Giuseppe
Emeritus
Selected Research Articles Abstracts.
Contents:
(1.1) Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein.
(1.2) Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity.
(1.3) Complete genome analysis of a highly pathogenic H5N1 influenza A virus isolated from a tiger in China.
(1.4) Inactivation and morphological changes of avian influenza virus by copper ions.
(1.5) DC-SIGN mediates avian H5N1 influenza virus infection in cis and in trans.
(1.6) Subtyping of H1 to H15 Hemagglutinin Genes of Avian Influenza Virus by RT-PCR Assay and Molecular Determination of the Pathogenic Potential.
(1.7) Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs.
(1.8) Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells.
(1.9) Influenza pandemics, immune cross-reactivity, and pandemic control strategies.
(1.10) S-acylation of HA of influenza viruses: Mass-spectrometry reveals site-specific attachment of stearic acid to a transmembrane cysteine.
(1.11) Typing (A/B) and subtyping (H1/H3/H5) of influenza A viruses by multiplex real-time RT-PCR assays.
(1.12) Influenza activity--United States and worldwide, 2007-08 season.
(1.13) A clinical trial of a whole-virus H5N1 vaccine derived from cell culture.
(1.14) Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults.
(1.15) Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children.
(1.16) Sampling for low-pathogenic avian influenza A virus in wild Mallard ducks: Oropharyngeal versus cloacal swabbing.
(1.17) Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease.
(1.18) FDA/NIH/WHO public workshop on immune correlates of protection against influenza A viruses in support of pandemic vaccine development, Bethesda, Maryland, US, December 10-11, 2007.
(1.19) Selection bias in evaluating of influenza vaccine effectiveness: A lesson from an observational study of elderly nursing home residents.
(1.20) Structure of an avian influenza A virus NS1 protein effector domain.
(1.21) A live attenuated cold-adapted influenza A H7N3 virus vaccine provides protection against homologous and heterologous H7 viruses in mice and ferrets.
(1.22) Attenuation of the type I interferon response in cells infected with human rhinovirus.
(1.23) Countywide school-based influenza immunization: direct and indirect impact on student absenteeism.
See original abstracts at the source site. EDITED.]
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(1.1): Antiviral Res. 2008 Jun 30. [Epub ahead of print]
Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein.
Wang R, Song A, Levin J, Dennis D, Zhang NJ, Yoshida H, Koriazova L, Madura L, Shapiro L, Matsumoto A, Yoshida H, Mikayama T, Kubo RT, Sarawar S, Cheroutre H, Kato S. - Kirin Pharma USA, Inc., La Jolla, CA, USA.
Influenza is one of the most prevalent viral diseases in humans.
For some high-risk human populations, including the infant, the elderly, and the immunocompromised, who may not benefit from active immunization, passive immunotherapy with antibodies reactive with all influenza A strains may be an alternative.
In this study, we characterized several fully human monoclonal antibodies (MAb) reactive with M2e, which were generated from transchromosomic mice engineered to produce fully human antibodies following immunization with a consensus-sequence M2e peptide.
The MAbs showed strong binding to M2e peptide and to virus infected MDCK cells.
One MAb recognizing the highly conserved N-terminal portion of consensus M2e displayed high binding to the majority of M2e variants from natural viral isolates, including highly pathogenic avian strains, which were recently reported to infect humans.
Passive immunotherapy with this MAb in mice resulted in significant reduction in virus replication in the lung and protection from lethal infection when administered either prophylactically or therapeutically.
These results suggest the potential of the anti-M2e human MAb with broad binding spectrum as a universal passive immunotherapeutic agent to infection by influenza A virus.
PMID: 18598723 [PubMed - as supplied by publisher]
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(1.2): Antiviral Res. 2008 Jun 13. [Epub ahead of print]
Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity.
Hoffmann HH, Palese P, Shaw ML. - Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA; Institute of Chemistry and Biochemistry, Free University of Berlin, 14195 Berlin, Germany.
In recent years, increasing levels of resistance to the four FDA-approved anti-influenza virus drugs have been described and vaccine manufacturers have experienced demands that exceed their capacity.
This situation underlines the urgent need for novel antivirals as well as innovations in vaccine production in preparation for the next influenza epidemic.
Here we report the development of a cell-based high-throughput screen which we have used for the identification of compounds that modulate influenza virus growth either negatively or positively.
We screened a library of compounds with known biological activity and identified distinct groups of inhibitors and enhancers that target sodium channels or protein kinase C (PKC).
We confirmed these results in viral growth assays and find that treatment with a sodium channel opener or PKC inhibitor significantly reduces viral replication.
In contrast, inhibition of sodium channels or activation of PKC leads to enhanced virus production in tissue culture.
These diametrically opposing effects strongly support a role for PKC activity and the regulation of Na(+) currents in influenza virus replication and both may serve as targets for antiviral drugs.
Furthermore, we raise the possibility that compounds that result in increased viral titers may be beneficial for boosting the production of tissue culture-grown influenza vaccines.
PMID: 18585796 [PubMed - as supplied by publisher]
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(1.3): Arch Virol. 2008 Jul 1. [Epub ahead of print]
Complete genome analysis of a highly pathogenic H5N1 influenza A virus isolated from a tiger in China.
Mushtaq MH, Juan H, Jiang P, Li Y, Li T, Du Y, Mukhtar MM. - Key Laboratory of Animal Diseases Diagnostic and Immunology, College of Veterinary Medicine, Nanjing Agricultural University, Ministry of Agriculture, 210095, Nanjing, China.
An influenza A virus (A/Tig/SH/01/2005 (H5N1) was isolated from lung tissue samples of a dead zoo tiger with respiratory disease in China in July 2005.
Complete genome analysis indicated that the isolate was highly identical to an H5N1 virus isolated from a migratory duck at Poyang lake in China in that year.
The genotype of the isolate was K,G,D,5J,F,1J,F,1E, and phylogenetically it was a clade 2.2 virus.
Molecular characterization of all of the gene segments revealed characteristics of highly pathogenic influenza A viruses.
These results may help to identify molecular determinants of virulence and highlight the necessity for continuous surveillance.
PMID: 18592132 [PubMed - as supplied by publisher
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(1.4): Arch Virol. 2008 Jul 1. [Epub ahead of print]
Inactivation and morphological changes of avian influenza virus by copper ions.
Horie M, Ogawa H, Yoshida Y, Yamada K, Hara A, Ozawa K, Matsuda S, Mizota C, Tani M, Yamamoto Y, Yamada M, Nakamura K, Imai K. - Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
The infectivity of the H9N2 virus to MDCK cells was time-dependently inhibited by Cu(2+) at concentrations of 2.5-250 muM.
In 25 muM Cu(2+) solution, the virus titer decreased by approximately 3 and 4 log within 3 and 6 h, respectively.
Compared to Cu(2+), Zn(2+) was much less effective in virus inactivation.
The H9N2 virus hemagglutinin activity was not affected by 2.5-250 muM Cu(2+).
The H9N2 virus neuraminidase (NA) activity was drastically reduced by 25 mM Cu(2+), marginally reduced by 250 muM Cu(2+), and not affected by 25 muM Cu(2+).
Thus, we found that copper ions suppress the infectivity of influenza virus at lower concentrations at which neither NA nor hemagglutination inhibition occurs.
Electron microscopic analysis revealed morphological abnormalities of the Cu(2+)-treated H9N2 virus.
Additional studies should be undertaken to clarify the mechanism underlying the antiviral effect of copper ions on influenza virus.
PMID: 18592130 [PubMed - as supplied by publisher]
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(1.5): Biochem Biophys Res Commun. 2008 Jun 28. [Epub ahead of print]
DC-SIGN mediates avian H5N1 influenza virus infection in cis and in trans.
Wang SF, Huang JC, Lee YM, Liu SJ, Chan YJ, Chau YP, Chong P, Chen YM. - Department of Biotechnology and Laboratory Science in Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; AIDS Prevention and Research Center, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
DC-SIGN, a C-type lectin receptor expressed in dendritic cells (DCs), has been identified as a receptor for human immunodeficiency virus type 1, hepatitis C virus, Ebola virus, cytomegalovirus, dengue virus, and the SARS coronavirus.
We used H5N1 pseudotyped and reverse-genetics (RG) virus particles to study their ability to bind with DC-SIGN.
Electronic microscopy and functional assay results indicate that pseudotyped viruses containing both HA and NA proteins express hemagglutination and are capable of infecting cells expressing alpha-2,3-linked sialic acid receptors.
Results from a capture assay show that DC-SIGN-expressing cells (including B-THP-1/DC-SIGN and T-THP-1/DC-SIGN) and peripheral blood dendritic cells are capable of transferring H5N1 pseudotyped and RG virus particles to target cells; this action can be blocked by anti-DC-SIGN monoclonal antibodies.
In summary, (a) DC-SIGN acts as a capture or attachment molecule for avian H5N1 virus, and (b) DC-SIGN mediates infections in cis and in trans.
PMID: 18593570 [PubMed - as supplied by publisher]
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(1.6): J Clin Microbiol. 2008 Jul 2. [Epub ahead of print]
Subtyping of H1 to H15 Hemagglutinin Genes of Avian Influenza Virus by RT-PCR Assay and Molecular Determination of the Pathogenic Potential.
Tsukamoto K, Ashizawa H, Nakanishi K, Kaji N, Suzuki K, Okamatsu M, Yamaguchi S, Mase M. - Research Team for Zoonotic Diseases, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856, Japan; Tyuou Livestock Hygiene Service Center of Chiba Prefecture, Iwatomi, Sakura, Chiba 285-0072, Japan; Livestock Hygiene Service Center of Shiga Prefecture, Nishihongo, Omihachiman, Shiga 523-0813, Japan; Livestock Hygiene Service Center of Shimane Prefecture, Kaminishioki, Izumo, Shimane 699-0822, Japan.
Serious concern about the worldwide transmission of the Asian H5N1 highly pathogenic (HP) avian influenza (AI) virus by migratory birds surrounds the importance of the AI global surveillance in wild aquatic birds and underscores the requirement for a reliable subtyping method of AI viruses.
PCR is advantageous due to its simplicity, less cross-reactivity and unlimited reagent supply.
Currently, the only available HA subtyping primer set that can subtype H1 through H15 is not fully evaluated and, since it only targets HA1, is unavailable for molecular pathotyping of AI viruses.
Our preliminary experiments found that these primer sets were cross-reactive and missed some recent AI viruses.
In this study, we developed new primer sets against HA cleavage sites for subtyping of H1 to H15 genes and for molecular pathotyping.
Our primer sets were subtype-specific and detected 99% of previously identified HA genes (115/116, 1949 - March 2006), and the correct amplification of HA genes were confirmed by sequence analyses of all 115 PCR products.
The primer sets successfully subtyped most of the recent AI viruses isolated in Japan (96%, 101/105, October 2006 - March 2007).
Taken together, our primer sets could efficiently detect HA genes (98%, 216/221) of both previous and recent HA genes or of both American (29/29) and Eurasian (187/192) lineages.
All 38 H5 and 13 H7 viruses were molecularly pathotyped by sequencing analyses of the HA cleavage site.
In contrast, despite efficient detection of previously identified strains (114/116, 98 %), the published primer sets exhibited lower specificity and lower detection efficiency against recent AI viruses (84/105, 80%).
These results indicate that our primers are useful not only for HA subtyping but also for molecular pathotyping of both previous and recent AI viruses.
These advancements will enable general diagnostic laboratories to subtype AI viruses for the surveillance in wild aquatic birds.
PMID: 18596143 [PubMed - as supplied by publisher]
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(1.7): J Exp Med. 2008 Jun 30. [Epub ahead of print]
Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs.
McGill J, Van Rooijen N, Legge KL. - Department of Pathology, Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52241.
Influenza infections induce a rapid, but transient, dendritic cell (DC) migration from the lungs to the lymph nodes (LNs) that is followed by substantial recruitment of DCs into the lungs without subsequent migration to the LNs.
Given that peripheral DCs are primarily thought to be involved in the initiation of adaptive immunity after migration into lymphoid tissues, what role these newly lung-recruited DCs play in influenza virus immunity is unclear.
In this study, we demonstrate that loss of non-LN migratory pulmonary DC subsets increases mortality, sustains higher viral titers, and impairs pulmonary CD8 T cell responses.
Reconstitution of the lungs with pulmonary plasmacytoid DCs, CD8alpha(+) DCs, or interstitial DCs restores CD8 T cell responses in a cell contact-, major histocompatability complex I-, and influenza peptide-dependent manner.
Thus, after their initial activation in the LN, protective influenza-specific CD8 T cell responses require additional antigen-dependent interactions, specifically with DCs in the lungs.
PMID: 18591411 [PubMed - as supplied by publisher]
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(1.8): J Exp Med. 2008 Jun 30. [Epub ahead of print]
Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells.
Geurtsvankessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, Thielemans K, Bennett C, Clausen BE, Hoogsteden HC, Osterhaus AD, Rimmelzwaan GF, Lambrecht BN. - Department of Pulmonary Medicine and 2Department of Virology, Erasmus University Medical Centre Rotterdam, 3015 GE Rotterdam, Netherlands.
Although dendritic cells (DCs) play an important role in mediating protection against influenza virus, the precise role of lung DC subsets, such as CD11b(-) and CD11b(+) conventional DCs or plasmacytoid DCs (pDCs), in different lung compartments is currently unknown.
Early after intranasal infection, tracheal CD11b(-)CD11c(hi) DCs migrated to the mediastinal lymph nodes (MLNs), acquiring co-stimulatory molecules in the process.
This emigration from the lung was followed by an accumulation of CD11b(+)CD11c(hi) DCs in the trachea and lung interstitium. In the MLNs, the CD11b(+) DCs contained abundant viral nucleoprotein (NP), but these cells failed to present antigen to CD4 or CD8 T cells, whereas resident CD11b(-)CD8alpha(+) DCs presented to CD8 cells, and migratory CD11b(-)CD8alpha(-) DCs presented to CD4 and CD8 T cells.
When lung CD11c(hi) DCs and macrophages or langerin(+)CD11b(-)CD11c(hi) DCs were depleted using either CD11c-diphtheria toxin receptor (DTR) or langerin-DTR mice, the development of virus-specific CD8(+) T cells was severely delayed, which correlated with increased clinical severity and a delayed viral clearance. 120G8(+) CD11c(int) pDCs also accumulated in the lung and LNs carrying viral NP, but in their absence, there was no effect on viral clearance or clinical severity.
Rather, in pDC-depleted mice, there was a reduction in antiviral antibody production after lung clearance of the virus.
This suggests that multiple DCs are endowed with different tasks in mediating protection against influenza virus.
PMID: 18591406 [PubMed - as supplied by publisher]
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(1.9): J Infect Dis. 2008 Jul 15;198(2):294-5.
Influenza pandemics, immune cross-reactivity, and pandemic control strategies.
Gioia C, Agrati C, Castilletti C, Capobianchi MR, Martini F. - National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy.
PMID: 18593297 [PubMed - in process]
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(1.10): J Virol. 2008 Jul 2. [Epub ahead of print]
S-acylation of HA of influenza viruses: Mass-spectrometry reveals site-specific attachment of stearic acid to a transmembrane cysteine.
Kordyukova LV, Serebryakova MV, Baratova LA, Veit M. - A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119991, Russia; Institute of Physico-Chemical Medicine, Federal Agency for Health Care and Social Development, Moscow 119992, Russia; Immunology and Molecular Biology,Vet.-Med. Faculty, Free University Berlin, Germany.
S-acylation of cysteines located in the transmembrane and/or cytoplasmic region of influenza virus hemagglutinins (HA) contributes to membrane fusion and assembly of virions.
Using mass-spectrometry (MS) we show that influenza B virus HA possessing two cytoplasmic cysteines contains palmitate, whereas HEF of influenza C virus having one transmembrane cysteine is stearoylated.
HAs of influenza A virus having one transmembrane and two cytoplasmic cysteines contain both palmitate and stearate.
MS-analysis of recombinant viruses with deletions of individual cysteines as well as MS/MS-sequencing revealed the surprising result that stearate is exclusively attached to the cysteine positioned in the transmembrane region of HA.
PMID: 18596092 [PubMed - as supplied by publisher]
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(1.11): J Virol Methods. 2008 Jun 30. [Epub ahead of print]
Typing (A/B) and subtyping (H1/H3/H5) of influenza A viruses by multiplex real-time RT-PCR assays.
Suwannakarn K, Payungporn S, Chieochansin T, Samransamruajkit R, Amonsin A, Songserm T, Chaisingh A, Chamnanpood P, Chutinimitkul S, Theamboonlers A, Poovorawan Y. - Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
In this study, a specific and sensitive one-step multiplex real-time RT-PCR was developed in two assays by using primers and a number of specific locked nucleic acid (LNA)-mediated TaqMan probes which increase the thermal stability of oligonucleotides.
The first assay consisted of primers and probes specific to the matrix (M1) gene of influenza A virus, matrix (M1) gene of influenza B virus and GAPDH gene of host cells for typing of influenza virus and verification by an internal control, respectively.
The other assay employed primers and probes specific to the hemagglutinin gene of H1, H3 and H5 subtypes in order to identify the three most prominent subtypes of influenza A capabe of infecting humans.
The specificity results did not produce any cross reactivity with other respiratory viruses or other subtypes of influenza A viruses (H2, H4 and H6-H15), indicating the high specificity of the primers and probes used.
The sensitivity of the assays which depend on the type or subtype being detected was approximately 10 to 10(3)copies/mul that depended on the types or subtypes being detected.
Furthermore, the assays demonstrated 100% concordance with 35 specimens infected with influenza A viruses and 34 specimens infected with other respiratory viruses, which were identified by direct nucleotide sequencing.
In conclusion, the multiplex real-time RT-PCR assays have proven advantageous in terms of rapidity, specificity and sensitivity for human specimens and thus present a feasible and attractive method for large-scale detection aimed at controlling influenza outbreaks.
PMID: 18598722 [PubMed - as supplied by publisher]
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(1.12): MMWR Morb Mortal Wkly Rep. 2008 Jun 27;57(25):692-7.
Influenza activity--United States and worldwide, 2007-08 season.
Centers for Disease Control and Prevention (CDC).
PMID: 18583957 [PubMed - indexed for MEDLINE]
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(1.13): N Engl J Med. 2008 Jun 12;358(24):2573-84.
Comment in: N Engl J Med. 2008 Jun 12;358(24):2540-3.
A clinical trial of a whole-virus H5N1 vaccine derived from cell culture.
Ehrlich HJ, M?ller M, Oh HM, Tambyah PA, Joukhadar C, Montomoli E, Fisher D, Berezuk G, Fritsch S, L?w-Baselli A, Vartian N, Bobrovsky R, Pavlova BG, P?llabauer EM, Kistner O, Barrett PN; Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team. - Collaborators (49) - Marth E, Konior R, Sonnenburg F, Birthistle K, Dvorak T, Geyer S, Kraft M, Leitgeb MC, Maritsch F, Phillipson L, Robotka E, Abrahim A, Bauer M, Brunner M, Cornea A, Drucker C, Erdogan Z, Griss J, Heinisch B, Kovar F, Lackner E, Lambers C, Langer O, Leitner I, Marsik C, Poeppl W, Popovic M, Sauermann R, Schaberl R, Sodeck G, Thallinger C, Traunmueller F, Wagner C, Zeitlinger M, Chua SK, Chuin S, Fong R, Foo AS, Koh AG, Lim PK, Yap SY, Yew LH, Goh JW, Hsu LY, Loke CW, Ng JY, Toh EL, Weatherill P, Zhou YP.
Department of Global Research and Development, Baxter BioScience, Vienna, Austria.
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.) 2008 Massachusetts Medical Society
PMID: 18550874 [PubMed - indexed for MEDLINE]
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(1.14): Vaccine. 2008 Jun 13. [Epub ahead of print]
Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults.
Nolan TM, Richmond PC, Skeljo MV, Pearce G, Hartel G, Formica NT, H?schler K, Bennet J, Ryan D, Papanaoum K, Basser RL, Zambon MC. - Murdoch Childrens Research Institute, and the Melbourne School of Population Health, University of Melbourne, Carlton, Victoria, Australia.
OBJECTIVE:
The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains.
METHODS:
In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5mug or 15mug H5 haemagglutinin (HA) vaccine+/-AlPO(4) adjuvant (phase I trial; N=400) or two doses of 30mug or 45mug H5 HA with AlPO(4) adjuvant (phase II trial; N=400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation.
FINDINGS:
All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30mug or 45mug H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (>/=1:20) persistence up to 6 months post-vaccination. The 7.5 and 15mug formulations (+/-adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains.
INTERPRETATION:
Two doses of prototype 30mug or 45mug aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains
[ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; Funding: CSL Limited, Australia].
PMID: 18599164 [PubMed - as supplied by publisher]
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(1.15): Vaccine. 2008 Jun 10. [Epub ahead of print]
Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children.
Levin MJ, Song LY, Fenton T, Nachman S, Patterson J, Walker R, Kemble G, Allende M, Hultquist M, Yi T, Nowak B, Weinberg A. - University of Colorado School of Medicine, Aurora, CO, United States.
HIV-infected children (N=243), >/=5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated influenza vaccine (TIV).
The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection.
Post-vaccination hemagglutination inhibition (HAI) antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to antibody responses and shedding previously reported for children without HIV infection.
LAIV should be further evaluated for a role in immunizing HIV-infected children.
PMID: 18597900 [PubMed - as supplied by publisher]
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(1.16): Vaccine. 2008 Jun 26. [Epub ahead of print]
Sampling for low-pathogenic avian influenza A virus in wild Mallard ducks: Oropharyngeal versus cloacal swabbing.
Ellstr?m P, Latorre-Margalef N, Griekspoor P, Waldenstr?m J, Olofsson J, Wahlgren J, Olsen B. - Section for Zoonotic Ecology and Epidemiology, School of Pure and Applied Natural Sciences, Kalmar University, SE-391 82 Kalmar, Sweden.
PMID: 18586061 [PubMed - as supplied by publisher]
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(1.17): Vaccine. 2008 Jun 5. [Epub ahead of print]
Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease.
Furumoto A, Ohkusa Y, Chen M, Kawakami K, Masaki H, Sueyasu Y, Iwanaga T, Aizawa H, Nagatake T, Oishi K. - Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
To determine the clinical efficacy of combined vaccination with 23-valent pneumococcal vaccine (PV) and influenza vaccine (IV) against pneumonia and acute exacerbation of chronic lung diseases (CLD), we conducted an open-label, randomized, controlled study among 167 adults with CLD over a 2-year period.
Subjects were randomly assigned to a PV+IV group (n=87) or an IV group (n=80).
The number of patients with CLD experiencing infectious acute exacerbation (P=0.022), but not pneumonia (P=0.284), was significantly lower in the PV+IV group compared with the IV group.
When these subjects were divided into subgroups, an additive effect of PV with IV in preventing infectious acute exacerbation was significant only in patients with chronic obstructive pulmonary diseases (P=0.037).
In patients with CLD, the Kaplan-Meier survival curves demonstrated a significant difference for infectious acute exacerbation (P=0.016) between the two groups.
An additive effect of PV with IV on infectious acute exacerbation was found during the first year after vaccination (P=0.019), but not during the second year (P=0.342), and was associated with serotype-specific immune response in sera of these patients who used PV during the same period.
PMID: 18585831 [PubMed - as supplied by publisher]
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(1.18): Vaccine. 2008 Jun 26. [Epub ahead of print]
FDA/NIH/WHO public workshop on immune correlates of protection against influenza A viruses in support of pandemic vaccine development, Bethesda, Maryland, US, December 10-11, 2007.
Eichelberger M, Golding H, Hess M, Weir J, Subbarao K, Luke CJ, Friede M, Wood D. - US Food and Drug Administration, Center for Biologics Evaluation and Research Office of Vaccines Research and Review/Division of Viral Products, Bethesda, MD 20892, USA.
The goals of the workshop were to identify gaps in our knowledge and abilities to address the unique challenges encountered in the development of vaccines intended to protect against pandemic influenza and to facilitate implementation of a global research agenda to improve efficacy assessment of pandemic influenza vaccines.
This workshop included discussions on:
(i) current knowledge regarding immune correlates of protection against seasonal influenza;
(ii) human immune responses to avian influenza infection and vaccines for novel influenza viruses;
(iii) limitations of currently available assays to evaluate vaccine immunogenicity; and
(iv) potential insights from animal models for correlates of protection against avian influenza.
PMID: 18582523 [PubMed - as supplied by publisher]
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(1.19): Vaccine. 2008 Jun 23. [Epub ahead of print]
Selection bias in evaluating of influenza vaccine effectiveness: A lesson from an observational study of elderly nursing home residents.
Fukushima W, Hayashi Y, Mizuno Y, Suzuki K, Kase T, Ohfuji S, Fujieda M, Maeda A, Hirota Y. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Selection bias is of critical concern in the study of influenza vaccine effectiveness when using an observational study design.
This bias is attributable to the inherently different characteristics between vaccinees and non-vaccinees.
The differences, which are related both to vaccination and signs of clinical disease as an outcome, may lead to erroneous estimation of the effectiveness.
In this report, we describe how selection bias among elderly nursing home residents may lead to a spurious interpretation of the protective effect of influenza vaccine.
Our results should be a lesson in the importance of regarding selection bias when assessing influenza vaccine effectiveness.
PMID: 18582520 [PubMed - as supplied by publisher]
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(1.20): Virology. 2008 Jun 26. [Epub ahead of print]
Structure of an avian influenza A virus NS1 protein effector domain.
Hale BG, Barclay WS, Randall RE, Russell RJ. - Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, KY16 9ST, UK.
Influenza A virus NS1 protein is a multifunctional virulence factor.
Here, we report a crystal structure for the NS1 effector domain of avian influenza virus A/Duck/Albany/76.
Comparison of this structure with that reported for a human strain shows both proteins share a common monomer conformation, albeit with subtle differences.
Strikingly, our data reveal a novel helix-helix dimeric interface between monomers of the avian NS1 protein, which is also found in the human NS1 crystal lattice.
We re-evaluate the current model of NS1 dimeric assembly, and provide biochemical evidence to show tryptophan-187 (a residue located at the helix-helix interface) is essential for dimerization of this effector domain.
PMID: 18585749 [PubMed - as supplied by publisher]
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(1.21): Virology. 2008 Jun 26. [Epub ahead of print]
A live attenuated cold-adapted influenza A H7N3 virus vaccine provides protection against homologous and heterologous H7 viruses in mice and ferrets.
Joseph T, McAuliffe J, Lu B, Vogel L, Swayne D, Jin H, Kemble G, Subbarao K. - Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA; MedImmune Inc., Mountain View, CA 94043, USA.
The appearance of human infections caused by avian influenza A H7 subtype viruses underscores their pandemic potential and the need to develop vaccines to protect humans from viruses of this subtype.
A live attenuated H7N3 virus vaccine was generated by reverse genetics using the HA and NA genes of a low pathogenicity A/chicken/BC/CN-6/04 (H7N3) virus and the six internal protein genes of the cold-adapted A/Ann Arbor/6/60 ca (H2N2) virus.
The reassortant H7N3 BC 04 ca vaccine virus was temperature sensitive and showed attenuation in mice and ferrets.
Intranasal immunization with one dose of the vaccine protected mice and ferrets when challenged with homologous and heterologous H7 viruses.
The reassortant H7N3 BC 04 ca vaccine virus showed comparable levels of attenuation, immunogenicity and efficacy in mice and ferret models.
The safety, immunogenicity, and efficacy of this vaccine in mice and ferrets support the evaluation of this vaccine in clinical trials.
PMID: 18585748 [PubMed - as supplied by publisher
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(1.22): Virology. 2008 May 10;374(2):399-410. Epub 2008 Feb 12.
Attenuation of the type I interferon response in cells infected with human rhinovirus.
Kotla S, Peng T, Bumgarner RE, Gustin KE. - Department of Microbiology, Molecular Biology and Biochemistry, University of Idaho, Moscow, Idaho 83844-3052, USA.
The type I interferon (IFN) response requires the coordinated activation of the latent transcription factors NF-kappaB, IRF-3 and ATF-2 which in turn activate transcription from the IFN-beta promoter.
Here we have examined the type I interferon response in rhinovirus type 14-infected A549 cells, with particular emphasis on the status of the transcription factor IRF-3.
Our results indicate that although rhinovirus type 14 (RV14) infection induces the activation of NF-kappaB and ATF-2, only very low levels of IFN-beta mRNA are detected.
Analysis of ISG54 mRNA levels revealed very little induction of this IRF-3 responsive transcript and suggested that IRF-3 activation might be impaired.
Examination of IRF-3 in RV14-infected cells demonstrated only low levels of phosphorylation, a lack of homodimer formation and an absence of nuclear accumulation indicating that this transcription factor is not activated.
Inhibition of viral protein synthesis following infection resulted in an increase in IFN-beta mRNA levels indicating that viral gene products prevent induction of this pathway.
Collectively, these results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation.
PMID: 18272195 [PubMed - indexed for MEDLINE]
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(1.23): Pediatrics. 2008 Jul;122(1):e260-5.
Countywide school-based influenza immunization: direct and indirect impact on student absenteeism.
Davis MM, King JC Jr, Moag L, Cummings G, Magder LS. - Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland 21205, USA. mdavis93@jhmi.edu
OBJECTIVE:
Live attenuated influenza vaccine was given to 5319 (44%) of the 12090 students enrolled in public elementary schools in Carroll County, Maryland, during the fall of 2005. We examined the impact of this community-based intervention on countywide student absenteeism during the subsequent influenza outbreak.
METHODS:
This study used existing, anonymous information: census data, community influenza tests, and public school absenteeism data. The intervention group was Carroll County, years 2005-2006. The control group included Carroll County, years 2001-2005, and adjacent Frederick County, years 2001-2006. Weekly student absenteeism was determined during baseline influenza-free periods and influenza outbreak periods for all of the public schools.
RESULTS:
The absolute change in absenteeism during the influenza outbreak periods over baseline in elementary schools was 0.61% for the intervention group and 1.79% for the control group. Similarly, the change in absenteeism during the influenza outbreak period over baseline for high schools was 0.32% for the intervention group and 1.80% for the control group. Although not statistically significant, trends in middle schools were similar.
CONCLUSIONS:
Countywide school-based influenza vaccination was associated with reduced absenteeism during an influenza outbreak. The data suggest not only a direct impact on elementary schools but also an indirect impact on high schools. School-based programs provide an efficient method of providing influenza vaccination to children, and protection may extend to unvaccinated community members. Additional research is needed to determine whether school-based vaccination of children reduces morbidity and mortality associated with influenza outbreaks.
PMID: 18595972 [PubMed - in process]
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Contents:
(1.1) Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein.
(1.2) Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity.
(1.3) Complete genome analysis of a highly pathogenic H5N1 influenza A virus isolated from a tiger in China.
(1.4) Inactivation and morphological changes of avian influenza virus by copper ions.
(1.5) DC-SIGN mediates avian H5N1 influenza virus infection in cis and in trans.
(1.6) Subtyping of H1 to H15 Hemagglutinin Genes of Avian Influenza Virus by RT-PCR Assay and Molecular Determination of the Pathogenic Potential.
(1.7) Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs.
(1.8) Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells.
(1.9) Influenza pandemics, immune cross-reactivity, and pandemic control strategies.
(1.10) S-acylation of HA of influenza viruses: Mass-spectrometry reveals site-specific attachment of stearic acid to a transmembrane cysteine.
(1.11) Typing (A/B) and subtyping (H1/H3/H5) of influenza A viruses by multiplex real-time RT-PCR assays.
(1.12) Influenza activity--United States and worldwide, 2007-08 season.
(1.13) A clinical trial of a whole-virus H5N1 vaccine derived from cell culture.
(1.14) Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults.
(1.15) Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children.
(1.16) Sampling for low-pathogenic avian influenza A virus in wild Mallard ducks: Oropharyngeal versus cloacal swabbing.
(1.17) Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease.
(1.18) FDA/NIH/WHO public workshop on immune correlates of protection against influenza A viruses in support of pandemic vaccine development, Bethesda, Maryland, US, December 10-11, 2007.
(1.19) Selection bias in evaluating of influenza vaccine effectiveness: A lesson from an observational study of elderly nursing home residents.
(1.20) Structure of an avian influenza A virus NS1 protein effector domain.
(1.21) A live attenuated cold-adapted influenza A H7N3 virus vaccine provides protection against homologous and heterologous H7 viruses in mice and ferrets.
(1.22) Attenuation of the type I interferon response in cells infected with human rhinovirus.
(1.23) Countywide school-based influenza immunization: direct and indirect impact on student absenteeism.
See original abstracts at the source site. EDITED.]
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(1.1): Antiviral Res. 2008 Jun 30. [Epub ahead of print]
Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein.
Wang R, Song A, Levin J, Dennis D, Zhang NJ, Yoshida H, Koriazova L, Madura L, Shapiro L, Matsumoto A, Yoshida H, Mikayama T, Kubo RT, Sarawar S, Cheroutre H, Kato S. - Kirin Pharma USA, Inc., La Jolla, CA, USA.
Influenza is one of the most prevalent viral diseases in humans.
For some high-risk human populations, including the infant, the elderly, and the immunocompromised, who may not benefit from active immunization, passive immunotherapy with antibodies reactive with all influenza A strains may be an alternative.
In this study, we characterized several fully human monoclonal antibodies (MAb) reactive with M2e, which were generated from transchromosomic mice engineered to produce fully human antibodies following immunization with a consensus-sequence M2e peptide.
The MAbs showed strong binding to M2e peptide and to virus infected MDCK cells.
One MAb recognizing the highly conserved N-terminal portion of consensus M2e displayed high binding to the majority of M2e variants from natural viral isolates, including highly pathogenic avian strains, which were recently reported to infect humans.
Passive immunotherapy with this MAb in mice resulted in significant reduction in virus replication in the lung and protection from lethal infection when administered either prophylactically or therapeutically.
These results suggest the potential of the anti-M2e human MAb with broad binding spectrum as a universal passive immunotherapeutic agent to infection by influenza A virus.
PMID: 18598723 [PubMed - as supplied by publisher]
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(1.2): Antiviral Res. 2008 Jun 13. [Epub ahead of print]
Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity.
Hoffmann HH, Palese P, Shaw ML. - Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA; Institute of Chemistry and Biochemistry, Free University of Berlin, 14195 Berlin, Germany.
In recent years, increasing levels of resistance to the four FDA-approved anti-influenza virus drugs have been described and vaccine manufacturers have experienced demands that exceed their capacity.
This situation underlines the urgent need for novel antivirals as well as innovations in vaccine production in preparation for the next influenza epidemic.
Here we report the development of a cell-based high-throughput screen which we have used for the identification of compounds that modulate influenza virus growth either negatively or positively.
We screened a library of compounds with known biological activity and identified distinct groups of inhibitors and enhancers that target sodium channels or protein kinase C (PKC).
We confirmed these results in viral growth assays and find that treatment with a sodium channel opener or PKC inhibitor significantly reduces viral replication.
In contrast, inhibition of sodium channels or activation of PKC leads to enhanced virus production in tissue culture.
These diametrically opposing effects strongly support a role for PKC activity and the regulation of Na(+) currents in influenza virus replication and both may serve as targets for antiviral drugs.
Furthermore, we raise the possibility that compounds that result in increased viral titers may be beneficial for boosting the production of tissue culture-grown influenza vaccines.
PMID: 18585796 [PubMed - as supplied by publisher]
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(1.3): Arch Virol. 2008 Jul 1. [Epub ahead of print]
Complete genome analysis of a highly pathogenic H5N1 influenza A virus isolated from a tiger in China.
Mushtaq MH, Juan H, Jiang P, Li Y, Li T, Du Y, Mukhtar MM. - Key Laboratory of Animal Diseases Diagnostic and Immunology, College of Veterinary Medicine, Nanjing Agricultural University, Ministry of Agriculture, 210095, Nanjing, China.
An influenza A virus (A/Tig/SH/01/2005 (H5N1) was isolated from lung tissue samples of a dead zoo tiger with respiratory disease in China in July 2005.
Complete genome analysis indicated that the isolate was highly identical to an H5N1 virus isolated from a migratory duck at Poyang lake in China in that year.
The genotype of the isolate was K,G,D,5J,F,1J,F,1E, and phylogenetically it was a clade 2.2 virus.
Molecular characterization of all of the gene segments revealed characteristics of highly pathogenic influenza A viruses.
These results may help to identify molecular determinants of virulence and highlight the necessity for continuous surveillance.
PMID: 18592132 [PubMed - as supplied by publisher
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(1.4): Arch Virol. 2008 Jul 1. [Epub ahead of print]
Inactivation and morphological changes of avian influenza virus by copper ions.
Horie M, Ogawa H, Yoshida Y, Yamada K, Hara A, Ozawa K, Matsuda S, Mizota C, Tani M, Yamamoto Y, Yamada M, Nakamura K, Imai K. - Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
The infectivity of the H9N2 virus to MDCK cells was time-dependently inhibited by Cu(2+) at concentrations of 2.5-250 muM.
In 25 muM Cu(2+) solution, the virus titer decreased by approximately 3 and 4 log within 3 and 6 h, respectively.
Compared to Cu(2+), Zn(2+) was much less effective in virus inactivation.
The H9N2 virus hemagglutinin activity was not affected by 2.5-250 muM Cu(2+).
The H9N2 virus neuraminidase (NA) activity was drastically reduced by 25 mM Cu(2+), marginally reduced by 250 muM Cu(2+), and not affected by 25 muM Cu(2+).
Thus, we found that copper ions suppress the infectivity of influenza virus at lower concentrations at which neither NA nor hemagglutination inhibition occurs.
Electron microscopic analysis revealed morphological abnormalities of the Cu(2+)-treated H9N2 virus.
Additional studies should be undertaken to clarify the mechanism underlying the antiviral effect of copper ions on influenza virus.
PMID: 18592130 [PubMed - as supplied by publisher]
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(1.5): Biochem Biophys Res Commun. 2008 Jun 28. [Epub ahead of print]
DC-SIGN mediates avian H5N1 influenza virus infection in cis and in trans.
Wang SF, Huang JC, Lee YM, Liu SJ, Chan YJ, Chau YP, Chong P, Chen YM. - Department of Biotechnology and Laboratory Science in Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; AIDS Prevention and Research Center, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
DC-SIGN, a C-type lectin receptor expressed in dendritic cells (DCs), has been identified as a receptor for human immunodeficiency virus type 1, hepatitis C virus, Ebola virus, cytomegalovirus, dengue virus, and the SARS coronavirus.
We used H5N1 pseudotyped and reverse-genetics (RG) virus particles to study their ability to bind with DC-SIGN.
Electronic microscopy and functional assay results indicate that pseudotyped viruses containing both HA and NA proteins express hemagglutination and are capable of infecting cells expressing alpha-2,3-linked sialic acid receptors.
Results from a capture assay show that DC-SIGN-expressing cells (including B-THP-1/DC-SIGN and T-THP-1/DC-SIGN) and peripheral blood dendritic cells are capable of transferring H5N1 pseudotyped and RG virus particles to target cells; this action can be blocked by anti-DC-SIGN monoclonal antibodies.
In summary, (a) DC-SIGN acts as a capture or attachment molecule for avian H5N1 virus, and (b) DC-SIGN mediates infections in cis and in trans.
PMID: 18593570 [PubMed - as supplied by publisher]
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(1.6): J Clin Microbiol. 2008 Jul 2. [Epub ahead of print]
Subtyping of H1 to H15 Hemagglutinin Genes of Avian Influenza Virus by RT-PCR Assay and Molecular Determination of the Pathogenic Potential.
Tsukamoto K, Ashizawa H, Nakanishi K, Kaji N, Suzuki K, Okamatsu M, Yamaguchi S, Mase M. - Research Team for Zoonotic Diseases, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856, Japan; Tyuou Livestock Hygiene Service Center of Chiba Prefecture, Iwatomi, Sakura, Chiba 285-0072, Japan; Livestock Hygiene Service Center of Shiga Prefecture, Nishihongo, Omihachiman, Shiga 523-0813, Japan; Livestock Hygiene Service Center of Shimane Prefecture, Kaminishioki, Izumo, Shimane 699-0822, Japan.
Serious concern about the worldwide transmission of the Asian H5N1 highly pathogenic (HP) avian influenza (AI) virus by migratory birds surrounds the importance of the AI global surveillance in wild aquatic birds and underscores the requirement for a reliable subtyping method of AI viruses.
PCR is advantageous due to its simplicity, less cross-reactivity and unlimited reagent supply.
Currently, the only available HA subtyping primer set that can subtype H1 through H15 is not fully evaluated and, since it only targets HA1, is unavailable for molecular pathotyping of AI viruses.
Our preliminary experiments found that these primer sets were cross-reactive and missed some recent AI viruses.
In this study, we developed new primer sets against HA cleavage sites for subtyping of H1 to H15 genes and for molecular pathotyping.
Our primer sets were subtype-specific and detected 99% of previously identified HA genes (115/116, 1949 - March 2006), and the correct amplification of HA genes were confirmed by sequence analyses of all 115 PCR products.
The primer sets successfully subtyped most of the recent AI viruses isolated in Japan (96%, 101/105, October 2006 - March 2007).
Taken together, our primer sets could efficiently detect HA genes (98%, 216/221) of both previous and recent HA genes or of both American (29/29) and Eurasian (187/192) lineages.
All 38 H5 and 13 H7 viruses were molecularly pathotyped by sequencing analyses of the HA cleavage site.
In contrast, despite efficient detection of previously identified strains (114/116, 98 %), the published primer sets exhibited lower specificity and lower detection efficiency against recent AI viruses (84/105, 80%).
These results indicate that our primers are useful not only for HA subtyping but also for molecular pathotyping of both previous and recent AI viruses.
These advancements will enable general diagnostic laboratories to subtype AI viruses for the surveillance in wild aquatic birds.
PMID: 18596143 [PubMed - as supplied by publisher]
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(1.7): J Exp Med. 2008 Jun 30. [Epub ahead of print]
Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs.
McGill J, Van Rooijen N, Legge KL. - Department of Pathology, Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52241.
Influenza infections induce a rapid, but transient, dendritic cell (DC) migration from the lungs to the lymph nodes (LNs) that is followed by substantial recruitment of DCs into the lungs without subsequent migration to the LNs.
Given that peripheral DCs are primarily thought to be involved in the initiation of adaptive immunity after migration into lymphoid tissues, what role these newly lung-recruited DCs play in influenza virus immunity is unclear.
In this study, we demonstrate that loss of non-LN migratory pulmonary DC subsets increases mortality, sustains higher viral titers, and impairs pulmonary CD8 T cell responses.
Reconstitution of the lungs with pulmonary plasmacytoid DCs, CD8alpha(+) DCs, or interstitial DCs restores CD8 T cell responses in a cell contact-, major histocompatability complex I-, and influenza peptide-dependent manner.
Thus, after their initial activation in the LN, protective influenza-specific CD8 T cell responses require additional antigen-dependent interactions, specifically with DCs in the lungs.
PMID: 18591411 [PubMed - as supplied by publisher]
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(1.8): J Exp Med. 2008 Jun 30. [Epub ahead of print]
Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells.
Geurtsvankessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, Thielemans K, Bennett C, Clausen BE, Hoogsteden HC, Osterhaus AD, Rimmelzwaan GF, Lambrecht BN. - Department of Pulmonary Medicine and 2Department of Virology, Erasmus University Medical Centre Rotterdam, 3015 GE Rotterdam, Netherlands.
Although dendritic cells (DCs) play an important role in mediating protection against influenza virus, the precise role of lung DC subsets, such as CD11b(-) and CD11b(+) conventional DCs or plasmacytoid DCs (pDCs), in different lung compartments is currently unknown.
Early after intranasal infection, tracheal CD11b(-)CD11c(hi) DCs migrated to the mediastinal lymph nodes (MLNs), acquiring co-stimulatory molecules in the process.
This emigration from the lung was followed by an accumulation of CD11b(+)CD11c(hi) DCs in the trachea and lung interstitium. In the MLNs, the CD11b(+) DCs contained abundant viral nucleoprotein (NP), but these cells failed to present antigen to CD4 or CD8 T cells, whereas resident CD11b(-)CD8alpha(+) DCs presented to CD8 cells, and migratory CD11b(-)CD8alpha(-) DCs presented to CD4 and CD8 T cells.
When lung CD11c(hi) DCs and macrophages or langerin(+)CD11b(-)CD11c(hi) DCs were depleted using either CD11c-diphtheria toxin receptor (DTR) or langerin-DTR mice, the development of virus-specific CD8(+) T cells was severely delayed, which correlated with increased clinical severity and a delayed viral clearance. 120G8(+) CD11c(int) pDCs also accumulated in the lung and LNs carrying viral NP, but in their absence, there was no effect on viral clearance or clinical severity.
Rather, in pDC-depleted mice, there was a reduction in antiviral antibody production after lung clearance of the virus.
This suggests that multiple DCs are endowed with different tasks in mediating protection against influenza virus.
PMID: 18591406 [PubMed - as supplied by publisher]
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(1.9): J Infect Dis. 2008 Jul 15;198(2):294-5.
Influenza pandemics, immune cross-reactivity, and pandemic control strategies.
Gioia C, Agrati C, Castilletti C, Capobianchi MR, Martini F. - National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy.
PMID: 18593297 [PubMed - in process]
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(1.10): J Virol. 2008 Jul 2. [Epub ahead of print]
S-acylation of HA of influenza viruses: Mass-spectrometry reveals site-specific attachment of stearic acid to a transmembrane cysteine.
Kordyukova LV, Serebryakova MV, Baratova LA, Veit M. - A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119991, Russia; Institute of Physico-Chemical Medicine, Federal Agency for Health Care and Social Development, Moscow 119992, Russia; Immunology and Molecular Biology,Vet.-Med. Faculty, Free University Berlin, Germany.
S-acylation of cysteines located in the transmembrane and/or cytoplasmic region of influenza virus hemagglutinins (HA) contributes to membrane fusion and assembly of virions.
Using mass-spectrometry (MS) we show that influenza B virus HA possessing two cytoplasmic cysteines contains palmitate, whereas HEF of influenza C virus having one transmembrane cysteine is stearoylated.
HAs of influenza A virus having one transmembrane and two cytoplasmic cysteines contain both palmitate and stearate.
MS-analysis of recombinant viruses with deletions of individual cysteines as well as MS/MS-sequencing revealed the surprising result that stearate is exclusively attached to the cysteine positioned in the transmembrane region of HA.
PMID: 18596092 [PubMed - as supplied by publisher]
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(1.11): J Virol Methods. 2008 Jun 30. [Epub ahead of print]
Typing (A/B) and subtyping (H1/H3/H5) of influenza A viruses by multiplex real-time RT-PCR assays.
Suwannakarn K, Payungporn S, Chieochansin T, Samransamruajkit R, Amonsin A, Songserm T, Chaisingh A, Chamnanpood P, Chutinimitkul S, Theamboonlers A, Poovorawan Y. - Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
In this study, a specific and sensitive one-step multiplex real-time RT-PCR was developed in two assays by using primers and a number of specific locked nucleic acid (LNA)-mediated TaqMan probes which increase the thermal stability of oligonucleotides.
The first assay consisted of primers and probes specific to the matrix (M1) gene of influenza A virus, matrix (M1) gene of influenza B virus and GAPDH gene of host cells for typing of influenza virus and verification by an internal control, respectively.
The other assay employed primers and probes specific to the hemagglutinin gene of H1, H3 and H5 subtypes in order to identify the three most prominent subtypes of influenza A capabe of infecting humans.
The specificity results did not produce any cross reactivity with other respiratory viruses or other subtypes of influenza A viruses (H2, H4 and H6-H15), indicating the high specificity of the primers and probes used.
The sensitivity of the assays which depend on the type or subtype being detected was approximately 10 to 10(3)copies/mul that depended on the types or subtypes being detected.
Furthermore, the assays demonstrated 100% concordance with 35 specimens infected with influenza A viruses and 34 specimens infected with other respiratory viruses, which were identified by direct nucleotide sequencing.
In conclusion, the multiplex real-time RT-PCR assays have proven advantageous in terms of rapidity, specificity and sensitivity for human specimens and thus present a feasible and attractive method for large-scale detection aimed at controlling influenza outbreaks.
PMID: 18598722 [PubMed - as supplied by publisher]
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(1.12): MMWR Morb Mortal Wkly Rep. 2008 Jun 27;57(25):692-7.
Influenza activity--United States and worldwide, 2007-08 season.
Centers for Disease Control and Prevention (CDC).
PMID: 18583957 [PubMed - indexed for MEDLINE]
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(1.13): N Engl J Med. 2008 Jun 12;358(24):2573-84.
Comment in: N Engl J Med. 2008 Jun 12;358(24):2540-3.
A clinical trial of a whole-virus H5N1 vaccine derived from cell culture.
Ehrlich HJ, M?ller M, Oh HM, Tambyah PA, Joukhadar C, Montomoli E, Fisher D, Berezuk G, Fritsch S, L?w-Baselli A, Vartian N, Bobrovsky R, Pavlova BG, P?llabauer EM, Kistner O, Barrett PN; Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team. - Collaborators (49) - Marth E, Konior R, Sonnenburg F, Birthistle K, Dvorak T, Geyer S, Kraft M, Leitgeb MC, Maritsch F, Phillipson L, Robotka E, Abrahim A, Bauer M, Brunner M, Cornea A, Drucker C, Erdogan Z, Griss J, Heinisch B, Kovar F, Lackner E, Lambers C, Langer O, Leitner I, Marsik C, Poeppl W, Popovic M, Sauermann R, Schaberl R, Sodeck G, Thallinger C, Traunmueller F, Wagner C, Zeitlinger M, Chua SK, Chuin S, Fong R, Foo AS, Koh AG, Lim PK, Yap SY, Yew LH, Goh JW, Hsu LY, Loke CW, Ng JY, Toh EL, Weatherill P, Zhou YP.
Department of Global Research and Development, Baxter BioScience, Vienna, Austria.
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.) 2008 Massachusetts Medical Society
PMID: 18550874 [PubMed - indexed for MEDLINE]
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(1.14): Vaccine. 2008 Jun 13. [Epub ahead of print]
Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults.
Nolan TM, Richmond PC, Skeljo MV, Pearce G, Hartel G, Formica NT, H?schler K, Bennet J, Ryan D, Papanaoum K, Basser RL, Zambon MC. - Murdoch Childrens Research Institute, and the Melbourne School of Population Health, University of Melbourne, Carlton, Victoria, Australia.
OBJECTIVE:
The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains.
METHODS:
In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5mug or 15mug H5 haemagglutinin (HA) vaccine+/-AlPO(4) adjuvant (phase I trial; N=400) or two doses of 30mug or 45mug H5 HA with AlPO(4) adjuvant (phase II trial; N=400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation.
FINDINGS:
All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30mug or 45mug H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (>/=1:20) persistence up to 6 months post-vaccination. The 7.5 and 15mug formulations (+/-adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains.
INTERPRETATION:
Two doses of prototype 30mug or 45mug aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains
[ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; Funding: CSL Limited, Australia].
PMID: 18599164 [PubMed - as supplied by publisher]
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(1.15): Vaccine. 2008 Jun 10. [Epub ahead of print]
Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children.
Levin MJ, Song LY, Fenton T, Nachman S, Patterson J, Walker R, Kemble G, Allende M, Hultquist M, Yi T, Nowak B, Weinberg A. - University of Colorado School of Medicine, Aurora, CO, United States.
HIV-infected children (N=243), >/=5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated influenza vaccine (TIV).
The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection.
Post-vaccination hemagglutination inhibition (HAI) antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to antibody responses and shedding previously reported for children without HIV infection.
LAIV should be further evaluated for a role in immunizing HIV-infected children.
PMID: 18597900 [PubMed - as supplied by publisher]
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(1.16): Vaccine. 2008 Jun 26. [Epub ahead of print]
Sampling for low-pathogenic avian influenza A virus in wild Mallard ducks: Oropharyngeal versus cloacal swabbing.
Ellstr?m P, Latorre-Margalef N, Griekspoor P, Waldenstr?m J, Olofsson J, Wahlgren J, Olsen B. - Section for Zoonotic Ecology and Epidemiology, School of Pure and Applied Natural Sciences, Kalmar University, SE-391 82 Kalmar, Sweden.
PMID: 18586061 [PubMed - as supplied by publisher]
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(1.17): Vaccine. 2008 Jun 5. [Epub ahead of print]
Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease.
Furumoto A, Ohkusa Y, Chen M, Kawakami K, Masaki H, Sueyasu Y, Iwanaga T, Aizawa H, Nagatake T, Oishi K. - Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
To determine the clinical efficacy of combined vaccination with 23-valent pneumococcal vaccine (PV) and influenza vaccine (IV) against pneumonia and acute exacerbation of chronic lung diseases (CLD), we conducted an open-label, randomized, controlled study among 167 adults with CLD over a 2-year period.
Subjects were randomly assigned to a PV+IV group (n=87) or an IV group (n=80).
The number of patients with CLD experiencing infectious acute exacerbation (P=0.022), but not pneumonia (P=0.284), was significantly lower in the PV+IV group compared with the IV group.
When these subjects were divided into subgroups, an additive effect of PV with IV in preventing infectious acute exacerbation was significant only in patients with chronic obstructive pulmonary diseases (P=0.037).
In patients with CLD, the Kaplan-Meier survival curves demonstrated a significant difference for infectious acute exacerbation (P=0.016) between the two groups.
An additive effect of PV with IV on infectious acute exacerbation was found during the first year after vaccination (P=0.019), but not during the second year (P=0.342), and was associated with serotype-specific immune response in sera of these patients who used PV during the same period.
PMID: 18585831 [PubMed - as supplied by publisher]
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(1.18): Vaccine. 2008 Jun 26. [Epub ahead of print]
FDA/NIH/WHO public workshop on immune correlates of protection against influenza A viruses in support of pandemic vaccine development, Bethesda, Maryland, US, December 10-11, 2007.
Eichelberger M, Golding H, Hess M, Weir J, Subbarao K, Luke CJ, Friede M, Wood D. - US Food and Drug Administration, Center for Biologics Evaluation and Research Office of Vaccines Research and Review/Division of Viral Products, Bethesda, MD 20892, USA.
The goals of the workshop were to identify gaps in our knowledge and abilities to address the unique challenges encountered in the development of vaccines intended to protect against pandemic influenza and to facilitate implementation of a global research agenda to improve efficacy assessment of pandemic influenza vaccines.
This workshop included discussions on:
(i) current knowledge regarding immune correlates of protection against seasonal influenza;
(ii) human immune responses to avian influenza infection and vaccines for novel influenza viruses;
(iii) limitations of currently available assays to evaluate vaccine immunogenicity; and
(iv) potential insights from animal models for correlates of protection against avian influenza.
PMID: 18582523 [PubMed - as supplied by publisher]
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(1.19): Vaccine. 2008 Jun 23. [Epub ahead of print]
Selection bias in evaluating of influenza vaccine effectiveness: A lesson from an observational study of elderly nursing home residents.
Fukushima W, Hayashi Y, Mizuno Y, Suzuki K, Kase T, Ohfuji S, Fujieda M, Maeda A, Hirota Y. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Selection bias is of critical concern in the study of influenza vaccine effectiveness when using an observational study design.
This bias is attributable to the inherently different characteristics between vaccinees and non-vaccinees.
The differences, which are related both to vaccination and signs of clinical disease as an outcome, may lead to erroneous estimation of the effectiveness.
In this report, we describe how selection bias among elderly nursing home residents may lead to a spurious interpretation of the protective effect of influenza vaccine.
Our results should be a lesson in the importance of regarding selection bias when assessing influenza vaccine effectiveness.
PMID: 18582520 [PubMed - as supplied by publisher]
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(1.20): Virology. 2008 Jun 26. [Epub ahead of print]
Structure of an avian influenza A virus NS1 protein effector domain.
Hale BG, Barclay WS, Randall RE, Russell RJ. - Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, KY16 9ST, UK.
Influenza A virus NS1 protein is a multifunctional virulence factor.
Here, we report a crystal structure for the NS1 effector domain of avian influenza virus A/Duck/Albany/76.
Comparison of this structure with that reported for a human strain shows both proteins share a common monomer conformation, albeit with subtle differences.
Strikingly, our data reveal a novel helix-helix dimeric interface between monomers of the avian NS1 protein, which is also found in the human NS1 crystal lattice.
We re-evaluate the current model of NS1 dimeric assembly, and provide biochemical evidence to show tryptophan-187 (a residue located at the helix-helix interface) is essential for dimerization of this effector domain.
PMID: 18585749 [PubMed - as supplied by publisher]
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(1.21): Virology. 2008 Jun 26. [Epub ahead of print]
A live attenuated cold-adapted influenza A H7N3 virus vaccine provides protection against homologous and heterologous H7 viruses in mice and ferrets.
Joseph T, McAuliffe J, Lu B, Vogel L, Swayne D, Jin H, Kemble G, Subbarao K. - Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA; MedImmune Inc., Mountain View, CA 94043, USA.
The appearance of human infections caused by avian influenza A H7 subtype viruses underscores their pandemic potential and the need to develop vaccines to protect humans from viruses of this subtype.
A live attenuated H7N3 virus vaccine was generated by reverse genetics using the HA and NA genes of a low pathogenicity A/chicken/BC/CN-6/04 (H7N3) virus and the six internal protein genes of the cold-adapted A/Ann Arbor/6/60 ca (H2N2) virus.
The reassortant H7N3 BC 04 ca vaccine virus was temperature sensitive and showed attenuation in mice and ferrets.
Intranasal immunization with one dose of the vaccine protected mice and ferrets when challenged with homologous and heterologous H7 viruses.
The reassortant H7N3 BC 04 ca vaccine virus showed comparable levels of attenuation, immunogenicity and efficacy in mice and ferret models.
The safety, immunogenicity, and efficacy of this vaccine in mice and ferrets support the evaluation of this vaccine in clinical trials.
PMID: 18585748 [PubMed - as supplied by publisher
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(1.22): Virology. 2008 May 10;374(2):399-410. Epub 2008 Feb 12.
Attenuation of the type I interferon response in cells infected with human rhinovirus.
Kotla S, Peng T, Bumgarner RE, Gustin KE. - Department of Microbiology, Molecular Biology and Biochemistry, University of Idaho, Moscow, Idaho 83844-3052, USA.
The type I interferon (IFN) response requires the coordinated activation of the latent transcription factors NF-kappaB, IRF-3 and ATF-2 which in turn activate transcription from the IFN-beta promoter.
Here we have examined the type I interferon response in rhinovirus type 14-infected A549 cells, with particular emphasis on the status of the transcription factor IRF-3.
Our results indicate that although rhinovirus type 14 (RV14) infection induces the activation of NF-kappaB and ATF-2, only very low levels of IFN-beta mRNA are detected.
Analysis of ISG54 mRNA levels revealed very little induction of this IRF-3 responsive transcript and suggested that IRF-3 activation might be impaired.
Examination of IRF-3 in RV14-infected cells demonstrated only low levels of phosphorylation, a lack of homodimer formation and an absence of nuclear accumulation indicating that this transcription factor is not activated.
Inhibition of viral protein synthesis following infection resulted in an increase in IFN-beta mRNA levels indicating that viral gene products prevent induction of this pathway.
Collectively, these results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation.
PMID: 18272195 [PubMed - indexed for MEDLINE]
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(1.23): Pediatrics. 2008 Jul;122(1):e260-5.
Countywide school-based influenza immunization: direct and indirect impact on student absenteeism.
Davis MM, King JC Jr, Moag L, Cummings G, Magder LS. - Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland 21205, USA. mdavis93@jhmi.edu
OBJECTIVE:
Live attenuated influenza vaccine was given to 5319 (44%) of the 12090 students enrolled in public elementary schools in Carroll County, Maryland, during the fall of 2005. We examined the impact of this community-based intervention on countywide student absenteeism during the subsequent influenza outbreak.
METHODS:
This study used existing, anonymous information: census data, community influenza tests, and public school absenteeism data. The intervention group was Carroll County, years 2005-2006. The control group included Carroll County, years 2001-2005, and adjacent Frederick County, years 2001-2006. Weekly student absenteeism was determined during baseline influenza-free periods and influenza outbreak periods for all of the public schools.
RESULTS:
The absolute change in absenteeism during the influenza outbreak periods over baseline in elementary schools was 0.61% for the intervention group and 1.79% for the control group. Similarly, the change in absenteeism during the influenza outbreak period over baseline for high schools was 0.32% for the intervention group and 1.80% for the control group. Although not statistically significant, trends in middle schools were similar.
CONCLUSIONS:
Countywide school-based influenza vaccination was associated with reduced absenteeism during an influenza outbreak. The data suggest not only a direct impact on elementary schools but also an indirect impact on high schools. School-based programs provide an efficient method of providing influenza vaccination to children, and protection may extend to unvaccinated community members. Additional research is needed to determine whether school-based vaccination of children reduces morbidity and mortality associated with influenza outbreaks.
PMID: 18595972 [PubMed - in process]
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