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_|SELECTED RESEARCH ARTICLES ABSTRACTS, JUNE 29, 2008|_
[In this post: (1) Selected Research Articles Abstracts:
Contents:
(1.1) Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice.
(1.2) Characterization of a pathogenic H9N2 influenza A virus isolated from central China in 2007.
(1.3) Genetic analysis of H9N2 avian influenza viruses isolated from India.
(1.4) Chronic alcohol consumption increases the severity of murine influenza virus infections.
(1.5) An Adjuvanted, Low-Dose, Pandemic Influenza A (H5N1) Vaccine Candidate Is Safe, Immunogenic, and Induces Cross-Reactive Immune Responses in Healthy Adults.
(1.6) Anomalies in the Influenza Genome Database: New Biology or Lab Errors?
(1.7) Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral.
(1.8) Loss of the N-linked Glycan at Residue 173 on Human Parainfluenza Virus Type 1 Hemagglutinin-Neuraminidase Exposes a Second Receptor-Binding Site.
(1.9) Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development.
(1.10) Development of reverse transcription loop-mediated isothermal amplification for rapid detection of H9 avian influenza virus.
(1.11) Influenza vaccination coverage among persons with asthma--United States, 2005-06 influenza season.
(1.12) Coverage and predictors of influenza vaccination among adults living in a large metropolitan area in Spain: A comparison between the immigrant and indigenous populations.
(1.13) School-based influenza immunization.
(1.14) Ecological fallacy and scepticism about influenza vaccine efficacy in Japan: The Maebashi Study.
(1.15) The effect of misclassification on evaluating the effectiveness of influenza vaccines.
(1.16) Influenza vaccine effectiveness among elderly persons living in the community during the 2003-2004 season.
(1.17) Confounding in evaluating the effectiveness of influenza vaccine.
(1.18) Influenza vaccine effectiveness and confounding factors among young children.
(1.19) History of influenza vaccination programs in Japan: Prologue to the symposium.
(1.20) Essential tools for assessing influenza vaccine efficacy in improperly conducted studies: A Japanese perspective.
(1.21) Ecological studies on influenza infection and the effect of vaccination: Their advantages and limitations.
(1.22) Hsp90 inhibitors reduce influenza virus replication in cell culture.
See original abstracts at the source site. EDITED.]
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(1.1): Antiviral Res. 2008 Jun 20. [Epub ahead of print]
Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice.
Boltz DA, Ilyushina NA, Arnold CS, Babu YS, Webster RG, Govorkova EA. - Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid (re)evaluation of the available antiviral strategies.
We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus.
The regimens differed by:
(1) frequency of administration on first day (once vs twice);
(2) duration of administration (1 day vs 8 days);
(3) route of administration (intramuscular [IM] injection alone or followed by oral administration).
In all regimens, BALB/c mice were administered 30mg/kg peramivir IM 1h after lethal challenge with 5 MLD(50) of A/Vietnam/1203/04 (H5N1) influenza virus.
When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections.
Eight-day regimens significantly increased survival; two IM injections followed by seven daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain).
When this 8-day regimen began at 24h after inoculation, 78% of mice survived; 56% survived when treatment began at 48 after hours.
Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease.
Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.
PMID: 18573280 [PubMed - as supplied by publisher]
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(1.2): Arch Virol. 2008 Jun 24. [Epub ahead of print]
Characterization of a pathogenic H9N2 influenza A virus isolated from central China in 2007.
Wu R, Sui ZW, Zhang HB, Chen QJ, Liang WW, Yang KL, Xiong ZL, Liu ZW, Chen Z, Xu DP. - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei, Wuhan, 430071, China.
The entire genome of the A/Chicken/Hubei/C1/2007 (H9N2) virus, isolated from central China in 2007, was completely sequenced and phylogenetically analyzed.
Phylogenetic analysis demonstrated that A/Chicken/Hubei/C1/2007 (H9N2) virus represents multiple reassortant lineages, with genes coming from the early mainland China strain (Ck/Bejing/1/94), an H9N2 virus with special genotype (Ck/shanghai/F/98) and other lineages from poultry in Asia.
Infection studies indicated that A/Chicken/Hubei/C1/2007 (H9N2) virus replicated efficiently in MDCK cells and in BALB/c mice.
The H9N2 virus also replicated to high titers in chicken respiratory tracts and caused overt clinical signs in chickens.
Our results suggest that attention should be paid to the natural evolution of H9N2 influenza viruses and to the control of H9N2 influenza viruses in animals.
PMID: 18574551 [PubMed - as supplied by publisher]
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(1.3): Arch Virol. 2008 Jun 22. [Epub ahead of print]
Genetic analysis of H9N2 avian influenza viruses isolated from India.
Tosh C, Nagarajan S, Behera P, Rajukumar K, Purohit K, Kamal RP, Murugkar HV, Gounalan S, Pattnaik B, Vanamayya PR, Pradhan HK, Dubey SC. - High Security Animal Disease Laboratory, Indian Veterinary Research Institute, Anand Nagar, Bhopal, 462 021, India.
H9N2 avian influenza viruses are endemic in domestic poultry in Asia and are grouped into three major sublineages represented by their prototype strains A/Duck/Hong Kong/Y280/97 (Y280-like), A/Quail/Hong Kong/G1/97 (G1-like) and A/Chicken/Korea/38349-p96323/96 (Korean-like).
To understand the genetic relationship of Indian viruses, we determined the partial nucleotide sequence of five H9N2 avian influenza viruses isolated from chicken in India during 2003-2004 and compared them with H9N2 sequences available in GenBank.
Deduced amino acid sequence analysis revealed that four isolates shared an R-S-S-R/G motif at the cleavage site of HA, representing low pathogenicity in chickens, while one virus harbors an R-S-N-R/G motif at the same position.
All the viruses maintained the human-like motif 226Lysine (H3 numbering) at the HA receptor binding site.
Phylogenetic analysis showed that 50% of the genes (HA, NA, NP and M) were similar to G1-like viruses, whereas the remaining genes of the Indian isolates formed a separate, not yet defined, sublineage in the Eurasian lineage.
Our finding provides evidence of a novel reassortant H9N2 genotype of G1-like viruses circulating in India.
PMID: 18568381 [PubMed - as supplied by publisher]
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(1.4): J Immunol. 2008 Jul 1;181(1):641-8.
Chronic alcohol consumption increases the severity of murine influenza virus infections.
Meyerholz DK, Edsen-Moore M, McGill J, Coleman RA, Cook RT, Legge KL. - Department of Pathology and.
Respiratory infections with both seasonal as well as potential pandemic Influenza viruses represent a significant burden on human health.
Furthermore, viruses such as Influenza are increasingly recognized as important etiologic agents in community acquired pneumonia.
Within the U.S. alone, approximately 12.9 million people are heavy drinkers and chronic abuse of alcohol is known to increase the risk and severity of community acquired pneumonia.
Given the lack of knowledge regarding Influenza disease in this population, we determined the effects of chronic alcohol consumption on Influenza virus infection.
Herein, we report that mice exposed to chronic ethanol have sharp increases in morbidity, mortality, and pulmonary virus titers relative to controls.
These increases in influenza severity correspond with inhibited pulmonary influenza-specific CD8 T cell responses.
Further, chronic ethanol consumption results in an enhanced pulmonary lesion severity, similar to that recently described for pandemic influenzas.
Together, our results suggest that chronic alcohol consumption may increase the risk for severe influenza virus infections by altering the pulmonary inflammatory environment and CD8 T cell response.
PMID: 18566431 [PubMed - in process]
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(1.5): J Infect Dis. 2008 Jun 24. [Epub ahead of print]
An Adjuvanted, Low-Dose, Pandemic Influenza A (H5N1) Vaccine Candidate Is Safe, Immunogenic, and Induces Cross-Reactive Immune Responses in Healthy Adults.
Levie K, Leroux-Roels I, Hoppenbrouwers K, Kervyn AD, Vandermeulen C, Forgus S, Leroux-Roels G, Pichon S, Kusters I. - 1Ecole de Sant? Publique, Universit? Catholique de Louvain, Brussels, 2Center for Vaccinology, Ghent University and Hospital, Ghent, and 3Centre for Youth Health Care, Katholieke Universiteit, Leuven, Belgium; 4Sanofi Pasteur, Marcy l?Etoile, France.
Background.
To protect a naive global population against pandemic influenza, pandemic vaccines should be effective at low antigen doses, because of limited manufacturing capacity.
Methods.
In a multicenter, randomized, blind-observer phase 1 trial, groups of 50 healthy young adults received 2 doses, 21 days apart, of influenza A/Vietnam/1194/2004 NIBRG-14 (H5N1) vaccine containing 1.9, 3.8, 7.5 or 15 mug of hemagglutinin with oil-in-water emulsion adjuvant or 7.5 mug of hemagglutinin without adjuvant. Safety was monitored to day 42. Homologous hemagglutination-inhibition (HI) and microneutralization titers were determined after each vaccination. Cross-reactivity against A/Indonesia/05/2005 RG2 was tested after the second vaccination.
Results.
No vaccine-related significant or serious adverse events occurred. Injection site reactions, but not systemic reactions, were more frequent with adjuvant than without. Even with only 1.9 mug of hemagglutinin plus adjuvant, 72% of subjects had HI titers >/=1:32 after 2 doses. This proportion was 81%-89% with higher adjuvanted doses but was only 34% without adjuvant. Adjuvanted vaccine induced cross-neutralizing antibodies in 39%-65% of samples, versus 7% without adjuvant.
Conclusions.
The emulsion-adjuvanted pandemic influenza vaccine candidate was safe, immunogenic, and induced cross-reactive antibodies. This adjuvanted 1.9-mug candidate is the lowest effective dose tested to date. This could have a major impact on prepandemic vaccination strategies with stockpiled batches of vaccine.
Trial registration. @nbsp; ClinicalTrials.gov identifier: NCT00457509 .
PMID: 18576945 [PubMed - as supplied by publisher]
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(1.6): J Virol. 2008 Jun 25. [Epub ahead of print]
Anomalies in the Influenza Genome Database: New Biology or Lab Errors?
Krasnitz M, Levine AJ, Rabadan R. - Institute for Advanced Study, Einstein Dr., Princeton, NJ 08540, USA.
A search of the influenza genome database reveals anomalies associated with a non-negligible number of submitted sequences.
There are many pairs of viral segments that are very close to each other in nucleotide sequence but relatively far apart in reported time of isolation, resulting in an abnormally low evolutionary rate.
Also, some sequences show clear evidence of apparent homologous recombination, a process normally assumed to be extremely rare or nonexistent in this virus.
These findings may point to surprising new biology, but are perhaps more readily explained by stock contamination or other errors in the sequencing laboratories.
PMID: 18579605 [PubMed - as supplied by publisher]
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(1.7): J Virol. 2008 Jun 25. [Epub ahead of print]
Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral.
Dimmock NJ, Rainsford EW, Scott PD, Marriott AC. - Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK.
Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed.
Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza RNA that has the potential to protect against any influenza A virus in any animal host.
This protecting RNA (244 RNA) is incorporated into virions which although non-infectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus.
A 120 ng intranasal dose of this 244 protecting virus completely protected mice against a simultaneous lethal (10 LD50) challenge with influenza A/WSN (H1N1) virus.
244 virus also protected mice against a strong challenge dose of all other subtypes tested (H2N2, H3N2, H3N8).
This prophylactic activity was maintained in the animal for at least 1 week prior to challenge.
244 virus was 10 to 100-fold more active than previously characterised influenza A defective viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA.
There was clear therapeutic benefit when 244 virus was administered 24-48 h after lethal challenge, an effect which has not been previously observed with any defective virus.
Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments.
Protecting virus is a novel antiviral having the potential to combat human influenza infections, particularly when the infecting strain is not known, or is resistant to antiviral drugs.
PMID: 18579602 [PubMed - as supplied by publisher]
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(1.8): J Virol. 2008 Jun 25. [Epub ahead of print]
Loss of the N-linked Glycan at Residue 173 on Human Parainfluenza Virus Type 1 Hemagglutinin-Neuraminidase Exposes a Second Receptor-Binding Site.
Alymova IV, Taylor G, Mishin VP, Watanabe M, Murti KG, Boyd K, Chand P, Babu YS, Portner A. - Departments of Infectious Diseases, Molecular Biotechnology, and Animal Resources Center, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA; Center for Biomolecular Science, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland; BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA.
BCX 2798 effectively inhibited the activities of the hemagglutinin-neuraminidase (HN) of human parainfluenza viruses (hPIV) in vitro, and protected mice from lethal infection with a recombinant Sendai virus whose HN was replaced with that of hPIV-1 (rSeV[hPIV-1HN]) (Alymova, I. V., G. Taylor, T. Takimoto, T. H. Lin., P. Chand, Y. S. Babu, C. Li, X. Xiong, and A. Portner. 2004. Antimicrob. Agents Chemother. 48:1495-1502).
The ability of BCX 2798 to select drug-resistant variants in vivo was examined.
A variant with mutation Asn to Ser at residue 173 (N173S) in HN was recovered from mice after a second passage of rSeV(hPIV-1HN) in the presence of BCX 2798 (10 mg/kg daily).
The N173S mutant remained sensitive to BCX 2798 in neuraminidase-inhibition assays, but was more than 10,000-fold less sensitive to the compound in hemagglutination-inhibition tests, as compared to that of rSev(hPIV-1HN).
Its susceptibility to BCX 2798 in plaque-reduction assays was reduced 5-fold and did not differ from that of rSeV(hPIV-1HN) in mice.
The N173S mutant failed to efficiently elute from erythrocytes and release from cells.
It demonstrated reduced growth in cell culture and superior growth in mice.
Gel electrophoresis analysis was consistent with the loss of the N-linked glycan at residue 173 in the mutant.
Sequence and structural comparisons revealed that residue 173 on hPIV-1 HN is closely located to the region of the second receptor-binding site identified in Newcastle disease virus HN.
Our study suggests that the N-linked glycan at residue 173 masks a second receptor-binding site on hPIV-1 HN.
PMID: 18579600 [PubMed - as supplied by publisher]
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(1.9): J Virol. 2008 May;82(9):4441-8. Epub 2008 Feb 20.
Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development.
Pribul PK, Harker J, Wang B, Wang H, Tregoning JS, Schwarze J, Openshaw PJ. - Department of Respiratory Medicine, Paddington Campus of Imperial College, Norfolk Place, London W2 1PG, United Kingdom. p.openshaw@imperial.ac.uk
Macrophages are abundant in the lower respiratory tract.
They play a central role in the innate response to infection but may also modulate excessive inflammation.
Both macrophages and ciliated epithelial cells respond to infection by releasing soluble mediators, leading to the recruitment of innate and adaptive effector cells.
To study the role of lung macrophages in acute respiratory viral infection, we depleted them by the inhalation of clodronate liposomes in an established mouse model of respiratory syncytial virus (RSV) disease.
Infection caused an immediate local release of inflammatory cytokines and chemokines, peaking on day 1, which was virtually abolished by clodronate liposome treatment.
Macrophage depletion inhibited the activation (days 1 to 2) and recruitment (day 4) of natural killer (NK) cells and enhanced peak viral load in the lung (day 4).
However, macrophage depletion did not affect the recruitment of activated CD4 or CD8 T cells, weight loss, or virus-induced changes in lung function.
Therefore, lung macrophages play a central role in the early responses to viral infection but have remarkably little effect on the adaptive response occurring at the time of peak disease severity.
PMID: 18287232 [PubMed - indexed for MEDLINE]
PMCID: PMC2293049 [Available on 09/01/08]
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(1.10): J Virol Methods. 2008 Jun 20. [Epub ahead of print]
Development of reverse transcription loop-mediated isothermal amplification for rapid detection of H9 avian influenza virus.
Chen HT, Zhang J, Sun DH, Ma LN, Liu XT, Cai XP, Liu YS. - Key Laboratory of Animal Virology of Ministry of Agriculture, State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China.
Reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a unique gene amplification method that can be completed within 45min at 63 degrees C.
In this study, RT-LAMP was used to develop a rapid and sensitive laboratory diagnostic system for the H9 subtype of avian influenza virus (AIV).
The experiment results from the reference strains demonstrated that the established RT-LAMP sensitivity was 10-fold higher than that of RT-PCR, with the detection limit of 10 copies per reaction, and no cross-reactivity was observed from the samples of other related viruses including H5N1, H3N2 subtype of AIV and Newcastle disease virus.
Furthermore, a total of 112 clinical samples were tested by RT-LAMP, RT-PCR, and virus isolation, respectively.
All of the 85 positive specimens identified by virus isolation were also positive by RT-LAMP, while 7 of these samples were missed by RT-PCR.
These results suggest that the present RT-LAMP system may provide a new avenue for the recognition of H9 subtype virus, and may be employed to screen for potential carriers in wild and domestic birds.
PMID: 18572258 [PubMed - as supplied by publisher]
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(1.11): MMWR Morb Mortal Wkly Rep. 2008 Jun 20;57(24):653-7.
Influenza vaccination coverage among persons with asthma--United States, 2005-06 influenza season.
Centers for Disease Control and Prevention (CDC).
During 2006, approximately 6.8 million (9.3%) U.S. children and 16.1 million (7.3%) U.S. adults were reported to have asthma.
Since 1964, the Advisory Committee on Immunization Practices (ACIP) has recommended influenza vaccination of all persons with asthma because of the higher risk for medical complications from influenza for those persons.
Influenza vaccination coverage of persons with asthma varies by age group and remains below Healthy People 2010 targets of 60% coverage of persons aged 18--64 years with high-risk conditions (14-29 c) and 90% of all persons aged > or =65 years (14-29 a).
Influenza vaccination rates of children and older adults with asthma have not been well studied.
Using 2006 National Health Interview Survey (NHIS) data, this report provides the first examination of influenza vaccination rates and related factors across a national sample of persons with asthma aged > or =2 years.
The results indicated that 36.2% received influenza vaccination during the 2005--06 influenza season.
Vaccination rates remained below target levels among all subgroups examined, including those reporting the greatest number of health-care visits in the past 12 months.
The results of this study indicate that influenza vaccination coverage of all persons with asthma can be improved by increasing access to health care and using opportunities for vaccination during health-care visits.
PMID: 18566564 [PubMed - indexed for MEDLINE]
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(1.12): Vaccine. 2008 Jun 6. [Epub ahead of print]
Coverage and predictors of influenza vaccination among adults living in a large metropolitan area in Spain: A comparison between the immigrant and indigenous populations.
Jim?nez-Garc?a R, Hern?ndez-Barrera V, Carrasco-Garrido P, de Andres AL, Esteban Y Pe?a MM, de Miguel AG. - Preventive Medicine and Public Health Teaching and Research Unit, Health Sciences Faculty, Rey Juan Carlos University, Avda de Atenas s/n, Alcorc?n 28402 Madrid, Spain.
This study sought to evaluate influenza vaccination coverage in Madrid (Spain).
Coverages were estimated for vaccine target groups and special attention was placed on the immigrant population.
Individual data from 7341 adults included in the Madrid City Health Survey conducted in 2005 was used.
Overall influenza vaccination coverage was 24%.
Compliance with age-based influenza vaccine guidelines (>/=65 years) was 63.9%, among those <65 years who had an associated chronic condition, it was 37.9% and 24.1% among HCWs.
Immigrants accounted for 12.4% of the sample.
Overall crude coverage was significantly lower among immigrants than among the indigenous population (11.2% vs. 25.9%), but once the multivariate analysis had been performed, the association became non-significant.
In conclusion, it must be said that all the available evidence indicates an inadequate level of influenza vaccination coverage among HCWs and high-risk subjects <65 years.
On the other hand, coverages among subjects aged >/=65 years are acceptable and there is no observable difference in vaccine use between immigrants and indigenous subjects.
Strategies that have demonstrated their effectiveness in enhancing vaccination coverages should be applied in Madrid.
PMID: 18579263 [PubMed - as supplied by publisher]
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(1.13): Vaccine. 2008 Jun 21. [Epub ahead of print]
School-based influenza immunization.
Hull HF, Frauendienst RS, Gundersen ML, Monsen SM, Fishbein DB. - HF Hull and Associates, 1140 St. Dennis Ct., Saint Paul, MN 55116, United States.
Annual influenza vaccination of schoolchildren will protect individual vaccines and, with high coverage, may protect entire communities.
Because schoolchildren are more difficult to reach than preschoolers, school-based immunization programs may be needed to reach a high percentage of children.
We offered free live, attenuated influenza vaccine to all healthy schoolchildren (K-12) in three Minnesota counties.
Counties vaccinated from 33% to 58% of students. Overall, 41% of enrolled children were vaccinated.
Elementary students were vaccinated at higher rates than older students.
Administrative costs averaged $9.78 per dose delivered. School-based immunization programs offer the potential to achieve higher vaccination coverage of schoolchildren at modest cost.
PMID: 18577411 [PubMed - as supplied by publisher]
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(1.14): Vaccine. 2008 Jun 20. [Epub ahead of print]
Ecological fallacy and scepticism about influenza vaccine efficacy in Japan: The Maebashi Study.
Hirota Y. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
In 1979, Maebashi City discontinued influenza mass vaccination immediately after a case of vaccine-related convulsion occurred.
A research group of the Maebashi City Medical Association studied the effects of mass vaccination on influenza activity in two cities without mass vaccination programs and three cities with mass vaccination programs (Maebashi Study).
Due to possible issues of validity arising from the non-randomized design of the study, the authors of the Maebashi Study reserved discussion on the vaccine efficacy that they calculated from the attack rates among the non-vaccinees and vaccinees.
Instead, they compared the overall attack rates in Maebashi and among the twice-vaccinees in the cities with mass vaccination programs.
The authors limited their discussion to the fact that influenza activity in Maebashi was not materially different from that in cities with mass vaccination programs.
Anti-vaccination activists misconstrued this to mean that the absence of a correlation between attack rate and vaccine coverage implies that influenza vaccine has no efficacy.
This is a good example of the "ecological fallacy", which refers to the fact that a relationship between two variables at the population level does not necessarily imply the same relationship at an individual level.
PMID: 18573298 [PubMed - as supplied by publisher]
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(1.15): Vaccine. 2008 Jun 20. [Epub ahead of print]
The effect of misclassification on evaluating the effectiveness of influenza vaccines.
Ozasa K. - Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medicine, Japan.
Misclassification is a measurement error and can be considered a type of information bias.
Misclassification can occur at both exposure and outcome levels.
Nondifferential misclassification causes only a dilution effect leading to underestimation, whereas differential misclassification can have more complicated and serious consequences.
To avoid nondifferential diagnosis misclassification, it is necessary to use highly specific diagnostic examinations or criteria such as virus detection to exclude 'false positive' cases, and to limit the observation period to an intensive epidemic period if using less specific diagnostic criteria such as symptoms of influenza-like illness (ILI) or absence from school or workplace.
To avoid differential diagnosis misclassification, vaccinated and unvaccinated groups must be equally scrutinized, and such scrutiny is more important than the specificity of diagnosis.
So, passive findings from patients with influenza at clinics can cause complicated differential misclassification despite use of highly specific diagnostic procedures because vaccinated and unvaccinated patients may participate differently.
Also important is standardization of diagnostic procedure that vaccination anamnesis does not influence diagnosis of influenza, or examination of the influence.
Exposure misclassification would mainly underestimate vaccine effectiveness in most situations.
Consequently, misclassification of diagnosis, especially differential misclassification, affects evaluation of influenza vaccine effectiveness.
PMID: 18573297 [PubMed - as supplied by publisher]
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(1.16): Vaccine. 2008 Jun 20. [Epub ahead of print]
Influenza vaccine effectiveness among elderly persons living in the community during the 2003-2004 season.
Hara M, Sakamoto T, Tanaka K. - Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
To examine the effectiveness of influenza vaccine among community-dwelling elderly (65-79 years old), we conducted a population-based cohort study during the 2003-2004 influenza season.
A total of 4787 elderly individuals were interviewed regarding acute febrile illness, hospital visits, hospitalization and death by telephone every month.
The vaccination status and physician-diagnosed clinical influenza (hereinafter referred as clinical influenza) were determined based on data obtained from the city office and hospitals, respectively.
After adjusting for confounders, the odds ratio (OR) of vaccination for influenza-like illness (ILI) with high-fever, which was defined as an acute febrile illness (>/=38.5 degrees C) during the epidemic period, was 0.38 (95% confidence interval [CI], 0.17-0.85) and the OR for clinical influenza was 0.76 (95%CI, 0.28-2.06).
Due to the inadequate sample size, ORs for preventing hospitalization for influenza or pneumonia (OR, 0.37; 95%CI, 0.09-1.47) and death (OR, 3.68; 95%CI, 0.75-18.12) were not conclusive.
These results suggested that vaccination was therefore effective for elderly persons living in the community.
PMID: 18573296 [PubMed - as supplied by publisher]
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(1.17): Vaccine. 2008 Jun 20. [Epub ahead of print]
Confounding in evaluating the effectiveness of influenza vaccine.
Mori M, Oura A, Ohnishi H, Washio M. - Department of Public Health, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan.
Confounding is a kind of bias which occurs in a research.
Confounding is less frequent in randomized controlled trials (RCT) for evaluation of influenza vaccines.
However, there are obstacles or difficulties in conducting RCT for evaluation of influenza vaccines, particularly, in the elderly people.
Therefore, a retrospective or prospective cohort study has been primarily performed to evaluate effectiveness of influenza vaccine in elderly people.
Confounding by indication or other confounding exist in most observational studies.
Accordingly, at the stage of designing or analyzing a study, confounding should be controlled with a restriction, matching, stratified or multivariate analysis technique.
PMID: 18573295 [PubMed - as supplied by publisher]
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(1.18): Vaccine. 2008 Jun 20. [Epub ahead of print]
Influenza vaccine effectiveness and confounding factors among young children.
Fujieda M, Maeda A, Kondo K, Fukushima W, Ohfuji S, Kaji M, Hirota Y. - Department of Public Health, Osaka City University Faculty of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan.
This study, done during the 2002-2003 season among children <6 years of age to investigate influenza vaccine effectiveness and confounding factors, involved 2913 children (1512 vaccinees, 1401 non-vaccinees) recruited from 54 paediatric clinics.
Between December 2002 and April 2003, parents reported their children's maximum body temperatures weekly. Influenza-like illness (ILI) was defined as an acute febrile illness (>/=38.0 degrees C) during the peak epidemic period.
Adjusted odds ratios (ORs) for ILI were obtained using a logistic regression model.
In analysis for total subjects, the ORs were significantly decreased for vaccinees (OR: 0.76, 95% CI: 0.66-0.88) and significantly increased for younger age groups, including children aged 2.0-3.9 years (1.42, 1.18-1.72) and those <2.0 years (2.02,1.61-2.54), compared to those between 4.0 and 5.9 years.
ORs were significantly increased for children who visited a physician within the last 6 months for a cold (1.27, 1.08-1.50), attended preschool (1.72, 1.45-2.04), and had >/=3 siblings (1.42, 1.15-1.74).
These confounding factors are suggested to be considered in estimating vaccine effectiveness among young children.
In subgroup analysis by age groups, significantly decreased ORs were seen in 2.0-3.9-year-old (0.59, 0.47-0.74) and 4.0-5.9-year-old (0.75, 0.58-0.98) vaccinees; no significant vaccine effectiveness was detected for those <2.0 years (1.07, 0.80-1.44).
Thus, among very young children vaccine effectiveness could not be demonstrated.
PMID: 18573294 [PubMed - as supplied by publisher]
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(1.19): Vaccine. 2008 Jun 20. [Epub ahead of print]
History of influenza vaccination programs in Japan: Prologue to the symposium.
Hirota Y, Kaji M. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
In 1976, influenza mass vaccination among schoolchildren was started under the Preventive Vaccination Law, which was intended to control epidemics in the community.
However, in the late 1980s, questions about this policy and vaccine efficacy arose, and a campaign against vaccination began.
In 1994, influenza was excluded from the target diseases list in the Preventive Vaccination Law, without considering the immunization policy with respect to the common indications in high-risk groups.
In 2001, the Law was again amended, specifying target groups, such as the elderly aged 65 or over, for influenza vaccination.
In the 2005-2006 season, vaccine coverage among the elderly reached 52%.
This shows that the need for vaccination has gradually become understood.
However, the anti-vaccination campaign, which claims that the influenza vaccine has no efficacy, is still active.
Vaccine efficacy studies that were not properly conducted are also being reported. In 2002, the Ministry of Health, Labor, and Welfare organized a research group on vaccine efficacy consisting of epidemiologists.
The present symposium, as part of the 9th Annual Meeting of the Japanese Society for Vaccinology in 2005, was planned to further introduce epidemiological concepts useful in studying influenza vaccine efficacy.
PMID: 18573292 [PubMed - as supplied by publisher]
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(1.20): Vaccine. 2008 Jun 20. [Epub ahead of print]
Essential tools for assessing influenza vaccine efficacy in improperly conducted studies: A Japanese perspective.
Hirota Y, Fukushima W, Fujieda M, Ohfuji S, Maeda A. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
The fundamental issue in assessing influenza vaccine efficacy is to observe all study subjects with equal intensity throughout the surveillance period.
The case definition can be adopted within the scope of the budget and the logistics of the study; however, there is no doubt that culture-proven influenza is currently the best outcome index.
More pronounced vaccine efficacy can be detected if stricter case definition criteria are applied and/or if observations are confined to the peak epidemic period.
Patients identified through passive case-finding in clinics do not properly represent all influenza cases that occur in the study subjects.
Almost all non-randomized studies which have so far been conducted by Japanese clinicians do not take confounders into consideration.
Even though laboratory-confirmed influenza is identified, vaccine efficacy should primarily be estimated based on the presence of any influenzal illness, since efficacy calculated by virus type or subtype often results in loss of statistical power.
The results from post hoc subgroup analysis may not offer a solid base for assessing vaccine efficacy and should be cautiously interpreted.
PMID: 18573291 [PubMed - as supplied by publisher]
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(1.21): Vaccine. 2008 Jun 20. [Epub ahead of print]
Ecological studies on influenza infection and the effect of vaccination: Their advantages and limitations.
Washio M, Oura A, Mori M. - Department of Public Health, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo 060-8556, Japan; Department of Community Health and Clinical Epidemiology, St Mary's College, 422 Tsubuku-hon-machi, Kurume, Fukuoka 830-8558, Japan.
Ecological studies lack the ability to control for the effects of confounding factors.
The findings of a linear relationship between average exposure and disease frequency in ecological studies do not imply that such a linear relationship will be present at the individual levels.
This is known as the 'ecological fallacy'.
Despite these limitations, ecological studies may be the best approach to studying exposures that are easier to measure at the group rather than the individual level because most ecological studies make use of routinely collected data.
They are also useful for monitoring the effectiveness of population interventions such as vaccination programs, health education campaigns and mass screening programs.
Thus, ecological studies are useful epidemiologic tools for public health surveillance if we know their limitations and interpret their results carefully.
Ecological studies often help to generate hypotheses, although they rarely provide a strong test of a causal hypothesis.
PMID: 18573289 [PubMed - as supplied by publisher]
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(1.22): Virology. 2008 Aug 1;377(2):431-9.
Hsp90 inhibitors reduce influenza virus replication in cell culture.
Chase G, Deng T, Fodor E, Leung BW, Mayer D, Schwemmle M, Brownlee G. - Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
The viral RNA polymerase complex of influenza A virus consists of three subunits PB1, PB2 and PA.
Recently, the cellular chaperone Hsp90 was shown to play a role in nuclear import and assembly of the trimeric polymerase complex by binding to PB1 and PB2.
Here we show that Hsp90 inhibitors, geldanamycin or its derivative 17-AAG, delay the growth of influenza virus in cell culture resulting in a 1-2 log reduction in viral titre early in infection.
We suggest that this is caused by the reduced half-life of PB1 and PB2 and inhibition of nuclear import of PB1 and PA which lead to reduction in viral RNP assembly.
Hsp90 inhibitors may represent a new class of antiviral compounds against influenza viruses.
PMID: 18570972 [PubMed - in process]
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Contents:
(1.1) Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice.
(1.2) Characterization of a pathogenic H9N2 influenza A virus isolated from central China in 2007.
(1.3) Genetic analysis of H9N2 avian influenza viruses isolated from India.
(1.4) Chronic alcohol consumption increases the severity of murine influenza virus infections.
(1.5) An Adjuvanted, Low-Dose, Pandemic Influenza A (H5N1) Vaccine Candidate Is Safe, Immunogenic, and Induces Cross-Reactive Immune Responses in Healthy Adults.
(1.6) Anomalies in the Influenza Genome Database: New Biology or Lab Errors?
(1.7) Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral.
(1.8) Loss of the N-linked Glycan at Residue 173 on Human Parainfluenza Virus Type 1 Hemagglutinin-Neuraminidase Exposes a Second Receptor-Binding Site.
(1.9) Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development.
(1.10) Development of reverse transcription loop-mediated isothermal amplification for rapid detection of H9 avian influenza virus.
(1.11) Influenza vaccination coverage among persons with asthma--United States, 2005-06 influenza season.
(1.12) Coverage and predictors of influenza vaccination among adults living in a large metropolitan area in Spain: A comparison between the immigrant and indigenous populations.
(1.13) School-based influenza immunization.
(1.14) Ecological fallacy and scepticism about influenza vaccine efficacy in Japan: The Maebashi Study.
(1.15) The effect of misclassification on evaluating the effectiveness of influenza vaccines.
(1.16) Influenza vaccine effectiveness among elderly persons living in the community during the 2003-2004 season.
(1.17) Confounding in evaluating the effectiveness of influenza vaccine.
(1.18) Influenza vaccine effectiveness and confounding factors among young children.
(1.19) History of influenza vaccination programs in Japan: Prologue to the symposium.
(1.20) Essential tools for assessing influenza vaccine efficacy in improperly conducted studies: A Japanese perspective.
(1.21) Ecological studies on influenza infection and the effect of vaccination: Their advantages and limitations.
(1.22) Hsp90 inhibitors reduce influenza virus replication in cell culture.
See original abstracts at the source site. EDITED.]
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(1.1): Antiviral Res. 2008 Jun 20. [Epub ahead of print]
Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice.
Boltz DA, Ilyushina NA, Arnold CS, Babu YS, Webster RG, Govorkova EA. - Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid (re)evaluation of the available antiviral strategies.
We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus.
The regimens differed by:
(1) frequency of administration on first day (once vs twice);
(2) duration of administration (1 day vs 8 days);
(3) route of administration (intramuscular [IM] injection alone or followed by oral administration).
In all regimens, BALB/c mice were administered 30mg/kg peramivir IM 1h after lethal challenge with 5 MLD(50) of A/Vietnam/1203/04 (H5N1) influenza virus.
When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections.
Eight-day regimens significantly increased survival; two IM injections followed by seven daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain).
When this 8-day regimen began at 24h after inoculation, 78% of mice survived; 56% survived when treatment began at 48 after hours.
Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease.
Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.
PMID: 18573280 [PubMed - as supplied by publisher]
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(1.2): Arch Virol. 2008 Jun 24. [Epub ahead of print]
Characterization of a pathogenic H9N2 influenza A virus isolated from central China in 2007.
Wu R, Sui ZW, Zhang HB, Chen QJ, Liang WW, Yang KL, Xiong ZL, Liu ZW, Chen Z, Xu DP. - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei, Wuhan, 430071, China.
The entire genome of the A/Chicken/Hubei/C1/2007 (H9N2) virus, isolated from central China in 2007, was completely sequenced and phylogenetically analyzed.
Phylogenetic analysis demonstrated that A/Chicken/Hubei/C1/2007 (H9N2) virus represents multiple reassortant lineages, with genes coming from the early mainland China strain (Ck/Bejing/1/94), an H9N2 virus with special genotype (Ck/shanghai/F/98) and other lineages from poultry in Asia.
Infection studies indicated that A/Chicken/Hubei/C1/2007 (H9N2) virus replicated efficiently in MDCK cells and in BALB/c mice.
The H9N2 virus also replicated to high titers in chicken respiratory tracts and caused overt clinical signs in chickens.
Our results suggest that attention should be paid to the natural evolution of H9N2 influenza viruses and to the control of H9N2 influenza viruses in animals.
PMID: 18574551 [PubMed - as supplied by publisher]
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(1.3): Arch Virol. 2008 Jun 22. [Epub ahead of print]
Genetic analysis of H9N2 avian influenza viruses isolated from India.
Tosh C, Nagarajan S, Behera P, Rajukumar K, Purohit K, Kamal RP, Murugkar HV, Gounalan S, Pattnaik B, Vanamayya PR, Pradhan HK, Dubey SC. - High Security Animal Disease Laboratory, Indian Veterinary Research Institute, Anand Nagar, Bhopal, 462 021, India.
H9N2 avian influenza viruses are endemic in domestic poultry in Asia and are grouped into three major sublineages represented by their prototype strains A/Duck/Hong Kong/Y280/97 (Y280-like), A/Quail/Hong Kong/G1/97 (G1-like) and A/Chicken/Korea/38349-p96323/96 (Korean-like).
To understand the genetic relationship of Indian viruses, we determined the partial nucleotide sequence of five H9N2 avian influenza viruses isolated from chicken in India during 2003-2004 and compared them with H9N2 sequences available in GenBank.
Deduced amino acid sequence analysis revealed that four isolates shared an R-S-S-R/G motif at the cleavage site of HA, representing low pathogenicity in chickens, while one virus harbors an R-S-N-R/G motif at the same position.
All the viruses maintained the human-like motif 226Lysine (H3 numbering) at the HA receptor binding site.
Phylogenetic analysis showed that 50% of the genes (HA, NA, NP and M) were similar to G1-like viruses, whereas the remaining genes of the Indian isolates formed a separate, not yet defined, sublineage in the Eurasian lineage.
Our finding provides evidence of a novel reassortant H9N2 genotype of G1-like viruses circulating in India.
PMID: 18568381 [PubMed - as supplied by publisher]
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(1.4): J Immunol. 2008 Jul 1;181(1):641-8.
Chronic alcohol consumption increases the severity of murine influenza virus infections.
Meyerholz DK, Edsen-Moore M, McGill J, Coleman RA, Cook RT, Legge KL. - Department of Pathology and.
Respiratory infections with both seasonal as well as potential pandemic Influenza viruses represent a significant burden on human health.
Furthermore, viruses such as Influenza are increasingly recognized as important etiologic agents in community acquired pneumonia.
Within the U.S. alone, approximately 12.9 million people are heavy drinkers and chronic abuse of alcohol is known to increase the risk and severity of community acquired pneumonia.
Given the lack of knowledge regarding Influenza disease in this population, we determined the effects of chronic alcohol consumption on Influenza virus infection.
Herein, we report that mice exposed to chronic ethanol have sharp increases in morbidity, mortality, and pulmonary virus titers relative to controls.
These increases in influenza severity correspond with inhibited pulmonary influenza-specific CD8 T cell responses.
Further, chronic ethanol consumption results in an enhanced pulmonary lesion severity, similar to that recently described for pandemic influenzas.
Together, our results suggest that chronic alcohol consumption may increase the risk for severe influenza virus infections by altering the pulmonary inflammatory environment and CD8 T cell response.
PMID: 18566431 [PubMed - in process]
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(1.5): J Infect Dis. 2008 Jun 24. [Epub ahead of print]
An Adjuvanted, Low-Dose, Pandemic Influenza A (H5N1) Vaccine Candidate Is Safe, Immunogenic, and Induces Cross-Reactive Immune Responses in Healthy Adults.
Levie K, Leroux-Roels I, Hoppenbrouwers K, Kervyn AD, Vandermeulen C, Forgus S, Leroux-Roels G, Pichon S, Kusters I. - 1Ecole de Sant? Publique, Universit? Catholique de Louvain, Brussels, 2Center for Vaccinology, Ghent University and Hospital, Ghent, and 3Centre for Youth Health Care, Katholieke Universiteit, Leuven, Belgium; 4Sanofi Pasteur, Marcy l?Etoile, France.
Background.
To protect a naive global population against pandemic influenza, pandemic vaccines should be effective at low antigen doses, because of limited manufacturing capacity.
Methods.
In a multicenter, randomized, blind-observer phase 1 trial, groups of 50 healthy young adults received 2 doses, 21 days apart, of influenza A/Vietnam/1194/2004 NIBRG-14 (H5N1) vaccine containing 1.9, 3.8, 7.5 or 15 mug of hemagglutinin with oil-in-water emulsion adjuvant or 7.5 mug of hemagglutinin without adjuvant. Safety was monitored to day 42. Homologous hemagglutination-inhibition (HI) and microneutralization titers were determined after each vaccination. Cross-reactivity against A/Indonesia/05/2005 RG2 was tested after the second vaccination.
Results.
No vaccine-related significant or serious adverse events occurred. Injection site reactions, but not systemic reactions, were more frequent with adjuvant than without. Even with only 1.9 mug of hemagglutinin plus adjuvant, 72% of subjects had HI titers >/=1:32 after 2 doses. This proportion was 81%-89% with higher adjuvanted doses but was only 34% without adjuvant. Adjuvanted vaccine induced cross-neutralizing antibodies in 39%-65% of samples, versus 7% without adjuvant.
Conclusions.
The emulsion-adjuvanted pandemic influenza vaccine candidate was safe, immunogenic, and induced cross-reactive antibodies. This adjuvanted 1.9-mug candidate is the lowest effective dose tested to date. This could have a major impact on prepandemic vaccination strategies with stockpiled batches of vaccine.
Trial registration. @nbsp; ClinicalTrials.gov identifier: NCT00457509 .
PMID: 18576945 [PubMed - as supplied by publisher]
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(1.6): J Virol. 2008 Jun 25. [Epub ahead of print]
Anomalies in the Influenza Genome Database: New Biology or Lab Errors?
Krasnitz M, Levine AJ, Rabadan R. - Institute for Advanced Study, Einstein Dr., Princeton, NJ 08540, USA.
A search of the influenza genome database reveals anomalies associated with a non-negligible number of submitted sequences.
There are many pairs of viral segments that are very close to each other in nucleotide sequence but relatively far apart in reported time of isolation, resulting in an abnormally low evolutionary rate.
Also, some sequences show clear evidence of apparent homologous recombination, a process normally assumed to be extremely rare or nonexistent in this virus.
These findings may point to surprising new biology, but are perhaps more readily explained by stock contamination or other errors in the sequencing laboratories.
PMID: 18579605 [PubMed - as supplied by publisher]
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(1.7): J Virol. 2008 Jun 25. [Epub ahead of print]
Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral.
Dimmock NJ, Rainsford EW, Scott PD, Marriott AC. - Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK.
Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed.
Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza RNA that has the potential to protect against any influenza A virus in any animal host.
This protecting RNA (244 RNA) is incorporated into virions which although non-infectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus.
A 120 ng intranasal dose of this 244 protecting virus completely protected mice against a simultaneous lethal (10 LD50) challenge with influenza A/WSN (H1N1) virus.
244 virus also protected mice against a strong challenge dose of all other subtypes tested (H2N2, H3N2, H3N8).
This prophylactic activity was maintained in the animal for at least 1 week prior to challenge.
244 virus was 10 to 100-fold more active than previously characterised influenza A defective viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA.
There was clear therapeutic benefit when 244 virus was administered 24-48 h after lethal challenge, an effect which has not been previously observed with any defective virus.
Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments.
Protecting virus is a novel antiviral having the potential to combat human influenza infections, particularly when the infecting strain is not known, or is resistant to antiviral drugs.
PMID: 18579602 [PubMed - as supplied by publisher]
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(1.8): J Virol. 2008 Jun 25. [Epub ahead of print]
Loss of the N-linked Glycan at Residue 173 on Human Parainfluenza Virus Type 1 Hemagglutinin-Neuraminidase Exposes a Second Receptor-Binding Site.
Alymova IV, Taylor G, Mishin VP, Watanabe M, Murti KG, Boyd K, Chand P, Babu YS, Portner A. - Departments of Infectious Diseases, Molecular Biotechnology, and Animal Resources Center, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA; Center for Biomolecular Science, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland; BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA.
BCX 2798 effectively inhibited the activities of the hemagglutinin-neuraminidase (HN) of human parainfluenza viruses (hPIV) in vitro, and protected mice from lethal infection with a recombinant Sendai virus whose HN was replaced with that of hPIV-1 (rSeV[hPIV-1HN]) (Alymova, I. V., G. Taylor, T. Takimoto, T. H. Lin., P. Chand, Y. S. Babu, C. Li, X. Xiong, and A. Portner. 2004. Antimicrob. Agents Chemother. 48:1495-1502).
The ability of BCX 2798 to select drug-resistant variants in vivo was examined.
A variant with mutation Asn to Ser at residue 173 (N173S) in HN was recovered from mice after a second passage of rSeV(hPIV-1HN) in the presence of BCX 2798 (10 mg/kg daily).
The N173S mutant remained sensitive to BCX 2798 in neuraminidase-inhibition assays, but was more than 10,000-fold less sensitive to the compound in hemagglutination-inhibition tests, as compared to that of rSev(hPIV-1HN).
Its susceptibility to BCX 2798 in plaque-reduction assays was reduced 5-fold and did not differ from that of rSeV(hPIV-1HN) in mice.
The N173S mutant failed to efficiently elute from erythrocytes and release from cells.
It demonstrated reduced growth in cell culture and superior growth in mice.
Gel electrophoresis analysis was consistent with the loss of the N-linked glycan at residue 173 in the mutant.
Sequence and structural comparisons revealed that residue 173 on hPIV-1 HN is closely located to the region of the second receptor-binding site identified in Newcastle disease virus HN.
Our study suggests that the N-linked glycan at residue 173 masks a second receptor-binding site on hPIV-1 HN.
PMID: 18579600 [PubMed - as supplied by publisher]
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(1.9): J Virol. 2008 May;82(9):4441-8. Epub 2008 Feb 20.
Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development.
Pribul PK, Harker J, Wang B, Wang H, Tregoning JS, Schwarze J, Openshaw PJ. - Department of Respiratory Medicine, Paddington Campus of Imperial College, Norfolk Place, London W2 1PG, United Kingdom. p.openshaw@imperial.ac.uk
Macrophages are abundant in the lower respiratory tract.
They play a central role in the innate response to infection but may also modulate excessive inflammation.
Both macrophages and ciliated epithelial cells respond to infection by releasing soluble mediators, leading to the recruitment of innate and adaptive effector cells.
To study the role of lung macrophages in acute respiratory viral infection, we depleted them by the inhalation of clodronate liposomes in an established mouse model of respiratory syncytial virus (RSV) disease.
Infection caused an immediate local release of inflammatory cytokines and chemokines, peaking on day 1, which was virtually abolished by clodronate liposome treatment.
Macrophage depletion inhibited the activation (days 1 to 2) and recruitment (day 4) of natural killer (NK) cells and enhanced peak viral load in the lung (day 4).
However, macrophage depletion did not affect the recruitment of activated CD4 or CD8 T cells, weight loss, or virus-induced changes in lung function.
Therefore, lung macrophages play a central role in the early responses to viral infection but have remarkably little effect on the adaptive response occurring at the time of peak disease severity.
PMID: 18287232 [PubMed - indexed for MEDLINE]
PMCID: PMC2293049 [Available on 09/01/08]
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(1.10): J Virol Methods. 2008 Jun 20. [Epub ahead of print]
Development of reverse transcription loop-mediated isothermal amplification for rapid detection of H9 avian influenza virus.
Chen HT, Zhang J, Sun DH, Ma LN, Liu XT, Cai XP, Liu YS. - Key Laboratory of Animal Virology of Ministry of Agriculture, State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China.
Reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a unique gene amplification method that can be completed within 45min at 63 degrees C.
In this study, RT-LAMP was used to develop a rapid and sensitive laboratory diagnostic system for the H9 subtype of avian influenza virus (AIV).
The experiment results from the reference strains demonstrated that the established RT-LAMP sensitivity was 10-fold higher than that of RT-PCR, with the detection limit of 10 copies per reaction, and no cross-reactivity was observed from the samples of other related viruses including H5N1, H3N2 subtype of AIV and Newcastle disease virus.
Furthermore, a total of 112 clinical samples were tested by RT-LAMP, RT-PCR, and virus isolation, respectively.
All of the 85 positive specimens identified by virus isolation were also positive by RT-LAMP, while 7 of these samples were missed by RT-PCR.
These results suggest that the present RT-LAMP system may provide a new avenue for the recognition of H9 subtype virus, and may be employed to screen for potential carriers in wild and domestic birds.
PMID: 18572258 [PubMed - as supplied by publisher]
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(1.11): MMWR Morb Mortal Wkly Rep. 2008 Jun 20;57(24):653-7.
Influenza vaccination coverage among persons with asthma--United States, 2005-06 influenza season.
Centers for Disease Control and Prevention (CDC).
During 2006, approximately 6.8 million (9.3%) U.S. children and 16.1 million (7.3%) U.S. adults were reported to have asthma.
Since 1964, the Advisory Committee on Immunization Practices (ACIP) has recommended influenza vaccination of all persons with asthma because of the higher risk for medical complications from influenza for those persons.
Influenza vaccination coverage of persons with asthma varies by age group and remains below Healthy People 2010 targets of 60% coverage of persons aged 18--64 years with high-risk conditions (14-29 c) and 90% of all persons aged > or =65 years (14-29 a).
Influenza vaccination rates of children and older adults with asthma have not been well studied.
Using 2006 National Health Interview Survey (NHIS) data, this report provides the first examination of influenza vaccination rates and related factors across a national sample of persons with asthma aged > or =2 years.
The results indicated that 36.2% received influenza vaccination during the 2005--06 influenza season.
Vaccination rates remained below target levels among all subgroups examined, including those reporting the greatest number of health-care visits in the past 12 months.
The results of this study indicate that influenza vaccination coverage of all persons with asthma can be improved by increasing access to health care and using opportunities for vaccination during health-care visits.
PMID: 18566564 [PubMed - indexed for MEDLINE]
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(1.12): Vaccine. 2008 Jun 6. [Epub ahead of print]
Coverage and predictors of influenza vaccination among adults living in a large metropolitan area in Spain: A comparison between the immigrant and indigenous populations.
Jim?nez-Garc?a R, Hern?ndez-Barrera V, Carrasco-Garrido P, de Andres AL, Esteban Y Pe?a MM, de Miguel AG. - Preventive Medicine and Public Health Teaching and Research Unit, Health Sciences Faculty, Rey Juan Carlos University, Avda de Atenas s/n, Alcorc?n 28402 Madrid, Spain.
This study sought to evaluate influenza vaccination coverage in Madrid (Spain).
Coverages were estimated for vaccine target groups and special attention was placed on the immigrant population.
Individual data from 7341 adults included in the Madrid City Health Survey conducted in 2005 was used.
Overall influenza vaccination coverage was 24%.
Compliance with age-based influenza vaccine guidelines (>/=65 years) was 63.9%, among those <65 years who had an associated chronic condition, it was 37.9% and 24.1% among HCWs.
Immigrants accounted for 12.4% of the sample.
Overall crude coverage was significantly lower among immigrants than among the indigenous population (11.2% vs. 25.9%), but once the multivariate analysis had been performed, the association became non-significant.
In conclusion, it must be said that all the available evidence indicates an inadequate level of influenza vaccination coverage among HCWs and high-risk subjects <65 years.
On the other hand, coverages among subjects aged >/=65 years are acceptable and there is no observable difference in vaccine use between immigrants and indigenous subjects.
Strategies that have demonstrated their effectiveness in enhancing vaccination coverages should be applied in Madrid.
PMID: 18579263 [PubMed - as supplied by publisher]
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(1.13): Vaccine. 2008 Jun 21. [Epub ahead of print]
School-based influenza immunization.
Hull HF, Frauendienst RS, Gundersen ML, Monsen SM, Fishbein DB. - HF Hull and Associates, 1140 St. Dennis Ct., Saint Paul, MN 55116, United States.
Annual influenza vaccination of schoolchildren will protect individual vaccines and, with high coverage, may protect entire communities.
Because schoolchildren are more difficult to reach than preschoolers, school-based immunization programs may be needed to reach a high percentage of children.
We offered free live, attenuated influenza vaccine to all healthy schoolchildren (K-12) in three Minnesota counties.
Counties vaccinated from 33% to 58% of students. Overall, 41% of enrolled children were vaccinated.
Elementary students were vaccinated at higher rates than older students.
Administrative costs averaged $9.78 per dose delivered. School-based immunization programs offer the potential to achieve higher vaccination coverage of schoolchildren at modest cost.
PMID: 18577411 [PubMed - as supplied by publisher]
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(1.14): Vaccine. 2008 Jun 20. [Epub ahead of print]
Ecological fallacy and scepticism about influenza vaccine efficacy in Japan: The Maebashi Study.
Hirota Y. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
In 1979, Maebashi City discontinued influenza mass vaccination immediately after a case of vaccine-related convulsion occurred.
A research group of the Maebashi City Medical Association studied the effects of mass vaccination on influenza activity in two cities without mass vaccination programs and three cities with mass vaccination programs (Maebashi Study).
Due to possible issues of validity arising from the non-randomized design of the study, the authors of the Maebashi Study reserved discussion on the vaccine efficacy that they calculated from the attack rates among the non-vaccinees and vaccinees.
Instead, they compared the overall attack rates in Maebashi and among the twice-vaccinees in the cities with mass vaccination programs.
The authors limited their discussion to the fact that influenza activity in Maebashi was not materially different from that in cities with mass vaccination programs.
Anti-vaccination activists misconstrued this to mean that the absence of a correlation between attack rate and vaccine coverage implies that influenza vaccine has no efficacy.
This is a good example of the "ecological fallacy", which refers to the fact that a relationship between two variables at the population level does not necessarily imply the same relationship at an individual level.
PMID: 18573298 [PubMed - as supplied by publisher]
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(1.15): Vaccine. 2008 Jun 20. [Epub ahead of print]
The effect of misclassification on evaluating the effectiveness of influenza vaccines.
Ozasa K. - Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medicine, Japan.
Misclassification is a measurement error and can be considered a type of information bias.
Misclassification can occur at both exposure and outcome levels.
Nondifferential misclassification causes only a dilution effect leading to underestimation, whereas differential misclassification can have more complicated and serious consequences.
To avoid nondifferential diagnosis misclassification, it is necessary to use highly specific diagnostic examinations or criteria such as virus detection to exclude 'false positive' cases, and to limit the observation period to an intensive epidemic period if using less specific diagnostic criteria such as symptoms of influenza-like illness (ILI) or absence from school or workplace.
To avoid differential diagnosis misclassification, vaccinated and unvaccinated groups must be equally scrutinized, and such scrutiny is more important than the specificity of diagnosis.
So, passive findings from patients with influenza at clinics can cause complicated differential misclassification despite use of highly specific diagnostic procedures because vaccinated and unvaccinated patients may participate differently.
Also important is standardization of diagnostic procedure that vaccination anamnesis does not influence diagnosis of influenza, or examination of the influence.
Exposure misclassification would mainly underestimate vaccine effectiveness in most situations.
Consequently, misclassification of diagnosis, especially differential misclassification, affects evaluation of influenza vaccine effectiveness.
PMID: 18573297 [PubMed - as supplied by publisher]
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(1.16): Vaccine. 2008 Jun 20. [Epub ahead of print]
Influenza vaccine effectiveness among elderly persons living in the community during the 2003-2004 season.
Hara M, Sakamoto T, Tanaka K. - Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
To examine the effectiveness of influenza vaccine among community-dwelling elderly (65-79 years old), we conducted a population-based cohort study during the 2003-2004 influenza season.
A total of 4787 elderly individuals were interviewed regarding acute febrile illness, hospital visits, hospitalization and death by telephone every month.
The vaccination status and physician-diagnosed clinical influenza (hereinafter referred as clinical influenza) were determined based on data obtained from the city office and hospitals, respectively.
After adjusting for confounders, the odds ratio (OR) of vaccination for influenza-like illness (ILI) with high-fever, which was defined as an acute febrile illness (>/=38.5 degrees C) during the epidemic period, was 0.38 (95% confidence interval [CI], 0.17-0.85) and the OR for clinical influenza was 0.76 (95%CI, 0.28-2.06).
Due to the inadequate sample size, ORs for preventing hospitalization for influenza or pneumonia (OR, 0.37; 95%CI, 0.09-1.47) and death (OR, 3.68; 95%CI, 0.75-18.12) were not conclusive.
These results suggested that vaccination was therefore effective for elderly persons living in the community.
PMID: 18573296 [PubMed - as supplied by publisher]
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(1.17): Vaccine. 2008 Jun 20. [Epub ahead of print]
Confounding in evaluating the effectiveness of influenza vaccine.
Mori M, Oura A, Ohnishi H, Washio M. - Department of Public Health, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan.
Confounding is a kind of bias which occurs in a research.
Confounding is less frequent in randomized controlled trials (RCT) for evaluation of influenza vaccines.
However, there are obstacles or difficulties in conducting RCT for evaluation of influenza vaccines, particularly, in the elderly people.
Therefore, a retrospective or prospective cohort study has been primarily performed to evaluate effectiveness of influenza vaccine in elderly people.
Confounding by indication or other confounding exist in most observational studies.
Accordingly, at the stage of designing or analyzing a study, confounding should be controlled with a restriction, matching, stratified or multivariate analysis technique.
PMID: 18573295 [PubMed - as supplied by publisher]
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(1.18): Vaccine. 2008 Jun 20. [Epub ahead of print]
Influenza vaccine effectiveness and confounding factors among young children.
Fujieda M, Maeda A, Kondo K, Fukushima W, Ohfuji S, Kaji M, Hirota Y. - Department of Public Health, Osaka City University Faculty of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan.
This study, done during the 2002-2003 season among children <6 years of age to investigate influenza vaccine effectiveness and confounding factors, involved 2913 children (1512 vaccinees, 1401 non-vaccinees) recruited from 54 paediatric clinics.
Between December 2002 and April 2003, parents reported their children's maximum body temperatures weekly. Influenza-like illness (ILI) was defined as an acute febrile illness (>/=38.0 degrees C) during the peak epidemic period.
Adjusted odds ratios (ORs) for ILI were obtained using a logistic regression model.
In analysis for total subjects, the ORs were significantly decreased for vaccinees (OR: 0.76, 95% CI: 0.66-0.88) and significantly increased for younger age groups, including children aged 2.0-3.9 years (1.42, 1.18-1.72) and those <2.0 years (2.02,1.61-2.54), compared to those between 4.0 and 5.9 years.
ORs were significantly increased for children who visited a physician within the last 6 months for a cold (1.27, 1.08-1.50), attended preschool (1.72, 1.45-2.04), and had >/=3 siblings (1.42, 1.15-1.74).
These confounding factors are suggested to be considered in estimating vaccine effectiveness among young children.
In subgroup analysis by age groups, significantly decreased ORs were seen in 2.0-3.9-year-old (0.59, 0.47-0.74) and 4.0-5.9-year-old (0.75, 0.58-0.98) vaccinees; no significant vaccine effectiveness was detected for those <2.0 years (1.07, 0.80-1.44).
Thus, among very young children vaccine effectiveness could not be demonstrated.
PMID: 18573294 [PubMed - as supplied by publisher]
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(1.19): Vaccine. 2008 Jun 20. [Epub ahead of print]
History of influenza vaccination programs in Japan: Prologue to the symposium.
Hirota Y, Kaji M. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
In 1976, influenza mass vaccination among schoolchildren was started under the Preventive Vaccination Law, which was intended to control epidemics in the community.
However, in the late 1980s, questions about this policy and vaccine efficacy arose, and a campaign against vaccination began.
In 1994, influenza was excluded from the target diseases list in the Preventive Vaccination Law, without considering the immunization policy with respect to the common indications in high-risk groups.
In 2001, the Law was again amended, specifying target groups, such as the elderly aged 65 or over, for influenza vaccination.
In the 2005-2006 season, vaccine coverage among the elderly reached 52%.
This shows that the need for vaccination has gradually become understood.
However, the anti-vaccination campaign, which claims that the influenza vaccine has no efficacy, is still active.
Vaccine efficacy studies that were not properly conducted are also being reported. In 2002, the Ministry of Health, Labor, and Welfare organized a research group on vaccine efficacy consisting of epidemiologists.
The present symposium, as part of the 9th Annual Meeting of the Japanese Society for Vaccinology in 2005, was planned to further introduce epidemiological concepts useful in studying influenza vaccine efficacy.
PMID: 18573292 [PubMed - as supplied by publisher]
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(1.20): Vaccine. 2008 Jun 20. [Epub ahead of print]
Essential tools for assessing influenza vaccine efficacy in improperly conducted studies: A Japanese perspective.
Hirota Y, Fukushima W, Fujieda M, Ohfuji S, Maeda A. - Department of Public Health, Osaka City University Faculty of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
The fundamental issue in assessing influenza vaccine efficacy is to observe all study subjects with equal intensity throughout the surveillance period.
The case definition can be adopted within the scope of the budget and the logistics of the study; however, there is no doubt that culture-proven influenza is currently the best outcome index.
More pronounced vaccine efficacy can be detected if stricter case definition criteria are applied and/or if observations are confined to the peak epidemic period.
Patients identified through passive case-finding in clinics do not properly represent all influenza cases that occur in the study subjects.
Almost all non-randomized studies which have so far been conducted by Japanese clinicians do not take confounders into consideration.
Even though laboratory-confirmed influenza is identified, vaccine efficacy should primarily be estimated based on the presence of any influenzal illness, since efficacy calculated by virus type or subtype often results in loss of statistical power.
The results from post hoc subgroup analysis may not offer a solid base for assessing vaccine efficacy and should be cautiously interpreted.
PMID: 18573291 [PubMed - as supplied by publisher]
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(1.21): Vaccine. 2008 Jun 20. [Epub ahead of print]
Ecological studies on influenza infection and the effect of vaccination: Their advantages and limitations.
Washio M, Oura A, Mori M. - Department of Public Health, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo 060-8556, Japan; Department of Community Health and Clinical Epidemiology, St Mary's College, 422 Tsubuku-hon-machi, Kurume, Fukuoka 830-8558, Japan.
Ecological studies lack the ability to control for the effects of confounding factors.
The findings of a linear relationship between average exposure and disease frequency in ecological studies do not imply that such a linear relationship will be present at the individual levels.
This is known as the 'ecological fallacy'.
Despite these limitations, ecological studies may be the best approach to studying exposures that are easier to measure at the group rather than the individual level because most ecological studies make use of routinely collected data.
They are also useful for monitoring the effectiveness of population interventions such as vaccination programs, health education campaigns and mass screening programs.
Thus, ecological studies are useful epidemiologic tools for public health surveillance if we know their limitations and interpret their results carefully.
Ecological studies often help to generate hypotheses, although they rarely provide a strong test of a causal hypothesis.
PMID: 18573289 [PubMed - as supplied by publisher]
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(1.22): Virology. 2008 Aug 1;377(2):431-9.
Hsp90 inhibitors reduce influenza virus replication in cell culture.
Chase G, Deng T, Fodor E, Leung BW, Mayer D, Schwemmle M, Brownlee G. - Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
The viral RNA polymerase complex of influenza A virus consists of three subunits PB1, PB2 and PA.
Recently, the cellular chaperone Hsp90 was shown to play a role in nuclear import and assembly of the trimeric polymerase complex by binding to PB1 and PB2.
Here we show that Hsp90 inhibitors, geldanamycin or its derivative 17-AAG, delay the growth of influenza virus in cell culture resulting in a 1-2 log reduction in viral titre early in infection.
We suggest that this is caused by the reduced half-life of PB1 and PB2 and inhibition of nuclear import of PB1 and PA which lead to reduction in viral RNP assembly.
Hsp90 inhibitors may represent a new class of antiviral compounds against influenza viruses.
PMID: 18570972 [PubMed - in process]
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