Robert E.

2007-01-01

152

Protection of mice from respiratory Sendai virus infections by recombinant vaccinia viruses.  

PubMed Central

Mechanisms of protection of mice from Sendai virus, which is exclusively pneumotropic and causes a typical respiratory disease, by immunization with recombinant vaccinia viruses (RVVs) were investigated. Although the RVV carrying a hemagglutinin-neuraminidase gene of Sendai virus (Vac-HN) propagated in the noses and lungs of mice by either intranasal (i.n.) or intraperitoneal (i.p.) inoculation, no vaccinia virus antigens were detected in the mucosal layer of upper and lower airways of the i.p.-inoculated mice. The mice immunized i.n. with Vac-HN or Vac-F (the RVV carrying a fusion protein gene of Sendai virus) demonstrated the strong resistance to Sendai virus challenge both in the lung and in the nose, whereas the i.p.-immunized mice showed almost no resistance in the nose but showed a partial resistance in the lung. Titration of Sendai virus-specific antibodies in the nasal wash (NW), bronchoalveolar lavage (BAL), and serum collected from the Vac-F-immunized mice showed that the NW from the i.n.-immunized mice contained immunoglobulin A (IgA) antibodies but no IgG and the BAL from the mice contained both IgA and IgG antibodies. On the other hand, neither IgA nor IgG antibodies were detected in the NW from the i.p.-immunized mice and only IgG antibodies were detected in the BAL, although both i.n.- and i.p.-immunized mice exhibited similar levels of serum IgG, IgA, and neutralizing antibodies. The resistance to Sendai virus in the noses of i.n.-immunized mice could be abrogated by the intranasal instillation of anti-mouse IgA but not of anti-IgG antiserum, while the resistance in the lung was not significantly abrogated by such treatments. These results demonstrate that IgA is a major mediator for the immunity against Sendai virus induced by the RVVs and IgG is a supplementary one, especially in the lung, and that the RVV should be intranasally inoculated to induce an efficient mucosal immunity even if it has a pantropic nature. PMID:8985426

Takao, S I; Kiyotani, K; Sakaguchi, T; Fujii, Y; Seno, M; Yoshida, T

1997-01-01

153

Prospective Surveillance for Cardiac Adverse Events in Healthy Adults Receiving Modified Vaccinia Ankara Vaccines: A Systematic Review  

PubMed Central

Background Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines. Methods Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. ‘Routine cardiac investigations’ (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and ‘Symptom-driven cardiac investigations’ are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine. Results Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine. Conclusions Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants. Trial Registration ClinicalTrials.gov NCT00082446?NCT003766090?NCT00252148?NCT00083603?NCT00301184?NCT00428337 PMID:23349878

Elizaga, Marnie L.; Vasan, Sandhya; Marovich, Mary A.; Sato, Alicia H.; Lawrence, Dale N.; Chaitman, Bernard R.; Frey, Sharon E.; Keefer, Michael C.

2013-01-01

154

Extracellular vesicles containing virus-encoded membrane proteins are a byproduct of infection with modified vaccinia virus Ankara.  

PubMed

Vaccinia virus is a structurally complex virus that multiplies in the cell cytoplasm. The assembly of Vaccinia virus particles and their egress from infected cells exploit cellular pathways. Most notably, intracellular mature viral particles are enwrapped by Golgi-derived or endosomal vesicles. These enveloped particles, enriched in virus-encoded proteins, migrate to the cell surface where they are released into the extracellular space through fusion of their outer envelope with the cell membrane. We report that baby hamster kidney cells productively infected with the modified vaccinia virus Ankara strain (MVA) also release extracellular vesicles containing virus-encoded envelope proteins but devoid of any virus cargo. Such vesicles were visualized on the cell surface by electron microscopy and immunogold labelling of the B5 envelope protein. A portion of the B5 protein was found to be associated with non-viral material in high speed ultracentrifugation pellets and displayed a buoyant density characteristic of exosomes released by some cell types. An unrelated transmembrane protein (CD40 ligand) encoded by the MVA genome was also incorporated into extracellular vesicles but not into the envelopes that surround extracellular enveloped virus. High speed pellets obtained by centrifugation of culture medium from cells infected with MVA encoding CD40 ligand displayed the ability to induce dendritic cell maturation suggesting that the ligand is on the outer surface of the extracellular vesicles. We propose that the formation of extracellular vesicles after vaccinia virus infection is a byproduct of the pathway leading to the formation of extracellular enveloped virus. PMID:18662728

Spehner, Danièle; Drillien, Robert

2008-10-01

155

Regulation of expression and nucleotide sequence of a late vaccinia virus gene.  

PubMed Central

A subset of vaccinia virus genes are expressed only after DNA replication. To investigate the regulation of such transcriptional units, a representative gene encoding a major late polypeptide (Mr, 28,000) was mapped and sequenced. Translatable mRNAs were heterogeneous in length and overlapped several early genes downstream. The 5' end of the message was located, and the DNA segment upstream was excised and ligated to the coding sequence of the easily assayable procaryotic chloramphenicol acetyltransferase gene. The resulting chimeric gene was recombined into the thymidine kinase locus of the vaccinia virus genome, and infectious recombinant virus was isolated. Both the time of chloramphenicol acetyltransferase synthesis in infected cells and the requirement for DNA replication indicate that the sequence upstream of the late gene contains cis-acting transcriptional regulatory signals. Images PMID:6088791

Weir, J P; Moss, B

1984-01-01

156

Stringent chemical and thermal regulation of recombinant gene expression by vaccinia virus vectors in mammalian cells.  

PubMed Central

We developed a stringently regulated expression system for mammalian cells that uses (i) the RNA polymerase, phi 10 promoter, and T phi transcriptional terminator of bacteriophage T7; (ii) the lac repressor, lac operator, rho-independent transcriptional terminators and the gpt gene of Escherichia coli; (iii) the RNA translational enhancer of encephalomyocarditis virus; and (iv) the genetic background of vaccinia virus. In cells infected with the recombinant vaccinia virus, reporter beta-galactosidase synthesis was not detected in the absence of inducer. An induction of at least 10,000- to 20,000-fold occurred upon addition of isopropyl beta-D-thiogalactopyranoside or by temperature elevation from 30 to 37 degrees C using a temperature-sensitive lac repressor. Regulated synthesis of the secreted and highly glycosylated human immunodeficiency virus 1 envelope protein gp120 was also demonstrated. Yields of both proteins were approximately 2 mg per 10(8) cells in 24 hr. Plasmid transfer vectors for cloning and expression of complete or incomplete open reading frames in recombinant vaccinia viruses are described. Images Fig. 2 Fig. 3 Fig. 4 PMID:7624318

Ward, G A; Stover, C K; Moss, B; Fuerst, T R

1995-01-01

157

Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68  

PubMed Central

Background Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo. Methods In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection. Results We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection. Conclusions Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection. PMID:22011439

2011-01-01

158

The vaccinia virus A56 protein: a multifunctional transmembrane glycoprotein that anchors two secreted viral proteins.  

PubMed

The vaccinia virus A56 protein was one of the earliest-described poxvirus proteins with an identifiable activity. While originally characterized as a haemagglutinin protein, A56 has other functions as well. The A56 protein is capable of binding two viral proteins, a serine protease inhibitor (K2) and the vaccinia virus complement control protein (VCP), and anchoring them to the surface of infected cells. This is important; while both proteins have biologically relevant functions at the cell surface, neither one can locate there on its own. The A56-K2 complex reduces the amount of virus superinfecting an infected cell and also prevents the formation of syncytia by infected cells; the A56-VCP complex can protect infected cells from complement attack. Deletion of the A56R gene results in varying effects on vaccinia virus virulence. In addition, since the gene encoding the A56 protein is non-essential, it can be used as an insertion point for foreign genes and has been deleted in some viruses that are in clinical development as oncolytic agents. PMID:21715594

Dehaven, Brian C; Gupta, Kushol; Isaacs, Stuart N

2011-09-01

159

The vaccinia virus A56 protein: a multifunctional transmembrane glycoprotein that anchors two secreted viral proteins  

PubMed Central

The vaccinia virus A56 protein was one of the earliest-described poxvirus proteins with an identifiable activity. While originally characterized as a haemagglutinin protein, A56 has other functions as well. The A56 protein is capable of binding two viral proteins, a serine protease inhibitor (K2) and the vaccinia virus complement control protein (VCP), and anchoring them to the surface of infected cells. This is important; while both proteins have biologically relevant functions at the cell surface, neither one can locate there on its own. The A56–K2 complex reduces the amount of virus superinfecting an infected cell and also prevents the formation of syncytia by infected cells; the A56–VCP complex can protect infected cells from complement attack. Deletion of the A56R gene results in varying effects on vaccinia virus virulence. In addition, since the gene encoding the A56 protein is non-essential, it can be used as an insertion point for foreign genes and has been deleted in some viruses that are in clinical development as oncolytic agents. PMID:21715594

DeHaven, Brian C.; Gupta, Kushol

2011-01-01

160

Protection against lethal Japanese encephalitis virus infection of mice by immunization with the highly attenuated MVA strain of vaccinia virus expressing JEV prM and E genes  

Microsoft Academic Search

Genes encoding the glycosylated precursor of the membrane (prM) and envelope (E) proteins of a Korean strain of Japanese encephalitis virus (JEV) were inserted into the genome of the host-range restricted, highly attenuated, and safety-tested MVA strain of vaccinia virus. MVA recombinants containing the JEV genes, under strong synthetic or modified H5 vaccinia virus promoters, were isolated. Synthesis of JEV

Jae-Hwan Nam; Linda S Wyatt; Soo-Lim Chae; Hae-Wol Cho; Young-Keun Park; Bernard Moss

1999-01-01

161

Human Vaccines & Immunotherapeutics: News  

PubMed Central

Oncolytic vaccinia virus vaccine: Promising in liver cancer patients FDA panel endorses quadrivalent influenza vaccines Approval for the first meningitis B vaccine Stallergenes seeks FDA approval for sublingual grass-pollen allergy tablet Live-attenuated dengue vaccine promising in Phase 1 GAVI funds HPV vaccines for girls in developing countries First human trials for new superantigen bioterrorism vaccine Hexyon hexavalent pediatric vaccine recommended for approval

Riedmann, Eva M.

2013-01-01

162

9 CFR 113.209 - Rabies Vaccine, Killed Virus.  

Code of Federal Regulations, 2010 CFR

... 1 2010-01-01 2010-01-01 false Rabies Vaccine, Killed Virus. 113.209 Section...REQUIREMENTS Killed Virus Vaccines § 113.209 Rabies Vaccine, Killed Virus. Rabies Vaccine (Killed Virus) shall be prepared...

2010-01-01

163

Apoptin enhances the oncolytic properties of vaccinia virus and modifies mechanisms of tumor regression  

PubMed Central

A recombinant vaccinia virus VVdGF-ApoS24/2 expressing apoptin selectively kills human cancer cells in vitro [Kochneva et al., 2013]. We compared the oncolytic activity of this recombinant with that of the parental strain L-IVP using a model of human A431 carcinoma xenografts in nude mice. Single intratumoral injections (2×107 PFU/mouse) of the viruses produced a dramatic decrease in tumor volumes, which was higher after injection of apoptin-producing virus. The tumor dried out after the injection of recombinant while injection of L-IVP strain resulted in formation of cavities filled with cell debris and liquid. Both viruses rapidly spread in xenografts and replicate exclusively in tumor cells causing their destruction within 8 days. Both viruses induced insignificant level of apoptosis in tumors. Unlike the previously described nuclear localization of apoptin in cancer cells the apoptin produced by recombinant virus was localized to the cytoplasm. The apoptin did not induce a typical apoptosis, but it rather influenced pathway of cell death and thereby caused tumor shrinkage. The replacement of destroyed cells by filamentous material is the main feature of tumor regression caused by the VVdGF-ApoS24/2 virus. The study points the presence of complicated mechanisms of apoptin effects at the background of vaccinia virus replication. PMID:25358248

Kochneva, Galina; Zonov, Evgeniy; Grazhdantseva, Antonina; Yunusova, Anastasiya; Sibolobova, Galina; Popov, Evgeniy; Taranov, Oleg; Netesov, Sergei; Chumakov, Peter; Ryabchikova, Elena

2014-01-01

164

Apoptin enhances the oncolytic properties of vaccinia virus and modifies mechanisms of tumor regression.  

PubMed

A recombinant vaccinia virus VVdGF-ApoS24/2 expressing apoptin selectively kills human cancer cells in vitro [Kochneva et al., 2013]. We compared the oncolytic activity of this recombinant with that of the parental strain L-IVP using a model of human A431 carcinoma xenografts in nude mice. Single intratumoral injections (2×10^7 PFU/mouse) of the viruses produced a dramatic decrease in tumor volumes, which was higher after injection of apoptin-producing virus. The tumor dried out after the injection of recombinant while injection of L-IVP strain resulted in formation of cavities filled with cell debris and liquid. Both viruses rapidly spread in xenografts and replicate exclusively in tumor cells causing their destruction within 8 days. Both viruses induced insignificant level of apoptosis in tumors. Unlike the previously described nuclear localization of apoptin in cancer cells the apoptin produced by recombinant virus was localized to the cytoplasm. The apoptin did not induce a typical apoptosis, but it rather influenced pathway of cell death and thereby caused tumor shrinkage. The replacement of destroyed cells by filamentous material is the main feature of tumor regression caused by the VVdGF-ApoS24/2 virus. The study points the presence of complicated mechanisms of apoptin effects at the background of vaccinia virus replication. PMID:25358248

Kochneva, Galina; Zonov, Evgeniy; Grazhdantseva, Antonina; Yunusova, Anastasiya; Sibolobova, Galina; Popov, Evgeniy; Taranov, Oleg; Netesov, Sergei; Chumakov, Peter; Ryabchikova, Elena

2014-11-30

165

Vaccinia reporter viruses for quantifying viral function at all stages of gene expression.  

PubMed

Poxviruses are a family of double stranded DNA viruses that include active human pathogens such as monkeypox, molluscum contagiousum, and Contagalo virus. The family also includes the smallpox virus, Variola. Due to the complexity of poxvirus replication, many questions still remain regarding their gene expression strategy. In this article we describe the conceptualization and usage of recombinant vaccinia viruses that enable real-time measurement of single and multiple stages of viral gene expression in a high-throughput format. This is enabled through the use of spectrally distinct fluorescent proteins as reporters for each of three stages of viral replication. These viruses provide a high signal-to-noise ratio while retaining stage specific expression patterns, enabling plate-based assays and microscopic observations of virus propagation and replication. These tools have uses for antiviral discovery, studies of the virus-host interaction, and evolutionary biology. PMID:24894622

Rozelle, Daniel K; Filone, Claire Marie; Dower, Ken; Connor, John H

2014-01-01

166

Attenuation of vaccinia virus by the expression of human Flt3 ligand  

PubMed Central

Background Vaccinia virus, one of the best known members of poxvirus family, has a wide host range both in vivo and in vitro. The expression of Flt3 ligand (FL) by recombinant vaccinia virus (rVACV) highly influenced properties of the virus in dependence on the level of expression. Results High production of FL driven by the strong synthetic promoter decreased the growth of rVACV in macrophage cell line J774.G8 in vitro as well as its multiplication in vivo when inoculated in mice. The inhibition of replication in vivo was mirrored in low levels of antibodies against vaccinia virus (anti-VACV) which nearly approached to the negative serum level in non-infected mice. Strong FL expression changed not only the host range of the recombinant but also the basic protein contents of virions. The major proteins - H3L and D8L - which are responsible for the virus binding to the cells, and 28 K protein that serves as a virulence factor, were changed in the membrane portion of P13-E/L-FL viral particles. The core virion fraction contained multiple larger, uncleaved proteins and a higher amount of cellular proteins compared to the control virus. The overexpression of FL also resulted in its incorporation into the viral core of P13-E/L-FL IMV particles. In contrary to the equimolar ratio of glycosylated and nonglycosylated FL forms found in cells transfected with the expression plasmid, the recombinant virus incorporated mainly the smaller, nonglycosylated FL. Conclusions It has been shown that the overexpression of the Flt3L gene in VACV results in the attenuation of the virus in vivo. PMID:20504356

2010-01-01

167

Functional Characterization of Glycosylation-Deficient Human P-Glycoprotein Using A Vaccinia Virus Expression System  

Microsoft Academic Search

.   P-glycoprotein (P-gp), the product of human MDR1 gene, which functions as an ATP-dependent drug efflux pump, is N-linked glycosylated at asparagine residues 91, 94, and\\u000a 99 located within the first extracellular loop. We report here the biochemical characterization of glycosylation-deficient\\u000a (Gly?) P-gp using a vaccinia virus based transient expression system. The staining of HeLa cells expressing Gly? P-gp (91,

J. J. Gribar; M. Ramachandra; C. A. Hrycyna; S. Dey; S. V. Ambudkar

2000-01-01

168

Crystal structure of vaccinia virus uracil-DNA glycosylase reveals dimeric assembly  

Microsoft Academic Search

BACKGROUND: Uracil-DNA glycosylases (UDGs) catalyze excision of uracil from DNA. Vaccinia virus, which is the prototype of poxviruses, encodes a UDG (vvUDG) that is significantly different from the UDGs of other organisms in primary, secondary and tertiary structure and characteristic motifs. It adopted a novel catalysis-independent role in DNA replication that involves interaction with a viral protein, A20, to form

Norbert Schormann; Alexei Grigorian; Alexandra Samal; Raman Krishnan; Lawrence DeLucas; Debasish Chattopadhyay

2007-01-01

169

Elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodeficiency Virus-Specific CD8 T Cells during Chronic Infection but Not after Vaccination  

Microsoft Academic Search

Here, we study the temporal expression of the inhibitory receptor programmed death 1 (PD-1) on simian immunodeficiency virus (SIV) Gag-specific T cells following pathogenic SIV infection or following vaccination with a DNA\\/modified vaccinia virus Ankara (DNA\\/MVA) vaccine and simian\\/human immunodeficiency virus (SHIV) challenge in macaques. Following infection, the majority (>95%) of Gag-specific CD8 T cells expressed PD-1, and the level

Vijayakumar Velu; Sunil Kannanganat; Chris Ibegbu; Lakshmi Chennareddi; Francois Villinger; Gordon J. Freeman; Rafi Ahmed; Rama Rao Amara

2007-01-01

170

A Vaccinia Virus Recombinant Transcribing an Alphavirus Replicon and Expressing Alphavirus Structural Proteins Leads to Packaging of Alphavirus Infectious Single Cycle Particles  

PubMed Central

Poxviruses and Alphaviruses constitute two promising viral vectors that have been used extensively as expression systems, or as vehicles for vaccine purposes. Poxviruses, like vaccinia virus (VV) are well-established vaccine vectors having large insertion capacity, excellent stability, and ease of administration. In turn, replicons derived from Alphaviruses like Semliki Forest virus (SFV) are potent protein expression and immunization vectors but stocks are difficult to produce and maintain. In an attempt to demonstrate the use of a Poxvirus as a means for the delivery of small vaccine vectors, we have constructed and characterized VV/SFV hybrid vectors. A SFV replicon cDNA was inserted in the VV genome and placed under the control of a VV early promoter. The replicon, transcribed from the VV genome as an early transcript, was functional, and thus capable of initiating its own replication and transcription. Further, we constructed a VV recombinant additionally expressing the SFV structural proteins under the control of a vaccinia synthetic early/late promoter. Infection with this recombinant produced concurrent transcription of the replicon and expression of SFV structural proteins, and led to the generation of replicon-containing SFV particles that were released to the medium and were able to infect additional cells. This combined VV/SFV system in a single virus allows the use of VV as a SFV delivery vehicle in vivo. The combination of two vectors, and the possibility of generating in vivo single-cycle, replicon containing alphavirus particles, may open new strategies in vaccine development or in the design of oncolytic viruses. PMID:24130722

Sánchez-Puig, Juana M.; Lorenzo, María M.; Blasco, Rafael

2013-01-01

171

Modified vaccinia virus Ankara expressing the hemagglutinin of pandemic (H1N1) 2009 virus induces cross-protective immunity against Eurasian ‘avian-like’ H1N1 swine viruses in mice  

PubMed Central

Objectives To examine cross-reactivity between hemagglutinin (HA) derived from A/California/7/09 (CA/09) virus and that derived from representative Eurasian “avian-like” (EA) H1N1 swine viruses isolated in Italy between 1999 and 2008 during virological surveillance in pigs. Design Modified vaccinia virus Ankara (MVA) expressing the HA gene of CA/09 virus (MVA-HA-CA/09) was used as a vaccine to investigate cross-protective immunity against H1N1 swine viruses in mice. Sample Two classical swine H1N1 (CS) viruses and four representative EA-like H1N1 swine viruses previously isolated during outbreaks of respiratory disease in pigs on farms in Northern Italy were used in this study. Setting Female C57BL/6 mice were vaccinated with MVA/HA/CA/09 and then challenged intranasally with H1N1 swine viruses. Main outcome measures Cross-reactive antibody responses were determined by hemagglutination- inhibition (HI) and virus microneutralizing (MN) assays of sera from MVA-vaccinated mice. The extent of protective immunity against infection with H1N1 swine viruses was determined by measuring lung viral load on days 2 and 4 post-challenge. Results and Conclusions Systemic immunization of mice with CA/09-derived HA, vectored by MVA, elicited cross-protective immunity against recent EA-like swine viruses. This immune protection was related to the levels of cross-reactive HI antibodies in the sera of the immunized mice and was dependent on the similarity of the antigenic site Sa of H1 HAs. Our findings suggest that the herd immunity elicited in humans by the pandemic (H1N1) 2009 virus could limit the transmission of recent EA-like swine HA genes into the influenza A virus gene pool in humans. PMID:24373385

Castrucci, Maria R; Facchini, Marzia; Di Mario, Giuseppina; Garulli, Bruno; Sciaraffia, Ester; Meola, Monica; Fabiani, Concetta; De Marco, Maria A; Cordioli, Paolo; Siccardi, Antonio; Kawaoka, Yoshihiro; Donatelli, Isabella

2014-01-01

172

Immunogenicity and protective efficacy of Semliki forest virus replicon-based DNA vaccines encoding goatpox virus structural proteins  

SciTech Connect

Goatpox, caused by goatpox virus (GTPV), is an acute feverish and contagious disease in goats often associated with high morbidity and high mortality. To resolve potential safety risks and vaccination side effects of existing live attenuated goatpox vaccine (AV41), two Semliki forest virus (SFV) replicon-based bicistronic expression DNA vaccines (pCSm-AAL and pCSm-BAA) which encode GTPV structural proteins corresponding to the Vaccinia virus proteins A27, L1, A33, and B5, respectively, were constructed. Then, theirs ability to induce humoral and cellular response in mice and goats, and protect goats against virulent virus challenge were evaluated. The results showed that, vaccination with pCSm-AAL and pCSm-BAA in combination could elicit strong humoral and cellular responses in mice and goats, provide partial protection against viral challenge in goats, and reduce disease symptoms. Additionally, priming vaccination with the above-mentioned DNA vaccines could significantly reduce the goats' side reactions from boosting vaccinations with current live vaccine (AV41), which include skin lesions at the inoculation site and fevers. Data obtained in this study could not only facilitate improvement of the current goatpox vaccination strategy, but also provide valuable guidance to suitable candidates for evaluation and development of orthopoxvirus vaccines.

Zheng Min [Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun 130062 (China); Guangxi Center for Animal Disease Control and Prevention, Nanning 530001 (China); College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062 (China); Jin Ningyi, E-mail: jinningyi2000@yahoo.com.c [Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun 130062 (China); Liu Qi, E-mail: gx_liuqi@yahoo.com.c [Guangxi Center for Animal Disease Control and Prevention, Nanning 530001 (China); Huo Xiaowei [Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun 130062 (China); Li Yang [Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun 130062 (China); College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062 (China); Hu Bo; Ma Haili; Zhu Zhanbo; Cong Yanzhao; Li Xiao; Jin Minglan; Zhu Guangze [Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun 130062 (China)

2009-08-15

173

Isolation and characterization of a Chinese hamster ovary mutant cell line with altered sensitivity to vaccinia virus killing.  

PubMed Central

The Chinese hamster ovary (CHO) cell line is nonpermissive for vaccinia virus, and translation of viral intermediate genes was reported to be blocked (A. Ramsey-Ewing and B. Moss, Virology 206:984-993, 1995). However, cells are readily killed by vaccinia virus. A vaccinia virus-resistant CHO mutant, VV5-4, was isolated by retroviral insertional mutagenesis. Parental CHO cells, upon infection with vaccinia virus, die within 2 to 3 days, whereas VV5-4 cells preferentially survive this cytotoxic effect. The survival phenotype of VV5-4 is partial and in inverse correlation with the multiplicity of infection used. In addition, viral infection fails to shut off host protein synthesis in VV5-4. VV5-4 was used to study the relationship of progression of the virus life cycle and cell fate. We found that in parental CHO cells, vaccinia virus proceeds through expression of viral early genes, uncoating, viral DNA replication, and expression of intermediate and late promoters. In contrast, we detect only expression of early genes and uncoating in VV5-4 cells, whereas viral DNA replication appears to be blocked. Consistent with the cascade regulation model of viral gene expression, we detect little intermediate- and late-gene expression in VV5-4 cells. Since vaccinia virus is known to be cytolytic, isolation of this mutant therefore demonstrates a new mode of the cellular microenvironment that affects progression of the virus life cycle, resulting in a different cell fate. This process appears to be mediated by a general mechanism, since VV5-4 is also resistant to Shope fibroma virus and myxoma virus killing. On the other hand, VV5-4 remains sensitive to cowpox virus killing. To examine the mechanism of VV5-4 survival, we investigated whether apoptosis is involved. DNA laddering and staining of apoptotic nuclei with Hoechst 33258 were observed in both CHO and VV5-4 cells infected with vaccinia virus. We concluded that the cellular pathway, which blocks viral DNA replication and allows VV5-4 to survive, is independent of apoptosis. This mutant also provides evidence that an inductive signal for apoptosis upon vaccinia virus infection occurs prior to viral DNA replication. PMID:8676492

Bair, C H; Chung, C S; Vasilevskaya, I A; Chang, W

1996-01-01

174

Human immunodeficiency virus vaccines.  

PubMed

Although some success was achieved in recent years in HIV prevention, an effective vaccine remains the means with the most potential of curtailing HIV-1 infections worldwide. Despite multiple failed attempts, a recent HIV vaccine regimen demonstrated modest protection from infection. Although the protective efficacy in this trial was not sufficient to warrant licensure, it spurred renewed optimism in the field and has provided valuable insights for improving future vaccine designs. This review summarizes the pertinent details of vaccine development and discusses ways the field is moving forward to develop a vaccine to prevent HIV infection and disease progression. PMID:25287587

Goepfert, Paul; Bansal, Anju

2014-12-01

175

Epstein–barr virus vaccines  

PubMed Central

Epstein–Barr virus (EBV) is the primary cause of infectious mononucleosis (IM) and is associated with epithelial cell malignancies such as nasopharyngeal carcinoma and gastric carcinoma, as well as lymphoid malignancies including Hodgkin lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. EBV vaccines to prevent primary infection or disease, or therapeutic vaccines to treat EBV malignancies have not been licensed. Most efforts to develop prophylactic vaccines have focused on EBV gp350, which is the major target of neutralizing antibody. A single phase 2 trial of an EBV gp350 vaccine has been reported; the vaccine reduced the rate of IM but not virus infection. The observation that infusion of EBV-specific T cells can reduce disease due to Hodgkin lymphoma and nasopharyngeal carcinoma provides a proof of principle that a therapeutic vaccine for these and other EBV-associated malignancies might be effective. Most therapeutic vaccines have targeted EBV LMP2 and EBV nuclear antigen-1. As EBV is associated with nearly 200?000 new malignancies each year worldwide, an EBV vaccine to prevent these diseases is needed. PMID:25671130

Cohen, Jeffrey I

2015-01-01

176

Coexpression by vaccinia virus recombinants of equine herpesvirus 1 glycoproteins gp13 and gp14 results in potentiated immunity.  

PubMed Central

The equine herpesvirus 1 glycoprotein 14 (EHV-1 gp14) gene was cloned, sequenced, and expressed by vaccinia virus recombinants. Recombinant virus vP613 elicited the production of EHV-1-neutralizing antibodies in guinea pigs and was effective in protecting hamsters from subsequent lethal EHV-1 challenge. Coexpression of EHV-1 gp14 in vaccinia virus recombinant vP634 along with EHV-1 gp13 (P. Guo, S. Goebel, S. Davis, M. E. Perkus, B. Languet, P. Desmettre, G. Allen, and E. Paoletti, J. Virol. 63:4189-4198, 1989) greatly enhanced the protective efficacy in the hamster challenge model over that obtained with single recombinants. The inoculum doses (log10) required for protection of 50% of hamsters were 6.1 (EHV-1 gp13), 5.2 (EHV-1 gp14), and less than 3.6 (vaccinia virus recombinant expressing both EHV-1 glycoproteins [gp13 and gp14]). PMID:2157895

Guo, P X; Goebel, S; Perkus, M E; Taylor, J; Norton, E; Allen, G; Languet, B; Desmettre, P; Paoletti, E

1990-01-01

177

ISG15 Is Counteracted by Vaccinia Virus E3 Protein and Controls the Proinflammatory Response against Viral Infection  

PubMed Central

Conjugation of ISG15 inhibits replication of several viruses. Here, using an expression system for assaying human and mouse ISG15 conjugations (ISGylations), we have demonstrated that vaccinia virus E3 protein binds and antagonizes human and mouse ISG15 modification. To study ISGylation importance in poxvirus infection, we used a mouse model that expresses deconjugating proteases. Our results indicate that ISGylation restricts in vitro replication of the vaccinia virus VV?E3L mutant but unconjugated ISG15 is crucial to counteract the inflammatory response produced after VV?E3L infection. PMID:24257616

Eduardo-Correia, Benedito; Martínez-Romero, Carles; García-Sastre, Adolfo

2014-01-01

178

Structural Insight into BH3 Domain Binding of Vaccinia Virus Antiapoptotic F1L  

PubMed Central

ABSTRACT Apoptosis is a tightly regulated process that plays a crucial role in the removal of virus-infected cells, a process controlled by both pro- and antiapoptotic members of the Bcl-2 family. The proapoptotic proteins Bak and Bax are regulated by antiapoptotic Bcl-2 proteins and are also activated by a subset of proteins known as BH3-only proteins that perform dual functions by directly activating Bak and Bax or by sequestering and neutralizing antiapoptotic family members. Numerous viruses express proteins that prevent premature host cell apoptosis. Vaccinia virus encodes F1L, an antiapoptotic protein essential for survival of infected cells that bears no discernible sequence homology to mammalian cell death inhibitors. Despite the limited sequence similarities, F1L has been shown to adopt a novel dimeric Bcl-2-like fold that enables hetero-oligomeric binding to both Bak and the proapoptotic BH3-only protein Bim that ultimately prevents Bak and Bax homo-oligomerization. However, no structural data on the mode of engagement of F1L and its Bcl-2 counterparts are available. Here we solved the crystal structures of F1L in complex with two ligands, Bim and Bak. Our structures indicate that F1L can engage two BH3 ligands simultaneously via the canonical Bcl-2 ligand binding grooves. Furthermore, by structure-guided mutagenesis, we generated point mutations within the binding pocket of F1L in order to elucidate the residues responsible for both Bim and Bak binding and prevention of apoptosis. We propose that the sequestration of Bim by F1L is primarily responsible for preventing apoptosis during vaccinia virus infection. IMPORTANCE Numerous viruses have adapted strategies to counteract apoptosis by encoding proteins responsible for sequestering proapoptotic components. Vaccinia virus, the prototypical member of the family Orthopoxviridae, encodes a protein known as F1L that functions to prevent apoptosis by interacting with Bak and the BH3-only protein Bim. Despite recent structural advances, little is known regarding the mechanics of binding between F1L and the proapoptotic Bcl-2 family members. Utilizing three-dimensional structures of F1L bound to host proapoptotic proteins, we generated variants of F1L that neutralize Bim and/or Bak. We demonstrate that during vaccinia virus infection, engagement of Bim and Bak by F1L is crucial for subversion of host cell apoptosis. PMID:24850748

Campbell, Stephanie; Thibault, John; Mehta, Ninad; Colman, Peter M.

2014-01-01

179

Distinct Gene Expression Profiles in Peripheral Blood Mononuclear Cells from Patients Infected with Vaccinia Virus, Yellow Fever 17D Virus, or Upper Respiratory Infections Running Title: PBMC Expression Response to Viral Agents  

PubMed Central

Gene expression in human peripheral blood mononuclear cells was systematically evaluated following smallpox and yellow fever vaccination, and naturally occurring upper respiratory infection (URI). All three infections were characterized by the induction of many interferon stimulated genes, as well as enhanced expression of genes involved in proteolysis and antigen presentation. Vaccinia infection was also characterized by a distinct expression signature composed of up-regulation of monocyte response genes, with repression of genes expressed by B and T-cells. In contrast, the yellow fever host response was characterized by a suppression of ribosomal and translation factors, distinguishing this infection from vaccinia and URI. No significant URI-specific signature was observed, perhaps reflecting greater heterogeneity in the study population and etiological agents. Taken together, these data suggest that specific host gene expression signatures may be identified that distinguish one or a small number of virus agents. PMID:17651872

Scherer, Christina A.; Magness, Charles L.; Steiger, Kathryn V.; Poitinger, Nicholas D.; Caputo, Christine M.; Miner, Douglas G.; Winokur, Patricia L.; Klinzman, Donna; McKee, Janice; Pilar, Christine; Ward, Patricia A.; Gillham, Martha H.; Haulman, N. Jean; Stapleton, Jack T.; Iadonato, Shawn P.

2007-01-01

180

Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses  

Microsoft Academic Search

Cidofovir {((S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine) (HPMPC)}-resistant forms of camel- pox, cowpox, monkeypox, and vaccinia viruses were developed by prolonged passage in Vero 76 cells in the presence of drug. Eight- to 27-fold-higher concentrations of cidofovir were required to inhibit the resistant viruses than were needed to inhibit the wild-type (WT) viruses. Resistant viruses were characterized by determining their cross-resistance to other antiviral compounds,

Donald F. Smee; Robert W. Sidwell; Debbie Kefauver; Mike Bray; John W. Huggins

2002-01-01

181

Viruses - from pathogens to vaccine carriers.  

PubMed

Vaccination is mankind's greatest public health success story. By now vaccines to many of the viruses that once caused fatal childhood diseases are routinely used throughout the world. Traditional methods of vaccine development through inactivation or attenuation of viruses have failed for some of the most deadly human pathogens, necessitating new approaches. Genetic modification of viruses not only allows for their attenuation but also for incorporation of sequences from other viruses, turning one pathogen into a vaccine carrier for another. Recombinant viruses have pros and cons as vaccine carriers, as discussed below using vectors based on adenovirus, herpesvirus, flavivirus, and rhabdovirus as examples. PMID:22003377

Small, Juliana C; Ertl, Hildegund C J

2011-10-01

182

Vaccinia virus protein F12 associates with intracellular enveloped virions through an interaction with A36.  

PubMed

Vaccinia virus is the prototypical member of the family Poxviridae. Three morphologically distinct forms are produced during infection: intracellular mature virions (IMV), intracellular enveloped virions (IEV), and extracellular enveloped virions (EEV). Two viral proteins, F12 and A36, are found exclusively on IEV but not on IMV and EEV. Analysis of membranes from infected cells showed that F12 was only associated with membranes and is not an integral membrane protein. A yeast two-hybrid assay revealed an interaction between amino acids 351 to 458 of F12 and amino acids 91 to 111 of A36. We generated a recombinant vaccinia virus that expresses an F12, which lacks residues 351 to 458. Characterization of this recombinant revealed a small-plaque phenotype and a subsequent defect in virus release similar to a recombinant virus that had F12L deleted. In addition, F12 lacking residues 351 to 458 was unable to associate with membranes in infected cells. These results suggest that F12 associates with IEV through an interaction with A36 and that this interaction is critical for the function of F12 during viral egress. PMID:19052096

Johnston, Sara C; Ward, Brian M

2009-02-01

183

CD4 and CD8 T cells participate in the immune memory response against Vaccinia virus after a previous natural infection?  

PubMed Central

The present study evaluates the immune response of memory CD4+ and CD8+ T cells from patients following a natural Vaccinia virus (VACV) infection. A total of 42 individuals were involved in the study being: 22 previously infected individuals (vaccinated or not against smallpox) and 20 non-infected individuals (vaccinated or not). A short-term in vitro stimulation with UV-inactivated VACV of whole blood cells was performed. Our study showed that previously infected individuals have a lower percentage of CD4+ T cells expressing lymph-node homing receptors (CD4+CD62L+CCR7+) and higher percentage of memory CD4+ T cells subsets (CD4+CD45ROHigh) when compared with non-infected subjects, after in vitro viral stimulation. We also showed that infected individuals presented higher percentages of CD4+ and CD8+ memory T lymphocytes expressing IFN-? when compared to non-infected individuals. We verified that the percentage of CD4+ and CD8+ T memory cells expressing TNF-? was higher in infected and non-infected vaccinated subjects when compared with non-infected unvaccinated individual. We also observed that previously infected individuals have higher percentages of CD8+ T cells expressing lymph-node homing receptors (CCR7+ and CD62L+) and that the memory T cells expressing IFN-? and TNF-? were at higher percentages in the whole blood cells from infected and non-infected vaccinated individuals, when compared to unvaccinated non-infected subjects. Thus, our findings suggest that CD4+ and CD8+ T cells are involved in the immune memory response against Vaccinia virus natural infection. PMID:24600565

Medeiros-Silva, Daniela Carla; dos Santos Moreira-Silva, Eduardo Augusto; Assis Silva Gomes, Juliana de; da Fonseca, Flávio Guimarães; Correa-Oliveira, Rodrigo

2013-01-01

184

Nucleotide sequence of a cluster of early and late genes in a conserved segment of the vaccinia virus genome.  

PubMed Central

The nucleotide sequence of a 7.6 kb vaccinia DNA segment from a genomic region conserved among different orthopox virus has been determined. This segment contains a tight cluster of 12 partly overlapping open reading frames most of which can be correlated with previously identified early and late proteins and mRNAs. Regulatory signals used by vaccinia virus have been studied. Presumptive promoter regions are rich in A, T and carry the consensus sequences TATA and AATAA spaced at 20-24 base pairs. Tandem repeats of a CTATTC consensus sequence are proposed to be involved in the termination of early transcription. PMID:2987815

Plucienniczak, A; Schroeder, E; Zettlmeissl, G; Streeck, R E

1985-01-01

185

Vaccinia virus encodes four putative DNA and/or RNA helicases distantly related to each other.  

PubMed

Computer-assisted analysis of the amino acid sequences of vaccinia virus proteins containing the purine NTP-binding pattern revealed the seven motifs typical of the DNA (RNA) helicase superfamily II in the proteins I8R and A18R. Together with the previously described putative helicases D6R and D11L, the number of putative helicases of this superfamily encoded by the genome of vaccinia virus now reaches four. Aside from the helicase motifs, the sequences of I8R and A18R showed no strong similarity to each other, nor to D6R and D11L. Statistically significant similarity was demonstrated between I8R and the putative RNA helicases involved in pre-mRNA splicing in yeast, PRP2, PRP16 and PRP22, whereas A18R appeared to be related to the putative helicases encoded by the human DNA repair gene ERCC3 and the D10 gene of bacteriophage T5. These findings suggest that I8R may be an RNA helicase. Based on the known properties of the virion NTPases of vaccinia virus, it is possible that the I8R protein may be identical to the previously characterized virion NTPase II. A18R is likely to possess DNA and/or RNA helicase activity. Circumstantial evidence suggests that this activity might be involved in melting duplex structures in late mRNAs. The possibility of independent acquisition of the putative helicases I8R, A18R and a common progenitor to D6R and D11L by an ancestral poxvirus is discussed. PMID:1321883

Koonin, E V; Senkevich, T G

1992-04-01

186

Subunit Recombinant Vaccine Protects against Monkeypox 1  

Microsoft Academic Search

The smallpox vaccine Dryvax, a live vaccinia virus (VACV), protects against smallpox and monkeypox, but is contraindicated in immunocompromised individuals. Because Abs to VACV mediate protection, a live virus vaccine could be substituted by a safe subunit protein-based vaccine able to induce a protective Ab response. We immunized rhesus macaques with plasmid DNA encoding the monkeypox orthologs of the VACV

Jean-Michel Heraud; Yvette Edghill-Smith; Victor Ayala; Irene Kalisz; Janie Parrino; Vaniambadi S. Kalyanaraman; Jody Manischewitz; Lisa R. King; Anna Hryniewicz; Christopher J. Trindade; Meredith Hassett; Wen-Po Tsai; David Venzon; Aysegul Nalca; Monica Vaccari; Peter Silvera; Mike Bray; Barney S. Graham; Hana Golding; Jay W. Hooper; Genoveffa Franchini

187

Recombinant Modified Vaccinia Virus Ankara Provides Durable Protection Against Disease Caused by an Immunodeficiency Virus as well as Long Term Immunity to an Orthopoxvirus in a Non-Human Primate  

PubMed Central

Recombinant and non-recombinant modified vaccinia virus Ankara (MVA) strains are currently in clinical trials as human immunodeficiency virus-1 (HIV) and attenuated smallpox vaccines, respectively. Here we tested the ability of a recombinant MVA delivered by alternative needle-free routes (intramuscular, intradermal, or into the palatine tonsil) to protect against immunodeficiency and orthopoxvirus diseases in a non-human primate model. Rhesus macaques were immunized twice one month apart with MVA expressing 5 genes from a pathogenic simian human immunodeficiency virus (SHIV)/89.6P and challenged intrarectally 9 months later with the pathogenic SHIV/89.6P and intravenously 2.7 years later with monkeypox virus. Irrespective of the route of vaccine delivery, binding and neutralizing antibodies and CD8 responses to SHIV and orthopoxvirus proteins were induced and the monkeys were successively protected against the diseases caused by the challenge viruses in unimmunized controls as determined by viral loads and clinical signs. These non-human primate studies support the clinical testing of recombinant MVA as an HIV vaccine and further demonstrate that MVA can provide long term poxvirus immunity, essential for use as an alternative smallpox vaccine. PMID:17499326

Earl, Patricia L.; Americo, Jeffrey L.; Wyatt, Linda S.; Eller, Leigh Anne; Montefiori, David C.; Byrum, Russ; Piatak, Michael; Lifson, Jeffrey D.; Amara, Rama Rao; Robinson, Harriet L.; Huggins, John W.; Moss, Bernard

2007-01-01

188

RAB1A promotes Vaccinia virus replication by facilitating the production of intracellular enveloped virions  

PubMed Central

Vaccinia virus (VACV) is a large double-stranded DNA virus with a complex cytoplasmic replication cycle that exploits numerous cellular proteins. This work characterises the role of a proviral cellular protein, the small GTPase RAB1A, in VACV replication. Using siRNA, we identified RAB1A as required for the production of extracellular enveloped virions (EEVs), but not intracellular mature virions (IMVs). Immunofluorescence and electron microscopy further refined the role of RAB1A as facilitating the wrapping of IMVs to become intracellular enveloped virions (IEVs). This is consistent with the known function of RAB1A in maintenance of ER to Golgi transport. VACV can therefore be added to the growing list of viruses which require RAB1A for optimal replication, highlighting this protein as a broadly proviral host factor. PMID:25462347

Pechenick Jowers, Tali; Featherstone, Rebecca J.; Reynolds, Danielle K.; Brown, Helen K.; James, John; Prescott, Alan; Haga, Ismar R.; Beard, Philippa M.

2015-01-01

189

Effective tumor immunotherapy directed against an oncogene-encoded product using a vaccinia virus vector.  

PubMed Central

We have constructed a vaccinia virus recombinant that expresses the extracellular domain of the rat neu oncogene-encoded protein, a 185-kDa transmembrane glycoprotein termed p185. Strain NFS mice immunized with this recombinant virus developed a strong antibody response against the neu oncogene product and were fully protected against subsequent tumor challenge with neu-transformed NIH 3T3 cells. No tumor immunoprotection was found when recombinant virus-immunized mice were challenged with Ha-ras-transformed NIH 3T3 cells. These data indicate that immunization with a single oncogene-encoded antigen can fully and specifically protect animals against tumor cells bearing this antigen. Images PMID:3477812

Bernards, R; Destree, A; McKenzie, S; Gordon, E; Weinberg, R A; Panicali, D

1987-01-01

190

Structural and Biochemical Characterization of the Vaccinia Virus Envelope Protein D8 and Its Recognition by the Antibody LA5  

PubMed Central

Smallpox vaccine is considered a gold standard of vaccines, as it is the only one that has led to the complete eradication of an infectious disease from the human population. B cell responses are critical for the protective immunity induced by the vaccine, yet their targeted epitopes recognized in humans remain poorly described. Here we describe the biochemical and structural characterization of one of the immunodominant vaccinia virus (VACV) antigens, D8, and its binding to the monoclonal antibody LA5, which is capable of neutralizing VACV in the presence of complement. The full-length D8 ectodomain was found to form a tetramer. We determined the crystal structure of the LA5 Fab-monomeric D8 complex at a resolution of 2.1 Å, as well as the unliganded structures of D8 and LA5-Fab at resolutions of 1.42 Å and 1.6 Å, respectively. D8 features a carbonic anhydrase (CAH) fold that has evolved to bind to the glycosaminoglycan (GAG) chondroitin sulfate (CS) on host cells. The central positively charged crevice of D8 was predicted to be the CS binding site by automated docking experiments. Furthermore, sequence alignment of various poxvirus D8 orthologs revealed that this crevice is structurally conserved. The D8 epitope is formed by 23 discontinuous residues that are spread across 80% of the D8 protein sequence. Interestingly, LA5 binds with a high-affinity lock-and-key mechanism above this crevice with an unusually large antibody-antigen interface, burying 2,434 Å2 of protein surface. PMID:22623786

Matho, Michael H.; Maybeno, Matt; Benhnia, Mohammed Rafii-El-Idrissi; Becker, Danielle; Meng, Xiangzhi; Xiang, Yan; Crotty, Shane; Peters, Bjoern

2012-01-01

191

Immunoglobulin-like transcript 2 (ILT2) is a biomarker of therapeutic response to oncolytic immunotherapy with vaccinia viruses  

PubMed Central

Background Oncolytic viruses represent a novel form of cancer immunotherapy. Vaccinia viruses encoding human T cell co-stimulatory molecules have demonstrated clinical activity in phase I clinical trials in patients with advanced melanoma. However, predictive biomarkers of therapeutic response have not yet been identified. Methods A customized microarray was performed to identify changes in peripheral blood mononuclear cell (PBMC) gene expression upon exposure to recombinant oncolytic vaccinia viruses. Up-regulated and down-regulated genes were identified and selected for further analysis using PBMC samples from normal donors and oncolytic virus-treated patients before and after viral injection. Quantitative PCR and flow cytometry of defined T cell subsets was performed to evaluate expression patterns and clinical correlations. Results The microarray identified 301 genes that were up-regulated and 960 genes that were down-regulated in T cells after exposure to oncolytic vaccinia virus. The B7.1 gene was highly up-regulated and the immunoglobulin-like transcript 2 (ILT2) gene was highly down-regulated by vaccinia-B7.1, which was consistent with the known inverse regulation of these two genes. We observed an inverse association between ILT2 expression in the tumor microenvironment and clinical response and further identified ILT2 as a marker of regulatory CD4+ and suppressor CD8+ T cell responses and whose down-regulation was predictive of therapeutic responses in patients treated with oncolytic virus immunotherapy. Conclusions ILT2 is a new putative biomarker of T cell and clinical response in patients treated with oncolytic vaccinia virus immunotherapy. Further confirmation of ILT2 as a biomarker requires prospective validation in a larger series of clinical trials. PMID:24829758

2014-01-01

192

Transmission of vaccinia virus, possibly through sexual contact, to a woman at high risk for adverse complications.  

PubMed

Severe adverse events, including eczema vaccinatum (EV), can result after smallpox vaccination. Persons at risk for EV include those with underlying dermatologic conditions, such as atopic dermatitis. We investigated a case of vaccinia infection, possibly acquired during sexual contact with a recently vaccinated military service member, in a female Maryland resident with atopic dermatitis. The U.S. Department of Defense's Vaccine Healthcare Centers Network (VHCN) and the Centers for Disease Control and Prevention (CDC) worked in conjunction with the patient's physician and the Maryland Department of Health and Mental Hygiene (DHMH) to confirm the diagnosis, ensure treatment, and prevent further transmission. Specimens collected from the patient were tested at the DHMH laboratories and were positive by real-time polymerase chain reaction for nonvariola orthopoxvirus. Testing at the CDC verified the presence of vaccinia-specific DNA signatures. Continuing spread of the patient's lesions led to the administration of vaccinia immune globulin and strict infection control measures to prevent tertiary transmission to vulnerable family members, also with atopic dermatitis. VHCN contacted the service member to reinforce vaccination site care and hygiene. This case underscores the importance of prevaccination education for those receiving the smallpox vaccine to protect contacts at risk for developing severe adverse reactions. PMID:24306023

Said, Maria A; Haile, Charles; Palabindala, Venkataraman; Barker, Naomi; Myers, Robert; Thompson, Ruth; Wilson, Lucy; Allan-Martinez, Frances; Montgomery, Jay; Monroe, Benjamin; Tack, Danielle; Reynolds, Mary; Damon, Inger; Blythe, David

2013-12-01

193

The Vaccinia virus complement control protein modulates adaptive immune responses during infection.  

PubMed

Complement activation is an important component of the innate immune response against viral infection and also shapes adaptive immune responses. Despite compelling evidence that complement activation enhances T cell and antibody (Ab) responses during viral infection, it is unknown whether inhibition of complement by pathogens alters these responses. Vaccinia virus (VACV) modulates complement activation by encoding a complement regulatory protein called the vaccinia virus complement control protein (VCP). Although VCP has been described as a virulence factor, the mechanisms by which VCP enhances VACV pathogenesis have not been fully defined. Since complement is necessary for optimal adaptive immune responses to several viruses, we hypothesized that VCP contributes to pathogenesis by modulating anti-VACV T cell and Ab responses. In this study, we used an intradermal model of VACV infection to compare pathogenesis of wild-type virus (vv-VCPwt) and a virus lacking VCP (vv-VCPko). vv-VCPko formed smaller lesions in wild-type mice but not in complement-deficient mice. Attenuation of vv-VCPko correlated with increased accumulation of T cells at the site of infection, enhanced neutralizing antibody responses, and reduced viral titers. Importantly, depleting CD8(+) T cells together with CD4(+) T cells, which also eliminated T helper cell-dependent Ab responses, restored vv-VCPko to wild-type levels of virulence. These results suggest that VCP contributes to virulence by dampening both antibody and T cell responses. This work provides insight into how modulation of complement by poxviruses contributes to virulence and demonstrates that a pathogen-encoded complement regulatory protein can modulate adaptive immunity. PMID:21191012

Girgis, Natasha M; Dehaven, Brian C; Xiao, Yuhong; Alexander, Edward; Viner, Kendra M; Isaacs, Stuart N

2011-03-01

194

The Vaccinia Virus Complement Control Protein Modulates Adaptive Immune Responses during Infection?  

PubMed Central

Complement activation is an important component of the innate immune response against viral infection and also shapes adaptive immune responses. Despite compelling evidence that complement activation enhances T cell and antibody (Ab) responses during viral infection, it is unknown whether inhibition of complement by pathogens alters these responses. Vaccinia virus (VACV) modulates complement activation by encoding a complement regulatory protein called the vaccinia virus complement control protein (VCP). Although VCP has been described as a virulence factor, the mechanisms by which VCP enhances VACV pathogenesis have not been fully defined. Since complement is necessary for optimal adaptive immune responses to several viruses, we hypothesized that VCP contributes to pathogenesis by modulating anti-VACV T cell and Ab responses. In this study, we used an intradermal model of VACV infection to compare pathogenesis of wild-type virus (vv-VCPwt) and a virus lacking VCP (vv-VCPko). vv-VCPko formed smaller lesions in wild-type mice but not in complement-deficient mice. Attenuation of vv-VCPko correlated with increased accumulation of T cells at the site of infection, enhanced neutralizing antibody responses, and reduced viral titers. Importantly, depleting CD8+ T cells together with CD4+ T cells, which also eliminated T helper cell-dependent Ab responses, restored vv-VCPko to wild-type levels of virulence. These results suggest that VCP contributes to virulence by dampening both antibody and T cell responses. This work provides insight into how modulation of complement by poxviruses contributes to virulence and demonstrates that a pathogen-encoded complement regulatory protein can modulate adaptive immunity. PMID:21191012

Girgis, Natasha M.; DeHaven, Brian C.; Xiao, Yuhong; Alexander, Edward; Viner, Kendra M.; Isaacs, Stuart N.

2011-01-01

195

A kinesin-1 binding motif in vaccinia virus that is widespread throughout the human genome.  

PubMed

Transport of cargoes by kinesin-1 is essential for many cellular processes. Nevertheless, the number of proteins known to recruit kinesin-1 via its cargo binding light chain (KLC) is still quite small. We also know relatively little about the molecular features that define kinesin-1 binding. We now show that a bipartite tryptophan-based kinesin-1 binding motif, originally identified in Calsyntenin is present in A36, a vaccinia integral membrane protein. This bipartite motif in A36 is required for kinesin-1-dependent transport of the virus to the cell periphery. Bioinformatic analysis reveals that related bipartite tryptophan-based motifs are present in over 450 human proteins. Using vaccinia as a surrogate cargo, we show that regions of proteins containing this motif can function to recruit KLC and promote virus transport in the absence of A36. These proteins interact with the kinesin light chain outside the context of infection and have distinct preferences for KLC1 and KLC2. Our observations demonstrate that KLC binding can be conferred by a common set of features that are found in a wide range of proteins associated with diverse cellular functions and human diseases. PMID:21915095

Dodding, Mark P; Mitter, Richard; Humphries, Ashley C; Way, Michael

2011-11-16

196

Co-administration of the broad-spectrum antiviral, brincidofovir (CMX001), with smallpox vaccine does not compromise vaccine protection in mice challenged with ectromelia virus.  

PubMed

Natural orthopoxvirus outbreaks such as vaccinia, cowpox, cattlepox and buffalopox continue to cause morbidity in the human population. Monkeypox virus remains a significant agent of morbidity and mortality in Africa. Furthermore, monkeypox virus's broad host-range and expanding environs make it of particular concern as an emerging human pathogen. Monkeypox virus and variola virus (the etiological agent of smallpox) are both potential agents of bioterrorism. The first line response to orthopoxvirus disease is through vaccination with first-generation and second-generation vaccines, such as Dryvax and ACAM2000. Although these vaccines provide excellent protection, their widespread use is impeded by the high level of adverse events associated with vaccination using live, attenuated virus. It is possible that vaccines could be used in combination with antiviral drugs to reduce the incidence and severity of vaccine-associated adverse events, or as a preventive in individuals with uncertain exposure status or contraindication to vaccination. We have used the intranasal mousepox (ectromelia) model to evaluate the efficacy of vaccination with Dryvax or ACAM2000 in conjunction with treatment using the broad spectrum antiviral, brincidofovir (BCV, CMX001). We found that co-treatment with BCV reduced the severity of vaccination-associated lesion development. Although the immune response to vaccination was quantifiably attenuated, vaccination combined with BCV treatment did not alter the development of full protective immunity, even when administered two days following ectromelia challenge. Studies with a non-replicating vaccine, ACAM3000 (MVA), confirmed that BCV's mechanism of attenuating the immune response following vaccination with live virus was, as expected, by limiting viral replication and not through inhibition of the immune system. These studies suggest that, in the setting of post-exposure prophylaxis, co-administration of BCV with vaccination should be considered a first response to a smallpox emergency in subjects of uncertain exposure status or as a means of reduction of the incidence and severity of vaccine-associated adverse events. PMID:25128688

Parker, Scott; Crump, Ryan; Foster, Scott; Hartzler, Hollyce; Hembrador, Ed; Lanier, E Randall; Painter, George; Schriewer, Jill; Trost, Lawrence C; Buller, R Mark

2014-11-01

197

A36-dependent actin filament nucleation promotes release of vaccinia virus.  

PubMed

Cell-to-cell transmission of vaccinia virus can be mediated by enveloped virions that remain attached to the outer surface of the cell or those released into the medium. During egress, the outer membrane of the double-enveloped virus fuses with the plasma membrane leaving extracellular virus attached to the cell surface via viral envelope proteins. Here we report that F-actin nucleation by the viral protein A36 promotes the disengagement of virus attachment and release of enveloped virus. Cells infected with the A36(YdF) virus, which has mutations at two critical tyrosine residues abrogating localised actin nucleation, displayed a 10-fold reduction in virus release. We examined A36(YdF) infected cells by transmission electron microscopy and observed that during release, virus appeared trapped in small invaginations at the plasma membrane. To further characterise the mechanism by which actin nucleation drives the dissociation of enveloped virus from the cell surface, we examined recombinant viruses by super-resolution microscopy. Fluorescently-tagged A36 was visualised at sub-viral resolution to image cell-virus attachment in mutant and parental backgrounds. We confirmed that A36(YdF) extracellular virus remained closely associated to the plasma membrane in small membrane pits. Virus-induced actin nucleation reduced the extent of association, thereby promoting the untethering of virus from the cell surface. Virus release can be enhanced via a point mutation in the luminal region of B5 (P189S), another virus envelope protein. We found that the B5(P189S) mutation led to reduced contact between extracellular virus and the host membrane during release, even in the absence of virus-induced actin nucleation. Our results posit that during release virus is tightly tethered to the host cell through interactions mediated by viral envelope proteins. Untethering of virus into the surrounding extracellular space requires these interactions be relieved, either through the force of actin nucleation or by mutations in luminal proteins that weaken these interactions. PMID:23555252

Horsington, Jacquelyn; Lynn, Helena; Turnbull, Lynne; Cheng, Delfine; Braet, Filip; Diefenbach, Russell J; Whitchurch, Cynthia B; Karupiah, Guna; Newsome, Timothy P

2013-03-01

198

Vaccinia Virus F1L Protein Is a Tail-Anchored Protein That Functions at the Mitochondria To Inhibit Apoptosis  

Microsoft Academic Search

Members of the poxvirus family encode multiple immune evasion proteins, including proteins that regulate apoptosis. We recently identified one such protein, F1L, encoded by vaccinia virus, the prototypic member of the poxvirus family. F1L localizes to the mitochondria and inhibits apoptosis by interfering with the release of cytochrome c, the pivotal commitment step in the apoptotic cascade. Sequence analysis of

Tara L. Stewart; Shawn T. Wasilenko; Michele Barry

2005-01-01

199

Postexposure Prevention of Progressive Vaccinia in SCID Mice Treated with Vaccinia Immune Globulin ?  

PubMed Central

A recently reported case of progressive vaccinia (PV) in an immunocompromised patient has refocused attention on this condition. Uniformly fatal prior to the licensure of vaccinia immune globulin (VIG) in 1978, PV was still fatal in about half of VIG-treated patients overall, with a greater mortality rate in infants and children. Additional therapies would be needed in the setting of a smallpox bioterror event, since mass vaccination following any variola virus release would inevitably result in exposure of immunocompromised people through vaccination or contact with vaccinees. Well-characterized animal models of disease can support the licensure of new products when human studies are not ethical or feasible, as in the case of PV. We chose vaccinia virus-scarified SCID mice to model PV. As in immunocompromised humans, vaccinia virus-scarified SCID animals develop enlarging primary lesions with minimal or no inflammation, eventual distal virus spread, and lethal outcomes if left untreated. Postexposure treatment with VIG slowed disease progression, caused local lesion regression, and resulted in the healthy survival of most of the mice for more than 120 days. Combination treatment with VIG and topical cidofovir also resulted in long-term disease-free survival of most of the animals, even when initiated 7 days postinfection. These results support the possibility that combination treatments may be effective in humans and support using this SCID model of PV to test new antibody therapies and combination therapies and to provide further insights into the pathogenesis and treatment of PV. PMID:21106779

Fisher, R. W.; Reed, J. L.; Snoy, P. J.; Mikolajczyk, M. G.; Bray, M.; Scott, D. E.; Kennedy, M. C.

2011-01-01

200

The E6 protein from vaccinia virus is required for the formation of immature virions  

SciTech Connect

An IPTG-inducible mutant in the E6R gene of vaccinia virus was used to study the role of the E6 virion core protein in viral replication. In the absence of the inducer, the mutant exhibited a normal pattern DNA replication, concatemer resolution and late gene expression, but it showed an inhibition of virion structural protein processing it failed to produce infectious particles. Electron microscopic analysis showed that in the absence of IPTG viral morphogenesis was arrested before IV formation: crescents, aberrant or empty IV-like structures, and large aggregated virosomes were observed throughout the cytoplasm. The addition of IPTG to release a 12-h block showed that virus infectious particles could be formed in the absence of de novo DNA synthesis. Our observations show that in the absence of E6 the association of viroplasm with viral membrane crescents is impaired.

Boyd, Olga; Turner, Peter C.; Moyer, Richard W.; Condit, Richard C. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Moussatche, Nissin, E-mail: nissin@ufl.ed [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)

2010-04-10

201

Expression of the highly conserved vaccinia virus E6 protein is required for virion morphogenesis  

SciTech Connect

The vaccinia virus E6R gene (VACVWR062) is conserved in all members of the poxvirus family and encodes a protein associated with the mature virion. We confirmed this association and provided evidence for an internal location. An inducible mutant that conditionally expresses E6 was constructed. In the absence of inducer, plaque formation and virus production were severely inhibited in several cell lines, whereas some replication occurred in others. This difference could be due to variation in the stringency of repression, since we could not isolate a stable deletion mutant even in the more 'permissive' cells. Under non-permissive conditions, viral late proteins were synthesized but processing of core proteins was inefficient, indicative of an assembly block. Transmission electron microscopy of sections of cells infected with the mutant in the absence of inducer revealed morphogenetic defects with crescents and empty immature virions adjacent to dense inclusions of viroplasm. Mature virions were infrequent and cores appeared to have lucent centers.

Resch, Wolfgang; Weisberg, Andrea S. [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3210 (United States); Moss, Bernard, E-mail: bmoss@nih.go [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3210 (United States)

2009-04-10

202

Vaccinia virus late transcription is activated in vitro by cellular heterogeneous nuclear ribonucleoproteins.  

PubMed

Vaccinia virus gene expression is temporally regulated, and three gene classes have been identified: early, intermediate, and late. Several virus-encoded proteins and an activity designated VLTF-X are required for maximum transcription in vitro of a template containing a late promoter. VLTF-X is present in both cytoplasmic and nuclear extracts prepared from uninfected mammalian cells and co-purifies with a late promoter DNA-binding activity. Here, extensive purification of VLTF-X has revealed that heterogeneous nuclear ribonucleoproteins A2/B1 and RBM3 co-purified with in vitro late transcription stimulation. Overexpression and purification of these proteins from Escherichia coli demonstrated that they both complemented for VLTF-X activity in in vitro transcription reactions. These studies identify two host cell factors potentially contributing to poxvirus replication in vivo. PMID:11546759

Wright, C F; Oswald, B W; Dellis, S

2001-11-01

203

Role of receptor-mediated endocytosis in the formation of vaccinia virus extracellular enveloped particles.  

PubMed

Infectious intracellular mature vaccinia virus particles are wrapped by cisternae, which may arise from trans-Golgi or early endosomal membranes, and are transported along microtubules to the plasma membrane where exocytosis occurs. We used EH21, a dominant-negative form of Eps15 that is an essential component of clathrin-coated pits, to investigate the extent and importance of endocytosis of viral envelope proteins from the cell surface. Several recombinant vaccinia viruses that inducibly or constitutively express an enhanced green fluorescent protein (GFP)-EH21 fusion protein were constructed. Expression of GFP-EH21 blocked uptake of transferrin, a marker for clathrin-mediated endocytosis, as well as association of adaptor protein-2 with clathrin-coated pits. When GFP-EH21 was expressed, there were increased amounts of viral envelope proteins, including A33, A36, B5, and F13, in the plasma membrane, and their internalization was inhibited. Wrapping of virions appeared to be qualitatively unaffected as judged by electron microscopy, a finding consistent with a primary trans-Golgi origin of the cisternae. However, GFP-EH21 expression caused a 50% reduction in released enveloped virions, decreased formation of satellite plaques, and delayed virus spread, indicating an important role for receptor-mediated endocytosis. Due to dynamic interconnection between endocytic and exocytic pathways, viral proteins recovered from the plasma membrane could be used by trans-Golgi or endosomal cisternae to form new viral envelopes. Adherence of enveloped virions to unrecycled viral proteins on the cell surface may also contribute to decreased virus release in the presence of GFP-EH21. In addition to a salvage function, the retrieval of viral proteins from the cell surface may reduce immune recognition. PMID:15767409

Husain, Matloob; Moss, Bernard

2005-04-01

204

Single-Virus Fusion Experiments Reveal Proton Influx into Vaccinia Virions and Hemifusion Lag Times  

PubMed Central

Recent studies have revealed new insights into the endocytosis of vaccinia virus (VACV). However, the mechanism of fusion between viral and cellular membranes remains unknown. We developed a microfluidic device with a cell-trap array for immobilization of individual cells, with which we analyzed the acid-dependent fusion of single virions. VACV particles incorporating enhanced green fluorescent protein (EGFP) and labeled with self-quenching concentrations of R18 membrane dye were used in combination with total internal reflection fluorescence microscopy to measure the kinetics of R18 dequenching and thus single hemifusion events initiated by a fast low-pH trigger. These studies revealed unexpectedly long lag phases between pH change and hemifusion. In addition, we found that EGFP fluorescence in the virus was quenched upon acidification, indicating that protons could access the virus core, possibly through a proton channel. In a fraction of virus particles, EGFP fluorescence was recovered, presumably after fusion-pore formation and exposure of the core to the physiological pH of the host-cell cytosol. Given that virus-encoded cation channels play a crucial role in the life cycle of many viruses and can serve as antiviral drug targets, further investigations into a potential VACV viroporin are justified. Our findings indicate that the microfluidic device described may be highly beneficial to similar studies requiring fast kinetic measurements. PMID:23870263

Schmidt, Florian I.; Kuhn, Phillip; Robinson, Tom; Mercer, Jason; Dittrich, Petra S.

2013-01-01

205

Oncolytic Viruses as Anticancer Vaccines  

PubMed Central

Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity, which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy. PMID:25101244

Woller, Norman; Gürlevik, Engin; Ureche, Cristina-Ileana; Schumacher, Anja; Kühnel, Florian

2014-01-01

206

Gene Expression and Cytopathic Effect of Vaccinia Virus Inactivated by Psoralen and Long-Wave UV Light  

Microsoft Academic Search

Induction of the cytopathic effect (CPE) in cells infected with poxvirus seems ubiquitous in that it has been associatedwithalldifferentstrainsandpreparationsofpoxviruses,regardlessofthereplicatingstatusofthese viruses. The study of the mechanisms by which CPE is induced by nonreplicating poxviruses is hampered by thelackofanynoncytopathicmutantstrainsandpreparations.Inthispaper,wereportonthepatternsofgene expression and induction of CPE by vaccinia viruses treated by limited cross-linking with psoralen and long-wave UV light (PLWUV). We show that treatment

KANGLA TSUNG; JOHN H. YIM; WALTER MARTI; R. MARK L. BULLER; ANDJEFFREY A. NORTON

1996-01-01

207

Efficacy of a Plasmodium vivax malaria vaccine using ChAd63 and modified vaccinia Ankara expressing thrombospondin-related anonymous protein as assessed with transgenic Plasmodium berghei parasites.  

PubMed

Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America. Despite this dramatic burden, very few vaccines have been assessed in humans. The clinically relevant vectors modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAd63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to induce protective immune responses against Plasmodium falciparum thrombospondin-related anonymous protein (TRAP) in clinical trials. Here, we describe the development of new recombinant ChAd63 and MVA vectors expressing P. vivax TRAP (PvTRAP) and show their ability to induce high antibody titers and T cell responses in mice. In addition, we report a novel way of assessing the efficacy of new candidate vaccines against P. vivax using a fully infectious transgenic Plasmodium berghei parasite expressing P. vivax TRAP to allow studies of vaccine efficacy and protective mechanisms in rodents. Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application. PMID:24379295

Bauza, Karolis; Malinauskas, Tomas; Pfander, Claudia; Anar, Burcu; Jones, E Yvonne; Billker, Oliver; Hill, Adrian V S; Reyes-Sandoval, Arturo

2014-03-01

208

Crystallization and preliminary X-ray diffraction analysis of vaccinia virus H1L phosphatase  

PubMed Central

The cysteine-based protein phosphatase H1L was the first reported dual-specificity protein phosphatase. H1L is encapsidated within the vaccinia virus and is required for successful host infection and for the production of viable vaccinia progeny. H1L has therefore been proposed as a target candidate for antiviral compounds. Recombinant H1L has been expressed in a catalytically inactive form using an Escherichia coli host, leading to purification and crystallization by the microbatch method. The crystals diffract to 2.1?Å resolution using synchrotron radiation. These crystals belong to space group P422, with unit-cell parameters a = b = 98.31, c = 169.15?Å, and are likely to contain four molecules in the asymmetric unit. A sulfur SAD data set was collected to 2.8?Å resolution on beamline BM14 at the ESRF to facilitate structure determination. Attempts to derivatize these crystals with xenon gas changed the space group to I422, with unit-cell parameters a = b = 63.28, c = 169.68?Å and a single molecule in the asymmetric unit. The relationship between these two crystal forms is discussed. PMID:18323605

Roces, Laura; Knowles, Phillip P.; Fox, Gavin; Juanhuix, Jordi; Scaplehorn, Nicki; Way, Michael; McDonald, Neil Q.

2008-01-01

209

Towards a universal influenza vaccine: volunteer virus challenge studies in quarantine to speed the development and subsequent licensing  

PubMed Central

There are now more than 5 experimental vaccine formulations which induce T and B cell immunity towards the internally situated virus proteins matrix (M1 and M2e) and nucleoprotein (NP), and towards stem and stalk regions of the HA which have a shared antigenic structure amongst many of the 17 influenza A virus sub types. Such ‘universal vaccines’ could be used, at least in theory, as a prophylactic stockpile vaccine for newly emerged epidemic and novel pandemic influenza A viruses or as a supplement to conventional HA/NA vaccines. My own laboratory has approached the problem from the clinical viewpoint by identifying CD4+ cells which are present in influenza infected volunteers who resist influenza infection. We have established precisely which peptides in M and NP proteins react with these immune CD4 cells. These experimental vaccines induce immunity in animal models but with a single exception no data have been published on protection against influenza virus infection in humans. The efficacy of the latter vaccine is based on vaccinia virus (MVA) as a carrier and was analyzed in a quarantine unit. Given the absence of induced HI antibody in the new universal vaccines a possible licensing strategy is a virus challenge model in quarantine whereby healthy volunteers can be immunized with the new vaccine and thereafter deliberately infected and clinical signs recorded alongside quantities of virus excreted and compared with unvaccinated controls. PMID:23617282

Oxford, John S

2013-01-01

210

Nonreplicating Vaccinia Virus Vectors Expressing the H5 Influenza Virus Hemagglutinin Produced in Modified Vero Cells Induce Robust Protection  

Microsoft Academic Search

The timely development of safe and effective vaccines against avian influenza virus of the H5N1 subtype will be of the utmost importance in the event of a pandemic. Our aim was first to develop a safe live vaccine which induces both humoral and cell-mediated immune responses against human H5N1 influenza viruses and second, since the supply of embryonated eggs for

Josef Mayrhofer; Sogue Coulibaly; Annett Hessel; Georg W. Holzer; Michael Schwendinger; Peter Bruhl; Marijan Gerencer; Brian A. Crowe; Shen Shuo; Wanjing Hong; Yee Joo Tan; Barbara Dietrich; Nicolas Sabarth; Helga Savidis-Dacho; Otfried Kistner; P. Noel Barrett; Falko G. Falkner

2009-01-01

211

Control of vaccinia virus skin lesions by long-term-maintained IFN-?+TNF-?+ effector/memory CD4+ lymphocytes in humans  

PubMed Central

Vaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responses have been widely proposed as a correlate of efficacy and protection in humans, the role of cellular and humoral immunity in VV-associated skin lesion formation was unknown. We therefore investigated whether long-term residual humoral and cellular immune memory to VV, persisting 30 years after vaccination, could control VV-induced skin lesion in revaccinated individuals. Here, we have shown that residual VV-specific IFN-?+TNF-?+ or IFN-?+IL-2+ CD4+ lymphocytes but not CD8+ effector/memory lymphocytes expressing a skin-homing marker are inversely associated with the size of the skin lesion formed in response to revaccination. Indeed, high numbers of residual effector T cells were associated with lower VV skin lesion size after revaccination. In contrast, long-term residual VV-specific neutralizing antibody (NAbs) titers did not affect skin lesion formation. However, the size of the skin lesion strongly correlated with high levels of NAbs boosted after revaccination. These findings demonstrate a potential role for VV-specific CD4+ responses at the site of VV-associated skin lesion, thereby providing new insight into immune responses at these sites and potentially contributing to the development of new approaches to measure the efficacy of VV vaccination. PMID:20364089

Puissant-Lubrano, Bénédicte; Bossi, Philippe; Gay, Frederick; Crance, Jean-Marc; Bonduelle, Olivia; Garin, Daniel; Bricaire, François; Autran, Brigitte; Combadière, Behazine

2010-01-01

212

Newcastle disease virus vaccine potency determination  

Technology Transfer Automated Retrieval System (TEKTRAN)

Potency of inactivated Newcastle disease virus (NDV) vaccines is determined using vaccination and challenge. If the minimum killed viral antigen necessary for clinical protection can be determined, vaccines meeting or exceeding this dose might be considered of adequate potency. In these studies, c...

213

Mumps vaccine virus strains and aseptic meningitis  

Microsoft Academic Search

Mumps immunization can easily be included in national schedules, particularly if combined with measles or measles and rubella vaccines, but debate continues concerning the relative safety of various licensed mumps vaccine strains. The opportunities for control of mumps are also being affected by differences in the cost of the vaccines prepared with different strains of mumps virus. The present report

Marie-Claude Bonnet; Anil Dutta; Clement Weinberger; Stanley A. Plotkin

2006-01-01

214

Polycyclic N-benzamido imides with potent activity against vaccinia virus.  

PubMed

The synthesis and antiviral activity of a series of novel polycyclic analogues of the orthopoxvirus egress inhibitor tecovirimat (ST-246) is presented. Several of these compounds display sub-micromolar activity against vaccinia virus, and were more potent than cidofovir (CDV). The more active compounds were about 10-fold more active than CDV, with minimum cytotoxic concentrations above 100??M. Chemical manipulations of the two carbon-carbon double bonds present in the compounds were carried out to further explore the structure-activity relationships of these new polycyclic imides. Hydrogenation of the two carbon-carbon double bonds decreases antiviral activity, whereas either cyclopropanation or epoxidation of the double bonds fully eliminates the antiviral activity. PMID:20967819

Torres, Eva; Duque, María D; Camps, Pelayo; Naesens, Lieve; Calvet, Teresa; Font-Bardia, Mercè; Vázquez, Santiago

2010-12-01

215

Myxoma and vaccinia viruses exploit different mechanisms to enter and infect human cancer cells  

SciTech Connect

Myxoma (MYXV) and vaccinia (VACV) viruses have recently emerged as potential oncolytic agents that can infect and kill different human cancer cells. Although both are structurally similar, it is unknown whether the pathway(s) used by these poxviruses to enter and cause oncolysis in cancer cells are mechanistically similar. Here, we compared the entry of MYXV and VACV-WR into various human cancer cells and observed significant differences: 1 - low-pH treatment accelerates fusion-mediated entry of VACV but not MYXV, 2 - the tyrosine kinase inhibitor genistein inhibits entry of VACV, but not MYXV, 3 - knockdown of PAK1 revealed that it is required for a late stage event downstream of MYXV entry into cancer cells, whereas PAK1 is required for VACV entry into the same target cells. These results suggest that VACV and MYXV exploit different mechanisms to enter into human cancer cells, thus providing some rationale for their divergent cancer cell tropisms.

Villa, Nancy Y.; Bartee, Eric [Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610 (United States); Mohamed, Mohamed R. [Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610 (United States); Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo (Egypt); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610 (United States); Barrett, John W. [Department of Microbiology and Immunology, BioTherapeutics Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario (Canada); McFadden, Grant, E-mail: grantmcf@ufl.ed [Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610 (United States)

2010-06-05

216

Vaccinia Virus Binds to the Scavenger Receptor MARCO on the Surface of Keratinocytes.  

PubMed

Patients with altered skin immunity, such as individuals with atopic dermatitis (AD), can have a life-threatening disruption of the epidermis known as eczema vaccinatum after vaccinia virus (VV) infection of the skin. Here, we sought to better understand the mechanism(s) by which VV associates with keratinocytes. The class A scavenger receptor known as MARCO (macrophage receptor with collagenous structure) is expressed on human and mouse keratinocytes and found to be abundantly expressed in the skin of patients with AD. VV bound directly to MARCO, and overexpression of MARCO increased susceptibility to VV infection. Furthermore, ligands with affinity for MARCO, or excess soluble MARCO, competitively inhibited VV infection. These findings indicate that MARCO promotes VV infection and highlights potential new therapeutic strategies for prevention of VV infection in the skin. PMID:25089661

MacLeod, Daniel T; Nakatsuji, Teruaki; Wang, Zhenping; di Nardo, Anna; Gallo, Richard L

2015-01-01

217

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins ? †  

PubMed Central

The vaccinia virus (VACV) E3 protein is essential for virulence and has antiapoptotic activity and the ability to impair the host innate immune response. Here we demonstrate that E3 interacts with SUMO1 through a small ubiquitin-like modifier (SUMO)-interacting motif (SIM). SIM integrity is required for maintaining the stability of the viral protein and for the covalent conjugation of E3 to SUMO1 or SUMO2, a modification that has a negative effect on the E3 transcriptional transactivation of the p53-upregulated modulator of apoptosis (PUMA) and APAF-1 genes. We also demonstrate that E3 is ubiquitinated, a modification that does not destabilize the wild-type protein but triggers the degradation of an E3-?SIM mutant. This report constitutes the first demonstration of the important roles that both SUMO and ubiquitin play in the regulation of the VACV protein E3. PMID:21957283

González-Santamaría, José; Campagna, Michela; García, María Angel; Marcos-Villar, Laura; González, Dolores; Gallego, Pedro; Lopitz-Otsoa, Fernando; Guerra, Susana; Rodríguez, Manuel S.; Esteban, Mariano; Rivas, Carmen

2011-01-01

218

Expression of wild-type and mutant p53 proteins by recombinant vaccinia viruses.  

PubMed Central

To facilitate the purification of wild type p53 protein, we established a recombinant p53 vaccinia viral expression system. Using this efficient eukaryotic expression vector, we found that the expressed p53 proteins retained their specific structural characteristics. A comparison between wild type and mutant p53 proteins showed the conservation of the typical subcellular localization and the expression of specific antigenic determinants. Furthermore, wild type p53 exhibited a typical binding with large T antigen, whereas no binding was detected with mutant p53. Both wild type and mutant p53 proteins were highly stable and constituted 5-7% of total protein expressed in the infected cells. These expression recombinant viruses offer a simple, valuable system for the purification of wild type and mutant p53 proteins that are expressed abundantly in eukaryotic cells. Images PMID:1630914

Ronen, D; Teitz, Y; Goldfinger, N; Rotter, V

1992-01-01

219

T-cell Engager-armed Oncolytic Vaccinia Virus Significantly Enhances Antitumor Therapy  

PubMed Central

Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. However, complete responses have rarely been observed. This lack of efficacy is most likely due to suboptimal virus spread through the tumor resulting in limited tumor cell destruction. We reasoned that redirecting T cells to the tumor has the potential to improve the antitumor activity of oncolytic VVs. We, therefore, constructed a VV encoding a secretory bispecific T-cell engager consisting of two single- chain variable fragments specific for CD3 and the tumor cell surface antigen EphA2 (EphA2-T-cell engager-armed VV (EphA2-TEA-VV)). In vitro, EphA2-TEA-VV's ability to replicate and induce oncolysis was similar to that of unmodified virus. However, only tumor cells infected with EphA2-TEA-VV induced T-cell activation as judged by the secretion of interferon-? and interleukin-2. In coculture assays, EphA2-TEA-VV not only killed infected tumor cells, but in the presence of T cells, it also induced bystander killing of noninfected tumor cells. In vivo, EphA2-TEA-VV plus T cells had potent antitumor activity in comparison with control VV plus T cells in a lung cancer xenograft model. Thus, arming oncolytic VVs with T-cell engagers may represent a promising approach to improve oncolytic virus therapy. PMID:24135899

Yu, Feng; Wang, Xingbing; Guo, Z Sheng; Bartlett, David L; Gottschalk, Stephen M; Song, Xiao-Tong

2014-01-01

220

Replication-defective viruses as vaccines and vaccine vectors Tim Dudek a,b  

E-print Network

Replication-defective viruses as vaccines and vaccine vectors Tim Dudek a,b , David M. Knipe b approaches using inactivated virus or live-attenuated virus have not been successful for some viruses, such as human immunodeficiency virus or herpes simplex virus. Therefore, new types of vaccines are needed

Knipe, David M.

221

RNA Virus Reverse Genetics and Vaccine Design  

PubMed Central

RNA viruses are capable of rapid spread and severe or potentially lethal disease in both animals and humans. The development of reverse genetics systems for manipulation and study of RNA virus genomes has provided platforms for designing and optimizing viral mutants for vaccine development. Here, we review the impact of RNA virus reverse genetics systems on past and current efforts to design effective and safe viral therapeutics and vaccines. PMID:24967693

Stobart, Christopher C.; Moore, Martin L.

2014-01-01

222

Cap-Independent Translation of mRNA Conferred by Encephalomyocarditis Virus 5' Sequence Improves the Performance of the Vaccinia Virus\\/Bacteriophage T7 Hybrid Expression System  

Microsoft Academic Search

A recombinant vaccinia virus that directs the synthesis of bacteriophage T7 RNA polymerase provides the basis for the expression of genes that are regulated by T7 promoters in mammalian cells. The T7 transcripts, which account for as much as 30% of the total cytoplasmic RNA at 24 hr after infection, are largely uncapped. To improve the translatability of the uncapped

Orna Elroy-Stein; Thomas R. Fuerst; Bernard Moss

1989-01-01

223

A role for vaccinia virus protein C16 in reprogramming cellular energy metabolism  

PubMed Central

Vaccinia virus (VACV) is a large DNA virus that replicates in the cytoplasm and encodes about 200 proteins of which approximately 50?% may be non-essential for viral replication. These proteins enable VACV to suppress transcription and translation of cellular genes, to inhibit the innate immune response, to exploit microtubule- and actin-based transport for virus entry and spread, and to subvert cellular metabolism for the benefit of the virus. VACV strain WR protein C16 induces stabilization of the hypoxia-inducible transcription factor (HIF)-1? by binding to the cellular oxygen sensor prolylhydroxylase domain-containing protein (PHD)2. Stabilization of HIF-1? is induced by several virus groups, but the purpose and consequences are unclear. Here, 1H-NMR spectroscopy and liquid chromatography-mass spectrometry are used to investigate the metabolic alterations during VACV infection in HeLa and 2FTGH cells. The role of C16 in such alterations was examined by comparing infection to WT VACV (strain WR) and a derivative virus lacking gene C16L (v?C16). Compared with uninfected cells, VACV infection caused increased nucleotide and glutamine metabolism. In addition, there were increased concentrations of glutamine derivatives in cells infected with WT VACV compared with v?C16. This indicates that C16 contributes to enhanced glutamine metabolism and this may help preserve tricarboxylic acid cycle activity. These data show that VACV infection reprogrammes cellular energy metabolism towards increased synthesis of the metabolic precursors utilized during viral replication, and that C16 contributes to this anabolic reprogramming of the cell, probably via the stabilization of HIF-1?. PMID:25351724

Mazzon, Michela; Castro, Cecilia; Roberts, Lee D.; Griffin, Julian L.

2015-01-01

224

A role for vaccinia virus protein C16 in reprogramming cellular energy metabolism.  

PubMed

Vaccinia virus (VACV) is a large DNA virus that replicates in the cytoplasm and encodes about 200 proteins of which approximately 50?% may be non-essential for viral replication. These proteins enable VACV to suppress transcription and translation of cellular genes, to inhibit the innate immune response, to exploit microtubule- and actin-based transport for virus entry and spread, and to subvert cellular metabolism for the benefit of the virus. VACV strain WR protein C16 induces stabilization of the hypoxia-inducible transcription factor (HIF)-1? by binding to the cellular oxygen sensor prolylhydroxylase domain-containing protein (PHD)2. Stabilization of HIF-1? is induced by several virus groups, but the purpose and consequences are unclear. Here, (1)H-NMR spectroscopy and liquid chromatography-mass spectrometry are used to investigate the metabolic alterations during VACV infection in HeLa and 2FTGH cells. The role of C16 in such alterations was examined by comparing infection to WT VACV (strain WR) and a derivative virus lacking gene C16L (v?C16). Compared with uninfected cells, VACV infection caused increased nucleotide and glutamine metabolism. In addition, there were increased concentrations of glutamine derivatives in cells infected with WT VACV compared with v?C16. This indicates that C16 contributes to enhanced glutamine metabolism and this may help preserve tricarboxylic acid cycle activity. These data show that VACV infection reprogrammes cellular energy metabolism towards increased synthesis of the metabolic precursors utilized during viral replication, and that C16 contributes to this anabolic reprogramming of the cell, probably via the stabilization of HIF-1?. PMID:25351724

Mazzon, Michela; Castro, Cecilia; Roberts, Lee D; Griffin, Julian L; Smith, Geoffrey L

2015-02-01

225

Cryo X-ray nano-tomography of vaccinia virus infected cells.  

PubMed

We have performed full-field cryo X-ray microscopy in the water window photon energy range on vaccinia virus (VACV) infected cells to produce tomographic reconstructions. PtK2 cells were infected with a GFP-expressing VACV strain and frozen by plunge fast freezing. The infected cells were selected by light fluorescence microscopy of the GFP marker and subsequently imaged in the X-ray microscope under cryogenic conditions. Tomographic tilt series of X-ray images were used to yield three-dimensional reconstructions showing different cell organelles (nuclei, mitochondria, filaments), together with other structures derived from the virus infection. Among them, it was possible to detect viral factories and two types of viral particles related to different maturation steps of VACV (immature and mature particles), which were compared to images obtained by standard electron microscopy of the same type of cells. In addition, the effect of radiation damage during X-ray tomographic acquisition was analyzed. Thin sections studied by electron microscopy revealed that the morphological features of the cells do not present noticeable changes after irradiation. Our findings show that cryo X-ray nano-tomography is a powerful tool for collecting three-dimensional structural information from frozen, unfixed, unstained whole cells with sufficient resolution to detect different virus particles exhibiting distinct maturation levels. PMID:22178221

Chichón, Francisco Javier; Rodríguez, Maria Josefa; Pereiro, Eva; Chiappi, Michele; Perdiguero, Beatriz; Guttmann, Peter; Werner, Stephan; Rehbein, Stefan; Schneider, Gerd; Esteban, Mariano; Carrascosa, José L

2012-02-01

226

Protein B5 is required on extracellular enveloped vaccinia virus for repulsion of superinfecting virions.  

PubMed

Vaccinia virus (VACV) spreads across cell monolayers fourfold faster than predicted from its replication kinetics. Early after infection, infected cells repulse some superinfecting extracellular enveloped virus (EEV) particles by the formation of actin tails from the cell surface, thereby causing accelerated spread to uninfected cells. This strategy requires the expression of two viral proteins, A33 and A36, on the surface of infected cells and upon contact with EEV this complex induces actin polymerization. Here we have studied this phenomenon further and investigated whether A33 and A36 expression in cell lines causes an increase in VACV plaque size, whether these proteins are able to block superinfection by EEV, and which protein(s) on the EEV surface are required to initiate the formation of actin tails from infected cells. Data presented show that VACV plaque size was not increased by expression of A33 and A36, and these proteins did not block entry of the majority of EEV binding to these cells. In contrast, expression of proteins A56 and K2 inhibited entry of both EEV and intracellular mature virus. Lastly, VACV protein B5 was required on EEV to induce the formation of actin tails at the surface of cells expressing A33 and A36, and B5 short consensus repeat 4 is critical for this induction. PMID:22622330

Doceul, Virginie; Hollinshead, Michael; Breiman, Adrien; Laval, Kathlyn; Smith, Geoffrey L

2012-09-01

227

Human CD4 T cell epitopes selective for Vaccinia versus Variola virus.  

PubMed

Due to the high degree of sequence identity between Orthopoxvirus species, the specific B and T cell responses raised against these viruses are largely cross-reactive and poorly selective. We therefore searched for CD4 T cell epitopes present in the conserved parts of the Vaccinia genome (VACV) but absent from Variola viruses (VARV), with a view to identifying immunogenic sequences selective for VACV. We identified three long peptide fragments from the B7R, B10R and E7R proteins by in silico comparisons of the poxvirus genomes, and evaluated the recognition of these fragments by VACV-specific T cell lines derived from healthy donors. For the 12 CD4 T cell epitopes identified, we assessed their binding to common HLA-DR allotypes and their capacity to induce peptide-specific CD4 T-cell lines. Four peptides from B7R and B10R displayed a broad binding specificity for HLA-DR molecules and induced multiple T cell lines from healthy donors. Besides their absence from VARV, the two B10R peptide sequences were mutated in the Cowpox virus and completely absent from the Monkeypox genome. This work contributes to the development of differential diagnosis of poxvirus infections. PMID:23147561

Probst, Alicia; Besse, Aurore; Favry, Emmanuel; Imbert, Gilles; Tanchou, Valérie; Castelli, Florence Anne; Maillere, Bernard

2013-04-01

228

Comparing Adjuvanted H28 and Modified Vaccinia Virus Ankara Expressing H28 in a Mouse and a Non-Human Primate Tuberculosis Model  

PubMed Central

Here we report for the first time on the immunogenicity and protective efficacy of a vaccine strategy involving the adjuvanted fusion protein “H28” (consisting of Ag85B-TB10.4-Rv2660c) and Modified Vaccinia Virus Ankara expressing H28. We show that a heterologous prime-boost regimen involving priming with H28 in a Th1 adjuvant followed by boosting with H28 expressed by MVA (H28/MVA28) induced the highest percentage of IFN-? expressing T cells, the highest production of IFN-? per single cell and the highest induction of CD8 T cells compared to either of the vaccines given alone. In contrast, in mice vaccinated with adjuvanted recombinant H28 alone (H28/H28) we observed the highest production of IL-2 per single cell and the highest frequency of antigen specific TNF-?/IL-2 expressing CD4 T cells pre and post infection. Interestingly, TNF-?/IL-2 expressing central memory-like CD4 T cells showed a significant positive correlation with protection at week 6 post infection, whereas the opposite was observed for post infection CD4 T cells producing only IFN-?. Moreover, as a BCG booster vaccine in a clinically relevant non-human primate TB model, the H28/H28 vaccine strategy induced a slightly more prominent reduction of clinical disease and pathology for up to one year post infection compared to H28/MVA28. Taken together, our data showed that the adjuvanted subunit and MVA strategies led to different T cell subset combinations pre and post infection and that TNF-?/IL-2 double producing but not IFN-? single producing CD4 T cell subsets correlated with protection in the mouse TB model. Moreover, our data demonstrated that the H28 vaccine antigen was able to induce strong protection in both a mouse and a non-human primate TB model. PMID:23977248

Billeskov, Rolf; Christensen, Jan P.; Aagaard, Claus; Andersen, Peter; Dietrich, Jes

2013-01-01

229

Vesicular Stomatitis Virus-Based Vaccines against Lassa and Ebola Viruses.  

PubMed

We demonstrated that previous vaccination with a vesicular stomatitis virus (VSV)-based Lassa virus vaccine does not alter protective efficacy of subsequent vaccination with a VSV-based Ebola virus vaccine. These findings demonstrate the utility of VSV-based vaccines against divergent viral pathogens, even when preexisting immunity to the vaccine vector is present. PMID:25625358

Marzi, Andrea; Feldmann, Friederike; Geisbert, Thomas W; Feldmann, Heinz; Safronetz, David

2015-02-01

230

Vesicular Stomatitis Virus–Based Vaccines against Lassa and Ebola Viruses  

PubMed Central

We demonstrated that previous vaccination with a vesicular stomatitis virus (VSV)–based Lassa virus vaccine does not alter protective efficacy of subsequent vaccination with a VSV-based Ebola virus vaccine. These findings demonstrate the utility of VSV-based vaccines against divergent viral pathogens, even when preexisting immunity to the vaccine vector is present. PMID:25625358

Marzi, Andrea; Feldmann, Friederike; Geisbert, Thomas W.; Feldmann, Heinz

2015-01-01

231

Five of 12 Forms of Vaccinia Virus-Expressed Human Hepatic Cytochrome P450 Metabolically Activate Aflatoxin B_1  

Microsoft Academic Search

Twelve forms of human hepatic cytochrome P450 were expressed in hepatoma cells by means of recombinant vaccinia viruses. The expressed P450s were analyzed for their abilities to activate the potent hepatocarcinogen aflatoxin B_1 to metabolites having mutagenic or DNA-binding properties. Five forms, P450s IA2, IIA3, IIB7, IIIA3, and IIIA4, activated aflatoxin B_1 to mutagenic metabolites as assessed by the production

Toshifumi Aoyama; Shigeru Yamano; Philip S. Guzelian; Harry V. Gelboin; Frank J. Gonzalez

1990-01-01

232

9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.  

Code of Federal Regulations, 2010 CFR

... Feline Calicivirus Vaccine, Killed Virus. 113.210 Section 113.210 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.210 Feline...

2010-01-01

233

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2013 CFR

...Avian Encephalomyelitis Vaccine, Killed Virus. 113.208 Section 113.208 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian...

2013-01-01

234

9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.  

Code of Federal Regulations, 2012 CFR

... Feline Calicivirus Vaccine, Killed Virus. 113.210 Section 113.210 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.210 Feline...

2012-01-01

235

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

...Avian Encephalomyelitis Vaccine, Killed Virus. 113.208 Section 113.208 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian...

2011-01-01

236

9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.  

Code of Federal Regulations, 2014 CFR

... Feline Calicivirus Vaccine, Killed Virus. 113.210 Section 113.210 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.210 Feline...

2014-01-01

237

9 CFR 113.206 - Wart Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

...2011-01-01 false Wart Vaccine, Killed Virus. 113.206 Section 113.206 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.206 Wart...

2011-01-01

238

9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

...Feline Rhinotracheitis Vaccine, Killed Virus. 113.211 Section 113.211 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.211 Feline...

2011-01-01

239

9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2014 CFR

...Feline Rhinotracheitis Vaccine, Killed Virus. 113.211 Section 113.211 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.211 Feline...

2014-01-01

240

9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.  

Code of Federal Regulations, 2013 CFR

... Feline Calicivirus Vaccine, Killed Virus. 113.210 Section 113.210 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.210 Feline...

2013-01-01

241

9 CFR 113.311 - Bovine Virus Diarrhea Vaccine.  

Code of Federal Regulations, 2011 CFR

...2011-01-01 2011-01-01 false Bovine Virus Diarrhea Vaccine. 113.311 Section...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Live Virus Vaccines § 113.311 Bovine...

2011-01-01

242

9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2013 CFR

...Feline Rhinotracheitis Vaccine, Killed Virus. 113.211 Section 113.211 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.211 Feline...

2013-01-01

243

9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

... Feline Calicivirus Vaccine, Killed Virus. 113.210 Section 113.210 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.210 Feline...

2011-01-01

244

9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2012 CFR

...Feline Rhinotracheitis Vaccine, Killed Virus. 113.211 Section 113.211 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.211 Feline...

2012-01-01

245

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2014 CFR

...Avian Encephalomyelitis Vaccine, Killed Virus. 113.208 Section 113.208 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian...

2014-01-01

246

9 CFR 113.206 - Wart Vaccine, Killed Virus.  

Code of Federal Regulations, 2010 CFR

...2010-01-01 false Wart Vaccine, Killed Virus. 113.206 Section 113.206 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.206 Wart...

2010-01-01

247

9 CFR 113.206 - Wart Vaccine, Killed Virus.  

Code of Federal Regulations, 2014 CFR

...2014-01-01 false Wart Vaccine, Killed Virus. 113.206 Section 113.206 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.206 Wart...

2014-01-01

248

9 CFR 113.206 - Wart Vaccine, Killed Virus.  

Code of Federal Regulations, 2012 CFR

...2012-01-01 false Wart Vaccine, Killed Virus. 113.206 Section 113.206 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.206 Wart...

2012-01-01

249

9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2010 CFR

...Feline Rhinotracheitis Vaccine, Killed Virus. 113.211 Section 113.211 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.211 Feline...

2010-01-01

250

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2012 CFR

...Avian Encephalomyelitis Vaccine, Killed Virus. 113.208 Section 113.208 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian...

2012-01-01

251

9 CFR 113.206 - Wart Vaccine, Killed Virus.  

Code of Federal Regulations, 2013 CFR

...2013-01-01 false Wart Vaccine, Killed Virus. 113.206 Section 113.206 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.206 Wart...

2013-01-01

252

9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

...Bovine Rhinotracheitis Vaccine, Killed Virus. 113.216 Section 113.216 Animals...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS...VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine...

2011-01-01

253

Modified Vaccinia Virus Ankara Triggers Type I IFN Production in Murine Conventional Dendritic Cells via a cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway  

PubMed Central

Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs), which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN) gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs), but not in plasmacytoid dendritic cells (pDCs). Transcription factors IRF3 (IFN regulatory factor 3) and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1), are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes) and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase). MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1) and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs. PMID:24743339

Cao, Hua; Avogadri, Francesca; Dai, Lianpan; Drexler, Ingo; Joyce, Johanna A.; Li, Xiao-Dong; Chen, Zhijian; Merghoub, Taha; Shuman, Stewart; Deng, Liang

2014-01-01

254

The formin FHOD1 and the small GTPase Rac1 promote vaccinia virus actin–based motility  

PubMed Central

Vaccinia virus dissemination relies on the N-WASP–ARP2/3 pathway, which mediates actin tail formation underneath cell-associated extracellular viruses (CEVs). Here, we uncover a previously unappreciated role for the formin FHOD1 and the small GTPase Rac1 in vaccinia actin tail formation. FHOD1 depletion decreased the number of CEVs forming actin tails and impaired the elongation rate of the formed actin tails. Recruitment of FHOD1 to actin tails relied on its GTPase binding domain in addition to its FH2 domain. In agreement with previous studies showing that FHOD1 is activated by the small GTPase Rac1, Rac1 was enriched and activated at the membrane surrounding actin tails. Rac1 depletion or expression of dominant-negative Rac1 phenocopied the effects of FHOD1 depletion and impaired the recruitment of FHOD1 to actin tails. FHOD1 overexpression rescued the actin tail formation defects observed in cells overexpressing dominant-negative Rac1. Altogether, our results indicate that, to display robust actin-based motility, vaccinia virus integrates the activity of the N-WASP–ARP2/3 and Rac1–FHOD1 pathways. PMID:24062339

Alvarez, Diego E.

2013-01-01

255

Extracts from rabbit skin inflamed by the vaccinia virus attenuate bupivacaine-induced spinal neurotoxicity in pregnant rats?  

PubMed Central

Extracts from rabbit skin inflamed by the vaccinia virus can relieve pain and promote repair of nerve injury. The present study intraperitoneally injected extracts from rabbit skin inflamed by the vaccinia virus for 3 and 4 days prior to and following intrathecal injection of bupivacaine into pregnant rats. The pain threshold test after bupivacaine injection showed that the maximum possible effect of tail-flick latency peaked 1 day after intrathecal injection of bupivacaine in the extract-pretreatment group, and gradually decreased, while the maximum possible effect in the bupivacaine group continued to increase after intrathecal injection of bupivacaine. Histological observation showed that after 4 days of intrathecal injection of bupivacaine, the number of shrunken, vacuolated, apoptotic and caspase-9-positive cells in the dorsal root ganglion in the extract-pretreatment group was significantly reduced compared with the bupivacaine group. These findings indicate that extracts from rabbit skin inflamed by the vaccinia virus can attenuate neurotoxicity induced by intrathecal injection of bupivacaine in pregnant rats, possibly by inhibiting caspase-9 protein expression and suppressing nerve cell apoptosis. PMID:25206391

Cui, Rui; Xu, Shiyuan; Wang, Liang; Lei, Hongyi; Cai, Qingxiang; Zhang, Hongfei; Wang, Dongmei

2013-01-01

256

Resistance to vaccinia virus (VV) is less dependent on TNF under conditions of heterologous immunity1  

PubMed Central

TNF has been shown to be important for controlling many pathogens. Here, we directly demonstrate using WT, TNF?/? and TNFR1?/? mice that TNF does play a role in protection against vaccinia virus (VV) infection in naïve mice. Since VV replication is also partially controlled in lymphocytic choriomeningitis virus (LCMV)-immune C57BL/6J mice through the process of heterologous immunity, we questioned whether TNF was required in mediating this protection. VV-infected LCMV-immune mice that were TNF-deficient as a consequence of genetic deletion or receptor blockade demonstrated normal recruitment and selective expansion of cross-reactive LCMV-specific memory CD8 T cells and controlled VV infection similar to LCMV-immune mice having TNF function. This indicates that neither TNF nor lymphotoxin, which uses the same receptor, was required in mediating protective heterologous immunity against VV. Indeed, prior immunity to LCMV made the role of TNF in protection against VV infection much less important, even under conditions of lethal dose inoculum. Thus, heterologous immunity may help explain why treatment of patients with anti-TNF compounds is reasonably well tolerated with relatively few infectious complications. PMID:19846867

Nie, Siwei; Cornberg, Markus; Selin, Liisa K.

2011-01-01

257

Cryo-X-ray tomography of vaccinia virus membranes and inner compartments.  

PubMed

Vitrified unstained purified vaccinia virus particles have been used as a test sample to evaluate the capabilities of cryo-X-ray tomography. Embedded in a thick layer of vitreous ice, the viral particles representing the mature form of the virus (MV) were visualized using full-field transmission X-ray tomography. The tomographic reconstructions reveal the viral brick-shaped characteristic structures with a size of 250x270x360nm(3). The X-ray tomograms show the presence of a clearly defined external envelope, together with an inner core surrounded by an internal envelope, including areas with clear differential density, which correlate well with those features previously described for these viral particles using electron microscopy analyses. A quantitative assessment of the resolution attained in X-ray and electron tomograms of the viral particles prepared under the same conditions yields values of 25.7 and 6.7nm half-pitch, respectively. Although the resolution of the X-ray microscope is well above the dimensions of the membranous compartments, the strong differential contrast exhibited makes it possible to precisely reveal them without any contrasting reagent within this small and complex biological sample. PMID:19616103

Carrascosa, José L; Chichón, Francisco Javier; Pereiro, Eva; Rodríguez, María Josefa; Fernández, Jose Jesús; Esteban, Mariano; Heim, Stefan; Guttmann, Peter; Schneider, Gerd

2009-11-01

258

Effective subunit vaccines against an enveloped animal virus  

Microsoft Academic Search

VACCINES are available to act against many of the diseases caused by enveloped viruses. The efficacy and safety of the vaccines depend on the method used to convert the virus into a vaccine. Whole viruses that have been attenuated or killed are effective, but both of these types of vaccines may give rise to undesirable side effects which limit their

B. Morein; A. Helenius; K. Simons; R. PETTERSSON; L. KÄÄRIÄINEN; V. SCHIRRMACHER

1978-01-01

259

DNA Vaccines Against Influenza Viruses  

Microsoft Academic Search

\\u000a As an attractive alternative to conventional vaccines, DNA vaccines play a critical role in inducing protection against several\\u000a infectious diseases. In this review, we discuss the advantages that DNA vaccines offer in comparison to conventional protein-based\\u000a vaccines. We discuss strategies to improve the potency and efficacy of DNA vaccines. Specifically, we focus on the potential\\u000a use of DNA-based vaccines to

Jin Hyang Kim; Joshy Jacob

260

Genetically Engineered Poxviruses for Recombinant Gene Expression, Vaccination, and Safety  

NASA Astrophysics Data System (ADS)

Vaccinia virus, no longer required for immunization against smallpox, now serves as a unique vector for expressing genes within the cytoplasm of mammalian cells. As a research tool, recombinant vaccinia viruses are used to synthesize and analyze the structure--function relationships of proteins, determine the targets of humoral and cell-mediated immunity, and investigate the types of immune response needed for protection against specific infectious diseases and cancer. The vaccine potential of recombinant vaccinia virus has been realized in the form of an effective oral wild-life rabies vaccine, although no product for humans has been licensed. A genetically altered vaccinia virus that is unable to replicate in mammalian cells and produces diminished cytopathic effects retains the capacity for high-level gene expression and immunogenicity while promising exceptional safety for laboratory workers and potential vaccine recipients.

Moss, Bernard

1996-10-01

261

Cell surface expression of the vaccinia virus complement control protein is mediated by interaction with the viral A56 protein and protects infected cells from complement attack.  

PubMed

The vaccinia virus (VACV) complement control protein (VCP) is the major protein secreted from VACV-infected cells. It has been reported that VCP binds to the surfaces of uninfected cells by interacting with heparan sulfate proteoglycans (HSPGs). In this study, we show that VCP is also expressed on the surfaces of infected cells and demonstrate that surface localization occurs independently of HSPGs. Since VCP does not contain a transmembrane domain, we hypothesized that VCP interacts with a membrane protein that localizes to the infected-cell surface. We show that the VACV A56 membrane protein is necessary for the cell surface expression of VCP and demonstrate that VCP and A56 interact in VACV-infected cells. Since the surface expression of VCP was abrogated by reducing agents, we examined the contribution of an unpaired cysteine residue on VCP to VCP surface expression and VCP's interaction with A56. To do this, we mutated the unpaired cysteine in VCP and generated a recombinant virus expressing the altered form of VCP. Following the infection of cells with the mutant virus, VCP was neither expressed on the cell surface nor able to interact with A56. Importantly, the cell surface expression of VCP was found to protect infected cells from complement-mediated lysis. Our findings suggest a new function for VCP that may be important for poxvirus pathogenesis and impact immune responses to VACV-based vaccines. PMID:18287241

Girgis, Natasha M; Dehaven, Brian C; Fan, Xin; Viner, Kendra M; Shamim, Mohammad; Isaacs, Stuart N

2008-05-01

262

A Heterologous Prime/Boost Vaccination Strategy Enhances the Immunogenicity of Therapeutic Vaccines for Hepatitis C Virus  

PubMed Central

Background.?We explored the concept of heterologous prime/boost vaccination using 2 therapeutic vaccines currently in clinical development aimed at treating chronically infected hepatitis C virus (HCV) patients: prime with a DNA-based vaccine expressing HCV genotype 1a NS3/4A proteins (ChronVac-C) and boost with a modified vaccinia virus Ankara vaccine expressing genotype 1b NS3/4/5B proteins (MVATG16643). Methods.?Two ChronVac-C immunizations 4 weeks apart were delivered intramuscularly in combination with in vivo electroporation and subsequently 5 or 12 weeks later boosted by 3 weekly subcutaneous injections of MVATG16643. Two mouse strains were used, and we evaluated quality, magnitude, and functionality of the T cells induced. Results.?DNA prime/MVA boost regimen induced significantly higher levels of interferon ? (IFN-?) or interleukin 2 (IL-2) ELISpot responses compared with each vaccine alone, independent of the time of analysis and the time interval between vaccinations. Both CD8+ and CD4+ T-cell responses as well as the spectrum of epitopes recognized was improved. A significant increase in polyfunctional IFN-?/tumor necrosis factor ? (TNF-?)/CD107a+ CD8+ T cells was detected following ChronVac-C/MVATG16643 vaccination (from 3% to 25%), and prime/boost was the only regimen that activated quadrifunctional T cells (IFN-?/TNF-?/CD107a/IL-2). In vivo functional protective capacity of DNA prime/MVA boost was demonstrated in a Listeria-NS3-1a challenge model. Conclusions.?We provide a proof-of-concept that immunogenicity of 2 HCV therapeutic vaccines can be improved using their combination, which merits further clinical development. PMID:23776192

Fournillier, Anne; Frelin, Lars; Jacquier, Emilie; Ahlén, Gustaf; Brass, Anette; Gerossier, Estelle; Holmström, Fredrik; Broderick, Kate E.; Sardesai, Niranjan Y.; Bonnefoy, Jean-Yves; Inchauspé, Geneviève; Sällberg, Matti

2013-01-01

263

Prospects for a dengue virus vaccine  

Microsoft Academic Search

The number of cases of severe dengue disease continues to grow in endemic areas of southeast Asia, Central and South America, and other subtropical regions. Children bear the greatest burden of disease, and the development of an effective vaccine remains a global public health priority. A tetravalent vaccine is urgently needed and must be effective against all four dengue virus

Joseph E. Blaney; Anna P. Durbin; Brian R. Murphy; Stephen S. Whitehead

2007-01-01

264

Vaccines in Development against West Nile Virus  

PubMed Central

West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine. PMID:24084235

Brandler, Samantha; Tangy, Frederic

2013-01-01

265

Attacking Postoperative Metastases using Perioperative Oncolytic Viruses and Viral Vaccines  

PubMed Central

Surgical resection of solid primary malignancies is a mainstay of therapy for cancer patients. Despite being the most effective treatment for these tumors, cancer surgery has been associated with impaired metastatic clearance due to immunosuppression. In preclinical surgery models and human cancer patients, we and others have demonstrated a profound suppression of both natural killer (NK) and T cell function in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Oncolytic viruses (OV) were originally designed to selectively infect and replicate in tumors, with the primary objective of directly lysing cancer cells. It is becoming increasingly clear, however, that OV infection results in a profound inflammatory reaction within the tumor, initiating innate and adaptive immune responses against it that is critical for its therapeutic benefit. This anti-tumor immunity appears to be mediated predominantly by NK and cytotoxic T cells. In preclinical models, we found that preoperative OV prevents postoperative NK cell dysfunction and attenuates tumor dissemination. Due to theoretical safety concerns of administering live virus prior to surgery in cancer patients, we characterized safe, attenuated versions of OV, and viral vaccines that could stimulate NK cells and reduce metastases when administered in the perioperative period. In cancer patients, we observed that in vivo infusion with oncolytic vaccinia virus and ex vivo stimulation with viral vaccines promote NK cell activation. These preclinical studies provide a novel and clinically relevant setting for OV therapy. Our challenge is to identify safe and promising OV therapies that will activate NK and T cells in the perioperative period preventing the establishment of micrometastatic disease in cancer patients. PMID:25161958

Tai, Lee-Hwa; Auer, Rebecca

2014-01-01

266

Vaccinia Virus Inhibits NF-?B-Dependent Gene Expression Downstream of p65 Translocation  

PubMed Central

The transcription factor nuclear factor kappa light-chain enhancer of activated B cells (NF-?B) plays a critical role in host defense against viral infection by inducing the production of proinflammatory mediators and type I interferon. Consequently, viruses have evolved many mechanisms to block its activation. The poxvirus vaccinia virus (VACV) encodes numerous inhibitors of NF-?B activation that target multiple points in the signaling pathway. A derivative of VACV strain Copenhagen, called vv811, lacking 55 open reading frames in the left and right terminal regions of the genome was reported to still inhibit NF-?B activation downstream of tumor necrosis factor alpha (TNF-?) and interleukin-1? (IL-1?), suggesting the presence of one or more additional inhibitors. In this study, we constructed a recombinant vv811 lacking the recently described NF-?B inhibitor A49 (vv811?A49), yielding a virus that lacked all currently described inhibitors downstream of TNF-? and IL-1?. Unlike vv811, vv811?A49 no longer inhibited degradation of the phosphorylated inhibitor of ?B? and p65 translocated into the nucleus. However, despite this translocation, vv811?A49 still inhibited TNF-?- and IL-1?-induced NF-?B-dependent reporter gene expression and the transcription and production of cytokines induced by these agonists. This inhibition did not require late viral gene expression. These findings indicate the presence of another inhibitor of NF-?B that is expressed early during infection and acts by a novel mechanism downstream of p65 translocation into the nucleus. PMID:24371075

Sumner, Rebecca P.; Maluquer de Motes, Carlos; Veyer, David L.

2014-01-01

267

Recombinant adenoviral vector expressing HCV NS4 induces protective immune responses in a mouse model of Vaccinia-HCV virus infection: a dose and route conundrum.  

PubMed

Hepatitis C virus (HCV) leads to chronic infection in the majority of infected patients presumably due to failure or inefficiency of the immune responses generated. Both antibody and cellular immune responses have been suggested to be important in viral clearance. Non-replicative adenoviral vectors expressing antigens of interest are considered as attractive vaccine vectors for a number of pathogens. In this study, we sought to evaluate cellular and humoral immune responses against HCV NS4 protein using recombinant adenovirus as a vaccine vector expressing NS4 antigen. We have also measured the effect of antigen doses and routes of immunization on the quality and extent of the immune responses, especially their role in viral load reduction, in a recombinant Vaccinia-HCV (Vac-HCV) infection mouse model. Our results show that an optimum dose of adenovirus vector (2×10(7)pfu/mouse) administered intramuscularly (i.m.) induces high T cell proliferation, granzyme B-expressing CD8(+) T cells, pro-inflammatory cytokines such as IFN-?, TNF-?, IL-2 and IL-6, and antibody responses that can significantly reduce the Vac-HCV viral load in the ovaries of female C57BL/6 mice. Our results demonstrate that recombinant adenovirus vector can induce both humoral and cellular protective immunity against HCV-NS4 antigen, and that immunity is intricately controlled by route and dose of immunizing vector. PMID:24631092

Singh, Shakti; Vedi, Satish; Li, Wen; Samrat, Subodh Kumar; Kumar, Rakesh; Agrawal, Babita

2014-05-13

268

Purification of Recombinant Vaccinia Virus-expressed Monomeric HIV-1 gp120 to Apparent Homogeneity  

PubMed Central

Vaccinia virus (VV) has been used to express a variety of heterologous proteins, including HIV envelope (Env) glycoproteins. The Env protein is synthesized as a precursor molecule, gp160, which is cleaved into the surface antigen gp120 and the transmembrane protein gp41. Even though production of gp160 by the VV expression system has been described, its use for gp120 production is not well documented. Here we report a new procedure for the purification of gp120 from serum-containing culture supernatant of VV infected cells. The gp120 protein was enriched to a purity better than 60% on a snowdrop (Galanthus nivalis) lectin affinity column in the presence of 0.25% zwitterionic detergent Empigen BB. After additional DEAE anion exchange and Superdex size exclusion chromatography steps, the gp120 monomer was purified free of contamination as determined by SDS-PAGE. The retention of structural integrity was confirmed by determining the affinity constant of purified gp120s to soluble CD4 and a monoclonal antibody IgG1b12, using surface plasmon resonance analysis. The purification procedure is robust and reproducible, and may find general use for glycoprotein purifications from sources where the presence of serum is desirable. PMID:23665667

Guo, Wenjin; Cleveland, Brad; Davenport, Thaddeus; Lee, Kelly; Hu, Shiu-Lok

2013-01-01

269

CD8 T cells are essential for recovery from a respiratory vaccinia virus infection.  

PubMed

The precise immune components required for protection against a respiratory Orthopoxvirus infection, such as human smallpox or monkeypox, remain to be fully identified. In this study, we used the virulent Western Reserve strain of vaccinia virus (VACV-WR) to model a primary respiratory Orthopoxvirus infection. Naive mice infected with VACV-WR mounted an early CD8 T cell response directed against dominant and subdominant VACV-WR Ags, followed by a CD4 T cell and Ig response. In contrast to other VACV-WR infection models that highlight the critical requirement for CD4 T cells and Ig, we found that only mice deficient in CD8 T cells presented with severe cachexia, pulmonary inflammation, viral dissemination, and 100% mortality. Depletion of CD8 T cells at specified times throughout infection highlighted that they perform their critical function between days 4 and 6 postinfection and that their protective requirement is critically dictated by initial viral load and virulence. Finally, the ability of adoptively transferred naive CD8 T cells to protect RAG?/? mice against a lethal VACV-WR infection demonstrated that they are both necessary and sufficient in protecting against a primary VACV-WR infection of the respiratory tract. PMID:22826318

Goulding, John; Bogue, Rebecka; Tahiliani, Vikas; Croft, Michael; Salek-Ardakani, Shahram

2012-09-01

270

Products and substrate/template usage of vaccinia virus DNA primase  

SciTech Connect

Vaccinia virus encodes a 90-kDa protein conserved in all poxviruses, with DNA primase and nucleoside triphosphatase activities. DNA primase products, synthesized with a single stranded {phi}X174 DNA template, were resolved as dinucleotides and long RNAs on denaturing polyacrylamide and agarose gels. Following phosphatase treatment, the dinucleotides GpC and ApC in a 4:1 ratio were identified by nearest neighbor analysis in which {sup 32}P was transferred from [{alpha}-{sup 32}P]CTP to initiating purine nucleotides. Differences in the nucleotide binding sites for initiation and elongation were suggested by the absence of CpC and UpC dinucleotides as well as the inability of deoxynucleotides to mediate primer synthesis despite their incorporation into mixed RNA/DNA primers. Strong primase activity was detected with an oligo(dC) template. However, there was only weak activity with an oligo(dT) template and none with oligo(dA) or oligo(dG). The absence of stringent template specificity is consistent with a role for the enzyme in priming DNA synthesis at the replication fork.

De Silva, Frank S.; Paran, Nir [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0445 (United States); Moss, Bernard [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0445 (United States)], E-mail: bmoss@nih.gov

2009-01-05

271

Gold nanorod vaccine for respiratory syncytial virus  

NASA Astrophysics Data System (ADS)

Respiratory syncytial virus (RSV) is a major cause of pneumonia and wheezing in infants and the elderly, but to date there is no licensed vaccine. We developed a gold nanorod construct that displayed the major protective antigen of the virus, the fusion protein (F). Nanorods conjugated to RSV F were formulated as a candidate vaccine preparation by covalent attachment of viral protein using a layer-by-layer approach. In vitro studies using ELISA, electron microscopy and circular dichroism revealed that conformation-dependent epitopes were maintained during conjugation, and transmission electron microscopy studies showed that a dispersed population of particles could be achieved. Human dendritic cells treated with the vaccine induced immune responses in primary human T cells. These results suggest that this vaccine approach may be a potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response.

Stone, John W.; Thornburg, Natalie J.; Blum, David L.; Kuhn, Sam J.; Wright, David W.; Crowe, James E., Jr.

2013-07-01

272

Gold nanorod vaccine for respiratory syncytial virus  

PubMed Central

Respiratory syncytial virus (RSV) is a major cause of pneumonia and wheezing in infants and the elderly, but to date there is no licensed vaccine. We developed a gold nanorod construct that displayed the major protective antigen of the virus, the fusion protein (F). Nanorods conjugated to RSV F were formulated as a candidate vaccine preparation by covalent attachment of viral protein using a layer-by-layer approach. In vitro studies using ELISA, confocal microscopy and circular dichroism revealed that conformation-dependent epitopes were maintained during conjugation, and transmission electron microscopy studies showed that a dispersed population of particles could be achieved. Human dendritic cells treated with the vaccine-induced immune responses in primary human T cells. These results suggest that this vaccine approach may be a potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response. PMID:23799651

Stone, John W.; Thornburg, Natalie J.; Blum, David L.; Kuhn, Sam J.; Wright, David W.; Crowe, James E.

2013-01-01

273

Immunization with influenza A NP-expressing vaccinia virus recombinant protects mice against experimental infection with human and avian influenza viruses  

Microsoft Academic Search

Summary.  Two-fold immunization of Balb\\/c mice with a vaccinia virus recombinant expressing the NP protein of influenza A\\/PR8\\/34 (H1N1)\\u000a virus under the control of a strong synthetic promoter induced specific antibodies and protected animals against low-dose\\u000a challenge by mouse-adapted heterosubtypic variants of human A\\/Aichi2\\/68 (H3N2) and avian A\\/Mallard\\/Pennsylvania\\/10218\\/84 (H5N2)\\u000a influenza virus strains. The surviving immunized animals had lower anti-hemagglutinin antibody titers

A. D. Altstein; A. K. Gitelman; Y. A. Smirnov; L. M. Piskareva; L. G. Zakharova; G. V. Pashvykina; M. M. Shmarov; O. P. Zhirnov; N. P. Varich; P. O. Ilyinskii; A. M. Shneider

2006-01-01

274

Primary human leukocyte subsets differentially express vaccinia virus receptors enriched in lipid rafts.  

PubMed

Poxviruses, including vaccinia virus (VV) and canarypox virus (ALVAC), do not indiscriminately infect all cell types of the primary human leukocytes (PHLs) that they encounter but instead demonstrate an extremely strong bias toward infection of monocytes and monocyte lineage cells. We studied the specific molecular events that determine the VV tropism for major PHL subsets including monocytes, B cells, neutrophils, NK cells, and T cells. We found that VV exhibited an extremely strong bias of cell surface protein-dependent binding to monocytes, B cells, and activated T cells to a similar degree and to neutrophils to a much lesser extent. Resting T cells and resting NK cells exhibited only trace amounts of VV binding. Activated T cells, however, became permissive to VV binding, infection, and replication, while activated NK cells still resisted VV binding. VV binding strongly colocalized with lipid rafts on the surfaces of all VV binding-susceptible PHL subsets, even when lipid rafts were relocated to cell uropods upon cell polarization. Immunosera raised against detergent-resistant membranes (DRMs) from monocytes or activated T cells, but not resting T cells, effectively cross-blocked VV binding to and infection of PHL subsets. CD29 and CD98, two lipid raft-associated membrane proteins that had been found to be important for VV entry into HeLa cells, had no effect on VV binding to and infection of primary activated T cells. Our data indicate that PHL subsets express VV protein receptors enriched in lipid rafts and that receptors are cross-presented on all susceptible PHLs. PMID:23785200

Byrd, Daniel; Amet, Tohti; Hu, Ningjie; Lan, Jie; Hu, Sishun; Yu, Qigui

2013-08-01

275

Primary Human Leukocyte Subsets Differentially Express Vaccinia Virus Receptors Enriched in Lipid Rafts  

PubMed Central

Poxviruses, including vaccinia virus (VV) and canarypox virus (ALVAC), do not indiscriminately infect all cell types of the primary human leukocytes (PHLs) that they encounter but instead demonstrate an extremely strong bias toward infection of monocytes and monocyte lineage cells. We studied the specific molecular events that determine the VV tropism for major PHL subsets including monocytes, B cells, neutrophils, NK cells, and T cells. We found that VV exhibited an extremely strong bias of cell surface protein-dependent binding to monocytes, B cells, and activated T cells to a similar degree and to neutrophils to a much lesser extent. Resting T cells and resting NK cells exhibited only trace amounts of VV binding. Activated T cells, however, became permissive to VV binding, infection, and replication, while activated NK cells still resisted VV binding. VV binding strongly colocalized with lipid rafts on the surfaces of all VV binding-susceptible PHL subsets, even when lipid rafts were relocated to cell uropods upon cell polarization. Immunosera raised against detergent-resistant membranes (DRMs) from monocytes or activated T cells, but not resting T cells, effectively cross-blocked VV binding to and infection of PHL subsets. CD29 and CD98, two lipid raft-associated membrane proteins that had been found to be important for VV entry into HeLa cells, had no effect on VV binding to and infection of primary activated T cells. Our data indicate that PHL subsets express VV protein receptors enriched in lipid rafts and that receptors are cross-presented on all susceptible PHLs. PMID:23785200

Byrd, Daniel; Amet, Tohti; Hu, Ningjie; Lan, Jie; Hu, Sishun

2013-01-01

276

Virotherapy of Canine Tumors with Oncolytic Vaccinia Virus GLV-1h109 Expressing an Anti-VEGF Single-Chain Antibody  

PubMed Central

Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single-chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients. PMID:23091626

Adelfinger, Marion; Donat, Ulrike; Hess, Michael; Weibel, Stephanie; Nolte, Ingo; Frentzen, Alexa; Szalay, Aladar A.

2012-01-01

277

Vaccination against acute respiratory virus infections and measles in man  

Microsoft Academic Search

Several viruses may cause more or less severe acute respiratory infections in man, some of which are followed by systemic infection. Only for influenza and measles are licensed vaccines available at present. The protection induced by influenza vaccines, which are based on inactivated whole virus or viral subunits, depends largely on the matching of vaccine strain and circulating virus. Measles

A. D. M. E. Osterhaus; Vries de P

1992-01-01

278

Structure and Function of A41, a Vaccinia Virus Chemokine Binding Protein  

PubMed Central

The vaccinia virus (VACV) A41L gene encodes a secreted 30 kDa glycoprotein that is nonessential for virus replication but affects the host response to infection. The A41 protein shares sequence similarity with another VACV protein that binds CC chemokines (called vCKBP, or viral CC chemokine inhibitor, vCCI), and strains of VACV lacking the A41L gene induced stronger CD8+ T-cell responses than control viruses expressing A41. Using surface plasmon resonance, we screened 39 human and murine chemokines and identified CCL21, CCL25, CCL26 and CCL28 as A41 ligands, with Kds of between 8 nM and 118 nM. Nonetheless, A41 was ineffective at inhibiting chemotaxis induced by these chemokines, indicating it did not block the interaction of these chemokines with their receptors. However the interaction of A41 and chemokines was inhibited in a dose-dependent manner by heparin, suggesting that A41 and heparin bind to overlapping sites on these chemokines. To better understand the mechanism of action of A41 its crystal structure was solved to 1.9 Å resolution. The protein has a globular ? sandwich structure similar to that of the poxvirus vCCI family of proteins, but there are notable structural differences, particularly in surface loops and electrostatic charge distribution. Structural modelling suggests that the binding paradigm as defined for the vCCI–chemokine interaction is likely to be conserved between A41 and its chemokine partners. Additionally, sequence analysis of chemokines binding to A41 identified a signature for A41 binding. The biological and structural data suggest that A41 functions by forming moderately strong (nM) interactions with certain chemokines, sufficient to interfere with chemokine-glycosaminoglycan interactions at the cell surface (?M–nM) and thereby to destroy the chemokine concentration gradient, but not strong enough to disrupt the (pM) chemokine–chemokine receptor interactions. PMID:18208323

Abrescia, Nicola G. A; Pease, James E; Wise, Emma L; Stuart, David I; Smith, Geoffrey L; Grimes, Jonathan M

2008-01-01

279

Developing vaccines against potential pandemic influenza viruses  

Microsoft Academic Search

In the event of an influenza pandemic, there will be an urgent need for a vaccine. The human infections with influenza A (H5N1) and A (H9N2) viruses served as pandemic warnings and initiated worldwide efforts to develop suitable vaccines. This was not straightforward however, due to safety considerations and many practical problems that were encountered. This is primarily on account

J. M. Wood; K. G. Nicholson; M. Zambon; R. Hinton; D. L. Major; R. W. Newman; U. Dunleavy; D. Melzack; J. S. Robertson; G. C. Schild

2001-01-01

280

A Novel Replication-Competent Vaccinia Vector MVTT Is Superior to MVA for Inducing High Levels of Neutralizing Antibody via Mucosal Vaccination  

PubMed Central

Mucosal vaccination offers great advantage for inducing protective immune response to prevent viral transmission and dissemination. Here, we report our findings of a head-to-head comparison of two viral vectors modified vaccinia Ankara (MVA) and a novel replication-competent modified vaccinia Tian Tan (MVTT) for inducing neutralizing antibodies (Nabs) via intramuscular and mucosal vaccinations in mice. MVTT is an attenuated variant of the wild-type VTT, which was historically used as a smallpox vaccine for millions of Chinese people. The spike glycoprotein (S) of SARS-CoV was used as the test antigen after the S gene was constructed in the identical genomic location of two vectors to generate vaccine candidates MVTT-S and MVA-S. Using identical doses, MVTT-S induced lower levels (?2-3-fold) of anti- SARS-CoV neutralizing antibodies (Nabs) than MVA-S through intramuscular inoculation. MVTT-S, however, was capable of inducing consistently 20-to-100-fold higher levels of Nabs than MVA-S when inoculated via either intranasal or intraoral routes. These levels of MVTT-S-induced Nab responses were substantially (?10-fold) higher than that induced via the intramuscular route in the same experiments. Moreover, pre-exposure to the wild-type VTT via intranasal or intraoral route impaired the Nab response via the same routes of MVTT-S vaccination probably due to the pre-existing anti-VTT Nab response. The efficacy of intranasal or intraoral vaccination, however, was still 20-to-50-fold better than intramuscular inoculation despite the subcutaneous pre-exposure to wild-type VTT. Our data have implications for people who maintain low levels of anti-VTT Nabs after historical smallpox vaccination. MVTT is therefore an attractive live viral vector for mucosal vaccination. PMID:19159014

Yu, Wenbo; Fang, Qing; Liu, Li; Zhuang, Ke; Shen, Tingting; Wang, Haibo; Tian, Po; Zhang, Linqi; Chen, Zhiwei

2009-01-01

281

Yellow fever vector live-virus vaccines: West Nile virus vaccine development  

Microsoft Academic Search

By combining molecular-biological techniques with our increased understanding of the effect of gene sequence modification on viral function, yellow fever 17D, a positive-strand RNA virus vaccine, has been manipulated to induce a protective immune response against viruses of the same family (e.g. Japanese encephalitis and dengue viruses). Triggered by the emergence of West Nile virus infections in the New World

Juan Arroyo; Charles A Miller; John Catalan; Thomas P Monath

2001-01-01

282

Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus  

PubMed Central

Cidofovir or (S)-HPMPC is one of the three antiviral drugs that might be used for the treatment of orthopoxvirus infections. (S)-HPMPC and its 2,6-diaminopurine counterpart, (S)-HPMPDAP, have been described to select, in vitro, for drug resistance mutations in the viral DNA polymerase (E9L) gene of vaccinia virus (VACV). Here, to extend our knowledge of drug resistance development among orthopoxviruses, we selected, in vitro, camelpox viruses (CMLV) resistant to (S)-HPMPDAP and identified a single amino acid change, T831I, and a double mutation, A314V+A684V, within E9L. The production of recombinant CMLV and VACV carrying these amino acid substitutions (T831I, A314V, or A314V+A684V) demonstrated clearly their involvement in conferring reduced sensitivity to viral DNA polymerase inhibitors, including (S)-HPMPDAP. Both CMLV and VACV harboring the A314V change showed comparable drug-susceptibility profiles to various antivirals and similar impairments in viral growth. In contrast, the single change T831I and the double change A314V+A684V in VACV were responsible for increased levels of drug resistance and for cross-resistance to viral DNA polymerase antivirals that were not observed with their CMLV counterparts. Each amino acid change accounted for an attenuated phenotype of VACV in vivo. Modeling of E9L suggested that the T?I change at position 831 might abolish hydrogen bonds between E9L and the DNA backbone and have a direct impact on the incorporation of the acyclic nucleoside phosphonates. Our findings demonstrate that drug-resistance development in two related orthopoxvirus species may impact drug-susceptibility profiles and viral fitness differently. PMID:22532673

Andrei, Graciela; Topalis, Dimitri; Kre?merová, Marcela; Crance, Jean-Marc; Garin, Daniel; Snoeck, Robert

2012-01-01

283

Ebola Virus: Immune Mechanisms of Protection and Vaccine Development  

Microsoft Academic Search

Vaccination is one of our most powerful antiviral strategies. Despite the emergence of deadly viruses such as Ebola virus, vaccination efforts have focused mainly on childhood communicable diseases. Although Ebola virus was once believed to be limited to isolated outbreaks in distant lands, forces of globalization potentiate outbreaks anywhere in the world through incidental transmission. Moreover, since this virus has

Adeline M. Nyamathi; John L. Fahey; Heather Sands; Adrian M. Casillas

2003-01-01

284

Infection of DBA\\/2 or C3H\\/HeJ mice by intraperitoneal injection of vaccinia virus elicits activated macrophages, cytolytic and cytostatic for S91-melanoma tumor cells  

Microsoft Academic Search

Murine peritoneal macrophages harvested 3–4 days after IP injection of vaccinia virus lysed S91-melanoma tumor cells in vitro; enhanced tumoricidal activity was measured with effector macrophages prepared 5–6 days after vaccinia virus infection. Treatment of virus-elicited macrophages prepared from DBA\\/2 mice with anti-asialo-GM1 antiserum, anti-Thy 1.2 antiserum or anti-Iad antiserum in the presence of complement so that cells sensitized with

Robert J. Natuk; Jacquelyn A. Byrne; J. A. Holowczak

1986-01-01

285

Vaccinia virus entry/fusion complex subunit A28 is a target of neutralizing and protective antibodies  

SciTech Connect

The vaccinia virus entry/fusion complex (EFC) is comprised of at least eight transmembrane proteins that are conserved in all poxviruses. However, neither the physical structure of the EFC nor the immunogenicity of the individual components has been determined. We prepared soluble forms of two EFC components, A28 and H2, by replacing the transmembrane domain with a signal peptide and adding a polyhistidine tail. The proteins were expressed by baculoviruses, secreted from insect cells, purified by affinity chromatography and used to raise antibodies in rabbits. The antibodies recognized the viral proteins but only the antibody to recombinant A28 bound intact virions and neutralized infectivity. Analyses with a set of overlapping peptides revealed a neutralizing epitope between residues 73 and 92 of A28. Passive immunization of mice with IgG purified from the anti-A28 serum provided partial protection against a vaccinia virus intranasal challenge, whereas IgG from the anti-H2 serum did not.

Nelson, Gretchen E.; Sisler, Jerry R.; Chandran, Dev [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3210 (United States); Moss, Bernard [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3210 (United States)], E-mail: bmoss@nih.gov

2008-10-25

286

First-in-man Study of Western Reserve Strain Oncolytic Vaccinia Virus: Safety, Systemic Spread, and Antitumor Activity.  

PubMed

Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3?×?10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity. PMID:25292189

Zeh, Herbert J; Downs-Canner, Stephanie; McCart, J Andrea; Guo, Zong Sheng; Rao, Uma N M; Ramalingam, Lekshmi; Thorne, Stephen H; Jones, Heather L; Kalinski, Pawel; Wieckowski, Eva; O'Malley, Mark E; Daneshmand, Manijeh; Hu, Kang; Bell, John C; Hwang, Tae-Ho; Moon, Anne; Breitbach, Caroline J; Kirn, David H; Bartlett, David L

2015-01-01

287

African Horse-Sickness Killed-Virus Tissue Culture Vaccine  

PubMed Central

Formalized African horse-sickness (AHS) type 9 virus cultivated in monkey kidney stable (MS) cell cultures was experimentally used for immunizing horses. Inactivated vaccines prepared either from viscerotropic or neurotropic type 9 AHS virus produced antibodies in vaccinated horses. Immunity developed in all horses vaccinated with various amounts of the vaccine, and protected them from infection, when challenged 5 weeks after vaccination. PMID:4226381

Ozawa, Y.; Bahrami, S.

1966-01-01

288

Vaccinia Virus A26 and A27 Proteins Form a Stable Complex Tethered to Mature Virions by Association with the A17 Transmembrane Protein  

Microsoft Academic Search

During vaccinia virus replication, mature virions (MVs) are wrapped with cellular membranes, transported to the periphery, and exported as extracellular virions (EVs) that mediate spread. The A26 protein is unusual in that it is present in MVs but not EVs. This distribution led to a proposal that A26 negatively regulates wrapping. A26 also has roles in the attachment of MVs

Amanda R. Howard; Tatiana G. Senkevich; Bernard Moss

2008-01-01

289

Biochem. J. (2009) 420, 2735 (Printed in Great Britain) doi:10.1042/BJ20082296 27 Characterization of the vaccinia virus D10 decapping enzyme provides  

E-print Network

of the vaccinia virus D10 decapping enzyme provides evidence for a two-metal-ion mechanism Marie F. SOULI Decapping enzymes are required for the removal of the 5 -end cap of mRNAs. These enzymes exhibit a specific m7 GDP and monophosphorylated RNA products. Decapping enzymes have been found in humans, plants

Perreault, Jean-Pierre

290

DIVA vaccination strategies for avian influenza virus  

Technology Transfer Automated Retrieval System (TEKTRAN)

Vaccination for both low pathogenic and highly pathogenic avian influenza is commonly used for countries that have been endemic for avian influenza influenza virus, but stamping out policies are common for countries that are normally free of the disease. Stamping out policies of euthanizing infecte...

291

Synthesis, cellular location, and immunogenicity of bovine herpesvirus 1 glycoproteins gI and gIII expressed by recombinant vaccinia virus.  

PubMed Central

Two of the major glycoproteins of bovine herpesvirus 1 (BHV-1) are gI, a polypeptide complex with apparent molecular weights of 130,000, 74,000, and 55,000, and gIII (a 91,000-molecular-weight [91K] glycoprotein), which also exists as a 180K dimer. Vaccinia virus (VAC) recombinants were constructed which carry full-length gI (VAC-I) or gIII (VAC-III) genes. The genes for gI and gIII were each placed under the control of the early VAC 7.5K gene promoter and inserted within the VAC gene for thymidine kinase. The recombinant viruses VAC-I and VAC-III retained infectivity and expressed both precursor and mature forms of glycoproteins gI and gIII. The polypeptide backbones, partially glycosylated precursors, and mature gI and gIII glycoproteins were indistinguishable from those produced in BHV-1-infected cells. Consequently, they were apparently cleaved, glycosylated, and transported in a manner similar to that seen during authentic BHV-1 infection, although the processing efficiencies of both gI and gIII were generally higher in recombinant-infected cells than in BHV-1-infected cells. Immunofluorescence studies further demonstrated that the mature gI and gIII glycoproteins were transported to and expressed on the surface of cells infected with the respective recombinants. Immunization of cattle with recombinant viruses VAC-I and VAC-III resulted in the induction of neutralizing antibodies to BHV-1, which were reactive with authentic gI and gIII. These data demonstrate the immunogenicity of VAC-expressed gI and gIII and indicate the potential of these recombinant glycoproteins as a vaccine against BHV-1. Images PMID:2539509

van Drunen Littel-van den Hurk, S; Zamb, T; Babiuk, L A

1989-01-01

292

Evaluation of radiation effects against C6 glioma in combination with vaccinia virus-p53 gene therapy  

NASA Technical Reports Server (NTRS)

The primary objective of this study was to evaluate the antitumor effects of recombinant vaccinia virus-p53 (rVV-p53) in combination with radiation therapy against the C6 rat glioma, a p53 deficient tumor that is relatively radioresistant. VV-LIVP, the parental virus (Lister strain), was used as a control. Localized treatment of subcutaneous C6 tumors in athymic mice with either rVV-p53 or VV-LIVP together with tumor irradiation resulted in low tumor incidence and significantly slower tumor progression compared to the agents given as single modalities. Assays of blood and spleen indicated that immune system activation may account, at least partly, for the enhance tumor inhibition seen with combined treatment. No overt signs of treatment-related toxicity were noted.

Gridley, D. S.; Andres, M. L.; Li, J.; Timiryasova, T.; Chen, B.; Fodor, I.; Nelson, G. A. (Principal Investigator)

1998-01-01

293

Vaccine platform for prevention of tuberculosis and mother-to-child transmission of human immunodeficiency virus type 1 through breastfeeding.  

PubMed

Most children in Africa receive their vaccine against tuberculosis at birth. Those infants born to human immunodeficiency virus type 1 (HIV-1)-positive mothers are at high risk of acquiring HIV-1 infection through breastfeeding in the first weeks of their lives. Thus, the development of a vaccine which would protect newborns against both of these major global killers is a logical yet highly scientifically, ethically, and practically challenging aim. Here, a recombinant lysine auxotroph of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a BCG strain that is safer than those currently used and expresses an African HIV-1 clade-derived immunogen, was generated and shown to be stable and to induce durable, high-quality HIV-1-specific CD4(+)- and CD8(+)-T-cell responses. Furthermore, when the recombinant BCG vaccine was used in a priming-boosting regimen with heterologous components, the HIV-1-specific responses provided protection against surrogate virus challenge, and the recombinant BCG vaccine alone protected against aerosol challenge with M. tuberculosis. Thus, inserting an HIV-1-derived immunogen into the scheduled BCG vaccine delivered at or soon after birth may prime HIV-1-specific responses, which can be boosted by natural exposure to HIV-1 in the breast milk and/or by a heterologous vaccine such as recombinant modified vaccinia virus Ankara delivering the same immunogen, and decrease mother-to-child transmission of HIV-1 during breastfeeding. PMID:17596303

Im, Eung-Jun; Saubi, Narcís; Virgili, Goretti; Sander, Clare; Teoh, Denise; Gatell, Jose M; McShane, Helen; Joseph, Joan; Hanke, Tomás

2007-09-01

294

Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques.  

PubMed

To support the licensure of a new and safer vaccine to protect people against smallpox, a monkeypox model of infection in cynomolgus macaques, which simulates smallpox in humans, was used to evaluate two vaccines, Acam2000 and Imvamune, for protection against disease. Animals vaccinated with a single immunization of Imvamune were not protected completely from severe and/or lethal infection, whereas those receiving either a prime and boost of Imvamune or a single immunization with Acam2000 were protected completely. Additional parameters, including clinical observations, radiographs, viral load in blood, throat swabs, and selected tissues, vaccinia virus-specific antibody responses, immunophenotyping, extracellular cytokine levels, and histopathology were assessed. There was no significant difference (P > 0.05) between the levels of neutralizing antibody in animals vaccinated with a single immunization of Acam2000 (132 U/ml) and the prime-boost Imvamune regime (69 U/ml) prior to challenge with monkeypox virus. After challenge, there was evidence of viral excretion from the throats of 2 of 6 animals in the prime-boost Imvamune group, whereas there was no confirmation of excreted live virus in the Acam2000 group. This evaluation of different human smallpox vaccines in cynomolgus macaques helps to provide information about optimal vaccine strategies in the absence of human challenge studies. PMID:23658452

Hatch, Graham J; Graham, Victoria A; Bewley, Kevin R; Tree, Julia A; Dennis, Mike; Taylor, Irene; Funnell, Simon G P; Bate, Simon R; Steeds, Kimberley; Tipton, Thomas; Bean, Thomas; Hudson, Laura; Atkinson, Deborah J; McLuckie, Gemma; Charlwood, Melanie; Roberts, Allen D G; Vipond, Julia

2013-07-01

295

Assessment of the Protective Effect of Imvamune and Acam2000 Vaccines against Aerosolized Monkeypox Virus in Cynomolgus Macaques  

PubMed Central

To support the licensure of a new and safer vaccine to protect people against smallpox, a monkeypox model of infection in cynomolgus macaques, which simulates smallpox in humans, was used to evaluate two vaccines, Acam2000 and Imvamune, for protection against disease. Animals vaccinated with a single immunization of Imvamune were not protected completely from severe and/or lethal infection, whereas those receiving either a prime and boost of Imvamune or a single immunization with Acam2000 were protected completely. Additional parameters, including clinical observations, radiographs, viral load in blood, throat swabs, and selected tissues, vaccinia virus-specific antibody responses, immunophenotyping, extracellular cytokine levels, and histopathology were assessed. There was no significant difference (P > 0.05) between the levels of neutralizing antibody in animals vaccinated with a single immunization of Acam2000 (132 U/ml) and the prime-boost Imvamune regime (69 U/ml) prior to challenge with monkeypox virus. After challenge, there was evidence of viral excretion from the throats of 2 of 6 animals in the prime-boost Imvamune group, whereas there was no confirmation of excreted live virus in the Acam2000 group. This evaluation of different human smallpox vaccines in cynomolgus macaques helps to provide information about optimal vaccine strategies in the absence of human challenge studies. PMID:23658452

Graham, Victoria A.; Bewley, Kevin R.; Dennis, Mike; Taylor, Irene; Funnell, Simon G. P.; Bate, Simon R.; Steeds, Kimberley; Tipton, Thomas; Bean, Thomas; Hudson, Laura; Atkinson, Deborah J.; McLuckie, Gemma; Charlwood, Melanie; Roberts, Allen D. G.; Vipond, Julia

2013-01-01

296

Traditional Smallpox Vaccines and Atopic Dermatitis  

MedlinePLUS

... children, pregnant women, and nursing mothers. I thought vaccination for smallpox ended decades ago. Who is still ... after vaccination. How is vaccinia transmitted from the vaccination site? Vaccinia is spread by touching a vaccination ...

297

Soluble Antigens of Vaccinia-infected Mammalian Cells I. Separation of Virus-induced Soluble Antigens into Two Classes on the Basis of Physical Characteristics  

PubMed Central

Cohen, Gary H. (University of Pennsylvania, Philadelphia), and Wesley C. Wilcox. Soluble antigens of vaccinia-infected mammalian cells. I. Separation of virus-induced soluble antigens into two classes on the basis of physical characteristics. J. Bacteriol. 92:676–686. 1966—Infection of mammalian cells with members of the poxvirus group elicits production of a number of virus-induced, soluble antigens. Immunoelectrophoresis and immunodiffusion techniques employing soluble antigen preparations obtained from vaccinia virus-infected KB cells revealed at least seven well-defined immunoprecipitin bands. On the basis of fractionation and subsequent characterization of the soluble antigen mixture by gel filtration, calcium phosphate chromatography, isoelectric precipitation, disc electrophoresis, and ultracentrifugation studies, two distinct classes of virus-induced antigens differing markedly in molecular weight were recognized. A high molecular weight class (200,000 and greater) contained at least three virus-induced antigens; a low molecular weight class (50,000 to 100,000 range) contained at least four immunoprecipitins. Further separation of the antigens within the two groups was accomplished. The two classes were distinguished also by their ability to stimulate synthesis of virus-neutralizing antibody. Antisera prepared against the high molecular weight class proved effective in neutralizing vaccinia virus. In contrast, the low molecular weight antigens showed little, if any, ability to induce formation of neutralizing antibody. PMID:5922541

Cohen, Gary H.; Wilcox, Wesley C.

1966-01-01

298

9 CFR 113.311 - Bovine Virus Diarrhea Vaccine.  

Code of Federal Regulations, 2010 CFR

...be conducted on a sample of the vaccine virus dilution used. (3) At least once during a period 14 to 28 days post-vaccination, individual serum samples shall be collected for virus-neutralization tests from each of the vaccinates. The test...

2010-01-01

299

9 CFR 113.311 - Bovine Virus Diarrhea Vaccine.  

Code of Federal Regulations, 2013 CFR

...be conducted on a sample of the vaccine virus dilution used. (3) At least once during a period 14 to 28 days post-vaccination, individual serum samples shall be collected for virus-neutralization tests from each of the vaccinates. The test...

2013-01-01

300

9 CFR 113.311 - Bovine Virus Diarrhea Vaccine.  

Code of Federal Regulations, 2014 CFR

...be conducted on a sample of the vaccine virus dilution used. (3) At least once during a period 14 to 28 days post-vaccination, individual serum samples shall be collected for virus-neutralization tests from each of the vaccinates. The test...

2014-01-01

301

9 CFR 113.311 - Bovine Virus Diarrhea Vaccine.  

Code of Federal Regulations, 2012 CFR

...be conducted on a sample of the vaccine virus dilution used. (3) At least once during a period 14 to 28 days post-vaccination, individual serum samples shall be collected for virus-neutralization tests from each of the vaccinates. The test...

2012-01-01

302

Scientific barriers to developing vaccines against avian influenza viruses  

Microsoft Academic Search

The increasing number of reports of direct transmission of avian influenza viruses to humans underscores the need for control strategies to prevent an influenza pandemic. Vaccination is the key strategy to prevent severe illness and death from pandemic influenza. Despite long-term experience with vaccines against human influenza viruses, researchers face several additional challenges in developing human vaccines against avian influenza

Tomy Joseph; Kanta Subbarao

2007-01-01

303

A Novel MVA Vectored Chikungunya Virus Vaccine Elicits Protective Immunity in Mice  

PubMed Central

Background Chikungunya virus (CHIKV) is a re-emerging arbovirus associated with febrile illness often accompanied by rash and arthralgia that may persist for several years. Outbreaks are associated with high morbidity and create a public health challenge for countries affected. Recent outbreaks have occurred in both Europe and the Americas, suggesting CHIKV may continue to spread. Despite the sustained threat of the virus, there is no approved vaccine or antiviral therapy against CHIKV. Therefore, it is critical to develop a vaccine that is both well tolerated and highly protective. Methodology/Principal Findings In this study, we describe the construction and characterization of a modified Vaccinia virus Ankara (MVA) virus expressing CHIKV E3 and E2 proteins (MVA-CHIK) that protected several mouse models from challenge with CHIKV. In particular, BALB/c mice were completely protected against viremia upon challenge with CHIKV after two doses of MVA-CHIK. Additionally, A129 mice (deficient in IFN?/?) were protected from viremia, footpad swelling, and mortality. While high anti-virus antibodies were elicited, low or undetectable levels of neutralizing antibodies were produced in both mouse models. However, passive transfer of MVA-CHIK immune serum to naïve mice did not protect against mortality, suggesting that antibodies may not be the main effectors of protection afforded by MVA-CHIK. Furthermore, depletion of CD4+, but not CD8+ T-cells from vaccinated mice resulted in 100% mortality, implicating the indispensable role of CD4+ T-cells in the protection afforded by MVA-CHIK. Conclusions/Significance The results presented herein demonstrate the potential of MVA to effectively express CHIKV E3-E2 proteins and generate protective immune responses. Our findings challenge the assumption that only neutralizing antibodies are effective in providing protection against CHIKV, and provides a framework for the development of novel, more effective vaccine strategies to combat CHIKV. PMID:25058320

Weger-Lucarelli, James; Chu, Haiyan; Aliota, Matthew T.; Partidos, Charalambos D.; Osorio, Jorge E.

2014-01-01

304

Safety, Immunogenicity, and Efficacy of Prime-Boost Immunization with Recombinant Poxvirus FP9 and Modified Vaccinia Virus Ankara Encoding the Full-Length Plasmodium falciparum Circumsporozoite Protein  

Microsoft Academic Search

Heterologous prime-boost immunization with DNA and various recombinant poxviruses encoding malaria antigens is capable of inducing strong cell-mediated immune responses and partial protection in human sporozoite challenges. Here we report a series of trials assessing recombinant fowlpox virus and modified vaccinia virus Ankara encoding the Plasmodium falciparum circumsporozoite protein in various prime-boost combinations, doses, and application routes. For the first

Michael Walther; Fiona M. Thompson; Susanna Dunachie; Sheila Keating; Stephen Todryk; Tamara Berthoud; Laura Andrews; Rikke F. Andersen; Anne Moore; Sarah C. Gilbert; Ian Poulton; Filip Dubovsky; Eveline Tierney; Simon Correa; Angela Huntcooke; Geoffrey Butcher; Jack Williams; Robert E. Sinden; Adrian V. S. Hill

2006-01-01

305

Nucleic acid vaccination primes hepatitis B virus surface antigen-specific cytotoxic T lymphocytes in nonresponder mice.  

PubMed Central

The efficiency of different vaccination techniques to prime in vivo major histocompatibility complex class I-restricted murine cytotoxic T-lymphocyte (CTL) precursors to hepatitis B virus small surface antigen (HBsAg) was investigated. Mice were immunized either by injection of a low dose of recombinant HBsAg protein preparations (native HBsAg particles or denatured HBsAg monomers) without adjuvants, by infection with recombinant vaccinia virus carrying an HBsAg-encoding gene, or by intramuscular transfer of plasmid DNA encoding HBsAg under appropriate promoter control. In H-2d mice, an Ld-restricted, S28-39-specific CTL response was efficiently primed by all alternative vaccination techniques tested, but the most potent priming of class I-restricted CTL to HBsAg in vivo was observed with DNA immunization. Priming of anti-HBsAg CTL in H-2b mice was not detectable after infection with a recombinant vaccinia virus or after injection with exogenous recombinant HBsAg preparations. After DNA immunization, however, both Kb- and Db-restricted CTL reactivity to HBsAg emerged in H-2b mice. Hence, nucleic acid immunization revealed class I-restricted CTL responsiveness to HBsAg in a mouse strain previously considered to be a nonresponder at the CTL level. These results demonstrate that the simple technique of nucleic acid immunization not only is extremely efficient but also reveals an extended spectrum of potentially immunogenic epitopes of protein antigens. PMID:7666497

Schirmbeck, R; Böhm, W; Ando, K; Chisari, F V; Reimann, J

1995-01-01

306

Expert Rev Vaccines . Author manuscript Development of hepatitis C virus vaccines: challenges and progress  

E-print Network

Expert Rev Vaccines . Author manuscript Page /1 14 Development of hepatitis C virus vaccines of an effective vaccine against hepatitis C virus (HCV) has long been defined as a difficult challenge due their efficacy. MESH Keywords Animals ; Biomedical Research ; trends ; Hepatitis C ; immunology ; prevention

Paris-Sud XI, Université de

307

Vaccination of Macaques against Pathogenic Simian Immunodeficiency Virus with Venezuelan Equine Encephalitis Virus Replicon Particles  

Microsoft Academic Search

Vaccine vectors derived from Venezuelan equine encephalitis virus (VEE) that expressed simian immuno- deficiency virus (SIV) immunogens were tested in rhesus macaques as part of the effort to design a safe and effective vaccine for human immunodeficiency virus. Immunization with VEE replicon particles induced both humoral and cellular immune responses. Four of four vaccinated animals were protected against disease for

NANCY L. DAVIS; IAN J. CALEY; KEVIN W. BROWN; MICHAEL R. BETTS; DAVID M. IRLBECK; KATHRYN M. MCGRATH; MARY J. CONNELL; DAVID C. MONTEFIORI; JEFFREY A. FRELINGER; RONALD SWANSTROM; PHILIP R. JOHNSON; ROBERT E. JOHNSTON

2000-01-01

308

Two putative African swine fever virus helicases similar to yeast 'DEAH' pre-mRNA processing proteins and vaccinia virus ATPases D11L and D6R.  

PubMed

Two open reading frames (ORFs) of African swine fever virus (ASFV) encoding putative helicases have been sequenced. The two genes, termed D1133L and B962L, are located in the central region of the viral genome, but are separated by about 40 kb of DNA. Both genes are expressed late during ASFV infection of Vero cells, after replication of viral DNA has begun. Contiguous to D1133L, three other ORFs (D129L, D79L and D339L), encoding putative proteins of unknown function, have been sequenced. Proteins D1133L and B962L contain the amino acid motifs that characterize helicases of superfamily II. D1133L is most similar to a group of putative helicases which includes two proteins of vaccinia virus (D11L and D6R) involved in transcription of the viral genome, their homologues in other poxviruses, the protein encoded by ORF 4 of the yeast plasmids, pGKL2 and pSKL, and the previously identified ASFV protein, Q706L. B962L resembles a group of RNA-helicase-like proteins which includes three proteins of Saccharomyces cerevisiae involved in pre-mRNA splicing (PRP2, PRP16 and PRP22), Drosophila melanogaster KURZ and MLE, and vaccinia virus 18R. PMID:8262374

Yáñez, R J; Rodríguez, J M; Boursnell, M; Rodríguez, J F; Viñuela, E

1993-12-01

309

Foot and mouth disease virus vaccines.  

PubMed

Foot and mouth disease (FMD) is a highly infectious and economically devastating disease of livestock. Although vaccines, available since the early 1900s, have been instrumental in eradicating FMD from parts of the world, the disease still affects millions of animals around the globe and remains the main sanitary barrier to the commerce of animals and animal products. Currently available inactivated antigen vaccines applied intramuscularly to individual animals, confer serotype and subtype specific protection in 1-2 weeks but fail to induce long-term protective immunity. Among the limitations of this vaccine are potential virus escape from the production facility, short shelf life of formulated product, short duration of immunity and requirement of dozens of antigens to address viral antigenic diversity. Here we review novel vaccine approaches that address some of these limitations. Basic research and the combination of reliable animal inoculation models, reverse genetics and computational biology tools will allow the rational design of safe and effective FMD vaccines. These vaccines should address not only the needs of FMD-free countries but also allow the progressive global control and eradication of this devastating disease. PMID:19837296

Rodriguez, Luis L; Grubman, Marvin J

2009-11-01

310

9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.  

Code of Federal Regulations, 2010 CFR

... (i) Ten pseudorabies susceptible pigs (five vaccinates and five controls...300 TCID50 of virus shall be used. Pigs shall be considered susceptible if there...Service may be used. (iii) The five pigs used as vaccinates shall be...

2010-01-01

311

Toward a universal influenza virus vaccine: prospects and challenges.  

PubMed

Current influenza virus vaccines are annually reformulated to elicit protection by generating an immune response toward the virus strains that are predicted to circulate in the upcoming influenza season. These vaccines provide limited protection in cases of antigenic mismatch, when the vaccine and the circulating viral strains differ. The emergence of unexpected pandemic viruses presents an additional challenge to vaccine production. To increase influenza virus preparedness, much work has been dedicated to the development of a universal vaccine. Focusing on regions of viral proteins that are highly conserved across virus subtypes, vaccine strategies involving the matrix 2 protein, stalk domain of the hemagglutinin, and multivalent approaches have provided broad-based protection in animal models and show much promise. This review summarizes the most encouraging advances in the field with a focus on novel vaccine designs that have yielded promising preclinical and clinical data. PMID:23327522

Pica, Natalie; Palese, Peter

2013-01-01

312

Kinetics and intracellular location of intramolecular disulfide bond formation mediated by the cytoplasmic redox system encoded by vaccinia virus  

SciTech Connect

Poxviruses encode a redox system for intramolecular disulfide bond formation in cytoplasmic domains of viral proteins. Our objectives were to determine the kinetics and intracellular location of disulfide bond formation. The vaccinia virus L1 myristoylated membrane protein, used as an example, has three intramolecular disulfide bonds. Reduced and disulfide-bonded forms of L1 were distinguished by electrophoretic mobility and reactivity with monoclonal and polyclonal antibodies. Because disulfide bonds formed during 5 min pulse labeling with radioactive amino acids, a protocol was devised in which dithiothreitol was present at this step. Disulfide bond formation was detected by 2 min after removal of reducing agent and was nearly complete in 10 min. When the penultimate glycine residue was mutated to prevent myristoylation, L1 was mistargeted to the endoplasmic reticulum and disulfide bond formation failed to occur. These data suggested that viral membrane association was required for oxidation of L1, providing specificity for the process.

Bisht, Himani; Brown, Erica [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894 (United States); Moss, Bernard, E-mail: bmoss@nih.go [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894 (United States)

2010-03-15

313

Joint production of prime/boost pairs of Fowlpox Virus and Modified Vaccinia Ankara recombinants carrying the same transgene.  

PubMed

Pairs of recombinant MVA (Modified Vaccinia Ankara) and FPV (Fowlpox Virus) expressing the same transgene are reasonable candidates for prime/boost regimens, because cross-reacting immune responses between the two vectors, both non-replicative in mammalian hosts, are very limited. The acceptor virus FPD-Red, a derivative of FPV, carrying a red fluorescent protein gene flanked by the homology regions of MVA deletion III, was constructed. The same MVA Transfer Plasmid Green, designed to insert transgenes into the MVA deletion III locus, can therefore be used to transfer transgenes into both acceptor viruses MVA-Red and FPD-Red with the described recently Red-to-Green gene swapping method. Cells infected by either recombinant virus can be sorted differentially by a simple and reliable FACS-based purification protocol. The procedure is carried out in primary chick embryo fibroblasts grown in serum-free media and was applied to the production of three rMVA/rFPV pairs expressing the H5N1 avian influenza antigens M1, M2 and NP. The viral genes were human codon-optimized and expressed at high levels in both chick and mammalian cells. Both single-step and multiple-step growth analyses showed no significant differences in growth due to the transgenes in either rMVA or rFPV derivatives. PMID:21419167

Soprana, Elisa; Panigada, Maddalena; Knauf, Mathias; Radaelli, Antonia; Vigevani, Luisa; Palini, Alessio; Villa, Chiara; Malnati, Mauro; Cassina, Giulia; Kurth, Reinhard; Norley, Stephen; Siccardi, Antonio G

2011-06-01

314

A small molecule screen in yeast identifies inhibitors targeting protein-protein interactions within the vaccinia virus replication complex.  

PubMed

Genetic and biochemical data have identified at least four viral proteins essential for vaccinia virus (VACV) DNA synthesis: the DNA polymerase E9, its processivity factor (the heterodimer A20/D4) and the primase/helicase D5. These proteins are part of the VACV replication complex in which A20 is a central subunit interacting with E9, D4 and D5. We hypothesised that molecules able to modulate protein-protein interactions within the replication complex may represent a new class of compounds with anti-orthopoxvirus activities. In this study, we adapted a forward duplex yeast two-hybrid assay to screen more than 27,000 molecules in order to identify inhibitors of A20/D4 and/or A20/D5 interactions. We identified two molecules that specifically inhibited both interactions in yeast. Interestingly, we observed that these compounds displayed a similar antiviral activity to cidofovir (CDV) against VACV in cell culture. We further showed that these molecules were able to inhibit the replication of another orthopoxvirus (i.e. cowpox virus), but not the herpes simplex virus type 1 (HSV-1), an unrelated DNA virus. We also demonstrated that the antiviral activity of both compounds correlated with an inhibition of VACV DNA synthesis. Hence, these molecules may represent a starting point for the development of new anti-orthopoxvirus drugs. PMID:22884885

Flusin, Olivier; Saccucci, Laurent; Contesto-Richefeu, Céline; Hamdi, Amel; Bardou, Carine; Poyot, Thomas; Peinnequin, André; Crance, Jean-Marc; Colas, Pierre; Iseni, Frédéric

2012-11-01

315

Experimental vaccines against potentially pandemic and highly pathogenic avian influenza viruses  

PubMed Central

Influenza A viruses continue to emerge and re-emerge, causing outbreaks, epidemics and occasionally pandemics. While the influenza vaccines licensed for public use are generally effective against seasonal influenza, issues arise with production, immunogenicity, and efficacy in the case of vaccines against pandemic and emerging influenza viruses, and highly pathogenic avian influenza virus in particular. Thus, there is need of improved influenza vaccines and vaccination strategies. This review discusses advances in alternative influenza vaccines, touching briefly on licensed vaccines and vaccine antigens; then reviewing recombinant subunit vaccines, virus-like particle vaccines and DNA vaccines, with the main focus on virus-vectored vaccine approaches. PMID:23440999

Mooney, Alaina J; Tompkins, S Mark

2013-01-01

316

Vaccination of rhesus macaques with a vif-deleted simian immunodeficiency virus proviral DNA vaccine  

SciTech Connect

Studies in non-human primates, with simian immunodeficiency virus (SIV) and simian/human immunodeficiency virus (SHIV) have demonstrated that live-attenuated viral vaccines are highly effective; however these vaccine viruses maintain a low level of pathogenicity. Lentivirus attenuation associated with deletion of the viral vif gene carries a significantly reduced risk for pathogenicity, while retaining the potential for virus replication of low magnitude in the host. This report describes a vif-deleted simian immunodeficiency virus (SIV)mac239 provirus that was tested as an attenuated proviral DNA vaccine by inoculation of female rhesus macaques. SIV-specific interferon-{gamma} enzyme-linked immunospot responses of low magnitude were observed after immunization with plasmid containing the vif-deleted SIV provirus. However, vaccinated animals displayed strong sustained virus-specific T cell proliferative responses and increasing antiviral antibody titers. These immune responses suggested either persistent vaccine plasmid expression or low level replication of vif-deleted SIV in the host. Immunized and unvaccinated macaques received a single high dose vaginal challenge with pathogenic SIVmac251. A transient suppression of challenge virus load and a greater median survival time was observed for vaccinated animals. However, virus loads for vaccinated and unvaccinated macaques were comparable by twenty weeks after challenge and overall survival curves for the two groups were not significantly different. Thus, a vif-deleted SIVmac239 proviral DNA vaccine is immunogenic and capable of inducing a transient suppression of pathogenic challenge virus, despite severe attenuation of the vaccine virus.

Sparger, Ellen E. [Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616 (United States)], E-mail: eesparger@ucdavis.edu; Dubie, Robert A. [Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616 (United States); Shacklett, Barbara L. [Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616 (United States); Cole, Kelly S. [Center for Vaccine Research, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 (United States); Chang, W.L.; Luciw, Paul A. [Center for Comparative Medicine, University of California, Davis, CA 95616 (United States)

2008-05-10

317

ORAL VACCINATION OF RACCOONS (PROCYON LOTOR) WITH AN ATTENUATED (SAD-B19) RABIES VIRUS VACCINE  

Microsoft Academic Search

Unlike previous reports to the contrary, raccoons (Proc yon lotor) were successfully vaccinated against rabies with a liquid SAD-B19 attenuated virus vaccine administered per os and given in vaccine-laden baits. There was neither evidence of vaccine-induced rabies in raccoons nior mia limited safety trial with opossums (Dideiphis virginiana) given SAD-B19. Protection from lethal street rabies virus infection was not absolute:

C. E. Rupprecht; B. Dietzschold; J. H. Cox; L. G. Schneider

318

Immunogenicity and protective efficacy of prime-boost regimens with recombinant (delta)ureC hly+ Mycobacterium bovis BCG and modified vaccinia virus ankara expressing M. tuberculosis antigen 85A against murine tuberculosis.  

PubMed

In the light of the recent emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, the epidemic of tuberculosis (TB) in populations coinfected with human immunodeficiency virus, and the failure of Mycobacterium bovis bacillus Calmette-Guerin (BCG) to protect against disease, new vaccines against TB are urgently needed. Two promising new vaccine candidates are the recombinant DeltaureC hly(+) BCG (recBCG), which has been developed to replace the current BCG vaccine strain, and modified vaccinia virus Ankara (MVA) expressing M. tuberculosis antigen 85A (MVA85A), which is a leading candidate vaccine designed to boost the protective efficacy of BCG. In the present study, we examined the effect of MVA85A boosting on the protection afforded at 12 weeks postchallenge by BCG and recBCG by using bacterial CFU as an efficacy readout. recBCG-immunized mice were significantly better protected against aerosol challenge with M. tuberculosis than mice immunized with the parental strain of BCG. Intradermal boosting with MVA85A did not reduce the bacterial burden any further. In order to identify a marker for the development of a protective immune response against M. tuberculosis challenge, we analyzed splenocytes after priming or prime-boosting by using intracytoplasmic cytokine staining and assays for cytokine secretion. Boosting with MVA85A, but not priming with BCG or recBCG, greatly increased the antigen 85A-specific T-cell response, suggesting that the mechanism of protection may differ from that against BCG or recBCG. We show that the numbers of systemic multifunctional cytokine-producing cells did not correlate with protection against aerosol challenge in BALB/c mice. This emphasizes the need for new biomarkers for the evaluation of TB vaccine efficacy. PMID:19064635

Tchilian, Elma Z; Desel, Christiane; Forbes, Emily K; Bandermann, Silke; Sander, Clare R; Hill, Adrian V S; McShane, Helen; Kaufmann, Stefan H E

2009-02-01

319

Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients  

PubMed Central

Recombinant poxviruses (vaccinia and fowlpox) expressing tumor-associated antigens are currently being evaluated in clinical trials as cancer vaccines to induce tumor-specific immune responses that will improve clinical outcome. To test whether a diversified prime and boost regimen targeting NY-ESO-1 will result in clinical benefit, we conducted two parallel phase II clinical trials of recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1), followed by booster vaccinations with recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in 25 melanoma and 22 epithelial ovarian cancer (EOC) patients with advanced disease who were at high risk for recurrence/progression. Integrated NY-ESO-1-specific antibody and CD4+ and CD8+ T cells were induced in a high proportion of melanoma and EOC patients. In melanoma patients, objective response rate [complete and partial response (CR+PR)] was 14%, mixed response was 5%, and disease stabilization was 52%, amounting to a clinical benefit rate (CBR) of 72% in melanoma patients. The median PFS in the melanoma patients was 9 mo (range, 0–84 mo) and the median OS was 48 mo (range, 3–106 mo). In EOC patients, the median PFS was 21 mo (95% CI, 16–29 mo), and median OS was 48 mo (CI, not estimable). CD8+ T cells derived from vaccinated patients were shown to lyse NY-ESO-1-expressing tumor targets. These data provide preliminary evidence of clinically meaningful benefit for diversified prime and boost recombinant pox-viral-based vaccines in melanoma and ovarian cancer and support further evaluation of this approach in these patient populations. PMID:22454499

Odunsi, Kunle; Matsuzaki, Junko; Karbach, Julia; Neumann, Antje; Mhawech-Fauceglia, Paulette; Miller, Austin; Beck, Amy; Morrison, Carl D.; Ritter, Gerd; Godoy, Heidi; Lele, Shashikant; duPont, Nefertiti; Edwards, Robert; Shrikant, Protul; Old, Lloyd J.; Gnjatic, Sacha; Jäger, Elke

2012-01-01

320

Development of a whole killed feline leukemia virus vaccine.  

PubMed

A whole killed FeLV vaccine was developed. By use of a chromatography method of purification and concentration, the resulting vaccine has been shown to be significantly lower in bovine serum albumin and total protein contents than were the same ingredients in the starting materials. The virus was inactivated or killed as an essential part of the vaccine development process. Vaccination trials with the vaccine without use of adjuvants indicated appreciable virus-neutralizing serum titer (greater than or equal to 1:10) in 107 of 110 vaccinated cats. Of 43 cats vaccinated and subsequently challenge exposed with virulent FeLV, only 2 developed persistent virus antigenemia (longer than 1 month), whereas 14 of 22 nonvaccinated control cats developed persistent viremia. In field tests, 2,770 cats from 6 states were vaccinated and observed. Postvaccinal reactions were not observed. PMID:1666095

York, S M; York, C J

1991-11-15

321

9 CFR 113.215 - Bovine Virus Diarrhea Vaccine, Killed Virus.  

Code of Federal Regulations, 2010 CFR

...2010-01-01 2010-01-01 false Bovine Virus Diarrhea Vaccine, Killed Virus. 113.215 Section 113.215 Animals and...INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS;...

2010-01-01

322

Structure Function Studies of Vaccinia Virus Host Range Protein K1 Reveal a Novel Functional Surface for Ankyrin Repeat Proteins  

SciTech Connect

Poxvirus host tropism at the cellular level is regulated by virus-encoded host range proteins acting downstream of virus entry. The functioning mechanisms of most host range proteins are unclear, but many contain multiple ankyrin (ANK) repeats, a motif that is known for ligand interaction through a concave surface. We report here the crystal structure of one of the ANK repeat-containing host range proteins, the vaccinia virus K1 protein. The structure, at a resolution of 2.3 {angstrom}, showed that K1 consists entirely of ANK repeats, including seven complete ones and two incomplete ones, one each at the N and C terminus. Interestingly, Phe82 and Ser83, which were previously shown to be critical for K1's function, are solvent exposed and located on a convex surface, opposite the consensus ANK interaction surface. The importance of this convex surface was further supported by our additional mutagenesis studies. We found that K1's host range function was negatively affected by substitution of either Asn51 or Cys47 and completely abolished by substitution of both residues. Cys47 and Asn51 are also exposed on the convex surface, spatially adjacent to Phe82 and Ser83. Altogether, our data showed that K1 residues on a continuous convex ANK repeat surface are critical for the host range function, suggesting that K1 functions through ligand interaction and does so with a novel ANK interaction surface.

Li, Yongchao; Meng, Xiangzhi; Xiang, Yan; Deng, Junpeng (Texas-HSC); (OKLU)

2010-06-15

323

Evaluation of normalization strategies for qPCR quantitation of intracellular viral DNA: the example of Vaccinia virus.  

PubMed

Quantitation of intracellular viral genomes is critical in both clinical and fundamental virology. Quantitative real time PCR (qPCR) is currently the gold standard to detect and monitor virus infections, due to its high sensitivity and reproducibility. The reliability of qPCR data depends primarily on the technical process. Normalization, which corrects inter-sample variations related to both pre-analytical and qPCR steps, is a key point of an accurate quantitation. Total DNA input and qPCR-measured standards were evaluated to normalize intracellular Vaccinia virus (VACV) genomes. Three qPCR assays targeting either a single-copy chromosomic gene, a repeated chromosomic DNA sequence, or a mitochondrial DNA sequence were compared. qPCR-measured standards, unlike total DNA input, allowed for accurate normalization of VACV genome, regardless of the cell number. Among PCR-measured standards, chromosomic DNA and mitochondrial DNA were equivalent to normalize VACV DNA and multi-copy standards displayed lower limits of quantitation than single-copy standards. The combination of two qPCR-measured standards slightly improved the reliability of the normalization. Using one or two multi-copy standards must be favored for relative quantitation of intracellular VACV DNA. This concept could be applied to other DNA viruses. PMID:22981457

Poyot, Thomas; Flusin, Olivier; Diserbo, Michel; Iseni, Frédéric; Peinnequin, Andre

2012-12-01

324

Pathogenesis of Newcastle Disease in Vaccinated Chickens: Pathogenicity of Isolated Virus and Vaccine Effect on Challenge of Its Virus  

PubMed Central

ABSTRACT The pathogenicity of Newcastle disease (ND) virus, isolated from ND outbreak in vaccinated chickens, was evaluated through experiments. The pathogenicity indexes (mean death time (MDT); 58 hr, intracerebral pathogenicity index (ICPI); 1.7 and intravenous pathogenicity index (IVPI); 2.51) indicated that the ND virus was velogenic. The ND virus caused lymphocytic necrosis in the spleen with fibrinous exudation and proliferation of macrophages, sinusoidal fibrin exudation in the liver, proliferation of macrophages in the lung, lymphocytic necrosis and depletion in the bursa of Fabricius, cecal tonsils and thymus, necrosis of bone marrow, tracheitis, conjunctivitis and necrosis of feather epithelial cells in specific-pathogen-free chickens. Immunohistochemically, ND virus antigens were seen in the lesions mentioned above. The ND virus could not induce the encephalitis and pancreatitis that were observed in the natural case of ND in vaccinated chickens. There was no clinical disease in vaccinated chickens after the challenge of the ND virus. In diluted ND vaccine experiments, chickens vaccinated with a high dilution of vaccine and then challenged with the ND virus showed clinical sign and mortality with pancreatic focal necrosis. Vaccine diluted with fresh tap water had no effect on protection against the challenge of the ND virus. This study suggests that improper vaccination may be involved in outbreaks of ND in vaccinated chickens. PMID:23966012

NAKAMURA, Kikuyasu; ITO, Mitsuru; NAKAMURA, Toshiki; YAMAMOTO, Yu; YAMADA, Manabu; MASE, Masaji; IMAI, Kunitoshi

2013-01-01

325

Endothelial cell DNA transfer and expression using Petri dish electroporation and the nonreplicating vaccinia virus\\/T7 RNA polymerase hybrid system  

Microsoft Academic Search

The nonreplicating vaccinia virus MVA\\/T7 RNA polymerase hybrid system was tested with Petri dish electroporation for ectopic gene expression in human umbilical vein endothelial cells (HUVECs). A range of voltages (150–450 V), pulse times (10–40 ms), DNA concentrations (0–20 ?g\\/ml) and infection levels (0–15 multiplicities of infection) were tested for effects on T7 promoter-directed chloramphenicol acetyltransferase (CAT) activity after MVA\\/T7RP

E W Lewis; T J Rudo; MA Rahman St John; J L Chu; A W Heinze; B H Howard; K A Engleka

1999-01-01

326

Microarray Analysis Reveals Characteristic Changes of Host Cell Gene Expression in Response to Attenuated Modified Vaccinia Virus Ankara Infection of Human HeLa Cells  

Microsoft Academic Search

The potential use of the modified vaccinia virus Ankara (MVA) strain as a live recombinant vector to deliver antigens and elicit protective immune responses against infectious diseases demands a comprehensive under- standing of the effect of MVA infection on human host gene expression. We used microarrays containing more than 15,000 human cDNAs to identify gene expression changes in human HeLa

Susana Guerra; Luis A. Lopez-Fernandez; Raquel Conde; Alberto Pascual-Montano; Keith Harshman; Mariano Esteban

2004-01-01

327

Control of Influenza and Poliomyelitis with Killed Virus Vaccines  

ERIC Educational Resources Information Center

Discusses control of poliomyelitis and influenza by live and killed virus vaccines. Considered are the etiological agents, pathogenic mechanisms and epidemiology of each disease. Reviews recent scientific studies of the diseases. Recommends use of killed virus vaccines in controlling both diseases. (CS)

Salk, Jonas; Salk, Darrell

1977-01-01

328

Viruses as vaccine vectors for infectious diseases and cancer  

Microsoft Academic Search

Recent developments in the use of viruses as vaccine vectors have been facilitated by a better understanding of viral biology. Advances occur as we gain greater insight into the interrelationship of viruses and the immune system. Viral-vector vaccines remain the best means to induce cellular immunity and are now showing promise for the induction of strong humoral responses. The potential

Jonathan L. Heeney; Simon J. Draper

2009-01-01

329

A propagation model of computer virus with nonlinear vaccination probability  

NASA Astrophysics Data System (ADS)

This paper is intended to examine the effect of vaccination on the spread of computer viruses. For that purpose, a novel computer virus propagation model, which incorporates a nonlinear vaccination probability, is proposed. A qualitative analysis of this model reveals that, depending on the value of the basic reproduction number, either the virus-free equilibrium or the viral equilibrium is globally asymptotically stable. The results of simulation experiments not only demonstrate the validity of our model, but also show the effectiveness of nonlinear vaccination strategies. Through parameter analysis, some effective strategies for eradicating viruses are suggested.

Gan, Chenquan; Yang, Xiaofan; Liu, Wanping; Zhu, Qingyi

2014-01-01

330

DNA vaccination against influenza viruses: a review with emphasis on equine and swine influenza  

Microsoft Academic Search

The influenza virus vaccines that are commercially-available for humans, horses and pigs in the United States are inactivated, whole-virus or subunit vaccines. While these vaccines may decrease the incidence and severity of clinical disease, they do not consistently provide complete protection from virus infection. DNA vaccines are a novel alternative to conventional vaccination strategies, and offer many of the potential

Christopher W. Olsen

2000-01-01

331

Combination of fractionated irradiation with anti-VEGF expressing vaccinia virus therapy enhances tumor control by simultaneous radiosensitization of tumor associated endothelium.  

PubMed

Oncolytic viruses are currently in clinical trials for a variety of tumors, including high grade gliomas. A characteristic feature of high grade gliomas is their high vascularity and treatment approaches targeting tumor endothelium are under investigation, including bevacizumab. The aim of this study was to improve oncolytic viral therapy by combining it with ionizing radiation and to radiosensitize tumor vasculature through a viral encoded anti-angiogenic payload. Here, we show how vaccinia virus-mediated expression of a single-chain antibody targeting VEGF resulted in radiosensitization of the tumor-associated vasculature. Cell culture experiments demonstrated that purified vaccinia virus encoded antibody targeting VEGF reversed VEGF-induced radioresistance specifically in endothelial cells but not tumor cells. In a subcutaneous model of U-87 glioma, systemically administered oncolytic vaccinia virus expressing anti-VEGF antibody (GLV-1h164) in combination with fractionated irradiation resulted in enhanced tumor growth inhibition when compared to nonanti-VEGF expressing oncolytic virus (GLV-1h68) and irradiation. Irradiation of tumor xenografts resulted in an increase in VACV replication of both GLV-1h68 and GLV-1h164. However, GLV-1h164 in combination with irradiation resulted in a drastic decrease in intratumoral VEGF levels and tumor vessel numbers in comparison to GLV-1h68 and irradiation. These findings demonstrate the incorporation of an oncolytic virus expressing an anti-VEGF antibody (GLV-1h164) into a fractionated radiation scheme to target tumor cells by enhanced VACV replication in irradiated tumors as well as to radiosensitize tumor endothelium which results in enhanced efficacy of combination therapy of human glioma xenografts. PMID:23729266

Buckel, Lisa; Advani, Sunil J; Frentzen, Alexa; Zhang, Qian; Yu, Yong A; Chen, Nanhai G; Ehrig, Klaas; Stritzker, Jochen; Mundt, Arno J; Szalay, Aladar A

2013-12-15

332

Influenza A virus hemagglutinin protein subunit vaccine elicits vaccine-associated enhanced respiratory disease in pigs.  

PubMed

Vaccine-associated enhanced respiratory disease (VAERD) can occur when pigs are challenged with heterologous virus in the presence of non-neutralizing but cross-reactive antibodies elicited by whole inactivated virus (WIV) vaccine. The aim of this study was to compare the effects of heterologous ?1-H1N2 influenza A virus (IAV) challenge of pigs after vaccination with 2009 pandemic H1N1 virus (H1N1pdm09) recombinant hemagglutinin (HA) subunit vaccine (HA-SV) or temperature-sensitive live attenuated influenza virus (LAIV) vaccine, and to assess the role of immunity to HA in the development of VAERD. Both HA-SV and LAIV vaccines induced high neutralizing antibodies to virus with homologous HA (H1N1pdm09), but not heterologous challenge virus (?1-H1N2). LAIV partially protected pigs, resulting in reduced virus shedding and faster viral clearance, as no virus was detected in the lungs by 5 days post infection (dpi). HA-SV vaccinated pigs developed more severe lung and tracheal lesions consistent with VAERD following challenge. These results demonstrate that the immune response against the HA protein alone is sufficient to cause VAERD following heterologous challenge. PMID:25077416

Rajão, Daniela S; Loving, Crystal L; Gauger, Phillip C; Kitikoon, Pravina; Vincent, Amy L

2014-09-01

333

Ebola virus: the search for vaccines and treatments  

Microsoft Academic Search

:   Ebola viruses belong to the family Filoviridae, which are among the most virulent infectious agents known. These viruses\\u000a cause acute, and frequently fatal, hemorrhagic fever in humans and nonhuman primates. Currently, no vaccines or treatments\\u000a are available for human use. This review describes Ebola viruses, with a particular focus on the status of research efforts\\u000a to develop vaccines and

J. A. Wilson; C. M. Bosio; M. K. Hart

2001-01-01

334

Nonreplicating Vaccinia Vector Efficiently Expresses Recombinant Genes  

Microsoft Academic Search

Modified vaccinia Ankara (MVA), a highly attenuated vaccinia virus strain that has been safety tested in humans, was evaluated for use as an expression vector. MVA has multiple genomic deletions and is severely host cell restricted: it grows well in avian cells but is unable to multiply in human and most other mammalian cells tested. Nevertheless, we found that replication

Gerd Sutter; Bernard Moss

1992-01-01

335

Signature for Long-Term Vaccine-Mediated Control of a Simian and Human Immunodeficiency Virus 89.6P Challenge: Stable Low-Breadth and Low-Frequency T-Cell Response Capable of Coproducing Gamma Interferon and Interleukin2  

Microsoft Academic Search

In 2001, we reported 20 weeks of control of challenge with the virulent 89.6P chimera of simian and human immunodeficiency viruses (SHIV-89.6P) by a Gag-Pol-Env vaccine consisting of DNA priming and modified vaccinia virus Ankara boosting. Here we report that 22 out of 23 of these animals successfully controlled their viremia until their time of euthanasia at 200 weeks postchallenge.

Shanmugalakshmi Sadagopal; Rama Rao Amara; David C. Montefiori; Linda S. Wyatt; Silvija I. Staprans; Natalia L. Kozyr; Harold M. McClure; Bernard Moss; Harriet L. Robinson

2005-01-01

336

Virus-like particles in picornavirus vaccine development.  

PubMed

Virus-like particles (VLP), which are similar to natural virus particles but do not contain viral genes, have brought about significant breakthroughs in many research fields because of their unique advantages. The ordered repeating epitopes of VLP can induce immunity responses similar to those prompted by natural viral infection; thus, VLP vaccines are regarded as candidate alternatives to whole-virus vaccines. As picornavirus has serious impacts on human and animal health, the development of efficient and safe vaccines is a key endeavor in preventing virus infections. The characteristics of picornavirus capsid proteins allow the development of VLP vaccines. This paper investigates research scenarios and progress on picornavirus VLP vaccines with the aim of providing a reference for researchers focusing on virology and vaccinology. PMID:24647496

Dong, Hu; Guo, Hui-Chen; Sun, Shi-Qi

2014-05-01

337

A plant-derived edible vaccine against hepatitis B virus  

Microsoft Academic Search

The infectious hepatitis B virus repre- sents 42 nm spherical double-shelled particles. How- ever, analysis of blood from hepatitis B virus carriers revealed the presence of smaller 22 nm particles consisting of a viral envelope surface protein. These particles are highly immunogenic and have been used in the design of hepatitis B virus vaccine produced in yeast. Upon expression in

J. KAPUSTA; A. MODELSKA; M. FIGLEROWICZ; T. PNIEWSKI; M. LETELLIER; O. LISOWA; V. YUSIBOV; H. KOPROWSKI; A. PLUCIENNICZAK; A. B. LEGOCKI

338

New Mouse Model for Dengue Virus Vaccine Testing  

Microsoft Academic Search

Several dengue (DEN) virus vaccines are in development; however, the lack of a reliable small animal model in which to test them is a major obstacle. Because evidence suggests that interferon (IFN) is involved in the human anti-DEN virus response, we tested mice deficient in their IFN functions as potential models. Intra- peritoneally administered mouse-adapted DEN 2 virus was uniformly

ALISON J. JOHNSON; JOHN T. ROEHRIG

1999-01-01

339

Structural insights into the mechanism and evolution of the vaccinia virus mRNA cap N7 methyl-transferase  

PubMed Central

The vaccinia virus mRNA capping enzyme is a multifunctional heterodimeric protein associated with the viral polymerase that both catalyses the three steps of mRNA capping and regulates gene transcription. The structure of a subcomplex comprising the C-terminal N7-methyl-transferase (MT) domain of the large D1 subunit, the stimulatory D12 subunit and bound S-adenosyl-homocysteine (AdoHcy) has been determined at 2.7 Å resolution and reveals several novel features of the poxvirus capping enzyme. The structure shows for the first time the critical role played by the proteolytically sensitive N-terminus of the MT domain in binding the methyl donor and in catalysis. In addition, the poxvirus enzyme has a completely unique mode of binding of the adenosine moiety of AdoHcy, a feature that could be exploited for design of specific anti-poxviral compounds. The structure of the poxvirus-specific D12 subunit suggests that it was originally an RNA cap 2?O-MT that has evolved to a catalytically inactive form that has been retained for D1 stabilisation and MT activity enhancement through an allosteric mechanism. PMID:17989694

De la Peña, Marcos; Kyrieleis, Otto J P; Cusack, Stephen

2007-01-01

340

Interaction between the G3 and L5 proteins of the vaccinia virus entry-fusion complex  

SciTech Connect

The vaccinia virus entry-fusion complex (EFC) consists of 10 to 12 proteins that are embedded in the viral membrane and individually required for fusion with the cell and entry of the core into the cytoplasm. The architecture of the EFC is unknown except for information regarding two pair-wise interactions: A28 with H2 and A16 with G9. Here we used a technique to destabilize the EFC by repressing the expression of individual components and identified a third pair-wise interaction: G3 with L5. These two proteins remained associated under several different EFC destabilization conditions and in each case were immunopurified together as demonstrated by Western blotting. Further evidence for the specific interaction of G3 and L5 was obtained by mass spectrometry. This interaction also occurred when G3 and L5 were expressed in uninfected cells, indicating that no other viral proteins were required. Thus, the present study extends our knowledge of the protein interactions important for EFC assembly and stability.

Wolfe, Cindy L.; Moss, Bernard, E-mail: bmoss@nih.go

2011-04-10

341

Biopolymer encapsulated live influenza virus as a universal CD8+ T cell vaccine against influenza virus  

PubMed Central

Current influenza virus vaccines primarily elicit antibodies and can be rendered ineffective by antigenic drift and shift. Vaccines that elicit CD8+ T cell responses targeting less variable proteins may function as universal vaccines that have broad reactivity against different influenza virus strains. To generate such a universal vaccine, we encapsulated live influenza virus in a biopolymer and delivered it to mice subcutaneously. This vaccine was safe, induced potent CD8+ T cell immunity and protected mice against heterosubtypic lethal challenge. Safety of subcutaneous (SQ) vaccination was tested in Rag2?/??c?/? double knockout mice which we show cannot control intranasal infection. Biopolymer encapsulation of live influenza virus could be used to develop universal CD8+ T cell vaccines against heterosubtypic and pandemic strains. PMID:21034826

Boesteanu, Alina C.; Babu, Nadarajan S.; Wheatley, Margaret; Papazoglou, Elisabeth S.; Katsikis, Peter D.

2010-01-01

342

Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.  

PubMed

MedImmune Vaccines (formerly Aviron) has developed a cold-adapted live influenza virus vaccine [FluMist] that can be administered by nasal spray. FluMist is the first live virus influenza vaccine and also the first nasally administered vaccine to be marketed in the US. The vaccine will be formulated to contain live attenuated (att) influenza virus reassortants of the strains recommended by the US Public Health Service for each 'flu season. The vaccine is termed cold-adapted (ca) because the virus has been adapted to replicate efficiently at 25 degrees C in the nasal passages, which are below normal body temperature. The strains used in the seasonal vaccine will also be made temperature sensitive (ts) so that their replication is restricted at 37 degrees C (Type B strains) and 39 degrees C (Type A strains). The combined effect of the antigenic properties and the att, ca and ts phenotypes of the influenza strains contained in the vaccine enables the viruses to replicate in the nasopharynx to produce protective immunity. The original formulation of FluMist requires freezer storage throughout distribution. Because many international markets do not have distribution channels well suited to the sale of frozen vaccines, Wyeth and MedImmune are collaborating to develop a second generation, refrigerator-stable, liquid trivalent cold-adapted influenza vaccine (CAIV-T), which is in phase III trials. Initially, the frozen formulation will only be available in the US. For the 2003-2004 season, FluMist will contain A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like) and B/Hong Kong/330/2001. Aviron was acquired by MedImmune on 15 January 2002. Aviron is now a wholly-owned subsidiary of MedImmune and is called MedImmune Vaccines. Aviron acquired FluMist in March 1995 through a Co-operative Research and Development Agreement (CRADA) with the US NIAID, and a licensing agreement with the University of Michigan, Ann Arbor, USA. In June 2000, the CRADA was extended through to June 2003. Aviron holds exclusive worldwide rights to the vaccine except for Japan, where Kaketsuken Pharmaceuticals (also known as Chemo-Sero-Therapeutic Research Institute) is the licensee. Aviron signed a development and licensing agreement with Sang-A in Korea, which was to manufacture and market FluMist in South Korea. However, in 2000, Aviron terminated all rights and licences to Sang-A relating to FluMist. Sang-A responded by filing a suit against Aviron in August 2000, for breach of contract and unfair and deceptive business practices. Aviron filed a counter claim denying the allegations in late Sept 2001. In 1999, Aviron entered into an agreement with Wyeth-Lederle Vaccines for worldwide collaboration in the marketing of FluMist. Under the $US400 million agreement, Aviron granted Wyeth-Lederle Vaccines exclusive worldwide rights to market FluMist. Wyeth-Lederle Vaccines and Aviron (now Med-Immune Vaccines) will co-promote FluMist in the US, while Wyeth-Lederle Vaccines will have the exclusive right to market the product ex-US. Wyeth will hold marketing rights for up to 11 years. The collaboration excludes Korea, Australia, New Zealand and certain South Pacific countries. The companies will collaborate on the regulatory, clinical and marketing programmes for FluMist and both will manufacture liquid FluMist. MedImmune Vaccines is to receive an average of 40% of revenues from FluMist; the percentage will be higher in the US and lower in other markets. Aviron received a $US15 million upfront payment upon initiation of the agreement. In December 2000, Aviron received a $US15.5 million milestone payment from American Home Products (now Wyeth) after the US FDA accepted the BLA for FluMist. MedImmune Vaccines will receive a $US20 million milestone payment upon US FDA approval. Aviron also received an additional $US20 million in milestone payments for expaory body recommendations. MedImmune Vaccines is entitled to receive a $US10 million payment for submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigera

2003-01-01

343

Norwalk virus-like particles as vaccines  

PubMed Central

Noroviruses (NoV) cause the great majority of epidemic nonbacterial gastroenteritis in humans. Expression of the capsid protein in recombinant systems, including insect and plant cells, yields assembly of virus-like particles (VLPs) that mimic the antigenic structure of authentic virions, and are relatively acid- and heat-stable. Norwalk virus (NV), the prototype NoV, has been studied extensively, and Norwalk virus-like particles (NVLPs) produced in insect cells and plants are immunogenic in mice and humans when delivered orally, stimulating the production of systemic and mucosal anti-NV antibodies. NVLPs are also highly immunogenic when delivered intranasally, provoking antibodies at levels similar to orally delivered VLP at much lower doses. Oral and nasal delivery of NVLPs efficiently produces antibodies at distal mucosal sites, which suggests that NVLPs could be used to deliver heterologous peptide antigens by production of genetic fusion chimeric capsid proteins. Examination of norovirus VLP surface structures and receptor binding motifs facilitates identification of potential sites for insertion of foreign peptides that will minimally affect the efficiency of VLP assembly and receptor binding. Thus, there is strong potential to use norovirus VLPs as vaccine-delivery vehicles. PMID:20218858

Herbst-Kralovetz, Melissa; Mason, Hugh S; Chen, Qiang

2010-01-01

344

9 CFR 113.215 - Bovine Virus Diarrhea Vaccine, Killed Virus.  

Code of Federal Regulations, 2013 CFR

...second dose shall be given according to the interval recommended on the label. (iv) Fourteen days or more after the last vaccination, blood samples shall be drawn and the individual serum samples inactivated and tested for bovine virus diarrhea virus...

2013-01-01

345

9 CFR 113.215 - Bovine Virus Diarrhea Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

...second dose shall be given according to the interval recommended on the label. (iv) Fourteen days or more after the last vaccination, blood samples shall be drawn and the individual serum samples inactivated and tested for bovine virus diarrhea virus...

2011-01-01

346

9 CFR 113.215 - Bovine Virus Diarrhea Vaccine, Killed Virus.  

Code of Federal Regulations, 2014 CFR

...second dose shall be given according to the interval recommended on the label. (iv) Fourteen days or more after the last vaccination, blood samples shall be drawn and the individual serum samples inactivated and tested for bovine virus diarrhea virus...

2014-01-01

347

9 CFR 113.215 - Bovine Virus Diarrhea Vaccine, Killed Virus.  

Code of Federal Regulations, 2012 CFR

...second dose shall be given according to the interval recommended on the label. (iv) Fourteen days or more after the last vaccination, blood samples shall be drawn and the individual serum samples inactivated and tested for bovine virus diarrhea virus...

2012-01-01

348

VACCINATION OF PIGS AGAINST SWINE INFLUENZA VIRUSES USING A NS1-DELETED MODIFIED LIVE VACCINE  

Technology Transfer Automated Retrieval System (TEKTRAN)

Swine influenza virus (SIV), a member of the genus influenza A virus, can naturally infect pigs and be transmitted to humans. In the pig, genetic reassortment to create novel influenza subtypes by mixing avian, human and swine influenza viruses is possible. A vaccine inducing cross-protective immuni...

349

Design of alternative live attenuated influenza virus vaccines.  

PubMed

Each year due to the ever-evolving nature of influenza, new influenza vaccines must be produced to provide protection against the influenza viruses in circulation. Currently, there are two mainstream strategies to generate seasonal influenza vaccines: inactivated and live-attenuated. Inactivated vaccines are non-replicating forms of whole influenza virus, while live-attenuated vaccines are viruses modified to be replication impaired. Although it is widely believed that by inducing both mucosal and humoral immune responses the live-attenuated vaccine provides better protection than that of the inactivated vaccine, there are large populations of individuals who cannot safely receive the LAIV vaccine. Thus, safer LAIV vaccines are needed to provide adequate protection to these populations. Improvement is also needed in the area of vaccine production. Current strategies relying on traditional tissue culture-based and egg-based methods are slow and delay production time. This chapter describes experimental vaccine generation and production strategies that address the deficiencies in current methods for potential human and agricultural use. PMID:25005928

Finch, Courtney; Li, Weizhong; Perez, Daniel R

2015-01-01

350

Antibody response of five bird species after vaccination with a killed West Nile virus vaccine.  

PubMed

West Nile virus has been associated with numerous bird mortalities in the United States since 1999. Five avian species at three zoological parks were selected to assess the antibody response to vaccination for West Nile virus: black-footed penguins (Spheniscus demersus), little blue penguins (Eudyptula minor), American flamingos (Phoenicopterus ruber), Chilean flamingos (Phoenicopterus chilensis), and Attwater's prairie chickens (Tympanuchus cupido attwateri). All birds were vaccinated intramuscularly at least twice with a commercially available inactivated whole virus vaccine (Innovator). Significant differences in antibody titer over time were detected for black-footed penguins and both flamingo species. PMID:17679507

Okeson, Danelle M; Llizo, Shirley Yeo; Miller, Christine L; Glaser, Amy L

2007-06-01

351

Oncolytic viruses as therapeutic cancer vaccines  

PubMed Central

Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines. PMID:24020520

2013-01-01

352

9 CFR 113.312 - Rabies Vaccine, Live Virus.  

Code of Federal Regulations, 2011 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccination, except as provided in paragraphs (b)(4), (b)(5), and (b)(6) of this section. The challenged...

2011-01-01

353

9 CFR 113.312 - Rabies Vaccine, Live Virus.  

Code of Federal Regulations, 2012 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccination, except as provided in paragraphs (b)(4), (b)(5), and (b)(6) of this section. The challenged...

2012-01-01

354

9 CFR 113.209 - Rabies Vaccine, Killed Virus.  

Code of Federal Regulations, 2014 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccinations, except as provided in (b)(4) of this section. The challenged animals shall be observed each day for 90 days as...

2014-01-01

355

9 CFR 113.209 - Rabies Vaccine, Killed Virus.  

Code of Federal Regulations, 2013 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccinations, except as provided in (b)(4) of this section. The challenged animals shall be observed each day for 90 days as...

2013-01-01

356

9 CFR 113.209 - Rabies Vaccine, Killed Virus.  

Code of Federal Regulations, 2012 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccinations, except as provided in (b)(4) of this section. The challenged animals shall be observed each day for 90 days as...

2012-01-01

357

9 CFR 113.312 - Rabies Vaccine, Live Virus.  

Code of Federal Regulations, 2010 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccination, except as provided in paragraphs (b)(4), (b)(5), and (b)(6) of this section. The challenged...

2010-01-01

358

9 CFR 113.312 - Rabies Vaccine, Live Virus.  

Code of Federal Regulations, 2013 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccination, except as provided in paragraphs (b)(4), (b)(5), and (b)(6) of this section. The challenged...

2013-01-01

359

9 CFR 113.312 - Rabies Vaccine, Live Virus.  

Code of Federal Regulations, 2014 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccination, except as provided in paragraphs (b)(4), (b)(5), and (b)(6) of this section. The challenged...

2014-01-01

360

9 CFR 113.209 - Rabies Vaccine, Killed Virus.  

Code of Federal Regulations, 2011 CFR

...intramuscularly with virulent rabies virus furnished or approved by Animal and Plant Health Inspection Service 1 year after vaccinations, except as provided in (b)(4) of this section. The challenged animals shall be observed each day for 90 days as...

2011-01-01

361

Rationalizing the development of live attenuated virus vaccines.  

PubMed

The design of vaccines against viral disease has evolved considerably over the past 50 years. Live attenuated viruses (LAVs)-those created by passaging a virus in cultured cells-have proven to be an effective means for preventing many viral diseases, including smallpox, polio, measles, mumps and yellow fever. Even so, empirical attenuation is unreliable in some cases and LAVs pose several safety issues. Although inactivated viruses and subunit vaccines alleviate many of these concerns, they have in general been less efficacious than their LAV counterparts. Advances in molecular virology--creating deleterious gene mutations, altering replication fidelity, deoptimizing codons and exerting control by microRNAs or zinc finger nucleases--are providing new ways of controlling viral replication and virulence and renewing interest in LAV vaccines. Whereas these rationally attenuated viruses may lead to a new generation of safer, more widely applicable LAV vaccines, each approach requires further testing before progression to human testing. PMID:20531338

Lauring, Adam S; Jones, Jeremy O; Andino, Raul

2010-06-01

362

Development of vaccines for prevention of Ebola virus infection.  

PubMed

Ebola virus infection causes severe hemorrhagic fevers with high fatality rates up to 90% in humans, for which no effective treatment is currently available. The ongoing Ebola outbreak in West Africa that has caused over 14,000 human infections and over 5000 deaths underscores its serious threat to the public health. While licensed vaccines against Ebola virus infection are still not available, a number of vaccine approaches have been developed and shown to protect against lethal Ebola virus infection in animal models. This review aims to summarize the advancement of different strategies for Ebola vaccine development with a focus on the discussion of their protective efficacies and possible limitations. In addition, the development of animal models for efficacy evaluation of Ebola vaccines and the mechanism of immune protection against Ebola virus infection are also discussed. PMID:25526819

Ye, Ling; Yang, Chinglai

2015-02-01

363

Neutralising antibody responses in cattle and sheep following booster vaccination with two commercial inactivated bluetongue virus serotype 8 vaccines.  

PubMed

Cattle and sheep that had received a primary course of vaccination with an inactivated bluetongue virus serotype 8 (BTV-8) vaccine were booster vaccinated 6 or 12 months later with the homologous vaccine or an alternative inactivated BTV-8 vaccine and neutralising antibody responses were determined. Antibody titres to the alternative vaccine were significantly higher than to the homologous vaccine (P=0.013) in cattle. There was no significant difference between the antibody responses to alternative and homologous vaccines in sheep. These data indicate that cattle and sheep primed with one inactivated BTV-8 vaccine may be effectively boosted with an alternative commercial inactivated BTV-8 vaccine. PMID:20466568

Bartram, David J; Heasman, Lindsay; Batten, Carrie A; Oura, Christopher A L; Plana-Durán, Joan; Yuen, Ho Ming; Wylie, Andrew D M

2011-05-01

364

Developing new smallpox vaccines.  

PubMed Central

New stockpiles of smallpox vaccine are required as a contingency for protecting civilian and military personnel against deliberate dissemination of smallpox virus by terrorists or unfriendly governments. The smallpox vaccine in the current stockpile consists of a live animal poxvirus (Vaccinia virus [VACV]) that was grown on the skin of calves. Because of potential issues with controlling this earlier manufacturing process, which included scraping VACV lesions from calfskin, new vaccines are being developed and manufactured by using viral propagation on well-characterized cell substrates. We describe, from a regulatory perspective, the various strains of VACV, the adverse events associated with calf lymph-propagated smallpox vaccine, the issues regarding selection and use of cell substrates for vaccine production, and the issues involved in demonstrating evidence of safety and efficacy. PMID:11747717

Rosenthal, S. R.; Merchlinsky, M.; Kleppinger, C.; Goldenthal, K. L.

2001-01-01

365

9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).  

Code of Federal Regulations, 2014 CFR

...quantity of vaccine virus as provided in paragraph (b)(2) of this section. (ii) Fourteen to 21 days after the last vaccination, a second serum sample shall be drawn from each dog and tested for neutralizing antibody to canine parvovirus in the...

2014-01-01

366

9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).  

Code of Federal Regulations, 2011 CFR

...quantity of vaccine virus as provided in paragraph (b)(2) of this section. (ii) Fourteen to 21 days after the last vaccination, a second serum sample shall be drawn from each dog and tested for neutralizing antibody to canine parvovirus in the...

2011-01-01

367

9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).  

Code of Federal Regulations, 2012 CFR

...quantity of vaccine virus as provided in paragraph (b)(2) of this section. (ii) Fourteen to 21 days after the last vaccination, a second serum sample shall be drawn from each dog and tested for neutralizing antibody to canine parvovirus in the...

2012-01-01

368

9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).  

Code of Federal Regulations, 2013 CFR

...quantity of vaccine virus as provided in paragraph (b)(2) of this section. (ii) Fourteen to 21 days after the last vaccination, a second serum sample shall be drawn from each dog and tested for neutralizing antibody to canine parvovirus in the...

2013-01-01

369

9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).  

Code of Federal Regulations, 2010 CFR

...quantity of vaccine virus as provided in paragraph (b)(2) of this section. (ii) Fourteen to 21 days after the last vaccination, a second serum sample shall be drawn from each dog and tested for neutralizing antibody to canine parvovirus in the...

2010-01-01

370

Prospects for a vaccine against the hepatitis C virus  

Microsoft Academic Search

The recent discovery of natural immunity to the hepatitis C virus and vaccine efficacy in the chimpanzee challenge model has allowed optimism about the development of at least a partly effective vaccine against this heterogeneous pathogen that is responsible for much of the chronic liver disease around the world. The immune systems of some infected individuals can spontaneously clear the

Michael Houghton; Sergio Abrignani

2005-01-01

371

Evaluation in Nonhuman Primates of Vaccines against Ebola Virus  

Microsoft Academic Search

Ebola virus (EBOV) causes acute hemorrhagic fever that is fatal in up to 90% of cases in both humans and nonhuman primates. No vaccines or treatments are available for human use. We evaluated the effects in nonhuman primates of vaccine strategies that had protected mice or guinea pigs from lethal EBOV infec- tion. The following immunogens were used: RNA replicon

Thomas W. Geisbert; Peter Pushko; Kevin Anderson; Jonathan Smith; Kelly J. Davis; Peter B. Jahrling

2002-01-01

372

Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.  

PubMed

Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-?) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-?, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-?/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-?/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted. PMID:24978211

Pencavel, Tim D; Wilkinson, Michelle J; Mansfield, David C; Khan, Aadil A; Seth, Rohit; Karapanagiotou, Eleni M; Roulstone, Victoria; Aguilar, Richard J; Chen, Nanhai G; Szalay, Aladar A; Hayes, Andrew J; Harrington, Kevin J

2015-02-15

373

Current Trends in West Nile Virus Vaccine Development  

PubMed Central

West Nile virus (WNV) is a mosquito-borne flavivirus that has become endemic in the United States. From 1999-2012, there have been 37,088 reported cases of WNV and 1,549 deaths, resulting in a 4.2% case-fatality rate. Despite development of effective WNV vaccines for horses, there is no vaccine to prevent human WNV infection. Several vaccines have been tested in preclinical studies and to date there have been 8 clinical trials, with promising results in terms of safety and induction of antiviral immunity. Although mass vaccination is unlikely to be cost-effective, implementation of a targeted vaccine program may be feasible if a safe and effective vaccine can be brought to market. Further evaluation of new and advanced vaccine candidates is strongly encouraged. PMID:24689659

Amanna, Ian J.; Slifka, Mark K.

2014-01-01

374

Vaccinia Virus G7L Protein Interacts with the A30L Protein and Is Required for Association of Viral Membranes with Dense Viroplasm To Form Immature Virions  

PubMed Central

The vaccinia virus A30L protein is required for the association of electron-dense, granular, proteinaceous material with the concave surfaces of crescent membranes, an early step in viral morphogenesis. For the identification of additional proteins involved in this process, we used an antibody to the A30L protein, or to an epitope appended to its C terminus, to capture complexes from infected cells. A prominent 42-kDa protein was resolved and identified by mass spectrometry as the vaccinia virus G7L protein. This previously uncharacterized protein was expressed late in infection and was associated with immature virions and the cores of mature particles. In order to study the role of the G7L protein, a conditional lethal mutant was made by replacing the G7L gene with an inducible copy. Expression of G7L and formation of infectious virus was dependent on the addition of inducer. Under nonpermissive conditions, morphogenesis was blocked and viral crescent membranes and immature virions containing tubular elements were separated from the electron-dense granular viroplasm, which accumulated in large spherical masses. This phenotype was identical to that previously obtained with an inducible, conditional lethal A30L mutant. Additional in vivo and in vitro experiments provided evidence for the direct interaction of the A30L and G7L proteins and demonstrated that the stability of each one was dependent on its association with the other. PMID:12610117

Szajner, Patricia; Jaffe, Howard; Weisberg, Andrea S.; Moss, Bernard

2003-01-01

375

Comparison of virus production in chicken embryo fibroblasts infected with the WR, IHD-J and MVA strains of vaccinia virus: IHD-J is most efficient in trans-Golgi network wrapping and extracellular enveloped virus release.  

PubMed

Modified vaccinia virus Ankara (MVA) is an attenuated strain derived from vaccinia virus (VV) Ankara that grows efficiently in primary chicken embryo fibroblasts (CEFs) and baby hamster kidney cells only. MVA produces significantly more of the enveloped forms of VV in infected CEFs compared with VV strain Copenhagen. In the present study, production of the different infectious forms of VV was compared in CEFs infected with MVA or with two well-characterized replication-competent VV strains, WR and IHD-J. In a time-course experiment, the infectivity associated with the extracellular enveloped virus (EEV), the cell-associated enveloped virus (CEV) and intracellular mature and enveloped viruses was determined. Further, the production of the different viral forms was quantified by electron microscopy (EM). The data collectively indicate that IHD-J is most efficient in producing all of the trans-Golgi network-wrapped forms and releases the highest titres of EEVs into the extracellular medium, with WR being least efficient. MVA initially replicated with faster kinetics, resulting in more intracellular virus and CEVs between 8 and 24 h post-infection (p.i.). As assessed by EM, the faster growth kinetics of MVA resulted in 3.5-fold more CEVs at the cell surface at 24 h p.i., compared with both WR and IHD-J. Accordingly, we found that despite the presence of two in-frame deletions in the A36R gene of MVA, this virus was able to make actin tails in CEFs. PMID:12771405

Meiser, Andrea; Boulanger, Denise; Sutter, Gerd; Krijnse Locker, Jacomine

2003-06-01

376

Coinfection by Vaccinia virus and an Orf virus-like parapoxvirus in an outbreak of vesicular disease in dairy cows in midwestern Brazil.  

PubMed

The current report describes an outbreak of vesicular disease affecting dairy cows in midwestern Brazil in which a coinfection with 2 poxviruses-Vaccinia virus (VACV) and a parapoxvirus-was demonstrated. Milking cows presented vesicles, painful reddish or whitish papules, and scabby proliferative lesions in the teats and udder, in a clinical course of approximately 10-21 days. Histologically, multifocal areas of moderate to severe acanthosis, spongiosis, hypergranulosis, and parakeratotic or orthokeratotic hyperkeratosis with adjacent focally extensive ulcers were observed in the epidermis. Rounded eosinophilic inclusion bodies were observed in the cytoplasm of epithelial cells of areas with acanthosis or necrosis. Moderate inflammatory infiltrate of lymphocytes, plasma cells, neutrophils, and macrophages were observed in some dermal areas. Two people milking the affected cows developed lesions on the hands, painful papules which progressed to ulcerative and scabby lesions in 4-7 days. Electron microscopy of scabs from 1 cow revealed the concomitant presence of orthopoxvirus and parapoxvirus particles. Scabs from 2 cows were positive by polymerase chain reaction for the parapoxvirus B2L gene; 1 of the scabs was also positive for the VACV vgf gene. Nucleotide sequencing of the B2L amplicon revealed a similarity of 96-99% with Orf virus (ORFV) and lower identity with Pseudocowpox virus (92-95%) and Bovine papular stomatitis virus (85-86%). Nucleotide sequencing of a region of parapoxvirus DNA polymerase gene revealed a high similarity (98-100%) with ORFV sequences. Thus, an unusual coinfection with VACV and a parapoxvirus, likely ORFV, was demonstrated in the outbreak. PMID:23404478

de Sant'Ana, Fabiano J F; Leal, Fábio A A; Rabelo, Rogério E; Vulcani, Valcinir A S; Moreira, Carlos A; Cargnelutti, Juliana F; Flores, Eduardo F

2013-03-01

377

Vaccinia virus anti-apoptotic F1L is a novel Bcl2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands  

Microsoft Academic Search

Apoptosis is an important part of the host's defense mechanism for eliminating invading pathogens. Some viruses express proteins homologous in sequence and function to mammalian pro-survival Bcl-2 proteins. Anti-apoptotic F1L expressed by vaccinia virus is essential for survival of infected cells, but it bears no discernable sequence homology to proteins other than its immediate orthologues in related pox viruses. Here

M Kvansakul; H Yang; W D Fairlie; P E Czabotar; S F Fischer; M A Perugini; D C S Huang; P M Colman

2008-01-01

378

Vaccine development for protecting swine against influenza virus.  

PubMed

Influenza virus infects a wide variety of species including humans, pigs, horses, sea mammals and birds. Weight loss caused by influenza infection and/or co-infection with other infectious agents results in significant financial loss in swine herds. The emergence of pandemic H1N1 (A/CA/04/2009/H1N1) and H3N2 variant (H3N2v) viruses, which cause disease in both humans and livestock constitutes a concerning public health threat. Influenza virus contains eight single-stranded, negative-sense RNA genome segments. This genetic structure allows the virus to evolve rapidly by antigenic drift and shift. Antigen-specific antibodies induced by current vaccines provide limited cross protection to heterologous challenge. In pigs, this presents a major obstacle for vaccine development. Different strategies are under development to produce vaccines that provide better cross-protection for swine. Moreover, overriding interfering maternal antibodies is another goal for influenza vaccines in order to permit effective immunization of piglets at an early age. Herein, we present a review of influenza virus infection in swine, including a discussion of current vaccine approaches and techniques used for novel vaccine development. PMID:23253165

Chen, Qi; Madson, Darin; Miller, Cathy L; Harris, D L Hank

2012-12-01

379

Recent progress in West Nile virus diagnosis and vaccination  

PubMed Central

West Nile virus (WNV) is a positive-stranded RNA virus belonging to the Flaviviridae family, a large family with 3 main genera (flavivirus, hepacivirus and pestivirus). Among these viruses, there are several globally relevant human pathogens including the mosquito-borne dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV) and West Nile virus (WNV), as well as tick-borne viruses such as tick-borne encephalitis virus (TBEV). Since the mid-1990s, outbreaks of WN fever and encephalitis have occurred throughout the world and WNV is now endemic in Africa, Asia, Australia, the Middle East, Europe and the Unites States. This review describes the molecular virology, epidemiology, pathogenesis, and highlights recent progress regarding diagnosis and vaccination against WNV infections. PMID:22380523

2012-01-01

380

Absence of lumpy skin disease virus in semen of vaccinated bulls following vaccination and subsequent experimental infection.  

PubMed

Twelve serologically negative bulls were used, six were vaccinated with a modified live LSD vaccine and six unvaccinated. All were then experimentally infected with a virulent field strain of LSDV. No clinical abnormality was detected following vaccination, and mild clinical signs were seen in four vaccinated bulls following challenge. Virus was not found in semen of vaccinated bulls. Two of the unvaccinated bulls developed severe LSD and four showed mild symptoms, all excreted the virus in the semen following challenge. This study confirmed the ability of LSD vaccination to prevent the excretion of LSDV in semen of vaccinated bulls. PMID:17250934

Osuagwuh, U I; Bagla, V; Venter, E H; Annandale, C H; Irons, P C

2007-03-01

381

Vaccination of pigs against swine influenza viruses by using an NS1-truncated modified live-virus vaccine  

Technology Transfer Automated Retrieval System (TEKTRAN)

Swine influenza viruses (SIV) naturally infect pigs and can be transmitted to humans. In the pig, genetic reassortment to create novel influenza subtypes by mixing avian, human and swine influenza viruses is possible. An SIV vaccine inducing cross-protective immunity between different subtypes and s...

382

Protection against anthrax with recombinant virus-expressed protective antigen in experimental animals.  

PubMed Central

We previously described the cloning and expression of the protective antigen (PA) gene of Bacillus anthracis in both vaccinia virus and a baculovirus. The antigenicity of the PA products was characterized. PA expressed by the recombinant vaccinia viruses elicited a partial protective immune response against a lethal B. anthracis spore challenge in guinea pigs and mice. The WR strain vaccinia virus recombinant (WR-PA) protected 60% of male mice and 50% of guinea pigs. WR-PA elicited high anti-PA antibody titers in mice but not in guinea pigs. Connaught strain vaccinia virus recombinants failed to protect any immunized animals. PA purified from baculovirus recombinant-infected cultures plus adjuvant partially protected male CBA/J mice and completely protected female Hartley guinea pigs from challenge. Both the recombinant and nonrecombinant PA preparations combined with adjuvant elicited high anti-PA antibody titers in Hartley guinea pigs and CBA/J mice. These data demonstrate that the recombinant baculovirus- and vaccinia virus-produced PAs were immunogenic in both guinea pigs and mice, that the baculovirus-PA recombinant was a useful source of immunogenic PA, and that vaccinia virus-PA recombinants may be feasible live anthrax vaccine candidates worthy of consideration for further development as live vaccines. PMID:1903769

Iacono-Connors, L C; Welkos, S L; Ivins, B E; Dalrymple, J M

1991-01-01

383

Virus Aggregating Peptide Enhances the Cell-Mediated Response to Influenza Virus Vaccine  

PubMed Central

Given the poor immunogenicity of current H5N1 influenza vaccines, additives and adjuvants remain a viable solution for increasing efficacy. Here, we demonstrate that a 20-amino acid peptide (EB) possessing influenza antiviral activity also enhances the immune response to H5N1 vaccination in mice. The addition of EB to formalin-inactivated whole-virus vaccine induced virion aggregation and these aggregates were readily engulfed by phagocytic cells in vitro. In vivo, mice vaccinated with a suboptimal dose of inactivated vaccine containing EB peptide had reduced morbidity, improved viral clearance, and faster recovery than mice receiving vaccine alone. This phenomenon was not accompanied by an increase in virus-specific antibodies. Instead, cell-mediated immunity was enhanced as demonstrated by increased interferon-? production from splenocytes. This data demonstrates that the EB peptide may a useful adjuvant for boosting the efficacy of poorly immunogenic influenza vaccines. PMID:21839131

Jones, Jeremy C.; Settles, Erik W.; Brandt, Curtis R.; Schultz-Cherry, Stacey

2011-01-01

384

Develop of new candidate H5N1 vaccine virus for pre-pandemic vaccine  

Technology Transfer Automated Retrieval System (TEKTRAN)

Abstract This study describes the development of new candidate H5N1 vaccine by reverse genetics. Anhui/01/2005(H5N1)-PR8-IBCDC-RG5 (Anhui/PR8) virus was produced under the condition in compliance with Good Laboratory Practice (GLP). The virus contains 6 internal genes from A/Puerto Rico/8/34 (PR8)...

385

Recent Progress in Herpes Simplex Virus Immunobiology and Vaccine Research  

PubMed Central

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) cause prevalent, chronic infections that have serious outcomes in some individuals. Neonatal herpes may occur when the infant traverses the cervix during maternal genital herpes. Genital herpes is a major risk factor for human immunodeficiency virus type 1 transmission. Considerable efforts have been made to design and test vaccines for HSV, focusing on genital infection with HSV-2. Several protein subunit vaccines based on HSV-2 envelope glycoproteins have reached advanced-phase clinical trials. These antigens were chosen because they are the targets of neutralizing-antibody responses and because they elicit cellular immunity. Encouraging results have been reported in studies of treatment of HSV-seronegative women with a vaccine consisting of truncated glycoprotein D of HSV-2 and a novel adjuvant. Because most sexual HSV transmission occurs during asymptomatic shedding, it is important to evaluate the impact of vaccination on HSV-2 infection, clinically apparent genital herpes, and HSV shedding among vaccine recipients who acquire infection. There are several other attractive formats, including subunit vaccines that target cellular immune responses, live attenuated virus strains, and mutant strains that undergo incomplete lytic replication. HSV vaccines have also been evaluated for the immunotherapy of established HSV infection. PMID:12525427

Koelle, David M.; Corey, Lawrence

2003-01-01

386

Could hantavirus circulation superpose areas of highly endemic vaccinia virus outbreaks? A retrospective seroepidemiological study in State of Minas Gerais.  

PubMed

Introduction Hantavirus infections have been described in several regions in Brazil through seroepidemiological studies. Usually, populations are associated with rural and wild environment mainly due to close contact to species of Sigmodontinae rodents, considered hantavirus reservoirs. Methods A retrospective serosurvey was conducted to access the hantavirus seroprevalence in people living in regions affected by bovine vaccinia outbreaks. Results Sera from 53 patients were analyzed and none of them presented anti-hantavirus IgG antibodies. Conclusions This study presents an opportunity to analyze seronegativity despite close and recurrent contact with known hantavirus reservoirs. Aspects of hantavirus and bovine vaccinia emergence are also discussed. PMID:25626659

Trindade, Giliane de Souza; Fernandes, André Tavares da Silva; Costa, Galileu Barbosa; Figueiredo, Poliana de Oliveira; Abrahão, Jônatas Santos; Kroon, Erna Geessien; Figueiredo, Luiz Tadeu Moraes; Fonseca, Flávio Guimarães da

2014-12-01

387

Comparative Evaluation of Vaccine Efficacy of Recombinant Marek's Disease Virus Vaccine Lacking Meq Oncogene in Commercial Chickens  

Technology Transfer Automated Retrieval System (TEKTRAN)

Marek's disease virus oncogene meq has been identified as the gene involved in tumorigenesis in chickens. We have recently developed a Meq-null virus, rMd5delMeq, in which the oncogene Meq was deleted. Vaccine efficacy experiments conducted in ADOL 15I5 x 71 chickens vaccinated with rMd5delMeq virus...

388

Practical aspects of vaccination of poultry against avian influenza virus.  

PubMed

Although little has changed in vaccine technology for avian influenza virus (AIV) in the past 20 years, the approach to vaccination of poultry (chickens, turkeys and ducks) for avian influenza has evolved as highly pathogenic AIV has become endemic in several regions of the world. Vaccination for low pathogenicity AIV is also becoming routine in regions where there is a high level of field challenge. In contrast, some countries will not use vaccination at all and some will only use it on an emergency basis during eradication efforts (i.e. stamping-out). There are pros and cons to each approach and, since every outbreak situation is different, no one method will work equally well in all situations. Numerous practical aspects must be considered when developing an AIV control program with vaccination as a component, such as: (1) the goals of vaccination must be defined; (2) the population to be vaccinated must be clearly identified; (3) there must be a plan to obtain and administer good quality vaccine in a timely manner and to achieve adequate coverage with the available resources; (4) risk factors for vaccine failure should be mitigated as much as possible; and, most importantly, (5) biosecurity must be maintained as much as possible, if not enhanced, during the vaccination period. PMID:25296849

Spackman, Erica; Pantin-Jackwood, Mary J

2014-12-01

389

Egg drop syndrome 1976 (EDS?76) virus infection in inadequately vaccinated chickens  

Microsoft Academic Search

Experiments were carried out to study the epizootiology of the egg drop syndrome 1976 virus infection in chickens that were not adequately protected by vaccination. Virus excretion was demonstrated when chickens vaccinated at the recommended level were challenged within 10 days of vaccination and when chickens were challenged 6 weeks after administration of low doses of vaccine. In the latter

Jane K. A. Cook

1983-01-01

390

Therapeutic vaccination to treat chronic infectious diseases  

PubMed Central

A famous milestone in the vaccine field has been the first successful vaccination against smallpox, in 1798, by Edward Jenner. Using the vaccinia cowpox virus, Jenner was able to protect vaccinees from variola or smallpox. The Modified Virus Ankara (MVA) poxvirus strain has been one of the vaccines subsequently developed to prevent smallpox infection and was selected by the US government in their Biodefense strategy. Progress in molecular biology and immunology associated with MVA infection has led to the development of MVA as vaccine platform, both in the field of preventive and therapeutic vaccines. This later class of therapeutics has witnessed growing interest that has translated into an increasing number of vaccine candidates reaching the clinics. Among those, MVA-based therapeutic vaccines have addressed four major chronic infections including viral hepatitis, AIDS, human papillomavirus-linked pathologies and tuberculosis. Clinical trials encompass phase 1 and 2 and have started to show significant results and promises. PMID:22894957

Boukhebza, Houda; Bellon, Nadine; Limacher, Jean Marc; Inchauspé, Geneviève

2012-01-01

391

Evidence for Recombination of Live, Attenuated Immunodeficiency Virus Vaccine with Challenge Virus to a More Virulent Strain  

PubMed Central

Live, attenuated immunodeficiency virus vaccines, such as nef deletion mutants, are the most effective vaccines tested in the simian immunodeficiency virus (SIV) macaque model. In two independent studies designed to determine the breadth of protection induced by live, attenuated SIV vaccines, we noticed that three of the vaccinated macaques developed higher set point viral load levels than unvaccinated control monkeys. Two of these vaccinated monkeys developed AIDS, while the control monkeys infected in parallel remained asymptomatic. Concomitant with an increase in viral load, a recombinant of the vaccine virus and the challenge virus could be detected. Therefore, the emergence of more-virulent recombinants of live, attenuated immunodeficiency viruses and less-aggressive wild-type viruses seems to be an additional risk of live, attenuated immunodeficiency virus vaccines. PMID:10729127

Gundlach, Björn R.; Lewis, Mark G.; Sopper, Sieghart; Schnell, Tanja; Sodroski, Joseph; Stahl-Hennig, Christiane; Überla, Klaus

2000-01-01

392

Protection and Virus Shedding of Falcons Vaccinated against Highly Pathogenic Avian Influenza A Virus (H5N1)  

PubMed Central

Because fatal infections with highly pathogenic avian influenza A (HPAI) virus subtype H5N1 have been reported in birds of prey, we sought to determine detailed information about the birds’ susceptibility and protection after vaccination. Ten falcons vaccinated with an inactivated influenza virus (H5N2) vaccine seroconverted. We then challenged 5 vaccinated and 5 nonvaccinated falcons with HPAI (H5N1). All vaccinated birds survived; all unvaccinated birds died within 5 days. For the nonvaccinated birds, histopathologic examination showed tissue degeneration and necrosis, immunohistochemical techniques showed influenza virus antigen in affected tissues, and these birds shed high levels of infectious virus from the oropharynx and cloaca. Vaccinated birds showed no influenza virus antigen in tissues and shed virus at lower titers from the oropharynx only. Vaccination could protect these valuable birds and, through reduced virus shedding, reduce risk for transmission to other avian species and humans. PMID:18217549

Hafez, Hafez M.; Klopfleisch, Robert; Lüschow, Dörte; Prusas, Christine; Teifke, Jens P.; Rudolf, Miriam; Grund, Christian; Kalthoff, Donata; Mettenleiter, Thomas; Beer, Martin; Harder, Timm

2007-01-01

393

Immunogenicity of combination DNA vaccines for Rift Valley fever virus, tick-borne encephalitis virus, Hantaan virus, and Crimean Congo hemorrhagic fever virus.  

PubMed

DNA vaccines for Rift Valley fever virus (RVFV), Crimean Congo hemorrhagic fever virus (CCHFV), tick-borne encephalitis virus (TBEV), and Hantaan virus (HTNV), were tested in mice alone or in various combinations. The bunyavirus vaccines (RVFV, CCHFV, and HTNV) expressed Gn and Gc genes, and the flavivirus vaccine (TBEV) expressed the preM and E genes. All vaccines were delivered by gene gun. The TBEV DNA vaccine and the RVFV DNA vaccine elicited similar levels of antibodies and protected mice from challenge when delivered alone or in combination with other DNAs. Although in general, the HTNV and CCHFV DNA vaccines were not very immunogenic in mice, there were no major differences in performance when given alone or in combination with the other vaccines. PMID:16174542

Spik, Kristin; Shurtleff, Amy; McElroy, Anita K; Guttieri, Mary C; Hooper, Jay W; SchmalJohn, Connie

2006-05-22

394

Potential impact of vaccination on the hepatitis C virus epidemic in injection Judith A. Hahn a,  

E-print Network

Potential impact of vaccination on the hepatitis C virus epidemic in injection drug users Judith A modeling Hepatitis C virus vaccine Background: Hepatitis C virus (HCV) causes significant morbidity and mortality in injecting drug users (IDU) worldwide. HCV vaccine candidates have shown promise for reducing

Getz, Wayne M.

395

Virus-like particles as universal influenza vaccines  

PubMed Central

Current influenza vaccines are primarily targeted to induce immunity to the influenza virus strain-specific hemagglutinin antigen and are not effective in controlling outbreaks of new pandemic viruses. An approach for developing universal vaccines is to present highly conserved antigenic epitopes in an immunogenic conformation such as virus-like particles (VLPs) together with an adjuvant to enhance the vaccine immunogenicity. In this review, the authors focus on conserved antigenic targets and molecular adjuvants that were presented in VLPs. Conserved antigenic targets that include the hemagglutinin stalk domain, the external domain of influenza M2 and neuraminidase are discussed in addition to molecular adjuvants that are engineered to be incorporated into VLPs in a membrane-anchored form. PMID:23002980

Kang, Sang-Moo; Kim, Min-Chul; Compans, Richard W

2012-01-01

396

Construction of HIV1 Virus-like Particle Vaccine  

Microsoft Academic Search

The virus-like particle(VLPs) vaccine is an ideal HIV-1 vaccine, which can simultaneously induce a neutralizing antibody reaction and cell-mediated immunity effectively. In this study, two kinds of plasmids have been used, one can express the HIV-1 main structure proteins, Gagpol and Env, and the other contains an antibiotic gene. The two kinds of plasmids have been cotransfected into 293 cells.

Dong-hai ZHAO; Xi-zhen ZHANG; Xiang-hui YU; Wei KONG

2008-01-01

397

Lessons for tuberculosis vaccines from respiratory virus infection.  

PubMed

There is a worldwide epidemic of increasingly drug-resistant TB. Bacillus Calmette-Guérin vaccination provides partial protection against disseminated disease in infants but poor protection against later pulmonary TB. Cell-mediated protection against respiratory virus infections requires the presence of T cells in lung tissues, and the most effective prime-boost immunizations for Mycobacterium tuberculosis also induce lung-resident lymphocytes. These observations need to be taken into account when designing future vaccines against M. tuberculosis. PMID:18844591

Beverley, Peter Charles Leonard; Tchilian, Elma Zaven

2008-10-01

398

Evaluating the protective efficacy of a trivalent vaccine containing Akabane virus, Aino virus and Chuzan virus against Schmallenberg virus infection  

PubMed Central

Schmallenberg virus (SBV), an arthropod borne pathogen, spread rapidly throughout the majority of Europe since 2011. It can cause a febrile disease, milk drop, diarrhea, and fetal malformation in ruminants. SBV, a member of the Simbu serogroup within the genus Orthobunyavirus, is closely related to Akabane virus (AKAV) and Aino virus (AINOV) among others. In the present study, 4 Holstein-Friesian calves were immunized twice four weeks apart with a multivalent, inactivated vaccine against AKAV and AINOV. Another 4 calves were kept as unvaccinated controls. All animals were clinically, serologically and virologically examined before and after challenge infection with SBV. AKAV- and AINOV-specific neutralizing antibodies were detected one week before challenge infection, while SBV-specific antibodies were detectable only thereafter. SBV genome was detected in all vaccinated animals and 3 out of 4 controls in serum samples taken after challenge infection. In conclusion, the investigated vaccine was not able to prevent an SBV-infection. Thus, vaccines for other related Simbu serogroup viruses can not substitute SBV-specific vaccines as an instrument for disease control. PMID:24313924

2013-01-01

399

Targeting DNA vaccines to myeloid cells using a small peptide.  

PubMed

Targeting DNA vaccines to dendritic cells (DCs) greatly enhances immunity. Although several approaches have been used to target protein Ags to DCs, currently there is no method that targets DNA vaccines directly to DCs. Here, we show that a small peptide derived from the rabies virus glycoprotein fused to protamine residues (RVG-P) can target DNA to myeloid cells, including DCs, which results in enhanced humoral and T-cell responses. DCs targeted with a DNA vaccine encoding the immunodominant vaccinia B8R gene via RVG-P were able to restimulate vaccinia-specific memory T cells in vitro. Importantly, a single i.v. injection of B8R gene bound to RVG-P was able to prime a vaccinia-specific T-cell response that was able to rapidly clear a subsequent vaccinia challenge in mice. Moreover, delivery of DNA in DCs was enough to induce DC maturation and efficient Ag presentation without the need for adjuvants. Finally, immunization of mice with a DNA-vaccine encoding West Nile virus (WNV) prM and E proteins via RVG-P elicited high titers of WNV-neutralizing Abs that protected mice from lethal WNV challenge. Thus, RVG-P provides a reagent to target DNA vaccines to myeloid cells and elicit robust T-cell and humoral immune responses. PMID:25270431

Ye, Chunting; Choi, Jang Gi; Abraham, Sojan; Shankar, Premlata; Manjunath, N

2015-01-01

400

The immunology of smallpox vaccines.  

PubMed

In spite of the eradication of smallpox over 30 years ago; orthopox viruses such as smallpox and monkeypox remain serious public health threats both through the possibility of bioterrorism and the intentional release of smallpox and through natural outbreaks of emerging infectious diseases such as monkeypox. The eradication effort was largely made possible by the availability of an effective vaccine based on the immunologically cross-protective vaccinia virus. Although the concept of vaccination dates back to the late 1800s with Edward Jenner, it is only in the past decade that modern immunologic tools have been applied toward deciphering poxvirus immunity. Smallpox vaccines containing vaccinia virus elicit strong humoral and cellular immune responses that confer cross-protective immunity against variola virus for decades after immunization. Recent studies have focused on: establishing the longevity of poxvirus-specific immunity, defining key immune epitopes targeted by T and B cells, developing subunit-based vaccines, and developing genotypic and phenotypic immune response profiles that predict either vaccine response or adverse events following immunization. PMID:19524427

Kennedy, Richard B; Ovsyannikova, Inna G; Jacobson, Robert M; Poland, Gregory A

2009-06-01

401

The immunology of smallpox vaccines  

PubMed Central

In spite of the eradication of smallpox over 30 years ago; orthopox viruses such as smallpox and monkeypox remain serious public health threats both through the possibility of bioterrorism and the intentional release of smallpox and through natural outbreaks of emerging infectious diseases such as monkeypox. The eradication effort was largely made possible by the availability of an effective vaccine based on the immunologically cross-protective vaccinia virus. Although the concept of vaccination dates back to the late 1800s with Edward Jenner, it is only in the past decade that modern immunologic tools have been applied toward deciphering poxvirus immunity. Smallpox vaccines containing vaccinia virus elicit strong humoral and cellular immune responses that confer cross-protective immunity against variola virus for decades after immunization. Recent studies have focused on: establishing the longevity of poxvirus-specific immunity, defining key immune epitopes targeted by T and B cells, developing subunit-based vaccines, and developing genotypic and phenotypic immune response profiles that predict either vaccine response or adverse events following immunization. PMID:19524427

Kennedy, Richard B; Ovsyannikova, Inna G; Jacobson, Robert M; Poland, Gregory A

2010-01-01

402

Immunogenicity and Protective Efficacy of a Dual Subunit Vaccine Against Respiratory Syncytial Virus and Influenza Virus  

PubMed Central

Respiratory syncytial virus (RSV) and influenza virus are the most significant pathogens causing respiratory tract diseases. Composite vaccines are useful in reducing the number of vaccination and confer protection against multiple infectious agents. In this study, we generated fusion of RSV G protein core fragment (amino acid residues 131 to 230) and influenza HA1 globular head domain (amino acid residues 62 to 284) as a dual vaccine candidate. This fusion protein, Gcf-HA1, was bacterially expressed, purified by metal resin affinity chromatography, and refolded in PBS. BALB/c mice were intranasally immunized with Gcf-HA1 in combination with a mucosal adjuvant, cholera toxin (CT). Both serum IgG and mucosal IgA responses specific to Gcf and HA1 were significantly increased in Gcf-HA1/CT-vaccinated mice. To determine the protective efficacy of Gcf-HA1/CT vaccine, immunized mice were challenged with RSV (A2 strain) or influenza virus (A/PR/8/34). Neither detectable viral replication nor pathology was observed in the lungs of the immune mice. These results demonstrate that immunity induced by intranasal Gcf-HA1/CT immunization confers complete protection against both RSV and homologous influenza virus infection, suggesting our Gcf-HA1 vaccine candidate could be further developed as a dual subunit vaccine against RSV and influenza virus. PMID:23396871

Park, Min-Hee

2012-01-01

403

A complex of seven vaccinia virus proteins conserved in all chordopoxviruses is required for the association of membranes and viroplasm to form immature virions  

SciTech Connect

Early events in vaccinia virus (VAC) morphogenesis, particularly the formation of viral membranes and their association with viroplasm, are poorly understood. Recently, we showed that repression of A30 or G7 expression results in the accumulation of normal viral membranes that form empty-looking immature virions (IV), which are separated from large masses of electron-dense viroplasm. In addition, A30 and G7 physically and functionally interact with each other and with the F10 protein kinase. To identify other proteins involved in early morphogenesis, proteins from cells that had been infected with vaccinia virus expressing an epitope-tagged copy of F10 were purified by immunoaffinity chromatography and analyzed by gel electrophoresis. In addition to F10, A30, and G7, viral proteins A15, D2, D3, and J1 were identified by mass spectrometry of tryptic peptides. Further evidence for the complex was obtained by immunopurification of proteins associated with epitope-tagged A15, D2, and D3. The previously unstudied A15, like other proteins in the complex, was expressed late in infection, associated with virus cores, and required for the stability and kinase activity of F10. Biochemical and electron microscopic analyses indicated that mutants in which A15 or D2 expression was regulated by the Escherichia coli lac operator system exhibited phenotypes characterized by the presence of large numbers of empty immature virions, similar to the results obtained with inducible A30 and G7 mutants. Empty immature virions were also seen by electron microscopy of cells infected with temperature-sensitive mutants of D2 or D3, though the numbers of membrane forms were reduced perhaps due to additional effects of high temperature.