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Clin Infect Dis 2002 Jul 1;35(1):84-6
 

Suboptimal measles-mumps-rubella vaccination coverage facilitates an imported measles outbreak in ireland.

Coughlan S, Connell J, Cohen B, Jin L, Hall WW

National Virus Reference Laboratory, University College Dublin, Dublin 4, Ireland. Suzie.Coughlan@ucd.ie

[Medline record in process]
 

The year 2000 saw a dramatic increase in the incidence of measles infections in Ireland, with >1500 cases documented. Initial cases were reported from an area of Dublin with low vaccine uptake and a large immigrant population. Molecular epidemiologic findings revealed that the strain of measles virus responsible for this outbreak was the genotype D2 strain, which is closely related to strains initially identified in South Africa. It is suggested that suboptimal vaccine uptake facilitated the spread of imported measles infection.

PMID: 12060880, UI: 22054930

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Infect Immun 2002 Jul;70(7):3969-3972
 

Molecular Cloning of a Vaccine Antigen against Infection with the Larval Stage of Echinococcus multilocularis.

Gauci C, Merli M, Muller V, Chow C, Yagi K, Mackenstedt U, Lightowlers MW

Molecular Parasitology Laboratory, Department of Veterinary Science, The University of Melbourne, Werribee, Victoria, Australia. Department of Parasitology, University of Hohenheim, Stuttgart, Germany. Biotechnology Division, Hokkaido Institute of Public Health, Sapporo, Hokkaido, Japan.

[Record supplied by publisher]
 

Alveolar and cystic hydatidosis are caused by infection with the larval stages of Echinococcus multilocularis and Echinococcus granulosus, respectively. A host-protective antigen has been identified in E. granulosus. Here we identify the presence of a closely related protein in E. multilocularis, characterize and express a cDNA encoding the antigen (designated EM95), determine the structure of the em95 gene, and demonstrate that the EM95 recombinant protein can be used to induce significant levels of protection against challenge infection with E. multilocularis eggs in mice.

PMID: 12065546

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Infect Immun 2002 Jul;70(7):3939-3943
 

Purified Malaria Pigment (Hemozoin) Enhances Dendritic Cell Maturation and Modulates the Isotype of Antibodies Induced by a DNA Vaccine.

Coban C, Ishii KJ, Sullivan DJ, Kumar N

Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore. Division of Viral Products, Center for Biological Evaluation and Research/Food and Drug Administration, Bethesda, Maryland.

[Record supplied by publisher]
 

Hemozoin (malaria pigment) has been implicated in the modulation of immune responses during malaria infection. This study was designed to evaluate the effect of purified hemozoin on the in vitro activation of myeloid dendritic cells. Our study also revealed that in addition to enhancing the maturation of dendritic cells, hemozoin also greatly promotes immunoglobulin G2a antibody responses when coadministered with a DNA vaccine plasmid encoding Pfs25, a Plasmodium falciparum transmission-blocking antigen.

PMID: 12065539

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Infect Immun 2002 Jul;70(7):3759-67
 

Cellular and Molecular Regulation of Vaccination with Heat Shock Protein 60 from Histoplasma capsulatum.

Deepe Jr GS, Gibbons RS

Veterans Affairs Hospital. Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio.

[Medline record in process]
 

Vaccination with heat shock protein 60 (Hsp60) from Histoplasma capsulatum induces a protective immune response in mice. We explored the cellular and molecular requirements for the efficacy of recombinant Hsp60 in mice. Depletion of CD4(+), but not CD8(+), cells during the inductive phase of vaccination abolished protection, as assessed by survival and by the fungal burden in lungs and spleens. In the expressive phase, the elimination of CD4(+) or CD8(+) cells after immunization did not significantly alter fungal recovery or survival from a lethal challenge. Depletion of both subpopulations after Hsp60 vaccination resulted in a failure to control a lethal infection and a higher fungal burden in lungs and spleens. Cytokine release by spleen cells from mice vaccinated with Hsp60 produced substantially more gamma interferon and interleukin-10 and -12 than that of cells from mice immunized with either H. capsulatum recombinant Hsp70 or bovine serum albumin. The generation of gamma interferon, but not of interleukin-10, was dependent on T cells, in particular CD4(+) cells. Treatment of Hsp60-immunized mice with monoclonal antibody to gamma interferon or interleukin-10 or -12 in the inductive phase of vaccination was accompanied by increased recovery of yeast cells from lungs and spleens and 100% mortality. Likewise, the neutralization of gamma interferon or interleukin-12 abolished the protective effect of Hsp60 in the expressive phase. These results delineate the complexity of the regulatory elements necessary for vaccination against this fungus.

PMID: 12065519, UI: 22060695

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Infect Immun 2002 Jul;70(7):3681-8
 

Improved tuberculosis DNA vaccines by formulation in cationic lipids.

D'Souza S, Rosseels V, Denis O, Tanghe A, De Smet N, Jurion F, Palfliet K, Castiglioni N, Vanonckelen A, Wheeler C, Huygen K

Mycobacterial Immunology, Pasteur Institute of Brussels, B1180 Brussels, Belgium, and. Vical, Inc., San Diego, California 92121.

[Medline record in process]
 

Mice were vaccinated with plasmid DNA (pDNA) encoding antigen 85A (Ag85A), Ag85B, or PstS-3 from Mycobacterium tuberculosis either in saline or formulated for intramuscular injections in VC1052:DPyPE (aminopropyl-dimethyl-myristoleyloxy-propanaminium bromide-diphytanoylphosphatidyl-ethanolamine) (Vaxfectin; Vical, Inc., San Diego, Calif.) or for intranasal instillations in GAP-DLRIE:DOPE (aminopropyl-dimethyl-bis-dodecyloxy-propanaminium bromide-dioleoylphosphatidyl-ethanolamine). These two novel cationic and neutral colipid formulations were previously reported to be effective adjuvants for pDNA-induced antibody responses. The levels of Ag85-specific total immunoglobulin G (IgG) and IgG isotypes were all increased 3- to 10-fold by formulation of pDNA in Vaxfectin. The level of production of splenic T-cell-derived Th1-type cytokines (interleukin-2 and gamma interferon) in response to purified Ag85 and to synthetic peptides spanning the entire Ag85A protein was also significantly higher in animals vaccinated with pDNA formulated in Vaxfectin. Cytolytic T-lymphocyte responses generated by pDNA encoding phosphate-binding protein PstS-3 in Vaxfectin were better sustained over time than were those generated by PstS-3 DNA in saline. Intranasal immunization with Ag85A DNA in saline was completely ineffective, whereas administration in GAP-DLRIE:DOPE induced a positive Th1-type cytokine response; however, the extent of the latter response was clearly lower than that obtained following intramuscular immunization with the same DNA dose. Combined intramuscular and intranasal administrations in cationic lipids resulted in stronger immune responses in the spleen and, more importantly, in the lungs as well. Finally, formulation in Vaxfectin increased the protective efficacy of the Ag85B DNA vaccine, as measured by reduced relative light unit counts and CFU counts in the spleen and lungs from mice challenged with bioluminescent M. tuberculosis H37Rv. These results may be of importance for future clinical use of DNA vaccines in humans.

PMID: 12065510, UI: 22060686

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Infect Immun 2002 Jul;70(7):3539-45
 

Role of Signal Sequence in Vaccine-Induced Protection against Experimental Coccidioidomycosis.

Jiang C, Magee DM, Ivey FD, Cox RA

Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.

[Medline record in process]
 

The vaccine efficacy of the gene sequence encoding the signal peptide of the antigen known as antigen 2 or proline-rich antigen (Ag2/PRA), an immunodominant antigen present in the cell wall of the fungal pathogen Coccidioides immitis, was investigated in a murine model of coccidioidomycosis. Expression plasmids for Ag2/PRA(1-18) DNA (signal sequence), Ag2/PRA(19-194) DNA (lacking the signal sequence), and Ag2/PRA(1-194) DNA (full length) were inserted in the pVR1012 vector, and the constructs were used to vaccinate the highly susceptible BALB/c mouse strain. Immunization with the signal gene sequence significantly reduced the fungal burden in the lungs and spleens of mice 12 days after intraperitoneal challenge with a lethal dose of 2,500 C. immitis arthroconidia, to a level comparable to the protection induced in mice immunized with the full-length Ag2/PRA(1-194) DNA. The Ag2/PRA(19-194) gene protected mice but to a significantly lower level than the signal sequence or the full-length Ag2 gene. The immunizing capacity of Ag2/PRA(1-18) was not attributable to a nonspecific immunostimulatory effect of DNA, as evidenced by the fact that mice immunized with a frameshift mutation of Ag2/PRA(1-18) were not protected against challenge. Furthermore, a synthetic peptide corresponding to the translated sequence of Ag2/PRA(1-18) DNA protected mice, albeit at a lower level than the Ag2/PRA(1-18) DNA vaccine. The protection induced with the signal gene vaccine correlated with the production of gamma interferon when splenocytes from Ag2/PRA(1-18)-immunized mice were stimulated with recombinant full-length Ag2 and was not associated with the production of anti-Coccidioides immunoglobulin G antibody. This is the first study to establish that a signal peptide sequence alone, administered as a gene vaccine or synthetic peptide, can induce protective immunity against a microbial pathogen.

PMID: 12065493, UI: 22060669

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Infect Immun 2002 Jul;70(7):3521-3528
 

Immunogenicity and Protective Efficacy of Neonatal Vaccination against Bordetella pertussis in a Murine Model: Evidence for Early Control of Pertussis.

Roduit C, Bozzotti P, Mielcarek N, Lambert PH, Del Giudice G, Locht C, Siegrist CA

World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Department of Pathology and Pediatrics, University of Geneva, Geneva, Switzerland. Unite INSERM U447, Institut Pasteur de Lille, Lille, France. Immunobiological Research Institute of Siena, Chiron S.p.A., 53100 Siena, Italy.

[Record supplied by publisher]
 

A significant resurgence of early cases of pertussis is being observed in infants too young to have yet completed their three-dose vaccination schedule. In this study, murine models of immunization and Bordetella pertussis challenge were adapted to early life. This allowed comparative evaluation of immunogenicity and protective efficacy of immunization initiated in the neonatal period (7-day-old mice) or in infancy (3-week-old mice) with diphtheria-tetanus-whole-cell pertussis (DTPw) and diphtheria-tetanus-acellular pertussis (DTPa) vaccines. Neonatal DTPa vaccination induced strong pertussis-specific antibody and memory responses. Patterns of bacterial clearance were similar in both age groups. In contrast, as observed in human neonates, neonatal DTPw priming did not induce significant antibody responses to pertussis toxin (PT) and filamentous hemagglutinin (FHA) and even interfered with subsequent antibody responses. However, this did not reflect induction of permanent neonatal tolerance, as antigen-specific antibodies could be elicited by subsequent exposure to DTPa. Furthermore, despite these blunted PT and FHA antibody responses, the protective efficacy of DTPw in neonatal mice proved similar to that in infant mice, resulting in complete bacterial clearance at day 8 after B. pertussis challenge. Thus, neonatal priming with antipertussis vaccines should be considered to reduce the window of vulnerability to pertussis at the time of its greatest severity.

PMID: 12065491

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Infect Immun 2002 Jul;70(7):3318-23
 

DNA immunization in a mouse model of latent tuberculosis: effect of DNA vaccination on reactivation of disease and on reinfection with a secondary challenge.

Repique CJ, Li A, Collins FM, Morris SL

Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892.

[Medline record in process]
 

Individuals who are latently infected with Mycobacterium tuberculosis can develop active disease via either endogenous reactivation of the latent bacilli or exogenous reinfection with a second mycobacterial strain. In this study, we investigated whether immunization with a tuberculosis DNA vaccine cocktail that induces significant protective responses in mice could prevent reactivation of disease in a murine latent-tuberculosis model. In addition, we assessed whether DNA vaccination could retard the growth of a secondary aerogenic infection with M. tuberculosis (exogenous reinfection) in latently infected mice. In the reactivation studies, administration of the DNA vaccine combination did not prevent recrudescence of the latent infection after injection of dexamethasone. Moreover, for the reinfection experiments, only a modest decrease in the growth of a secondary M. tuberculosis challenge in DNA-vaccinated animals, compared to controls, was observed 14 and 28 days after the reinfection of previously exposed mice. Interestingly, although proliferation of the secondary challenge was reduced significantly in a nonvaccinated chronic-infection group relative to the naive controls, the number of bacilli still increased by 500-fold 1 month after the secondary challenge in mice with active tuberculosis. These results indicate that novel immunotherapeutic approaches will be required to prevent reactivation of infection or reinfection of individuals with latent tuberculosis.

PMID: 12065468, UI: 22060644

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J Immunol 2002 Jun 15;168(12):6189-98
 

A Decaepitope Polypeptide Primes for Multiple CD8(+) IFN-gamma and Th Lymphocyte Responses: Evaluation of Multiepitope Polypeptides as a Mode for Vaccine Delivery.

Alexander J, Oseroff C, Dahlberg C, Qin M, Ishioka G, Beebe M, Fikes J, Newman M, Chesnut RW, Morton PA, Fok K, Appella E, Sette A

Epimmune, San Diego, CA 92121. Pharmacia, St. Louis, MO 63198. National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

[Medline record in process]
 

Proteins are generally regarded as ineffective immunogens for CTL responses. We synthesized a 100-mer decaepitope polypeptide and tested its capacity to induce multiple CD8(+) IFN-gamma and Th lymphocyte (HTL) responses in HLA transgenic mice. Following a single immunization in the absence of adjuvant, significant IFN-gamma in vitro recall responses were detected for all epitopes included in the construct (six A2.1-, three A11-restricted CTL epitopes, and one universal HTL epitope). Immunization with truncated forms of the decaepitope polypeptide was used to demonstrate that optimal immunogenicity was associated with a size of at least 30-40 residues (3-4 epitopes). Solubility analyses of the truncated constructs were used to identify a correlation between immunogenicity for IFN-gamma responses and the propensity of these constructs to form particulate aggregates. Although the decaepitope polypeptide and a pool of epitopes emulsified in IFA elicited similar levels of CD8(+) responses using fresh splenocytes, we found that the decaepitope polypeptide more effectively primed for in vitro recall CD8(+) T cell responses. Finally, immunogenicity comparisons were also made between the decaepitope polypeptide and a corresponding gene encoding the same polypeptide delivered by naked DNA immunization. Although naked DNA immunization induced somewhat greater direct ex vivo and in vitro recall responses 2 wk after a single immunization, only the polypeptide induced significant in vitro recall responses 6 wk following the priming immunization. These studies support further evaluation of multiepitope polypeptide vaccines for induction of CD8(+) IFN-gamma and HTL responses.

PMID: 12055232, UI: 22050755

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J Immunol 2002 Jun 15;168(12):6099-105
 

Vaccination with Tumor Peptide in CpG Adjuvant Protects Via IFN-gamma-Dependent CD4 Cell Immunity.

Stern BV, Boehm BO, Tary-Lehmann M

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106. Section of Endocrinology, University Hospitals, Ulm, Germany.

[Medline record in process]
 

The low frequency of tumor Ag-specific T cells in vivo has made it challenging to directly measure their clonal sizes and cytokine signatures. We used a new generation ELISPOT approach to study the constitutive immunogenicity of the RMA tumor in syngeneic B6 mice and adjuvant-guided immunity against an MHC class II-restricted RMA peptide, H11.1. The RMA tumor was found to activate cells of the innate immune system and to induce a type 1 polarized, RMA-specific CD4 and CD8 T cell response. With clonal sizes approximately 10/10(6), the magnitude of this constitutively induced immune response did not suffice to control the tumor cell growth. In contrast, immunization with H11.1 peptide, using an immunostimulatory CpG oligonucleotide or CFA as adjuvant, engaged approximately 25- or approximately 10-fold higher clonal sizes of type 1 polarized CD4 cells, respectively. Therefore, the CpG oligonucleotide functioned as a stronger type 1 adjuvant and, unlike CFA, elicited protective immunity. The protection was IFN-gamma dependent, as it was not inducible in IFN-gamma knockout mice. Therefore, CpG adjuvant-guided induction of type 1 immunity against tumor Ags might be a promising subunit vaccination approach.

PMID: 12055220, UI: 22050743

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J Immunol 2002 Jun 1;168(11):5893-9
 

Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines.

Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B

Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Central Institute for Blood Transfusion, University Clinics Innsbruck, Innsbruck, Austria.

Although it is generally recognized that the function of the immune system declines with age, the nature of the underlying defects is still poorly understood. We now demonstrate the predominance of CD8(+)CD28(-) T cell clonal expansions in elderly persons who fail to produce specific Abs following influenza vaccination. These clones express effector cell markers and are mostly CD45RA(+). When isolated and put into culture, they are unable to proliferate, but produce IFN-gamma (but no IL-5) upon stimulation with anti-CD3 or autoantigen. These autoreactive CD8(+) type 1 effector cells seem to trigger a Th1 polarization, as CD4(+) T cells from elderly persons without in vivo Ab production produce Th1, but only low amounts of Th2 cytokines upon in vitro stimulation with PHA. Therefore, the increased occurrence of CD8(+)CD28(-) clonal expansions may be decisive for the development of immune deficiency in the elderly.

PMID: 12023394, UI: 22018177

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J Infect Dis 2002 May 15;185(10):1468-75
 

Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis bacille calmette-guerin infection.

Elloumi-Zghal H, Barbouche MR, Chemli J, Bejaoui M, Harbi A, Snoussi N, Abdelhak S, Dellagi K

Laboratoire d'Immunologie, Vaccinologie, et Genetique Moleculaire, Institut Pasteur de Tunis, Tunis, Tunisia.

Five patients from 4 unrelated Tunisian families who presented with disseminated neonatal infection by Mycobacterium bovis bacille Calmette-Guerin strain were investigated. Two unrelated patients had different homozygous interleukin-12 receptor beta1 subunit gene splice-site mutations (64+5G-->A and 550-2A-->G). Two siblings and 1 unrelated patient, all of whom were from the same town, carried the same mutation (297del8) within the interleukin-12p40 gene. This is the first description of familial cytokine deficiency reported so far. All patients had complete lack of expression of the affected polypeptide and a profound deficiency of in vitro interferon-gamma production. The clinical severity of the mycobacterial infection was heterogeneous, even among affected members of the same family, which suggests the intervention of modifying genes.

PMID: 11992283, UI: 21988309

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J Virol 2002 Jun;76(11):5357-68
 

Modifications of the human immunodeficiency virus envelope glycoprotein enhance immunogenicity for genetic immunization.

Chakrabarti BK, Kong WP, Wu BY, Yang ZY, Friborg J, Ling X, King SR, Montefiori DC, Nabel GJ

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3005, USA.

In this study, we have investigated the effect of specific mutations in human immunodeficiency virus type 1 (HIV-1) envelope (Env) on antibody production in an effort to improve humoral immune responses to this glycoprotein by DNA vaccination. Mice were injected with plasmid expression vectors encoding HIV Env with modifications in regions that might affect this response. Elimination of conserved glycosylation sites did not substantially enhance humoral or cytotoxic-T-lymphocyte (CTL) immunity. In contrast, a modified gp140 with different COOH-terminal mutations intended to mimic a fusion intermediate and stabilize trimer formation enhanced humoral immunity without reducing the efficacy of the CTL response. This mutant, with deletions in the cleavage site, fusogenic domain, and spacing of heptad repeats 1 and 2, retained native antigenic conformational determinants as defined by binding to known monoclonal antibodies or CD4, oligomer formation, and virus neutralization in vitro. Importantly, this modified Env, gp140 Delta CFI, stimulated the antibody response to native gp160 while it retained its ability to induce a CTL response, a desirable feature for an AIDS vaccine.

PMID: 11991964, UI: 21988467

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Lancet 2002 Jun 1;359(9321):1948-9
 

Hepatitis A vaccine failure.

Elliott JH, Kunze M, Torresi J

Publication Types:
 

• Letter

PMID: 12057583, UI: 22053396

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Science 2002 May 10;296(5570):1012-5
 

Virology. Monkey virus link to cancer grows stronger.

Ferber D

Publication Types:
 

• News

PMID: 12004103, UI: 21999527

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Vaccine 2002 Jun 7;20(19-20):2623-2634
 

Comparative efficacy and immunogenicity of Q fever chloroform:methanol residue (CMR) and phase I cellular (Q-Vax) vaccines in cynomolgus monkeys challenged by aerosol.

Waag DM, England MJ, Tammariello RF, Byrne WR, Gibbs P, Banfield CM, Pitt ML

Pathogenesis and Immunology Branch, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, 21702-5011, Frederick, MD, USA

[Record supplied by publisher]
 

Preliminary evidence gathered in rodents and livestock suggested that a phase I chloroform:methanol residue (CMR) extracted vaccine was safe and efficacious in protecting these animals from challenge with the obligate phagolysosomal pathogen (Coxiella burnetii). Prior to the initiation of phase II studies in human volunteers, we compared, in non-human primates (Macaca fascicularis), the efficacy of CMR vaccine with Q-Vax, a licensed cellular Australian Q fever vaccine that has been demonstrated to provide complete protection in human volunteers. Vaccine efficacy was assessed by evaluating thoracic radiographs and the presence of fever and bacteremia in monkeys challenged by aerosol with Coxiella burnetii. Changes in blood chemistries, hematology, behavior and pulmonary function were also examined. CMR, whether administered in single 30 or 100&mgr;g doses or two 30&mgr;g subcutaneous doses, gave equivalent protection in vaccine recipients as a single 30&mgr;g dose of Q-Vax. In addition, vaccination resulted in significant, although temporary, increases in specific antibody titers against C. burnetii phases I and II antigens. The C. burnetii CMR vaccine may be an efficacious alternative to cellular Q fever vaccines in humans.

PMID: 12057622

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Vaccine 2002 Jun 7;20(19-20):2618-22
 

Clinical and serological studies on CAM-70 live attenuated measles vaccine: an 18-year survey at a pediatric clinic in Japan.

Ozaki T, Matsui Y, Kajita Y, Nishimura N

Department of Pediatrics, Showa Hospital, Kohnan, 483-8703, Aichi, Japan

[Medline record in process]
 

Live attenuated measles vaccine chorioallantonic membrane-70 (CAM-70) was administered to 471 healthy individuals over an 18-year period (1982-1999) at the pediatric clinic of Showa Hospital in Japan. Seroconversion occurred in 95.4% (418/438) of initially seronegative subjects. Reactions to the vaccine were generally insignificant, except for vaccine-related fever in about 20%. In February 2000, we made a questionnaire survey of 272 initially seronegative subjects who were vaccinated, from 0.7 to 18.1 years (mean: 5.5 years) earlier. Six (2.2%) of them contracted breakthrough measles during follow-up. The vaccine was generally safe and effective. However, it warrants investigation that the incidence of breakthrough measles may increase in the future in Japan.

PMID: 12057621, UI: 22053745

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Vaccine 2002 Jun 7;20(19-20):2611-7
 

Evaluation of adverse effects of vaccines: the case-control approach.

Smeeth L, Rodrigues LC, Hall AJ, Fombonne E, Smith PG

Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, WC1E 7HT, London, UK

[Medline record in process]
 

When the hypothesis of a link between vaccination and a possible adverse outcome arises, further investigation is required to confirm or refute the suspicion. Given the rarity of most serious adverse effects, a case-control approach will often be chosen. This paper discusses aspects of the design, analysis and interpretation of case-control studies to evaluate vaccine adverse effects. Potential biases (and how to minimise such biases) in the selection of cases and assessment of vaccine exposure and the potential for confounding are discussed. Finally the increasing use of electronic databases in the evaluation of vaccine adverse effects is considered.

PMID: 12057620, UI: 22053744

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Vaccine 2002 Jun 7;20(19-20):2603-2610
 

Effective synthetic peptide vaccine for foot-and-mouth disease in swine.

Wang CY, Chang TY, Walfield AM, Ye J, Shen M, Chen SP, Li MC, Lin YL, Jong MH, Yang PC, Chyr N, Kramer E, Brown F

United Biomedical Inc., 25 Davids Drive, 11788, Hauppauge, NY, USA

[Record supplied by publisher]
 

We have designed a peptide-based vaccine for foot-and-mouth disease (FMD) effective in swine. The peptide immunogen has a G-H loop domain from the VP1 capsid protein of foot-and-mouth disease virus (FMDV) and a novel promiscuous T helper (Th) site for broad immunogenicity in multiple species. The G-H loop VP1 site was optimised for cross-reactivity to FMDV by the inclusion into the peptide of cyclic constraint and adjoining sequences. The incorporation of consensus residues into the hypervariable positions of the VP1 site provided for broad immunogenicity. The vaccine protected 20 out of 21 immunised pigs from infectious challenge by FMDV O1 Taiwan using peptide doses as low as 12.5&mgr;g, and a mild adjuvant that caused no lesions. A safe chemically-defined product would have considerable advantages for vaccination against FMD.

PMID: 12057619

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Vaccine 2002 Jun 7;20(19-20):2597-2602
 

Immune response of HLA DQ2 positive subjects, vaccinated with HBsAg/AS04, a hepatitis B vaccine with a novel adjuvant.

Desombere I, Van der Wielen M, Van Damme P, Stoffel M, De Clercq N, Goilav C, Leroux-Roels G

Centre for Vaccinology, Ghent University Hospital, De Pintelaan 185 9000, Ghent, Belgium

[Record supplied by publisher]
 

About 5-10% of the general adult population respond inadequately to hepatitis B vaccination. The histocompatibility leucocyte antigen (HLA) DQ2, DR3 and DR7 phenotypes have been linked with non-responsiveness to hepatitis B vaccination. A first part of our study determined the prevalence of the HLA DQ2 allele in a healthy population, aged 15-50 years. We found 35% of our study population (n=1008) positive for the HLA DQ2 allele. Positive subjects for HLA DQ2 were subsequently invited to participate in a trial and were to be given either the HBsAg/AS04 hepatitis B vaccine or a licensed hepatitis B vaccine (Engerix-B).(1) Both contained 20&mgr;g of recombinant HBsAg. The HBsAg/AS04 vaccine was administered on a 0 and 6 months schedule whilst the comparator vaccine was given according to the standard 0, 1 and 6 months schedule. The experimental vaccine was formulated on a novel adjuvant containing 3' deacylated monophosphoryl lipid A (3D-MPL) and alum. A total of 230 subjects were enrolled into the vaccination study. At month 7, 99% of the subjects had a protective titre (>/=10mIU/ml) with a geometric mean titre (GMT) of 6613mIU/ml in the group receiving HBsAg/AS04 versus 97% seroprotected with a GMT of 2315mIU/ml in the other group. Both vaccines, with their respective schedule, give very high seroprotection rates (>96%). Our data suggest that HLA DQ2 positivity is not a good marker for non- or poor-responsiveness. The HBsAg/AS04 vaccine was more reactogenic mainly because of an increased local reactogenicity. Both vaccines, especially HBsAg/AS04, are highly immunogenic and well tolerated by the study subjects.

PMID: 12057618

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Vaccine 2002 Jun 7;20(19-20):2592-6
 

Avidity maturation following vaccination with a meningococcal recombinant hexavalent PorA OMV vaccine in UK infants.

Longworth E, Borrow R, Goldblatt D, Balmer P, Dawson M, Andrews N, Miller E, Cartwright K

Meningococcal Reference Unit, Manchester Public Health Laboratory, Withington Hospital, Nell Lane, M20 2LR, Manchester, UK

[Medline record in process]
 

To date, there are no data assessing the utility of avidity indices as a surrogate marker for the induction of immunological memory following meningococcal serogroup B outer membrane vesicle (OMV) vaccination. We studied infants who had been immunized with three doses of a recombinant hexavalent PorA OMV vaccine at ages 2-4 months, together with a fourth dose at age 12-18 months. A control group had received a single dose of the same vaccine at age 12-18 months. As previously reported, serum bactericidal antibody (SBA) titres increased after each of the first three doses, with a significant increase observed from 6 months post third dose to 1 month post fourth dose. The geometric mean avidity indices (GMAI), against strain H44/76 OMVs, increased from 1 month post first dose to 1 month post third dose. Significant increases in GMAI were observed at 6 months post third dose and again following the fourth dose. At 32-42 months of age, though the SBA titres had returned to post first dose levels, the GMAI remained elevated. No increase in avidity was observed in the control group. Antibody avidity indices are useful laboratory markers for the priming of immunological memory following vaccination with meningococcal serogroup B OMV vaccines.

PMID: 12057617, UI: 22053741

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Vaccine 2002 Jun 7;20(19-20):2585-91
 

Private demand for a HIV/AIDS vaccine: evidence from Guadalajara, Mexico.

Whittington D, Matsui-Santana O, Freiberger JJ, Van Houtven G, Pattanayak S

School of Public Health, University of North Carolina at Chapel Hill, Campus Box 7400, 27599 7400, Chapel Hill, NC, USA

[Medline record in process]
 

The private demand for a hypothetical vaccine that would provide lifetime protection against HIV/AIDS to an uninfected adult was measured in Guadalajara, Mexico, using the concept of willingness to pay (WTP). A 91-question survey instrument was administered by trained enumerators employing contingent valuation techniques to 234 adults, aged 18-60. Our estimates of private demand indicate that individuals anticipate sizable personal benefits from such a vaccine, and that they would be willing to allocate a substantial portion of their income to be protected in this way from HIV infection. A conservative estimate of the mean WTP of adults in the Guadalajara sample is 6358 pesos (US$ 669) and the median is 3000 pesos (US$ 316). A multivariate statistical analysis of the determinants of individuals' WTP shows that individuals with higher incomes, with spouses or partners, and with higher perceived risks of becoming infected with HIV are willing to pay more for the vaccine. Older respondents are willing to pay less. These results suggest that there is likely to be a potentially large private market for a HIV/AIDS vaccine in the middle-income developing countries such as Mexico. These findings have important implications both for the level of R&D effort that is devoted to a vaccine and, assuming these efforts are successful, for future policies to make the vaccine available to the public.

PMID: 12057616, UI: 22053740

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Vaccine 2002 Jun 7;20(19-20):2579-2584
 

Long term (24 months) follow-up of a hepatitis A and B vaccine, comparing a two and three dose schedule in adolescents aged 12-15 years.

Levie K, Beran J, Collard F, Nguyen C

Universite Catholique de Louvain, Brussels, Belgium

[Record supplied by publisher]
 

BACKGROUND: A two dose schedule (0 and 6 months) for a combined hepatitis A and B vaccine is currently being developed.METHODS: The present study compared the combined hepatitis A and B vaccines in 12-15-year-old: Twinrix paediatric (360 EL.U HAV antigen/10&mgr;g HBs antigen) on a three dose schedule (0, 1 and 6 months) to the adult formulation (720 EL.U HAV antigen/20&mgr;g HBs antigen) on a two dose schedule (0 and 6 months) and also reports on the follow-up until 24 months.RESULTS: Seroconversion (SC) rates to HAV in both regimens reached 100% by month 7 and remained 100% up to month 24. Anti-HAV, GMTs were slightly higher for the two dose than the three dose regimens at this time point. Seroprotection against hepatitis B was >99% in both groups by month 7 and 24, this was still 94 and 96%, respectively. Statistical non-inferiority of group 1 (two dose) versus group 2 (three dose) was demonstrated. All vaccines were well tolerated and the most frequently reported local and general symptoms were pain and fatigue. There were no vaccine-related serious adverse events reported during the study.CONCLUSION: The two dose regimen elicited similar immunogenicity to HAV and HBsAg and reactogenicity profiles as the three dose regimen in this group of healthy adolescents. The reduction in the number of doses from the current three dose schedule will make vaccination against hepatitis A and B more convenient to the vaccinee, reduce healthcare staff time required and may lower the overall costs associated with vaccination.

PMID: 12057615

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Vaccine 2002 Jun 7;20(19-20):2546-50
 

Identification of Brucella melitensis vaccine strain Rev.1 by PCR-RFLP based on a mutation in the rpsL gene.

Cloeckaert A, Grayon M, Grepinet O

Unite de Pathologie Aviaire et Parasitologie, Institut National de la Recherche Agronomique, 37380, Nouzilly, France

[Medline record in process]
 

The live attenuated strain B. melitensis Rev.1 is considered the best vaccine available for the prophylaxis of brucellosis in sheep and goats. The Rev.1 vaccine was obtained in the 1950s by a two-step selection involving firstly streptomycin resistance and dependence and secondly reversion of dependence but keeping streptomycin resistance. Chromosomally acquired streptomycin resistance is frequently due to mutations in the gene encoding the ribosomal protein S12, rpsL. Nucleotide sequencing revealed one mutation in the rpsL gene of vaccine strain Rev.1 compared to that of reference strain 16M leading to an amino acid Pro-to-Leu change at codon position 91 (Pro91Leu). This mutation resulted also in the lack of a NciI restriction site in the gene. PCR-restriction fragment length polymorphism (PCR-RFLP) using NciI applied to a large number of Brucella reference and field strains showed that the mutation detected was specific of vaccine strain Rev.1.

PMID: 12057611, UI: 22053735

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Vaccine 2002 Jun 7;20(19-20):2533-6
 

The effectiveness of serogroup C meningococcal vaccine estimated from routine surveillance data.

Rivest P, Allard R

Direction de la Sante publique, Regie regionale de la sante et des services sociaux de Montreal-Centre, 1301, rue Sherbrooke Est, Que., H2L 1M3, Montreal, Canada

[Medline record in process]
 

Serogroup C meningococcal vaccine effectiveness was estimated from routine surveillance data, based on a comparison of the proportion of vaccine and non-vaccine serogroups in vaccinated and unvaccinated reported cases. Between 1 April 1993 and 31 March 1998, 109 eligible cases were reported. Among the 54 cases caused by serogroup C, 38 had been vaccinated. Among the 55 cases caused by non-vaccine serogroups, 49 had been vaccinated. Vaccine effectiveness was estimated at 71% (95% CI: 21-89%), a value similar to that obtained in the same population by a cohort study. Effectiveness was lower in children immunized before the age of 10. This demonstrates that meningococcal vaccine effectiveness can be estimated from information obtained routinely from cases only, as an alternative to the more expensive cohort or case-control designs.

PMID: 12057609, UI: 22053733

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Vaccine 2002 Jun 7;20(19-20):2523-2532
 

Efficacy of a B virus gD DNA vaccine for induction of humoral and cellular immune responses in Japanese macaques.

Hirano M, Nakamura S, Mitsunaga F, Okada M, Shimizu K, Ueda M, Bennett A, Eberle R

Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University, Inuyama, 484-8506, Aichi, Japan

[Record supplied by publisher]
 

It is desirable to prevent dissemination of B virus (BV) in macaque colonies because transmission of BV to humans causes deadly encephalomyelitis. Vaccination of monkeys is one method that could confine spread of BV within macaque colonies. Availability of a BV DNA vaccine for use in macaques would eliminate the risk of working with infectious BV. Toward this end, we constructed a plasmid expressing the BV glycoprotein D (gD). Immunogenicity of this construct as a DNA vaccine was assessed in adult Japanese macaques by four intracutaneous injections at a dose of 500&mgr;g per head. Results of enzyme-linked immunosorbent assay (ELISA) using a recombinant herpes simplex virus type 1 (HSV1) gD, a homologue of BV gD, showed that significant levels of antibody was induced in all vaccinated animals following each booster injection. Western blot of sera from vaccinated macaques confirmed the specific recognition of authentic BV gD. Immune sera were also demonstrated to contain neutralizing activity against infectious BV. Weak lymphoproliferative responses were also observed in vaccinated macaques using recombinant HSV1 gD as a stimulating antigen and flow cytometry analysis of one individual revealed the presence of HSV1 gD-responsive effector T cells. Thus, the BV gD DNA vaccine was demonstrated to induce both humoral and cellular immune responses in macaques which recognized BV gD.

PMID: 12057608

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Vaccine 2002 Jun 7;20(19-20):2516-22
 

Influenza and pneumococcal vaccination in Scottish nursing homes: coverage, policies and reasons for receipt and non-receipt of vaccine.

Kyaw MH, Wayne B, Holmes EM, Jones IG, Campbell H

Department of Public Health Sciences, University of Edinburgh, Edinburgh, UK

[Medline record in process]
 

A national survey was carried out to determine the coverage of influenza and pneumococcal vaccines, policies, reasons for receipt, non-receipt of vaccine and strategies to improve vaccine coverage in Scottish nursing homes. Of the 550 nursing homes, 72% (394) participated in the study. Overall coverage was 85% for influenza vaccine in 2001-2002 season and 11% for pneumococcal vaccine in the last 5-year period. Only 6% (23/394) of homes were reported to have a systematic immunization record. The most frequently stated reasons for improved coverage of both vaccines were clear immunization policies (76%), awareness and education for staff and residents (68%), and consent on behalf of the incompetent residents (66%). The presence of vaccination policies was higher for influenza vaccine than pneumococcal vaccine expressed as verbal agreement (27% versus 3%), written policies with set target (24% versus 5%) and written policies without set target (17% versus 2%). Advice from the members of the community health care team was the principal reason for the receipt of both vaccines. The predominant reasons for non-receipt of vaccine were refusal by residents and family members (both vaccines) and lack of advice from general practitioners (pneumococcal vaccine). The substantial disparity in coverage of influenza and pneumococcal vaccine reflects the lack of national recommendations and policies for reimbursements for pneumococcal vaccination. These data suggest that greater efforts are needed to improve prevention behaviors of health care professionals and the public, organized vaccine delivery strategies and systematic vaccination documents to increase influenza and pneumococcal vaccination rates in nursing homes and other long-term care facilities.

PMID: 12057607, UI: 22053731

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Vaccine 2002 Jun 7;20(19-20):2500-7
 

Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox.

Brisson M, Gay NJ, Edmunds WJ, Andrews NJ

Immunisation Division, PHLS Communicable Disease Surveillance Centre, 61 Colindale Avenue, NW9 5EQ, London, UK

[Medline record in process]
 

We present data to confirm that exposure to varicella boosts immunity to herpes-zoster. We show that exposure to varicella is greater in adults living with children and that this exposure is highly protective against zoster (Incidence ratio=0.75, 95% CI, 0.63-0.89). The data is used to parameterise a mathematical model of varicella zoster virus (VZV) transmission that captures differences in exposure to varicella in adults living with and without children. Under the 'best-fit' model, exposure to varicella is estimated to boost cell-mediated immunity for an average of 20 years (95% CI, 7-41years). Mass varicella vaccination is expected to cause a major epidemic of herpes-zoster, affecting more than 50% of those aged 10-44 years at the introduction of vaccination.

PMID: 12057605, UI: 22053729

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Vaccine 2002 Jun 7;20(19-20):2494-9
 

Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community.

Wang CS, Wang ST, Chou P

A-Lein Community Health Center, Kaohsiung County, Taiwan

[Medline record in process]
 

For economic reasons, the few influenza vaccination programs seen in developing countries are aimed at the high-risk elderly. To evaluate its efficacy and cost-effectiveness, we conducted a 2-month influenza vaccination campaign in southern Taiwan's A-Lein township for all the elderly. Significant differences in hospitalization and mortality between the vaccinated and unvaccinated groups were found. Age, sex, and risk group were significant for hospitalization and mortality, but only vaccination was significant for prevention. Savings for each person vaccinated were at least three times the cost of vaccination. We strongly recommend that all the elderly-not only high-risk elderly-receive an annual influenza vaccination.

PMID: 12057604, UI: 22053728

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Vaccine 2002 Jun 7;20(19-20):2485-93
 

Characterization of a vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate.

Lin YC, Wu CN, Shih SR, Ho MS

Institute of Biomedical Sciences, Academia Sinica, 11529, Taipei, Taiwan

[Medline record in process]
 

Enterovirus 71 (EV71) is a neurotrophic virus that causes seasonal morbidity and mortality in children throughout the world with increasing frequency in recent years. Because of the lack of an effective antiviral agent, primary prevention, including the development of effective vaccines, is a top priority in terms of control strategies. Poliovirus vaccine technology, both live attenuated and inactivated, killed virus vaccines, can be adopted for use with EV71 because of their relatedness. In this study, we have characterized a laboratory-adapted EV71 strain, YN3-4a, which exhibits different characteristics from those of its parent isolate, neu, in having a rapid growth rate in Vero cells, a larger plaque size, and a lower LD(50) in newborn mice. The YN3-4a can be produced at a high viral titer of up to 10(10) tissue culture infective dose (TCID(50)) when grown in Vero cells, an approved substrate for virus vaccine production. Mouse antiserum raised against YN3-4a can neutralize a broad range of strains of EV71 isolated at different times from a variety of geographic regions. On passage in Vero cells, YN3-4a remained genetically and phenotypically stable. Many of the above-described features, such as high viral yield, strong immunogenicity, broad-based antigenic coverage, and passage stability, are desirable features in a prototype virus for the development of an inactivated viral vaccine.

PMID: 12057603, UI: 22053727

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Vaccine 2002 Jun 7;20(19-20):2454-62
 

Vaccination of cats with an attenuated recombinant myxoma virus expressing feline calicivirus capsid protein.

McCabe VJ, Tarpey I, Spibey N

Department of Molecular Studies, Intervet UK Ltd., The Elms, Houghton, Huntingdon, PE28 2BQ, Cambridge, UK

[Medline record in process]
 

Myxoma virus, a member of the Poxviridae family (genus Leporipoxvirus) is the agent responsible for myxomatosis in the European rabbit. Recombinant myxoma viruses expressing the capsid gene of an F9 strain of feline calicivirus (FCV) were constructed from an apathogenic, laboratory attenuated, isolate of myxoma virus. The FCV capsid genes were recombined into the myxoma growth factor (MGF) locus of the myxoma genome and expressed from synthetic poxvirus promoters. Myxoma virus is unable to replicate productively in feline cells in vitro, however, cells infected with recombinant viruses do express the heterologous antigens from both late and early/late synthetic promoters. Cats immunised with myxoma-FCV recombinant virus generated high levels of serum neutralising antibody and were protected from disease on subsequent challenge with virulent FCV. Furthermore, there was no evidence of transmission of myxoma-FCV recombinant virus from vaccinated to non-vaccinated cats. These results demonstrate the potential of myxoma virus as a safe vaccine vector for use in non-lepori species and in particular the cat.

PMID: 12057600, UI: 22053724

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Vaccine 2002 Jun 7;20(19-20):2448-53
 

Antibody responses induced by immunization with a Japanese rabies vaccine determined by neutralization test and enzyme-linked immunosorbent assay.

Arai YT, Kimura M, Sakaue Y, Hamada A, Yamada KI, Nakayama M, Takasaki T, Kurane I

Department of Virology 1, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, 162, Tokyo, Japan

[Medline record in process]
 

The immunogenicity of a Japanese purified chick embryo cell culture rabies vaccine (PCECV) was examined. Serum samples were obtained from 86 subjects after pre-exposure or post-exposure prophylaxis. Rabies antibody titres were determined by neutralization test and enzyme-linked immunosorbent assay (ELISA). Titres higher than 0.5 international units (IU)/ml were demonstrated by neutralization test in all the 19 subjects after three-time pre-exposure immunization on days 0, 30 and 180. Titres higher than 0.5IU/ml were also demonstrated by neutralization test in all the 23 subjects after four-time post-exposure immunization on days 0, 3, 7 and 14. There was a correlation between neutralization and ELISA antibody titres (r=0.697); however, neutralization titers were higher than ELISA titres for most of the samples. The results suggest that current Japanese rabies vaccine induces recommended levels of neutralizing antibodies after pre- and post-exposure prophylaxes.

PMID: 12057599, UI: 22053723

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Vaccine 2002 Jun 7;20(19-20):2439-47
 

Recombinant cysteine proteinases-based vaccines against Leishmania major in BALB/c mice: the partial protection relies on interferon gamma producing CD8(+) T lymphocyte activation.

Rafati S, Kariminia A, Seyde-Eslami S, Narimani M, Taheri T, Lebbatard M

Department of Immunology, Pasteur Institute of Iran, Tehran, Iran

[Medline record in process]
 

Together with poloxamer 407 as adjuvant the recombinant type I (rCPB) or type II (rCPA) cysteine proteinases of Leishmania major were screened as potential vaccines against L. major in a mouse model. The vaccines were delivered subcutaneously twice at 3 weeks intervals. Three weeks after booster injection, 5x10(5) stationary phase L. major promastigotes were inoculated subcutaneously in one footpad. Using the footpad thickness increase to monitor the clinical outcome/cutaneous lesion at site of L. major delivery, it was possible to document that rCPB but not rCPA allowed BALB/c mice to mount a partial protective response: indeed over the period under study (weeks 1-12) a clear delay was noticed after the immunization with rCPB. This partial protective effect was no more detectable if CD8 depleting antibody was given intravenously to rCPB-immunized mice, at the time of parasite challenge. Seven weeks after challenge, the draining lymph nodes were monitored for their frequencies of IFN-gamma positive CD4(+) and CD8(+) T lymphocytes using PMA and ionomycin as re-activating signals: interestingly the partial protection achieved in BALB/c mice immunized with rCPB together with poloxamer was correlated only to one immunological parameter, namely the higher frequency of IFN-gamma producing CD8(+) T lymphocytes. Of note also, in the lymph node draining the L. major-loaded footpad of C57BL/6 mice otherwise known to develop a transient lesion, the frequency of IFN-gamma producing CD8(+) T lymphocytes reach similar value 7 weeks after challenge and in absence of any prior immunization. Taken together, it was shown that the induced partial protection was mainly dependent on IFN-gamma producing CD8(+) T cells.

PMID: 12057598, UI: 22053722

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Vaccine 2002 Jun 7;20(19-20):2431-8
 

A dilemma for mucosal vaccination: efficacy versus toxicity using enterotoxin-based adjuvants.

Fujihashi K, Koga T, van Ginkel FW, Hagiwara Y, McGhee JR

Departments of Microbiology and Oral Biology, BBRB Room 716, Immunobiology Vaccine Center, University of Alabama at Birmingham, Medical Center, 35294-2170, Birmingham, AL, USA

[Medline record in process]
 

In the development of mucosal vaccines, cholera toxin (CT) has been shown to be an effective adjuvant and to induce both mucosal and systemic immune responses via a Th2 cell-dependent pathway. However, a major concern for use of mucosal adjuvants such as CT is that this molecule is not suitable for use in humans because of its innate toxicity. Recent vaccine development efforts have emphasized nasal application of antigen and CT for the induction of mucosal IgA responses. When we examined potential toxicity of CT for the central nervous system (CNS), both CT and CT-B accumulated in the olfactory nerves/epithelium and olfactory bulbs of mice when given by the nasal route. The development of effective mucosal vaccines for the elderly is also an important issue; however, only limited information is available. When mucosal adjuvanticity of CT was evaluated in aged mice, an early immune dysregulation was evident in the mucosal immune system. The present review discusses these potential problems for effective mucosal vaccine development.

PMID: 12057597, UI: 22053721

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Vaccine 2002 Jun 7;20(19-20):2411-30
 

Reduction of animal use in human vaccine quality control: opportunities and problems.

Metz B, Hendriksen CF, Jiskoot W, Kersten GF

Laboratory for Product and Process Development, National Institute of Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA, Bilthoven, The Netherlands

[Medline record in process]
 

In vivo assays play a crucial role in the assessment of the potency and safety of human vaccines. Robust vaccine production procedures, improved characterisation methods and development of well-characterised vaccines create possibilities to reduce animal use. In this paper the current status in this field is reviewed. Achievements with regard to in vivo and in vitro potency and safety testing are discussed as well as new developments and possibilities in the field of in vitro characterisation of vaccine components. Finally, validation and implementation issues will be dealt with. Although replacement of in vivo tests for batch release of existing vaccines is difficult, emerging technologies allow well-considered reduction of in vivo experiments during product and process development and improvement. Inextricably bound up with this approach is good manufacturing practice (GMP), resulting in robust, validated production processes.

PMID: 12057596, UI: 22053720

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