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Clin Infect Dis 2002 Sep 1;35(5):590-6
 

Influenza pandemic preparedness action plan for the United States: 2002 update.

Strikas RA, Wallace GS, Myers MG

National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. Rstrikas@cdc.gov

Preparation for the next influenza pandemic includes development of a national plan that has 3 goals: to limit the burden of disease, to minimize social disruption, and to reduce economic losses attributable to the pandemic. Priority areas to be addressed and improved in the plan to achieve these goals include global and national influenza surveillance, vaccine development and production, vaccine use and coverage, chemoprophylaxis and therapy, guidelines for clinical care and health resources management, emergency preparedness, and research. This multifaceted plan will require close collaboration between public and private sectors to ameliorate the potentially devastating impact of pandemic influenza.

PMID: 12173135, UI: 22161920

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Infect Immun 2002 Aug;70(8):4494-500
 

Identification and characterization of a novel heme-associated cell surface protein made by Streptococcus pyogenes.

Lei B, Smoot LM, Menning HM, Voyich JM, Kala SV, Deleo FR, Reid SD, Musser JM

Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA.

Analysis of the genome sequence of a serotype M1 group A Streptococcus (GAS) strain identified a gene encoding a previously undescribed putative cell surface protein. The gene was cloned from a serotype M1 strain, and the recombinant protein was overexpressed in Escherichia coli and purified to homogeneity. The purified protein was associated with heme in a 1:1 stoichiometry. This streptococcal heme-associated protein, designated Shp, was produced in vitro by GAS, located on the bacterial cell surface, and accessible to specific antibody raised against the purified recombinant protein. Mice inoculated subcutaneously with GAS and humans with invasive infections and pharyngitis caused by GAS seroconverted to Shp, indicating that Shp was produced in vivo. The blood of mice actively immunized with Shp had significantly higher bactericidal activity than the blood of unimmunized mice. The shp gene was cotranscribed with eight contiguous genes, including homologues of an ABC transporter involved in iron uptake in gram-negative bacteria. Our results indicate that Shp is a novel cell surface heme-associated protein.

PMID: 12117961, UI: 22112898

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Infect Immun 2002 Aug;70(8):4083-91
 

Recurrent variable region gene usage and somatic mutation in the human antibody response to the capsular polysaccharide of Streptococcus pneumoniae type 23F.

Zhou J, Lottenbach KR, Barenkamp SJ, Lucas AH, Reason DC

Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.

Combinatorial cloning and expression library analysis were used to isolate human antibody Fab fragments specific for the capsular polysaccharide of Streptococcus pneumoniae serotype 23F. Thirty 23F-specific Fabs were isolated from seven vaccinated donors, and the sequences of the heavy (H)- and light (L)-chain variable regions were determined. All individuals utilized either the Vkappa A23 L chain, the Vkappa L6 L chain, or both chains in forming the 23F-specific combining site. Vkappa A23 L chains paired primarily with VH3-23 H chains. Vkappa L6 L chains were more promiscuous in heavy-chain usage between individuals. Both H and L chains were mutated, primarily in the complementarity-determining regions, compared to their closest germ line counterpart, suggesting a recall response that has undergone affinity maturation. H-chain isotypes were reflective of those found in the serum. Shared somatic modifications demonstrated that immunoglobulin G2 (IgG2) and IgA antibodies arose from the same somatically matured B cell. Our results indicate that the response to the serotype 23F pneumococcal capsular polysaccharide is oligoclonal within the individual, with one or two paratope families accounting for the majority of expressed antibody. We also determined that, in spite of the combinatorial diversity available to the immune system, the 23F-specific response is highly restricted at the population level, with the same two L-chain-determined paratope families recurring in all individuals. Lastly, analysis of the isolated Fabs indicate all have undergone extensive somatic mutation, as well as class switch, maturational events that presumably require the participation of T cells.

PMID: 12117915, UI: 22112852

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Infect Immun 2002 Aug;70(8):4028-34
 

Immunization with the recombinant PorB outer membrane protein induces a bactericidal immune response against Neisseria meningitidis.

Wright JC, Williams JN, Christodoulides M, Heckels JE

Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair, University of Southampton Medical School, and Southampton General Hospital, United Kingdom.

Infections with Neisseria meningitidis are characterized by life-threatening meningitis and septicemia. The meningococcal porin proteins from serogroup B meningococci have been identified as candidates for inclusion in vaccines to prevent such infections. In this study, we investigated the vaccine potential of the PorB porin protein free of other meningococcal components. The porB gene from a strain of Neisseria meningitidis expressing the class 3 outer membrane porin protein (PorB3) was cloned into the pRSETB vector, and the protein was expressed at high levels in a heterologous host Escherichia coli. The recombinant protein was purified to homogeneity by affinity chromatography and used for immunization after incorporation into liposomes and into micelles composed either of zwitterionic detergent or nondetergent sulfobetaine. The immunogenicity of these preparations was compared to recombinant PorB protein adsorbed to Al(OH)(3) adjuvant as a control. Although sera raised against the protein adsorbed to Al(OH)(3) reacted with the purified recombinant protein, sera raised against liposomes and micelles showed greater activity with native protein, as measured by enzyme immunoassay with outer membranes and by whole-cell immunofluorescence. Reactivity with native protein was considerably enhanced by incorporation of the adjuvant monophosphoryl lipid A into the liposome or micelle preparations. Recognition of the native protein was in a serotype-specific manner and was associated with the ability of the antisera to promote high levels of serotype-specific complement-mediated killing of meningococci. These results demonstrate that the PorB protein should be considered as a component of a vaccine designed to prevent serogroup B meningococcal infection.

PMID: 12117908, UI: 22112845

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J Virol 2002 Oct 1;76(19):10038-43
 

Sustained Peptide-Specific Gamma Interferon T-Cell Response in Rhesus Macaques Immunized with Human Immunodeficiency Virus gag DNA Vaccines.

Caulfield MJ, Wang S, Smith JG, Tobery TW, Liu X, Davies ME, Casimiro DR, Fu TM, Simon A, Evans RK, Emini EA, Shiver J

Departments of Virus and Cell Biology. Viral Vaccine Research. Vaccine Pharmaceutical Research, Merck Research Laboratories, West Point, Pennsylvania 19486.

[Medline record in process]
 

We examined the influence of dose and method of antigen delivery on the dynamics and durability of T-cell responses to candidate human immunodeficiency virus (HIV) vaccines. Codon-optimized sequences from the HIV gag gene were inserted into alternative DNA vaccine vectors to express the coding sequence with or without the tissue plasminogen activator leader sequence. We delivered the vaccines by intramuscular injection as plasmid DNA without adjuvant or as plasmid DNA formulated with a novel block copolymer adjuvant (CRL8623) and then monitored the ensuing T-cell responses by using a gamma interferon enzyme-linked immunospot assay. We demonstrated persistence of the cell-mediated immune (CMI) response in rhesus macaques for at least 18 months following a four-dose vaccination regimen. The plasmid vaccine, with or without CRL8623, was immunogenic in macaques; however, the form coadministered with adjuvant exhibited improved T-cell responses, with a bias toward more antigen-specific CD8(+) T cells. Finally, we examined the fine specificity of the T-cell response to the gag vaccines by testing the response of 23 vaccinated macaques to individual Gag 20-mer peptides. Collectively, the monkeys responded to 25 epitopes, and, on average, each monkey recognized a minimum of 2.7 epitopes. The results indicate that a broad and durable CMI response to HIV DNA vaccines can be induced in a relevant nonhuman primate model.

PMID: 12208982, UI: 22199171

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J Virol 2002 Oct 1;76(19):9773-86
 

The Vaccinia Virus E8R Gene Product: a Viral Membrane Protein That Is Made Early in Infection and Packaged into the Virions' Core.

Doglio L, De Marco A, Schleich S, Roos N, Krijnse Locker J

Cell Biology and Biophysics Programme. Structures Programme, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. Electron Microscopy Unit for Biological Sciences, University of Oslo, Blindern, Oslo, Norway.

[Medline record in process]
 

Vaccinia virus (VV), a member of the poxvirus family, is unique among most other DNA viruses in that both transcription and DNA replication occur in the cytoplasm of the host cell. It was recently shown by electron microscopy (EM) that soon after viral DNA synthesis is initiated in HeLa cells, the replication sites become enwrapped by the membrane of the endoplasmic reticulum (ER). In the same study, a novel VV membrane protein, the E8R gene product, that may play a role in the ER wrapping process was identified (N. Tolonen, L. Doglio, S. Schleich, and J. Krijnse Locker, Mol. Biol. Cell 12:2031-2046, 2001). In the present study, the gene product of E8R was characterized both biochemically and morphologically. We show that E8R is made predominantly early in infection but is packaged into the virion. On two-dimensional gel electrophoresis, the protein appeared as a single spot throughout the VV life cycle; however, in the assembled virion, the protein underwent several modifications which resulted in a change in its molecular weight and its isoelectric point. EM of labeled cryosections of infected HeLa cells showed that the protein localized to the ER and to membranes located on one side of the Golgi complex as early as 1 h postinfection. Late in infection, E8R was additionally associated with membranes of immature virions and with intracellular mature viruses. Although E8R is predominantly associated with membranes, we show that the protein is associated with viral cores; the protein is present in cores made with NP-40-dithiothreitol as well as in incoming cores, the result of the viral entry process, early in infection. Finally, we show that E8R can be phosphorylated in vitro by the viral kinase F10L. It is able to bind DNA in vitro, and this binding may be modulated by phosphorylation by F10L. A putative role of the E8R gene product throughout the VV life cycle is discussed.

PMID: 12208956, UI: 22199145

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J Virol 2002 Oct 1;76(19):9575-87
 

Vaccinia Virus J1R Protein: a Viral Membrane Protein That Is Essential for Virion Morphogenesis.

Chiu WL, Chang W

Graduate Institute of Life Science, National Defense Medical Center. Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China.

[Medline record in process]
 

Vaccinia virus, a member of the poxvirus family, contains a conserved J1R open reading frame that encodes a late protein of 17.8 kDa. The 18-kDa J1R protein is associated mainly with the membrane fraction of intracellular mature virus particles. This study examines the biological function of J1R protein in the vaccinia virus life cycle. A recombinant vaccinia virus was constructed to conditionally express J1R protein in an isopropyl-beta-D-galactopyranoside (IPTG)-inducible manner. When J1R is not expressed during vaccinia virus infection, the virus titer is reduced approximately 100-fold. In contrast, J1R protein is not required for viral gene expression, as indicated by protein pulse-labeling. J1R protein is also not required for DNA processing, as the resolution of the concatemer junctions of replicated viral DNA was detected without IPTG. A deficiency of J1R protein caused a severe delay in the processing of p4a and p4b into mature core proteins 4a and 4b, indicating that J1R protein participates in virion morphogenesis. Infected cells grown in the absence of IPTG contained very few intracellular mature virions in the cytoplasm, and enlarged viroplasm structures accumulated with viral crescents attached at the periphery. Abundant intermediate membrane structures of abnormal shapes were observed, and many immature virions were either empty or partially filled, indicating that J1R protein is important for DNA packaging into immature virions. J1R protein also coimmunoprecipited with A45R protein in infected cells. In summary, these results indicate that vaccinia virus J1R is a membrane protein that is required for virus growth and plaque formation. J1R protein interacts with A45R protein and performs an important role during immature virion formation in cultured cells.

PMID: 12208937, UI: 22199126

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J Virol 2002 Sep;76(17):8890-9
 

Hantaan virus infection causes an acute neurological disease that is fatal in adult laboratory mice.

Wichmann D, Grone HJ, Frese M, Pavlovic J, Anheier B, Haller O, Klenk HD, Feldmann H

Institut fur Virologie, Philipps-Universitat, Marburg, Germany.

Hantaan virus, the etiological agent of Korean hemorrhagic fever, is transmitted to humans from persistently infected mice (Apodemus agrarius), which serve as the primary reservoir. Here we demonstrate that several strains of adult Mus musculus domesticus (C57BL/6, BALB/c, AKR/J, and SJL/J) were susceptible to Hantaan virus infection when infected intraperitoneally. First clinical signs were loss of weight, ruffled fur, and reduced activity, which were followed by neurological symptoms, such as paralyses and convulsions. Within 2 days of disease onset, the animals died of acute encephalitis. PCR analysis indicated a systemic infection with viral RNA present in all major organs. Immunohistochemical and in situ hybridization analyses of postmortem material detected viral antigen and RNA in the central nervous system (predominantly brain), liver, and spleen. In the central nervous system, viral antigen and RNA colocalized with perivascular infiltrations, the predominant pathological finding. To investigate the involvement of the interferon system in Hantaan virus pathogenesis, we infected alpha/beta interferon receptor knockout mice. These animals were more susceptible to Hantaan virus infection, indicating an important role of interferon-induced antiviral defense mechanisms in Hantaan virus pathogenesis. The present model may help to overcome shortcomings in the development of therapeutic and prophylactic measurements against hantavirus infections.

Publication Types:
 

• Evaluation studies

PMID: 12163608, UI: 22153717

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J Virol 2002 Sep;76(17):8729-36
 

Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling.

Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP, Wagner H, Kirschning CJ, Ter Meulen V, Schneider-Schaulies S

Institute for Virology and Immunobiology, University of Wurzburg, D-97078 Wurzburg, Germany.

Pattern recognition via Toll-like receptors (TLR) by antigen-presenting cells is an important element of innate immunity. We report that wild-type measles virus but not vaccine strains activate cells via both human and murine TLR2, and this is a property of the hemagglutinin (H) protein. The ability to activate cells via TLR2 by wild-type MV H protein is abolished by mutation of a single amino acid, asparagine at position 481 to tyrosine, as is found in attenuated strains, which is important for interaction with CD46, the receptor for these strains. TLR2 activation by MV wild-type H protein stimulates induction of proinflammatory cytokines such as interleukin-6 (IL-6) in human monocytic cells and surface expression of CD150, the receptor for all MV strains. Confirming the specificity of this interaction, wild-type H protein did not induce IL-6 release in macrophages from TLR2-/- mice. Thus, the unique property of MV wild-type strains to activate TLR2-dependent signals might essentially contribute not only to immune activation but also to viral spread and pathogenicity by upregulating the MV receptor on monocytes.

PMID: 12163593, UI: 22153702

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J Virol 2002 Sep;76(17):8609-20
 

Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: implications for immunotherapy of persistent viral infections.

Kakimi K, Isogawa M, Chung J, Sette A, Chisari FV

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

Persistent hepatitis B virus (HBV) infection is characterized by a weak and narrowly focused CD8+ T-cell response to HBV that is thought to reflect the induction of central and/or peripheral tolerance to HBV proteins in neonatal and adult onset infections, respectively. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may lead to viral clearance in chronically infected individuals. The present study was performed to compare the relative immunogenicities and tolerogenicities of HBV structural (envelope [ENV]) and nonstructural (polymerase [POL]) proteins at the CD8+ cytotoxic T lymphocyte (CTL) level in transgenic mice that replicate HBV in the liver and secrete infectious virus into the blood, thus representing an excellent model of persistent HBV infection. Interestingly, the mice were tolerant to the ENV but not to the POL proteins at the CTL level. Furthermore, the POL-specific CTLs had no impact on HBV replication or liver function in vivo, even though they were readily induced and reached the liver after DNA immunization, reflecting their relatively low avidity and the low level at which the POL protein is expressed by the hepatocyte. Collectively, these results suggest that the factors that make POL less tolerogenic also make POL-specific CTLs relatively inefficient effector cells when they reach the target organ. Immunotherapeutic strategies to control HBV infection by inducing virus-specific CTL responses in chronically infected subjects should be evaluated in light of this observation.

PMID: 12163580, UI: 22153689

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Nat Med 2002 Aug;8(8):768-9
 

IAVI creates antibody scientist team.

Birmingham K

Publication Types:
 

• News

PMID: 12152016, UI: 22146617

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Nat Med 2002 Aug;8(8):767-8
 

Eager Thailand takes on questionable therapies.

Birmingham K

Publication Types:
 

• News

PMID: 12152015, UI: 22146616

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Pediatrics 2002 Sep;110(3):648-9; discussion 648-9
 

Too many vaccinations?

Havinga W

[Medline record in process]
 

Publication Types:
 

• Letter

PMID: 12205276, UI: 22195002

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Vaccine 2002 Sep 10;20(27-28):3428
 

Corrigendum to "Aluminum salts in vaccines-US perspective" [Vaccine 20 (Suppl. 2) (2002) S18-S23].

Baylor N, Egan W, Richman P

Food and Drug Administration, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Bethesda, MD, USA

[Medline record in process]
 

PMID: 12213414, UI: 22202946

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Vaccine 2002 Sep 10;20(27-28):3422
 

A novel recombinant vaccine which protects mice against ricin intoxication.

Smallshaw J, Firan A, Fulmer J, Ruback S, Ghetie V, Vitetta E

The Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, 6000 Harry Hines Blvd., 75390-8576, Dallas, TX, USA

[Record supplied by publisher]
 

Ricin toxin (RT) is a plant-derived toxin of extraordinary toxicity; a single molecule successfully internalized into the cytoplasm of a cell is lethal for that cell. An estimated dose of 1-10&mgr;g/kg is lethal to humans, making aerosolized ricin a potential agent for bioterrorism. Vaccination against ricin using either denatured toxin or its modified A chain subunit (RTA) has been successful in experimental animals but both vaccines have potential toxicities. Recombinant (r) RTA has not been evaluated as a vaccine. However, the advantage of such a vaccine is that these potential toxicities can be deleted by appropriate mutations. In this study we have generated three mutants and shown that two lack toxicity as compared to the wild type rRTA. These mutants induce protective humoral immune responses in mice. One or both should be considered for use in humans.

PMID: 12213413

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Vaccine 2002 Sep 10;20(27-28):3413
 

Development of HIV-1 Nef vaccine components: immunogenicity study of Nef mutants lacking myristoylation and dileucine motif in mice.

Liang X, Fu T, Xie H, Emini E, Shiver J

Merck Research Laboratories, Department of Virus & Cell Biology, Merck and Co. Inc., Sumneytown Pike, P.O. Box 4, 19486, West Point, PA, USA

[Medline record in process]
 

In an effort to develop a safe Nef component for use in Cytotoxic T-lymphocyte (CTL)-based HIV-1 vaccines, several versions of Nef constructs lacking myristoylation and dileucine motif were engineered and their abilities to elicit T cell responses were evaluated in mice. Nef-specific murine T cell epitopes were first mapped in three strains of mice (Balb/c, C3H/HeN and C57BL/6), and a pair of dominant Nef-specific CD4(+) and CD8(+) T cell epitopes were identified in C57BL/6 mice. C57BL/6 mice were subsequently immunized with engineered Nef DNA constructs, and Nef-specific CD4(+) and CD8(+) T cell responses were determined. A Nef mutant with simple alanine substitutions at the myristoylation and dileucine sites was impaired in its ability to elicit Nef-specific CD4(+) and CD8(+) T cell responses. Addition of human tissue plasminogen activator (TPA) leader sequence to the N terminus of Nef, which concomitantly inactivates the myristoylation site, significantly enhanced the Nef-specific T cell responses. These findings may have practical implications for developing HIV-1 Nef vaccine component.

PMID: 12213412, UI: 22202944

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Vaccine 2002 Sep 10;20(27-28):3409
 

Anaphylactic reaction to diphtheria-tetanus vaccine in a child: specific IgE/IgG determinations and cross-reactivity studies.

Marti;n-Munoz M, Pereira M, Posadas S, Sanchez-Sabate E, Blanca M, Alvarez J

Allergy Service, University Hospital "La Paz", Paseo de la Castellana, 261, 28046, Madrid, Spain

[Record supplied by publisher]
 

The present study describes the occurrence of an anaphylactic reaction after the administration of the fifth booster dose of DT vaccine in a six-year-old child. Skin test, in vitro determinations of specific IgE antibodies and immunoblotting assays showed that the IgE response was directed against tetanus and diphtheria toxoids (Dtx). IgG antibodies were also detected by ELISA and immunoblotting. The RAST and immunoblotting inhibitions showed no cross-reactivity between the two toxoids, indicating the presence of co-existing but non-cross-reacting IgE and IgG antibodies. This was maintained in two subsequent determinations done 18 and 30 months after the episode. To our knowledge, this is the first study of cross-reactivity between tetanus and diphtheria antigens. We show that simultaneous IgE antibodies to two different toxoids may occur, indicating that after an immediate reaction to DT, a search for IgE antibodies to both tetanus and Dtx should be undertaken.

PMID: 12213411

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Vaccine 2002 Sep 10;20(27-28):3399
 

Electroporation improves the efficacy of DNA vaccines in large animals.

Babiuk S, Baca-Estrada M, Foldvari M, Storms M, Rabussay D, Widera G, Babiuk L

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, S7N 5C9, Sask., Canada

[Medline record in process]
 

It is generally recognized that DNA vaccines are often less effective in large animals than in mice. One possible reason for this reduced effectiveness may be transfection efficiency and the low level of expression elicited by plasmid vectors in large animals. A possible way to improve plasmid gene expression in vivo is electroporation. To determine whether we could enhance immune responses in pigs by electroporation, we used plasmids encoding two different genes (bovine herpesvirus glycoprotein D (gD) and hepatitis B surface antigen (HBsAg)) and two different electrodes, a single-needle electrode and a six-needle electrode. Electroporation significantly enhanced immune responses to both antigens. In addition, we demonstrated that co-administration of plasmids coding for two different antigens (pgD and pHBsAg) did not result in significant interference between the plasmids. We also incorporated a DNA prime/protein boost strategy to examine the effect of DNA priming with electroporation on the immune response after a protein boost.

PMID: 12213410, UI: 22202942

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Vaccine 2002 Sep 10;20(27-28):3379
 

PCR-generated linear DNA fragments utilized as a hantavirus DNA vaccine.

Johansson P, Lindgren T, Lundstrom M, Holmstrom A, Elgh F, Bucht G

Department of Medical Countermeasures, Division of NBC Defence, Swedish Defence Research Agency, SE-90182, Umea, Sweden

[Medline record in process]
 

The field of DNA vaccines has grown rapidly, and since most such vaccines involve the inoculation of large circular DNA molecules previously propagated in bacteria, several inconveniences (e.g. the presence of antibiotic resistance genes, impurities from bacterial cultures or inefficient uptake of the large and bulky plasmid DNA molecules to the nucleus) are debated. In this study, we have explored the possibility of using smaller and more flexible PCR-generated linear DNA fragments instead. Phosphorothioate (PTO)-modified primers were used successfully to protect the PCR-generated DNA fragments from exonuclease degradation, and by using a nuclear localization signal-peptide to target the linear DNA to the nucleus the immune response against the encoded antigen was further improved. This approach was tested in cell culture using a sensitive reporter system and in vivo with DNA encoding the amino-terminus of the Puumala hantavirus nucleocapsid protein. Our results indicate that linear DNA fragments have a great potential as a genetic vaccine and phosphorothioate modification in combination with a nuclear localization signal peptide increase the stability and targets the linear DNA molecules to the nucleus resulting in an improved biological response examined both in vitro and in vivo.

PMID: 12213408, UI: 22202940

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Vaccine 2002 Sep 10;20(27-28):3364
 

Sample size determination for phase II studies of new vaccines.

Rao M, Blackwelder W, Troendle J, Naficy A, Clemens J

National Institute of Child Health and Human Development, 20892, Bethesda, MD, USA

[Medline record in process]
 

Prior to the evaluation of protective efficacy, experimental vaccines conventionally undergo phase II randomized controlled clinical trials to evaluate safety and immunogenicity. Typically, an experimental vaccine is compared to another vaccine or to a placebo with respect to adverse events or immune responses, or both. Various strategies and methods are available for design and analysis of such studies. A key aspect of design is the determination of sample size. Often a sample size is chosen that gives a high probability ("power") of finding a statistically significant difference in an outcome of interest, if a difference of a specified size exists. This approach is appropriate when the primary goal of the study is to demonstrate that a difference exists between two groups or treatments. It may not, however, give adequate assurance that a confidence interval around the observed difference will be narrow enough to exclude the possibility of an unacceptably low immune response or unacceptably high adverse event frequency in recipients of the experimental vaccine. In this paper, we apply the "non-inferiority" trial design to phase II vaccine studies; that is, we design the trial to rule out a difference between the vaccine and control in immunogenicity or reactogenicity that is considered unacceptable. We also consider a setting in which the desire is to show that the difference between immune response rates for vaccine and control is greater than a specified value.

PMID: 12213406, UI: 22202938

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Vaccine 2002 Sep 10;20(27-28):3342
 

Liposomal immunostimulatory DNA sequence (ISS-ODN): an efficient parenteral and mucosal adjuvant for influenza and hepatitis B vaccines.

Joseph A, Louria-Hayon I, Plis-Finarov A, Zeira E, Zakay-Rones Z, Raz E, Hayashi T, Takabayashi K, Barenholz Y, Kedar E

The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, P.O. Box 12272, 91120, Jerusalem, Israel

[Record supplied by publisher]
 

Synthetic oligodeoxynucleotides (ODNs) containing immunostimulatory sequences (ISS-ODN, also known as CpG-ODNs) have been shown to display in experimental models potent Th1-biassed immunoadjuvant activity upon parenteral or mucosal co-administration with a variety of antigens. In an attempt to potentiate adjuvant activity, and to reduce dose and number of administrations, ISS-ODN was entrapped (up to 90% efficiency) in large (1.5&mgr;m) multilamellar liposomes using a simple and fast (5min) procedure. Mice were vaccinated once or twice intramuscularly (i.m.) or intranasally (i.n.) with subunit influenza vaccines (consisting of the viral hemagglutinin and neuraminidase, HN) or with hepatitis B surface antigen particles (HBsAg), either non-encapsulated or liposome-encapsulated, together with free or liposomal ISS-ODN (5-25&mgr;g per dose). At 3-12 weeks post-vaccination, the humoral (systemic, mucosal) and cellular responses and protective immunity were assessed. Vaccine formulations containing liposomal ISS-ODN co-administered with either soluble antigen or liposomal antigen (in the same vesicles or in separate vesicles) were up to 30 times more effective than formulations containing un-encapsulated ISS-ODN in inducing: (a) antigen-specific serum and mucosal IgG2a and IgA antibodies; (b) splenocyte proliferative response, cytotoxic activity and IFNgamma production; (c) a DTH response; and (d) protection against virus challenge. The response was Th1-dominant in the influenza model and a mixed Th1+Th2 response in the hepatitis B model. No adverse reactions were noted. Thus, liposomal encapsulation of ISS-ODN further enhances its inherent adjuvant activity.

PMID: 12213404

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Vaccine 2002 Sep 10;20(27-28):3292
 

Protective efficacy of a tandemly linked, multi-subunit recombinant leishmanial vaccine (Leish-111f) formulated in MPL((R)) adjuvant.

Skeiky Y, Coler R, Brannon M, Stromberg E, Greeson K, Thomas Crane R, Campos-Neto A, Reed S

Corixa Corporation, 1124 Columbia Street, Suite 200, 98104, Seattle, WA, USA

[Medline record in process]
 

Three immunodominant leishmanial antigens (TSA, LmSTI1 and LeIF) previously identified in the context of host response to infection in infected donors and BALB/c mice, as well as their ability to elicit at least partial protection against Leishmania major infection in the BALB/c mouse model, were selected for inclusion into a subunit based vaccine. This is based on the premise that an effective vaccine against leishmaniasis (a complex parasitic infection) would require a multivalent cocktail of several antigens containing a broader range of protective epitopes that would cover a wide range of MHC types in a heterogeneous population. For practical considerations of vaccine development, we report on the generation of a single recombinant polyprotein comprising the sequences of all three open reading frames genetically linked in tandem. The resulting molecule, Leish-111f, comprises an open reading frame that codes for a 111kDa polypeptide. Evaluation of the immunogenicity and protective efficacy of Leish-111f formulated with IL-12 revealed that the immune responses to the individual components were maintained and as well, rLeish-111f protected BALB/c mice against L. major infection to a magnitude equal or superior to those seen with any of the individual components of the vaccine construct or SLA, a soluble Leishmania lysate. But because rIL-12 is expensive and difficult to manufacture and its efficacy and safety as an adjuvant for human use is questionable, we screened for other adjuvants that could potentially substitute for IL-12. We report that monophosphoryl lipid A (MPL) plus squalene (MPL-SE) formulated with rLeish-111f elicited protective immunity against L. major infection. The demonstrated feasibility to manufacture a single recombinant vaccine comprising multiple protective open reading frames and the potential use of MPL-SE as a substitute for IL-12, takes us closer to the realization of an affordable and safe Leishmania vaccine.

PMID: 12213399, UI: 22202931

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Vaccine 2002 Sep 10;20(27-28):3285
 

Recombinant vaccine against hepatitis E: duration of protective immunity in rhesus macaques.

Zhang M, Emerson S, Nguyen H, Engle R, Govindarajan S, Blackwelder W, Gerin J, Purcell R

Hepatitis Viruses and Molecular Hepatitis Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 20892, Bethesda, MD, USA

[Medline record in process]
 

Hepatitis E virus (HEV) is an enterically transmitted virus that causes acute hepatitis. A candidate vaccine containing recombinant HEV capsid protein (56kDa) expressed in insect cells was shown previously to be highly immunogenic when administered in two doses to rhesus monkeys and to protect them from hepatitis E when challenged with a large intravenous dose of homologous or heterologous HEV. In the present study, the effect of a third dose of the same vaccine lot was evaluated and more importantly, the duration of protection following two doses was determined. Rhesus monkeys vaccinated twice with the 56kDa capsid protein were challenged with homologous virus 6 or 12 months after the last vaccination: 3 of 4 monkeys challenged 6 or 12 months later, respectively were protected against viral hepatitis. Similarly, all four of the rhesus monkeys given a third dose of vaccine 1 month prior to challenge were protected against hepatitis. In contrast, all four monkeys given placebo developed hepatitis following challenge. In summary, two doses of HEV vaccine partially protected rhesus monkeys from hepatitis E following intravenous challenge 6 or 12 months after vaccination.

PMID: 12213398, UI: 22202930

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Vaccine 2002 Sep 10;20(27-28):3277
 

Long lasting protection against canine kala-azar using the FML-QuilA saponin vaccine in an endemic area of Brazil (Sao Goncalo do Amarante, RN).

Borja-Cabrera G, Correia Pontes N, da Silva V, Paraguai de Souza E, Santos W, Gomes E, Luz K, Palatnik M, Palatnik de Sousa C

Instituto de Microbiologia, "Prof. Paulo de Goes", Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitaria, Ilha do Fundao, Caixa Postal 68040, CEP 21941-590, RJ, Rio de Janeiro, Brazil

[Medline record in process]
 

Naturally exposed dogs of an endemic area were vaccinated with the fucose mannose ligand (FML) antigen of Leishmania donovani in formulation with QuilA saponin. The 100% of vaccinees were seropositive to FML and showed intradermal reaction to L. donovani lysate, 2 months after vaccination. The absorbency values and size of intradermal reaction were both significantly higher in vaccinees than in controls along a 3.5 years period (ANOVA, P<0.0001). The 25% of the control animals (two dogs on the first year and six dogs on the fourth year, respectively) and 5% of the vaccinees (one dog during the fourth year) developed clinical and fatal disease until the end of experiment. This difference was significant (chi(2)=3.93, P<0.05). This means that 95% protection against kala-azar was achieved in vaccinees, after FML-QuilA vaccination (80% of vaccine efficacy (VE)). Leishmania infection was also confirmed, 3.5 years after vaccination, in saline controls that showed positive polymerase chain reaction (PCR) for Leishmania DNA and FML-serology with no intradermal reaction. Higher seropositivities and intradermal reactions with no Leishmanial DNA were detected in vaccinees. The FML-QuilA vaccine induced a significant, long lasting and strong protective effect against canine kala-azar in the field.

PMID: 12213397, UI: 22202929

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Vaccine 2002 Sep 10;20(27-28):3272
 

Rabies intradermal post-exposure vaccination of humans using reconstituted and stored vaccine.

Kamoltham T, Khawplod P, Wilde H

Provincial Health Department, Petchabun Province, Queen Saovabha Memorial Institute of the Thai Red Cross Society, Department of Medicine, Chulalongkorn University, Bangkok, Thailand

[Medline record in process]
 

Thailand's northern Petchabun province is endemic for canine rabies. There were 27 reported human rabies deaths between 1989 and 1998. A rabies control plan was formulated in 1997 between medical and veterinary public health officials. It started an intense education program and an ongoing dog vaccination campaign. Economic constraints and the high cost of biological were the main reasons for inadequate human post-exposure management (PET). It was therefore decided to use the economical Thai Red Cross Intradermal Vaccine Regimen (TRC-ID) throughout the province. The original TRC-ID method is only suitable for clinics that see more than one PET patient daily. TRC-ID was therefore modified by storing the reconstituted vaccine in a refrigerator for the same patient's next two visits. Data on a total of 8157 PET patients were collected. An additional modification of TRC-ID also eliminated the 90 day booster. There were no treatment failures and no human rabies deaths in 1999, 2000 and 2001. The modified TRC-ID method induces adequate levels of neutralizing antibodies, protects humans bitten by rabid dogs and results in significant savings in vaccine and travel costs.

PMID: 12213396, UI: 22202928

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Vaccine 2002 Sep 10;20(27-28):3263
 

DNA-based vaccination against hepatitis C virus (HCV): effect of expressing different forms of HCV E2 protein and use of CpG-optimized vectors in mice.

Ma X, Forns X, Gutierrez R, Mushahwar I, Wu T, Payette P, Bukh J, Purcell R, Davis H

Loeb Health Research Institute, 725 Parkdale Avenue, Ont., K1Y 4E9, Ottawa, Canada

[Medline record in process]
 

DNA-based immunization may be of prophylactic and therapeutic value for hepatitis C virus (HCV) infection. In efforts to improve the immunogenicity of a plasmid expressing the second envelope protein (E2) of HCV, we evaluated in mice the role of the antigen localization and demonstrated that membrane-bound and secreted forms induced higher titers of E2-specific antibodies, as well as earlier and higher seroconversion rates, than the intracellular form, but all three forms induced strong CTL. We also investigated whether E2-specific antibody responses could be enhanced by CpG optimization of the plasmid backbone and showed that removal of neutralizing CpG dinucleotides did not have a significant effect but addition of 64 immunostimulatory CpG motifs significantly enhanced anti-E2 titers. These results may have implications for the design and development of HCV DNA vaccines.

PMID: 12213395, UI: 22202927

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Vaccine 2002 Sep 10;20(27-28):3244
 

Construction and immunogenicity of a codon-optimized Entamoeba histolytica Gal-lectin-based DNA vaccine.

Gaucher D, Chadee K

Institute of Parasitology of McGill University, Macdonald Campus, 21,111 Lakeshore Road, Que., H9X 3V9, Ste. Anne de Bellevue, Canada

[Medline record in process]
 

Invasive amebiasis caused by Entamoeba histolytica is the third leading parasitic cause of mortality, and there are no vaccines available to help control the disease. The galactose-adherence lectin (Gal-lectin) is the parasite's major molecule allowing it to adhere to colonic mucin for colonization and to target cells for tissue destruction. It is immunodominant and is regarded as the most promising candidate molecule to be included in a subunit vaccine against amebiasis. In this study, we are reporting the construction of a codon-optimized DNA vaccine encoding a portion of the Gal-lectin heavy subunit that includes the carbohydrate recognition domain (CRD), and its in vivo testing in mice. The vaccine stimulated a Th1-type Gal-lectin-specific cellular immune response as well as the development of serum antibodies that recognized a recombinant portion of the heavy subunit, and that inhibited the adherence of trophozoites to target cells in vitro.

PMID: 12213393, UI: 22202925

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