Research Article's Abstracts - July 4 2009 Issue

In this post: Research Article's Abstracts.

Contents:

1. Replication and pathogenesis associated with H5N1, H5N2, and H5N3 low-pathogenic avian influenza virus infection in chickens and ducks.
2. Safety and Immunogenicity of Multiple and Higher Doses of an Inactivated Influenza A/H5N1 Vaccine.
3. "Prepandemic" immunization for novel influenza viruses, "swine flu" vaccine, guillain-barré syndrome, and the detection of rare severe adverse events.
4. Rapid-Test Sensitivity for Novel Swine-Origin Influenza A (H1N1) Virus in Humans.
5. Severe Respiratory Disease Concurrent with the Circulation of H1N1 Influenza.
6. Perspective -- Emergence of Influenza A (H1N1) Viruses.
7. Pneumonia and Respiratory Failure from Swine-Origin Influenza A (H1N1) in Mexico.
8. Spread of a Novel Influenza A (H1N1) Virus via Global Airline Transportation.
9. The Persistent Legacy of the 1918 Influenza Virus.
10. Live vaccination with an H5-hemagglutinin-expressing infectious laryngotracheitis virus recombinant protects chickens against different highly pathogenic avian influenza viruses of the H5 subtype.
11. New influenza A(H1N1) vaccine: How ready are we for large-scale production?
12. Plant-produced potato virus X chimeric particles displaying an influenza virus-derived peptide activate specific CD8+ T cells in mice.
13. Influenza control in the 21st century: Optimizing protection of older adults.
14. Use of MDCK cells for production of live attenuated influenza vaccine.
15. A prime-boost vaccination of mice with heterologous H5N1 strains.
16. TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity.
17. Effects of oseltamivir on influenza-related complications in children with chronic medical conditions.
18. Impact of electronic health record-based alerts on influenza vaccination for children with asthma.
19. Influenza virus infection and the risk of serious bacterial infections in young febrile infants.
20. Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice.

See original abstract following the link at the end of the post. EDITED.
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1: Arch Virol. 2009 Jul 3. [Epub ahead of print]

Replication and pathogenesis associated with H5N1, H5N2, and H5N3 low-pathogenic avian influenza virus infection in chickens and ducks.

Mundt E, Gay L, Jones L, Saavedra G, Tompkins SM, Tripp RA.
Department of Population Health, Poultry Diagnostic and Research Center, College of Veterinary Medicine, University of Georgia, Athens, 30602, GA, USA, emundt@uga.edu.


A comparative study examining replication and disease pathogenesis associated with low-pathogenic H5N1, H5N2, or H5N3 avian influenza virus (AIV) infection of chickens and ducks was performed. The replication and pathogenesis of highly pathogenic AIV (HPAIV) has received substantial attention; however, the behavior of low-pathogenic AIVs, which serve as precursors to HPAIVs, has received less attention. Thus, chickens or ducks were inoculated with an isolate from a wild bird [A/Mute Swan/MI/451072/06 (H5N1)] or isolates from chickens [A/Ck/PA/13609/93 (H5N2), A/Ck/TX/167280-4/02 (H5N3)], and virus replication, induction of a serological response, and disease pathogenesis were investigated, and the hemagglutinin and neuraminidase (NA) gene sequences of the isolates were determined. Virus isolated from tracheal and cloacal swabs showed that H5N1 replicated better in ducks, whereas H5N2 and H5N3 replicated better in chickens. Comparison of the NA gene sequences showed that chicken-adapted H5N2 and H5N3 isolates both have a deletion of 20 amino acids in the NA stalk region, which was absent in the H5N1 isolate. Histopathological examination of numerous organs showed that H5N2 and H5N3 isolates caused lesions in chickens in a variety of organs, but to a greater extent in the respiratory and intestinal tracts, whereas H5N1 lesions in ducks were observed mainly in the respiratory tract. This study suggests that the H5N1, H5N2, and H5N3 infections occurred at distinct sites in chicken and ducks, and that comparative studies in different model species are needed to better understand the factors influencing the evolution of these viruses.

PMID: 19575275 [PubMed - as supplied by publisher]
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2: J Infect Dis. 2009 Jul 1. [Epub ahead of print]

Safety and Immunogenicity of Multiple and Higher Doses of an Inactivated Influenza A/H5N1 Vaccine.

Beigel JH, Voell J, Huang CY, Burbelo PD, Lane HC.
National Institute of Allergy and Infectious Diseases and 2National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.


Background.
H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin.

Methods.
We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 mug of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered approximately 28 days apart.

Results.
No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-mug, 120-mug, and 180-mug cohorts were compared. When the cohorts were analyzed together to determine the effect of additional vaccinations, the GMTs of hemagglutination inhibition antibody after the first, second, third, and fourth vaccinations were 1:15.7, 1:22.2, 1:36.0, and 1:32.0, respectively (first vaccination vs. baseline, [Formula: see text]; second vs. first vaccination, [Formula: see text]; and third vs. second vaccination, [Formula: see text]). The microneutralization GMTs after the first, second, third, and fourth vaccinations were 1:17.5, 1:33.1, 1:55.7, and 1:68.4, respectively ([Formula: see text] for all comparisons).

Conclusion.
The results of our study suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses. There was no benefit to increasing the dose of the vaccine.

Trial registration. Clinical Trials.gov identifier: NCT00383071 .
PMID: 19569973 [PubMed - as supplied by publisher]
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3: J Infect Dis. 2009 Aug 1;200(3):321-8.

"Prepandemic" immunization for novel influenza viruses, "swine flu" vaccine, guillain-barré syndrome, and the detection of rare severe adverse events.

Evans D, Cauchemez S, Hayden FG.
The Wellcome Trust and 2MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Diseases Epidemiology, Imperial College London, London, United Kingdom; and 3The Wellcome Trust, London and University of Virginia, Charlottesville, Virginia.


The availability of immunogenic, licensed H5N1 vaccines and the anticipated development of vaccines against "swine" influenza A(H1N1) have stimulated debate about the possible use of these vaccines for protection of those exposed to potential pandemic influenza viruses and for immunization or "priming" of populations in the so-called "prepandemic" (interpandemic) era. However, the safety of such vaccines is a critical issue in policy development for wide-scale application of vaccines in the interpandemic period. For example, wide-scale interpandemic use of H5N1 vaccines could lead to millions of persons receiving vaccines of uncertain efficacy potentially associated with rare severe adverse events and against a virus that may not cause a pandemic. Here, we first review aspects of the 1976 National Influenza Immunization Programme against "swine flu" and its well-documented association with Guillain-Barré syndrome as a case study illustration of a suspected vaccine-associated severe adverse event in a mass interpandemic immunization setting. This case study is especially timely, given the recent spread of a novel influenza A(H1N1) virus in humans in Mexico and beyond. Following this, we examine available safety data from clinical trials of H5N1 vaccines and briefly discuss how vaccine safety could be monitored in a postmarketing surveillance setting.

PMID: 19563262 [PubMed - in process]
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4: N Engl J Med. 2009 Jun 29. [Epub ahead of print]

Rapid-Test Sensitivity for Novel Swine-Origin Influenza A (H1N1) Virus in Humans.

Faix DJ, Sherman SS, Waterman SH.
Naval Health Research Center, San Diego, CA 92106, dennis.faix@med.navy.mil, Naval Medical Center, San Diego, CA 92134, Centers for Disease Control and Prevention, San Diego, CA 92138.

PMID: 19564634 [PubMed - as supplied by publisher]
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5: N Engl J Med. 2009 Jun 29. [Epub ahead of print]

Severe Respiratory Disease Concurrent with the Circulation of H1N1 Influenza.

Chowell G, Bertozzi SM, Colchero MA, Lopez-Gatell H, Alpuche-Aranda C, Hernandez M, Miller MA.
From the Division of Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, MD (G.C., M.A.M.); the Mathematical, Computational and Modeling Sciences Center, School of Human Evolution and Social Change, Arizona State University, Tempe (G.C.); the National Institute of Public Health, Center for Evaluation Research and Surveys, Cuernavaca, Mexico (S.M.B., M.A.C.); the University of California, Berkeley (S.M.B.); and the Mexican Ministry of Health, Mexico City (H.L.-G., C.A.-A., M.H.).


This article (10.1056/NEJMoa0904023) was published on June 29, 2009, at NEJM.org.

BACKGROUND:
In the spring of 2009, an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza A (H1N1) virus (S-OIV), widely known as swine flu, in Mexico. Influenza A (H1N1) subtype viruses have rarely predominated since the 1957 pandemic. The analysis of epidemic pneumonia in the absence of routine diagnostic tests can provide information about risk factors for severe disease from this virus and prospects for its control.

METHODS:
From March 24 to April 29, 2009, a total of 2155 cases of severe pneumonia, involving 821 hospitalizations and 100 deaths, were reported to the Mexican Ministry of Health. During this period, of the 8817 nasopharyngeal specimens that were submitted to the National Epidemiological Reference Laboratory, 2582 were positive for S-OIV. We compared the age distribution of patients who were reported to have severe pneumonia with that during recent influenza epidemics to document an age shift in rates of death and illness.

RESULTS:
During the study period, 87% of deaths and 71% of cases of severe pneumonia involved patients between the ages of 5 and 59 years, as compared with average rates of 17% and 32%, respectively, in that age group during the referent periods. Features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population.

CONCLUSIONS:
During the early phase of this influenza pandemic, there was a sudden increase in the rate of severe pneumonia and a shift in the age distribution of patients with such illness, which was reminiscent of past pandemics and suggested relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic. If resources or vaccine supplies are limited, these findings suggest a rationale for focusing prevention efforts on younger populations.

Copyright 2009 Massachusetts Medical Society.
PMID: 19564633 [PubMed - as supplied by publishe
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6: N Engl J Med. 2009 Jun 29. [Epub ahead of print]

Perspective -- Emergence of Influenza A (H1N1) Viruses.

Zimmer SM, Burke DS.
From the School of Medicine (S.M.Z.) and the Graduate School of Public Health (D.S.B.), University of Pittsburgh, Pittsburgh.


This article (10.1056/NEJMra0904322) was published on June 29, 2009, at NEJM.org.

PMID: 19564632 [PubMed - as supplied by publisher]
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7: N Engl J Med. 2009 Jun 29. [Epub ahead of print]

Pneumonia and Respiratory Failure from Swine-Origin Influenza A (H1N1) in Mexico.

Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, Hernandez M, Quiñones-Falconi F, Bautista E, Ramirez-Venegas A, Rojas-Serrano J, Ormsby CE, Corrales A, Higuera A, Mondragon E, Cordova-Villalobos JA;
the INER Working Group on Influenza. From the National Institute of Respiratory Diseases (INER) (R.P.-P., D.R.-Z., F.Q.-F., E.B., A.R.-V., J.R.-S., C.E.O., A.C., A.H., E.M.), Biologicals and Reactives of Mexico (BIRMEX) (S.P.L.), and the Secretariat of Health (M.H., J.A.C.-V.) - all in Mexico City.


This article (10.1056/NEJMoa0904252) was published on June 29, 2009, at NEJM.org.

BACKGROUND:
In late March 2009, an outbreak of a respiratory illness later proved to be caused by novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. We describe the clinical and epidemiologic characteristics of persons hospitalized for pneumonia at the national tertiary hospital for respiratory illnesses in Mexico City who had laboratory-confirmed S-OIV infection, also known as swine flu.

METHODS:
We used retrospective medical chart reviews to collect data on the hospitalized patients. S-OIV infection was confirmed in specimens with the use of a real-time reverse-transcriptase-polymerase-chain-reaction assay.

RESULTS:
From March 24 through April 24, 2009, a total of 18 cases of pneumonia and confirmed S-OIV infection were identified among 98 patients hospitalized for acute respiratory illness at the National Institute of Respiratory Diseases in Mexico City. More than half of the 18 case patients were between 13 and 47 years of age, and only 8 had preexisting medical conditions. For 16 of the 18 patients, this was the first hospitalization for their illness; the other 2 patients were referred from other hospitals. All patients had fever, cough, dyspnea or respiratory distress, increased serum lactate dehydrogenase levels, and bilateral patchy pneumonia. Other common findings were an increased creatine kinase level (in 62% of patients) and lymphopenia (in 61%). Twelve patients required mechanical ventilation, and seven died. Within 7 days after contact with the initial case patients, a mild or moderate influenza-like illness developed in 22 health care workers; they were treated with oseltamivir, and none were hospitalized.

CONCLUSIONS:
S-OIV infection can cause severe illness, the acute respiratory distress syndrome, and death in previously healthy persons who are young to middle-aged. None of the secondary infections among health care workers were severe.

Copyright 2009 Massachusetts Medical Society.
PMID: 19564631 [PubMed - as supplied by publisher]
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8: N Engl J Med. 2009 Jun 29. [Epub ahead of print]

Spread of a Novel Influenza A (H1N1) Virus via Global Airline Transportation.

Khan K, Arino J, Hu W, Raposo P, Sears J, Calderon F, Heidebrecht C, Macdonald M, Liauw J, Chan A, Gardam M. St. Michael's Hospital, Toronto, ON M5B 1W8, Canada, khank@smh.toronto.on.ca, University of Manitoba, Winnipeg, MB R3T 2N2, Canada, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada, Ryerson University, Toronto, ON M5B 2K3, Canada, Queen's University, Kingston, ON K7L 3N6, Canada, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada, University Health Network, Toronto, ON M5G 2C4, Canada.

PMID: 19564630 [PubMed - as supplied by publisher]
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9: N Engl J Med. 2009 Jun 29. [Epub ahead of print]

The Persistent Legacy of the 1918 Influenza Virus.

Morens DM, Taubenberger JK, Fauci AS.
From the National Institute of Allergy and Infectious Diseases, Bethesda, MD.


This article (10.1056/NEJMp0904819) was published on June 29, 2009, at NEJM.org.
PMID: 19564629 [PubMed - as supplied by publisher]
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10: Vaccine. 2009 Jun 29. [Epub ahead of print]

Live vaccination with an H5-hemagglutinin-expressing infectious laryngotracheitis virus recombinant protects chickens against different highly pathogenic avian influenza viruses of the H5 subtype.

Pavlova SP, Veits J, Mettenleiter TC, Fuchs W.
Institute of Molecular Biology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Südufer 10, 17493 Greifswald - Insel Riems, Germany.


Recently, we described an infectious laryngotracheitis virus (ILTV, gallid herpesvirus 1) recombinant, which had been attenuated by deletion of the viral dUTPase gene UL50, and abundantly expressed the hemagglutinin (HA) gene of a H5N1 type highly pathogenic avian influenza virus (HPAIV) of Vietnamese origin. In the present study, efficacy of this vectored vaccine (ILTV-DeltaUL50IH5V) against different H5 HPAIV was evaluated in 6-week-old chickens. After a single ocular immunization all animals developed HA-specific antibodies, and were protected against lethal infection not only with the homologous HPAIV isolate A/duck/Vietnam/TG24-01/05 (H5N1, clade 1, hemagglutinin amino acid sequence identity 100%), but also with heterologous HPAIV A/swan/Germany/R65/2006 (H5N1, clade 2.2, identity 96.1%) or HPAIV A/chicken/Italy/8/98 (H5N2, identity 93.8%). No symptoms of disease were observed after challenge with the H5N1 viruses, and only 20% of H5N2 challenged animals developed minimal clinical signs. Real-time RT-PCR analyses of oropharyngeal swabs revealed limited challenge virus replication, but the almost complete absence of HPAIV RNA from cloacal swabs indicated that no generalized infections occurred. Thus, unlike several previous vectors, ILTV-DeltaUL50IH5V was able to protect chickens against different HPAIV isolates of the H5 subtype. Vaccination with HA-expressing ILTV also allowed differentiation of immunized from AIV-infected animals by serological tests for antibodies against influenza virus nucleoprotein.

PMID: 19573638 [PubMed - as supplied by publisher]
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11: Vaccine. 2009 Jun 26. [Epub ahead of print]

New influenza A(H1N1) vaccine: How ready are we for large-scale production?

Collin N, de Radiguès X, Kieny MP;
the World Health Organization H1N1 Vaccine Task Force. World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland.


The threat of an influenza pandemic has emerged once again, this time in the form of a new strain of influenza A(H1N1) virus. Fortunately, the international community, including influenza vaccine manufacturers, has been increasing its preparedness for such an event, triggered by the need to stem the spread of the highly pathogenic avian influenza A(H5N1) virus over recent years. Today, the development of a pandemic influenza vaccine in the fastest possible time is a global priority. However, two major issues need to be taken into consideration: how long will it take to produce sufficient pandemic vaccine doses to immunize the global population at risk, including poor populations that have no resources to purchase the vaccine; and how will pandemic vaccine production affect availability of trivalent vaccine for the forthcoming 2009-2010 influenza seasons. To address these questions, WHO carried out a survey in May 2009 among influenza vaccine manufacturers on their planned seasonal and pandemic production with a view to developing recommendations on the distribution and use of influenza vaccine in the case of a pandemic.

PMID: 19563891 [PubMed - as supplied by publishe
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12: Vaccine. 2009 Jun 26. [Epub ahead of print]

Plant-produced potato virus X chimeric particles displaying an influenza virus-derived peptide activate specific CD8+ T cells in mice.

Lico C, Mancini C, Italiani P, Betti C, Boraschi D, Benvenuto E, Baschieri S.
ENEA C.R. Casaccia, Sezione Genetica e Genomica Vegetale, Via Anguillarese 301, 000123 Roma, Italy.


Plant viruses can be genetically modified to produce chimeric virus particles (CVPs) carrying heterologous peptides. The efficacy of plant-produced CVPs in inducing antibody responses specific to the displayed peptide has been extensively demonstrated. To determine if plants can be used to produce CVPs able to activate peptide-specific major histocompatibility complex (MHC) class I-restricted CD8+ T cells, potato virus X (PVX) has been engineered to display the H-2D(b)-restricted epitope ASNENMETM of influenza A virus nucleoprotein (NP). Engineering criteria were devised to comply not only with plant virus genetic stability and infectivity but also with antigen processing rules. The immunological properties of different doses of endotoxin-free preparations of CVPs or unmodified PVX have been evaluated by s.c. immunizing C57BL/6J mice and testing at different time intervals splenocyte responses by interferon gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay. These experiments demonstrated that CVPs activate ASNENMTEM-specific CD8+ T cells. Remarkably, the best response was achieved without adjuvant co-delivery. These results represent the proof of concept that well-designed plant virus carriers of epitopes produced in plant can reasonably be used into peptide vaccine formulations aimed to activate cell-mediated immune responses.

PMID: 19563889 [PubMed - as supplied by publisher]
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13: Vaccine. 2009 Jun 23. [Epub ahead of print]

Influenza control in the 21st century: Optimizing protection of older adults.

Monto AS, Ansaldi F, Aspinall R, McElhaney JE, Montaño LF, Nichol KL, Puig-Barberà J, Schmitt J, Stephenson I.
University of Michigan School of Public Health, 109 Observatory Street, Ann Arbor, MI 48109-2029, USA.


Older adults (>/=65 years of age) are particularly vulnerable to influenza illness. This is due to a waning immune system that reduces their ability to respond to infection, which leads to more severe cases of disease. The majority ( approximately 90%) of influenza-related deaths occur in older adults and, in addition, catastrophic disability resulting from influenza-related hospitalization represents a significant burden in this vulnerable population. Current influenza vaccines provide benefits for older adults against influenza; however, vaccine effectiveness is lower than in younger adults. In addition, antigenic drift is also a concern, as it can impact on vaccine effectiveness due to a mismatch between the vaccine virus strain and the circulating virus strain. As such, vaccines that offer higher and broader protection against both homologous and heterologous virus strains are desirable. Approaches currently available in some countries to meet this medical need in older adults may include the use of adjuvanted vaccines. Future strategies under evaluation include the use of high-dose vaccines; novel or enhanced adjuvantation of current vaccines; use of live attenuated vaccines in combination with current vaccines; DNA vaccines; recombinant vaccines; as well as the use of different modes of delivery and alternative antigens. However, to truly evaluate the benefits that these solutions offer, further efficacy and effectiveness studies, and better correlates of protection, including a precise measurement of the T cell responses that are markers for protection, are needed. While it is clear that vaccines with greater immunogenicity are required for older adults, and that adjuvanted vaccines may offer a short-term solution, further research is required to exploit the many other new technologies.

PMID: 19559118 [PubMed - as supplied by publishe
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14: Vaccine. 2009 Jun 24. [Epub ahead of print]

Use of MDCK cells for production of live attenuated influenza vaccine.

Liu J, Shi X, Schwartz R, Kemble G. MedImmune, LLC., 3055 Patrick Henry Drive, Santa Clara, CA 95054, United States.


To develop a cell-based live attenuated influenza vaccine (LAIV) manufacturing process, several different cell lines were evaluated by comparing the titer of viruses after infection with LAIV strains. While several cell lines have been reported to support influenza virus replication, the degree of replication and the ability to support replication of LAIV strains have not been systematically examined. MDCK cells, which have been considered as potential substrates for influenza vaccine production were evaluated in addition to Vero, MRC-5, WI-38 and FRhL cells. MRC-5, WI-38 and FRhL cells produced low to moderate titers of virus with titers equal or below 5.0log(10) TCID(50)/mL. Both Vero and MDCK cells could support a higher level of virus replication for certain strains, however, Vero cells only produced high titers when grown in the presence of serum. MDCK cells supported high levels of vaccine virus production for multiple different LAIV subtypes in both serum containing and serum-free media. These results suggest that MDCK cell-based production can be used as an alternative production platform to the currently used egg-based LAIV production system.

PMID: 19559113 [PubMed - as supplied by publisher]
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15: Vaccine. 2009 May 18;27(23):3121-5.

A prime-boost vaccination of mice with heterologous H5N1 strains.

Ikeno D, Kimachi K, Kudo Y, Goto S, Itamura S, Odagiri T, Tashiro M, Kino Y.
The Chemo-Sero-Therapeutic Research Institute, Kikuchi Research Center, Kawabe Kyokushi, Kikuchi, Kumamoto, Japan. ikeno-da@kaketsuken.or.jp


We evaluated the priming effect of an H5N1 pandemic vaccine in a mouse model to investigate strategies for influenza pandemic vaccination. For priming, an alum-adjuvanted inactivated whole H5N1 vaccine (NIBRG-14, clade 1) was used. As booster vaccines, several formulations of Indo05/05/2005(H5N1)PR8-IBCDC-RG2 vaccines (clades 2-1)were evaluated, including split, whole, alum-adjuvanted split, and alum-adjuvanted whole vaccines. Any type of booster vaccination elicited a significant HI antibody response despite the difference in antigenicity between the priming and booster vaccines. The split vaccine elicited a much stronger booster response than the alum-adjuvanted whole vaccine. When the mice were primed with the H1N1 or H3N2 vaccines, this did not affect the booster response to the H5N1 vaccine. These results indicated that an alum-adjuvanted whole vaccine is able to confer immunological memory to haemagglutinin even if the primed and boosted vaccine strains are in different clades and, once vaccinated, a split vaccine is preferred to evoke recall responses.

PMID: 19514127 [PubMed - indexed for MEDLINE]
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16: Vaccine. 2009 May 18;27(23):3045-52. Epub 2009 Apr 3.

TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity.

Johnson TR, Rao S, Seder RA, Chen M, Graham BS.
Vaccine Research Center, Viral Pathogenesis Laboratory, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-3017, USA. teresaj@nih.gov


Agonists for TLR7, TLR8, and TLR9 have been shown to enhance vaccine immunogenicity. We evaluated the impact of TLR activation on RSV disease in a murine model by administering TLR7/8 and TLR9 agonists during FI-RSV immunization or RSV infection. CpG administered during immunization reduced disease following challenge as evidenced by decreased lung pathology, illness, and cytokines. In marked contrast, TLR7/8 agonist had little impact. To evaluate potential therapeutic use, TLR agonists were administered during primary infection. Although type 2 cytokine responses decreased and type 1 cytokines and MIP-1-alpha/beta increased, both TLR7/8 and TLR9 agonists increased clinical symptoms and pulmonary inflammation when administered during primary infection. Thus, TLR9-induced signaling during FI-RSV immunization reduced vaccine-enhanced disease whereas immunostimulatory properties of TLR agonists enhanced disease severity when used during RSV infection. Immunomodulation elicited by TLR9 agonist confirms the adjuvant potential of TLR agonists during RSV immunization. However, in contrast to work done with HIV-1 vaccines, the inability of TLR7/8 agonist to boost type 1 vaccine-induced RSV immunity demonstrates pathogen-TLR specificity. These data reveal that the timing of administration of immunomodulatory agents is critical. Furthermore, these data underscore that amplification of anti-viral immune responses may result in immunopathology rather than immune-mediated protection.

PMID: 19428918 [PubMed - indexed for MEDLINE]
PMCID: PMC2680782 [Available on 2010/05/18]
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17: Pediatrics. 2009 Jul;124(1):170-8.

Effects of oseltamivir on influenza-related complications in children with chronic medical conditions.

Piedra PA, Schulman KL, Blumentals WA.
Departments of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA. ppiedra@bcm.tmc.edu


OBJECTIVE:
This study investigated the influence of oseltamivir on influenza-related complications and hospitalizations for children and adolescents, 1 to 17 years of age, with chronic medical conditions or neurologic or neuromuscular disease.

METHODS:
In a retrospective study, outcomes for patients who were given oseltamivir within 1 day after influenza diagnosis were compared with those for patients who received no antiviral therapy. Anonymous data from MarketScan databases (Thomson Reuters, Cambridge, MA) were used to identify patients from 6 influenza seasons between 2000 and 2006. The study outcomes were frequencies of pneumonia, respiratory illnesses other than pneumonia, otitis media, and hospitalization.

RESULTS:
Oseltamivir was prescribed for 1634 patients according to the study criteria, and 3721 patients received no antiviral therapy for their influenza. After adjustment for demographic and medical history variables, oseltamivir was associated with significant reductions in the risks of respiratory illnesses other than pneumonia, otitis media and its complications, and all-cause hospitalization in the 14 days after influenza diagnosis. Analyses for 30 days after influenza diagnosis also showed significant risk reductions for respiratory illnesses other than pneumonia, otitis media and its complications, and all-cause hospitalization with oseltamivir.

CONCLUSION:
When it was prescribed at influenza diagnosis, oseltamivir was associated with reduced risks of influenza-related complications and hospitalizations for children and adolescents at high risk of influenza complications.

PMID: 19564297 [PubMed - in process]
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18: Pediatrics. 2009 Jul;124(1):159-69.

Comment in: Pediatrics. 2009 Jul;124(1):375-7.

Impact of electronic health record-based alerts on influenza vaccination for children with asthma.

Fiks AG, Hunter KF, Localio AR, Grundmeier RW, Bryant-Stephens T, Luberti AA, Bell LM, Alessandrini EA.
Pediatric Generalist Research Group, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. fiks@email.chop.edu


OBJECTIVE:
The goal was to assess the impact of influenza vaccine clinical alerts on missed opportunities for vaccination and on overall influenza immunization rates for children and adolescents with asthma.

METHODS:
A prospective, cluster-randomized trial of 20 primary care sites was conducted between October 1, 2006, and March 31, 2007. At intervention sites, electronic health record-based clinical alerts for influenza vaccine appeared at all office visits for children between 5 and 19 years of age with asthma who were due for vaccine. The proportion of captured immunization opportunities at visits and overall rates of complete vaccination for patients at intervention and control sites were compared with those for the previous year, after standardization for relevant covariates. The study had >80% power to detect an 8% difference in the change in rates between the study and baseline years at intervention versus control practices.

RESULTS:
A total of 23 418 visits and 11 919 children were included in the study year and 21 422 visits and 10 667 children in the previous year. The majority of children were male, 5 to 9 years of age, and privately insured. With standardization for selected covariates, captured vaccination opportunities increased from 14.4% to 18.6% at intervention sites and from 12.7% to 16.3% at control sites, a 0.3% greater improvement. Standardized influenza vaccination rates improved 3.4% more at intervention sites than at control sites. The 4 practices with the greatest increases in rates (>or=11%) were all in the intervention group. Vaccine receipt was more common among children who had been vaccinated previously, with increasing numbers of visits, with care early in the season, and at preventive versus acute care visits.

CONCLUSIONS:
Clinical alerts were associated with only modest improvements in influenza vaccination rates.

PMID: 19564296 [PubMed - in process]
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19: Pediatrics. 2009 Jul;124(1):30-9.

Influenza virus infection and the risk of serious bacterial infections in young febrile infants.

Krief WI, Levine DA, Platt SL, Macias CG, Dayan PS, Zorc JJ, Feffermann N, Kuppermann N;
Multicenter RSV-SBI Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Department of Pediatrics and Emergency Medicine, Schneider Children's Hospital/Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA. wkrief@NSHS.edu


OBJECTIVE:
We aimed to determine the risk of SBIs in febrile infants with influenza virus infections and compare this risk with that of febrile infants without influenza infections.

PATIENTS AND METHODS:
We conducted a multicenter, prospective, cross-sectional study during 3 consecutive influenza seasons. All febrile infants or=5 x 10(4) colony-forming units per mL or >or=10(4) colony-forming units per mL in association with a positive urinalysis. Bacteremia, bacterial meningitis, and bacterial enteritis were defined by growth of a known bacterial pathogen. SBI was defined as any of the 4 above-mentioned bacterial infections.

RESULTS:
During the 3-year study period, 1091 infants were enrolled. A total of 844 (77.4%) infants were tested for the influenza virus, of whom 123 (14.3%) tested positive. SBI status was determined in 809 (95.9%) of the 844 infants. Overall, 95 (11.7%) of the 809 infants tested for influenza virus had an SBI. Infants with influenza infections had a significantly lower prevalence of SBI (2.5%) and UTI (2.4%) when compared with infants who tested negative for the influenza virus. Although there were no cases of bacteremia, meningitis, or enteritis in the influenza-positive group, the differences between the 2 groups for these individual infections were not statistically significant.

CONCLUSIONS:
Febrile infants <or=60 days of age with influenza infections are at significantly lower risk of SBIs than febrile infants who are influenza-negative. Nevertheless, the rate of UTI remains appreciable in febrile, influenza-positive infants.

PMID: 19564280 [PubMed - in process]
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20: Antimicrob Agents Chemother. 2009 Jun 29. [Epub ahead of print]

Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice.

Watanabe M, Mishin VP, Brown SA, Russell CJ, Boyd K, Babu YS, Taylor G, Xiong X, Yan X, Portner A, Alymova IV.

Departments of Infectious Diseases, Immunology, Biostatistics, and Animal Resource Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA; BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA; Center for Biomolecular Science, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland.


Human parainfluenza virus type 3 (hPIV-3) is a major respiratory tract pathogen affecting young children, but no vaccines or antiviral drugs have yet been developed against it. We developed a mouse model to evaluate the efficacy of the novel parainfluenza virus hemagglutinin-neuraminidase (HN) inhibitors BCX 2798 and BCX 2855 against a recombinant Sendai virus in which the fusion and HN surface glycoproteins were substituted with those of hPIV-3 (rSeV[hPIV-3FHN]). In the prophylactic model, 129x1/SvJ mice were infected with a 90% or 20% lethal dose of the virus and treated intranasally for 5 days with 10 mg/kg/day of either compound, starting 4 h before infection. Prophylactic treatment of mice with either compound did not prevent their death in a 90% lethal model of rSeV(hPIV-3FHN) infection. However, it significantly reduced virus lung titers, weight loss, and mortality in mice infected with a 20% lethal virus dose. In the therapeutic model, mice were infected with a nonlethal dose of the virus (100 PFU/mouse) and treated intranasally with 1 or 10 mg/kg/day of either compound for 5 days, starting 24 or 48 h postinfection. Treatment of mice with either compound significantly reduced virus titer in the lungs, subsequently causing a reduction in the number of immune cells and level of cytokines in the bronchoalveolar lavage, and histopathologic changes in the airways. Our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of hPIV-3 HN in our mouse model and may be promising candidates for prophylaxis and treatment of hPIV-3 infection in humans.

PMID: 19564364 [PubMed - as supplied by publisher]
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