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1.
N Engl J Med ; 358(24): 2573-84, 2008 Jun 12.
Article in English | MEDLINE | ID: mdl-18550874

ABSTRACT

BACKGROUND: Widespread infections of avian species with avian influenza H5N1 virus and its limited spread to humans suggest that the virus has the potential to cause a human influenza pandemic. An urgent need exists for an H5N1 vaccine that is effective against divergent strains of H5N1 virus. METHODS: In a randomized, dose-escalation, phase 1 and 2 study involving six subgroups, we investigated the safety of an H5N1 whole-virus vaccine produced on Vero cell cultures and determined its ability to induce antibodies capable of neutralizing various H5N1 strains. In two visits 21 days apart, 275 volunteers between the ages of 18 and 45 years received two doses of vaccine that each contained 3.75 microg, 7.5 microg, 15 microg, or 30 microg of hemagglutinin antigen with alum adjuvant or 7.5 microg or 15 microg of hemagglutinin antigen without adjuvant. Serologic analysis was performed at baseline and on days 21 and 42. RESULTS: The vaccine induced a neutralizing immune response not only against the clade 1 (A/Vietnam/1203/2004) virus strain but also against the clade 2 and 3 strains. The use of adjuvants did not improve the antibody response. Maximum responses to the vaccine strain were obtained with formulations containing 7.5 microg and 15 microg of hemagglutinin antigen without adjuvant. Mild pain at the injection site (in 9 to 27% of subjects) and headache (in 6 to 31% of subjects) were the most common adverse events identified for all vaccine formulations. CONCLUSIONS: A two-dose vaccine regimen of either 7.5 microg or 15 microg of hemagglutinin antigen without adjuvant induced neutralizing antibodies against diverse H5N1 virus strains in a high percentage of subjects, suggesting that this may be a useful H5N1 vaccine. (ClinicalTrials.gov number, NCT00349141.)


Subject(s)
Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Adjuvants, Immunologic/administration & dosage , Adult , Animals , Antibodies, Viral/blood , Chlorocebus aethiops , Cross Reactions , Female , Humans , Influenza Vaccines/adverse effects , Influenza Vaccines/immunology , Influenza, Human/immunology , Injections, Intramuscular/adverse effects , Male , Neutralization Tests , Vero Cells
2.
Neuropsychopharmacology ; 28(7): 1317-27, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12784121

ABSTRACT

The adenosine A(2A) receptor and the dopamine D(2) receptor are prototypically coupled to G(s) and G(i)/G(o), respectively. In striatal intermediate spiny neurons, these receptors are colocalized in dendritic spines and act as mutual antagonists. This antagonism has been proposed to occur at the level of the receptors or of receptor-G protein coupling. We tested this model in PC12 cells which endogenously express A(2A) receptors. The human D(2) receptor was introduced into PC12 cells by stable transfection. A(2A)-agonist-mediated inhibition of D(2) agonist binding was absent in PC12 cell membranes but present in HEK293 cells transfected as a control. However, in the resulting PC12 cell lines, the action of the D(2) agonist quinpirole depended on the expression level of the D(2) receptor: at low and high receptor levels, the A(2A)-agonist-induced elevation of cAMP was enhanced and inhibited, respectively. Forskolin-stimulated cAMP formation was invariably inhibited by quinpirole. The effects of quinpirole were abolished by pretreatment with pertussis toxin. A(2A)-receptor-mediated cAMP formation was inhibited by other G(i)/G(o)-coupled receptors that were either endogenously present (P(2y12)-like receptor for ADP) or stably expressed after transfection (A(1) adenosine, metabotropic glutamate receptor-7A). Similarly, voltage activated Ca(2+) channels were inhibited by the endogenous P(2Y) receptor and by the heterologously expressed A(1) receptor but not by the D(2) receptor. These data indicate functional segregation of signaling components. Our observations are thus compatible with the proposed model that D(2) and A(2A) receptors are closely associated, but they highlight the fact that this interaction can also support synergism.


Subject(s)
Adenosine Diphosphate/analogs & derivatives , Adenosine/analogs & derivatives , Adenylyl Cyclases/metabolism , Receptors, Dopamine D2/physiology , Receptors, Purinergic P1/physiology , Xenopus Proteins , 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone/pharmacology , Adenine/pharmacokinetics , Adenosine/pharmacokinetics , Adenosine/pharmacology , Adenosine Deaminase/pharmacology , Adenosine Diphosphate/pharmacology , Animals , Benzamides/pharmacokinetics , Binding, Competitive , Cell Cycle/drug effects , Cell Membrane/drug effects , Cell Membrane/metabolism , Cofilin 1 , Colforsin/pharmacology , Cyclic AMP/metabolism , Cytoskeletal Proteins , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacokinetics , Dopamine D2 Receptor Antagonists , Enzyme Activation , Gene Expression , Glutamic Acid/pharmacology , Humans , Membrane Potentials/drug effects , PC12 Cells , Patch-Clamp Techniques/methods , Pertussis Toxin/pharmacology , Phenethylamines/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoproteins/pharmacology , Propionates/pharmacology , Purinergic P1 Receptor Agonists , Purinergic P1 Receptor Antagonists , Pyrrolidines/pharmacokinetics , Quinpirole/pharmacology , Radioligand Assay/methods , Rats , Receptors, Dopamine D2/genetics , Receptors, Purinergic P1/genetics , Thionucleotides/pharmacology , Transfection , Triazines/pharmacokinetics , Triazoles/pharmacokinetics
3.
Vaccine ; 21(7-8): 742-5, 2003 Jan 30.
Article in English | MEDLINE | ID: mdl-12531353

ABSTRACT

A new, highly purified, inactivated tick-borne encephalitis (TBE) vaccine FSME-IMMUN "NEW" has been developed by Baxter using a production virus seed derived from chick embryo cells instead of mouse brain. In clinical trials, the vaccine was shown to be highly immunogenic and well tolerated in adults and children. Following licensure in 2001, the tolerability of half the adult dose of FSME-IMMUN "NEW" (1.2 microg antigen/0.25 ml) was investigated in a post-marketing surveillance in 1899 children aged 6 months to 12 years. Rectal body temperature was measured daily for 3 days after the first vaccination. An overall fever rate of 20.3% (95% CI=18.5; 22%) was observed, which was mostly mild in nature (>38.0 to

Subject(s)
Encephalitis, Tick-Borne/prevention & control , Viral Vaccines/adverse effects , Antigens, Viral , Child , Child, Preschool , Fever/etiology , Humans , Infant , Product Surveillance, Postmarketing , Vaccination
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