SPECIAL FOCUS – INFLUENZA A (H1N1)

SCIENTIFIC INTELLIGENCE

ESSENTIAL INFORMATION FROM THOMSON REUTERS
EXCLUSIVE FREE BRIEFING

As the influenza A (H1N1) virus spreads across the world, attention is focused on the pharmaceutical industry: how it will respond to the crisis, and what is being done to prevent further epidemics.

Thomson Reuters is pleased to offer free to download its entire disease briefing on influenza, taken direct and unabridged from the wealth of information and knowledge in Thomson Reuters IntegritySM. We hope that making these data freely available will speed up world responses to the H1N1 outbreak and give investigators and researchers the information they need to better support efforts to limit its spread and severity.

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Overview

Special Focus: Influenza A (H1N1) and the Threat of Pandemic

Swine influenza (swine flu) is a respiratory disease of pigs caused by type A influenza virus that regularly causes outbreaks of influenza in pigs. Swine flu viruses cause high levels of illness and low death rates in pigs. Swine influenza viruses may circulate among swine throughout the year, although most outbreaks occur during the late fall and winter months, similar to outbreaks in humans. The classical swine flu virus (an influenza type A H1N1 virus) was first isolated from a pig in 1930 (Influenza: Pigs, people and public health. Public heath fact sheet (January 2004)).

Influenza Virus A/CA/4/09 (H1N1):
Ultrastructural Morphology (Photo)

Influenza A (h1n1)

Like all influenza viruses, swine flu viruses change constantly. Pigs can be infected by avian influenza and human influenza viruses as well as swine influenza viruses. When influenza viruses from different species infect pigs, the viruses can reassort (i.e. swap genes) and new viruses that are a mix of swine, human and/or avian influenza viruses can emerge. Over the years, different variations of swine flu viruses have emerged. At this time, four influenza type A virus subtypes are enzootic in pigs worldwide: H1N1, H1N2, H3N2, and H3N1 (Osterhaus, A. and Garau, J., 2009). However, most of the recently isolated influenza viruses from pigs have been H1N1 viruses.

Although it is not a common occurrence, swine flu may be transmitted from pigs to humans who are in close direct contact with the animals. The incidence of swine flu in humans is normally quite low: according to the Centers for Disease Control and Prevention (CDC), between 2005 and January 2009, there were only 12 confirmed cases of the illness in the entire U.S. (Shinde, V. et al., 2009). In spring 2009, however, an outbreak occurred in Mexico and spread quickly to parts of the U.S., with other travel-related cases reported soon thereafter in various European and Asian countries. A new strain of the H1N1 virus is responsible for these cases. The virus now circulating contains genetic elements from four different sources: North American swine influenza viruses, North American avian influenza viruses, human influenza viruses and a Eurasian swine influenza virus. The genome sequences of the virus, officially designated swine-origin influenza A/California/04/2009 (H1N1) influenza virus, available through GenBank (GenBank sequences from 2009 H1N1 influenza outbreak). The new virus manifests significant changes in both the hemagglutinin and neuraminidase proteins as compared to H1N1 isolates from 2008: 27.2% and 18.2% of the animo acid sequences of H and N, respectively, vary from comparator strains. A change of this magnitude may qualify as "antigenic shift", endowing the virus with pandemic potential (Gallaher, W.R., 2009). Furthermore, CDC investigators suggest that the gene segments of the novel influenza virus may have been circulating undetected for an extended period of time (Garten, R.J. et al., 2009). Of interest is the recent finding that the H1N1 virus currently lacks the protein PB1-F2, which is believed to be an important determinant of virulence and lethality in influenza viruses (Osterhaus, A. and Garau, J., 2009).

Predominant symptoms of the new influenza A (H1N1) virus, as reported in the first 642 laboratory-confirmed cases in the U.S., are similar to those of seasonal influenza and predominantly include fever, cough and sore throat. Some infected people (as many as 25%) may also have nausea, vomiting and diarrhea (Anonymous, 2009). The virus preferentially infects young people (i.e., under 25 years of age), although more severe disease has mainly been detected in children under 5 years, adults over 65 years, those with underlying chronic medical conditions —especially respiratory diseases such as asthma, cardiovascular disease, diabetes, autoimmune disorders and obesity— and pregnant women (Osterhaus, A. and Garau, J., 2009). The fact that the virus is so lethal in pregnant women is significant, given that young adults are so susceptible to this strain of influenza. The virus is transmitted by droplets (i.e., contaminated droplets in the air or on objects proceeding from an infected individual who coughs or sneezes. Aerosol transmission may also occur. The virus appears to be contagious beginning one day before symptoms emerge and lasting for at least seven days after symptoms appear. It is most contagious during the first five days, and in children may remain contagious for up to ten days (Osterhaus, A. and Garau, J., 2009).

On April 27, WHO raised the pandemic alert level to phase 4, meaning that the virus had shown a sustained ability for human-to-human transmission and the ability to cause community-level outbreaks. On April 29, WHO raised the pandemic alert level to phase 5. This acknowledges efficient community-level human-to-human transmission of the virus in at least two countries within a single WHO region. On June 11, the WHO raised the level of influenza pandemic alert from phase 5 to phase 6, reflecting the fact that, in addition to the criteria defined in phase 5, the virus has caused sustained community-level outbreaks in at least one other country in another WHO region.

For up-to-date informattion, check the specialized web sites from CDC (Centers for Disease Control and Prevention: H1N1 flu (swine flu) web site) and WHO (World Health Organization (Epidemic and Pandemic Alert and Response) swine influenza web site), as well as International SOS Pandemic Preparedness: Influenza H1N1 ("swine flu") homepage and New England Journal of Medicine: H1N1 Influenza Center.

Bibliography

Gallaher, W.R. 1 Record(s) Retrieved
Towards a sane and rational approach to management of Influenza H1N1 2009
Virol J 2009, 6(1): 51
Garten, R.J. et al. 1 Record(s) Retrieved
Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans
Science 2009 Adv. Publication
Osterhaus, A. and Garau, J.
Update on the H1N1 influenza A outbreak
19th Eur Congr Clin Microbiol Infect Dis (ECCMID) (May 16-19, Helsinki) 2009, Abst
Shinde, V. et al.
Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009
New Engl J Med 2009 Adv. Publication
Emergence of a novel swine-origin influenza A (H1N1) virus in humans
New Engl J Med 2009 Adv. Publication

 

Vaccine Pipeline

Influenza Vaccine Pipeline

Immunity to influenza is essentially mediated by secretory IgA and serum IgG antibodies specific for the surface proteins hemagglutinin and neuraminidase. H and N are contained in influenza vaccines. Because of antigenic drift, the strains that make up the vaccines must be changed annually, following the recommendations of the World Health Organization, and yearly vaccination is necessary. The most recent influenza vaccine composition recommendations (WHO recommendations for influenza vaccines) as well as a list of vaccine manufacturers (Influenza vaccine manufacturers (World Health Organization)) are available on the WHO web site.

An analysis of pooled data from 18 cohorts of community-dwelling elderly members of an American health maintenance organization (HMO) has confirmed the efficacy of influenza vaccination. During ten influenza seasons yielding nearly 714,000 person-seasons of observation, yearly administration of an adjuvanted influenza vaccine was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza, and a 48% decrease in the risk of death from any cause (Nichol, K.L. et al., 2007). While much progress has been made toward the massive vaccination of the elderly and other high-risk groups, it has been suggested that the chain of transmission may be more effectively broken if healthcare workers and/or children were also given the annual vaccine (Treanor, J.D., 2007).

In spite of the fact that yearly vaccination against influenza is standard policy in most developed countries, the technology used to produce the vaccines is extremely antiquated, dating back to the 1950s. Some experts have argued that this is because the private sector has traditionally shown little interest in researching vaccines, based on the perception that the economic returns on this type of investigation are not sufficient, and thus that investment from the public sector is necessary if any real advances are to be made.

Several strategies are being pursued in order to increase the quality and quantity of the influenza vaccines that are used each year. These strategies include increasing the immunogenicity of currently licensed inactivated vaccines; use of cell lines for virus production; use of live, attenuated vaccines; nasal delivery of inactivated vaccines; and the application of modern biological techniques to the development and evaluation of novel vaccine approaches (Kemble, G. and Greenberg, H., 2003; Arvin, A.M. and Greenberg, H.B., 2006).

 

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Recently marketed seasonal influenza vaccines are presented in the tables below.

Representative marketed influenza vaccines
Drug Name Organization Status
SPD-707 (Fluviral) ID Biomedical Launched-2000
CAIV-T (FluMist) MedImmune Launched-2003
Fluarix GlaxoSmithKline Launched-2005
TIV (Fluzone) sanofi pasteur Launched-2005
PowderJect Fluvirin Novartis Vaccines and Diagnostics Launched-2005
Anflu Sinovac Launched-2006
H5N1 avian flu vaccine (Emerflu) sanofi pasteur Launched-2007
Influenza virus vaccine (Afluria) CSL Biotherapies Launched-2007
Influenza vaccine (surface antigen, inactivated, prepared in cell culture) (Optaflu) Novartis Vaccines and Diagnostics Launched-2008
GSK-1562902A (Prepandrix) GlaxoSmithKline Launched-2008
Influenza A(H1N1) 2009 monovalent vaccine (Panvax H1N1) CSL Ltd. Launched-2009
Pandemic influenza vaccine (H1N1)v (split virion, inactivated, adjuvanted) (Pandemrix H1N1) GlaxoSmithKline Launched-2009
Influenza A (H1N1) 2009 Monovalent vaccine live MedImmune Launched-2009
Influenza A (H1N1) 2009 Monovalent Vaccine sanofi pasteur Launched-2009
Panflu.1 Sinovac Biotech Launched-2009
Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted) (Focetria [A/H1N1]) Novartis Launched-2009
Influenza A (H1N1) 2009 Monovalent vaccine Novartis Launched-2009
Celvapan (H1N1) Baxter Launched-2009
Fluval P Omnivest Launched-2009
Panenza sanofi pasteur Launched-2009
Influenza A(H1N1) monovalent vaccine (Celtura) Novartis Launched-2009
Grippol Neo Solvay/Petrovax Launched-2009

Copyright 2009 Prous Science. All rights reserved.

Swine flu vaccines in active preclinical and clinical investigation
Drug Name Organization Description Status
Influenza A(H1N1) monovalent vaccine GlaxoSmithKline Influenza A (H1N1) vaccine consisting of inactivated split influenza A/California/7/2009 (H1N1) virus and produced in embryonated eggs
Reg
680072 Jiangsu Yanshen Biological H1N1 swine influenza vaccine
Reg
673657 Hualan Biological Bacterin Split - virion monovalent influenza vaccine, prepared from reassortant virus A/California/7/2009 NYMC X - 179A (H1N1), in embryonated chicken eggs; formaldehyde inactivated
Reg
Humenza sanofi pasteur Monovalent inactivated subvirion A/California/07/2009 (H1N1) influenza vaccine adjuvanted with AF03
Pre- Reg
GSK-2340269A GlaxoSmithKline Pandemic influenza H1N1 vaccine
PH III
GSK-2340272A GlaxoSmithKline Pandemic influenza A/H1N1 vaccine
PH III
GSK-2340273A GlaxoSmithKline Influenza H1N1 vaccine
PH III
GSK-2340274A GlaxoSmithKline Influenza A/ H1N1(swine) vaccine based on A/california/7/2009(H1N1) strain
PH III
660702 Novavax Virus - like - Particle (VLP) vaccine containing the hemagglutinin (HA), neuramidase (NA) and matrix 1 (M1) proteins from H1N1 influenza virus
PH III
BVX-M001 BiondVax Pharmaceuticals Universal influenza vaccine consisting of a recombinant protein preparation that includes nine conserved linear epitopes in triplicate from Hemagglutinin (HA), Nucleoprotein (NP) and Matrix (M) proteins
PH I/II
665575 Vaxine H1N1 Swine flu vaccine combined with Vaxine's Advax (TM) polysaccaride adjuvant system
PH I/II
HN-VAC Bharat Biotech Cell culture based H1N1 influenza vaccine
PH I
VRC-FLUDDNA057-00-VP Nat. Inst. Allergy & Infectious Dis. DNA vaccine expressing H1 hemagglutinin(HA) from Influenza A/California/04/2009 H1N1
PH I
Adimflu-S(A/H1N1) ADImmune Influenza A(H1N1) vaccine manufactured in embryonated chickens' eggs
Clinical
Replikins H1N1 Swine Flu Vaccine Replikins H1N1 Swine influenza vaccine
Pre-
clinical
SynCom Universal flu vaccine Inovio Biomedical DNA vaccine targeting influenza HA: H1, H2, H3, and H5 (Avian) along with conserved regions of NA and M2e - NP using the Inovio's SynCom(TM) technology
Pre-
clinical
SynCon H1N1 Inovio Biomedical H1N1DNA swine influenza vaccine using the SynCon (TM)DNA Vaccine Platform
Pre-
clinical
667456 Medicago H1N1 virus - like particle swine flu vaccine
Pre-
clinical
665813 AlphaVax H1N1(Swine) Influenza vaccine containing the hemagglutinin gene from Influenza California 04/2009, developed with the alpha replicon vector (TM) system (Alphavax's alphavaccine technology)
Pre-
clinical
663747 Vical H1N1 Influenza DNA vaccine encoding H1 hemagglutinin from swine - origin A/California/04/09 wild - type influenza virus formulated with Vical's proprietary Vaxfectin(TM) adjuvant
Pre-
clinical
677762 NasVax H1N1 influenza vaccine based on A/California/7/2009(H1N1) antigen and adjuvanted with Vaxisome
Pre-
clinical

Copyright 2009 Prous Science. All rights reserved.

Investigational influenza vaccines are featured in the following table. Individual vaccines, classes and technologies are described in the following sections.

New seasonal influenza vaccines in active Pre- clinical and clinical development
Drug Name Organization Description Status
Grippol Plus Solvay Egg - based adjuvanted influenza vaccine
Reg
Influvac TC Solvay Inactivated trivalent subunit influenza virus vaccine produced on MDCK - culture cell
Reg
Intradermal seasonal flu vaccine sanofi pasteur Split influenza virus, inactivated, containing antigens equivalent to the following strains: A/New Caledonia/20/99 (H1N1) like strain (A/New Caledonia/20/99 (IVR - 115)), A/Wisconsin/67/2005 (H3N2) like strain (A/Wisconsin/67/2005 (NYMC x - 151)), B/Malaysia/2506/2004 like strain (B/Malaysia/2506/2004)
Reg
TIV sanofi pasteur Seasonal influenza inactivated trivalent split virion vaccine containing hemagglutinin (HA) of three prototype strains A/New Caledonia/20/99 (H1N1), A/Wisconsin/67/2005 (H3N2) and B/Malaysia/2506/2004
Reg
UMN-0502 Protein Sciences Trivalent influenza vaccine consisting of three insect cell culture produced recombinant hemagglutinin (rHA0) proteins corresponding to the flu strains selected by the World Health Organization and the Center for Disease Control for each year's vaccine and formulated in PBS
Pre- Reg
GC-501 Green Cross Trivalent split influenza vaccine
PH III
GSK-2186877A GlaxoSmithKline Seasonal influenza vaccine
PH III
GSK-576389A GlaxoSmithKline Adjuvanted split - viron influenza virus vaccine
PH III
MEDI-8662 MedImmune Quadrivalent live attenuated influenza virus vaccine
PH III
SPD-707 GlaxoSmithKline Trivalent, inactivated, split - virion influenza virus vaccine consisting of influenza virus hemagglutinin (HA) of 3 strains (A/New Caledonia/20/99 (H1N1), A/Wisconsin/67/2005 (H3N2) and B/Malaysia/2506/2004)
PH III
VCIV Baxter Seasonal influenza vaccine consisting of inactivated split influenza virus based on Baxter´s Vero - cell technology
PH III
MEDI-3250 MedImmune Quadrivalent seasonal influenza vaccine
PH II/III
CSL-412 CSL Influenza vaccine adjuvanted with ISCOMATRIX(TM)
PH II
FluCell sanofi pasteur/ Crucell PER.C6 cell culture technology - based trivalent split inactivated seasonal influenza vaccine
PH II
Fluzone/JVRS-100 Juvaris Fluzone influenza vaccine adjuvanted with JVRS - 100
PH II
GHB-11L1 Avir Green Hills Biotechnology Intranasal live attenuated influenza vaccine based on the deletion of the pathogenicity factor NS1 gene of influenza H1N1virus and produced in cell cultures (Vero cells)
PH II
GSK-2321138A GlaxoSmithKline PH II
MVA-NP+M1 University of Oxford Influenza vaccine consisting of a recombinant MVA virus expressing influenza A nucleoprotein (NP) fused to matrix protein (M1) via a flexible linker (GGGPGGG)
PH II
VAX-125 VaxInnate Influenza vaccine consisting of fusion protein comprising the globular head domain of hemagglutinin (HA) antigen from A/Solomon Islands/3/2006 (H1N1) fused to TLR5 ligand, flagellin (STF2)
PH II
426173 Solvay/ Norwood Immunology Intranasal influenza vaccine based on Virosome Biologicals' adjuvanted technology
PH II
678336 sanofi-aventis Quadrivalent influenza vaccine
PH II
430974 Novavax Seasonal influenza vaccine consisting of three virus - like particles from H3N2, H1N1 and B influenza subtypes given as a single trivalent vaccine
PH II
AVX-502 AlphaVax Influenza vaccine containing the hemagglutinin gene from Influenza A/Wyoming/03/2003, developed with the alpha replicon vector (TM) system (Alphavax's alphavaccine technology)
PH I/II
BVX-M001 BiondVax Pharmaceuticals Universal influenza vaccine consisting of a recombinant protein preparation that includes nine conserved linear epitopes in triplicate from Hemagglutinin (HA), Nucleoprotein (NP) and Matrix (M) proteins
PH I/II
Flagellin.HuM2e VaxInnate Influenza A vaccine consisting of a recombinant protein comprising the TLR5 ligand flagellin (STF2) fused to four tandem copies of a consensus M2e (influenza matrix protein ectodomain) sequence based on human H1N1, H2N1 and H3N2 virus and expressed in Escherichia coli
PH I/II
VaxiSome-Influenza NasVax Influenza vaccine formulated with VaxiSome(TM) adjuvant technology
PH I/II
424477 Vaxine Trivalent inactivated seasonal influenza vaccine formulated with Advax adjuvant
PH I/II
Agrippal-IC31 Novartis/ Intercell Agrippal vaccine formulated with Intercell's proprietary adjuvant IC31
PH I
Flagellin.HuHa/flagellin.AvHA VaxInnate Influenza vaccine consisting of fusion proteins linking bacterial flagellin (STF2) to the globular head of viral hemagglutinin (HA) of human and avian influenza virus, respectively
PH I
Fluzone/Vaxfectin Vical Seasonal influenza inactivated trivalent split virion vaccine containing hemagglutinin (HA) of three prototype strains A/New Caledonia/20/99 (H1N1), A/Wisconsin/67/2005 (H3N2) and B/Malaysia/2506/2004 adjuvanted with Vaxfectin
PH I
GHB-01L1 Avir Green Hills Biotechnology Influenza A (H1N1) vaccine based on live - attenuated virus by deletion of pathogenicity factor NS1, produced in Vero cells
PH I
GSK-2115160A GlaxoSmithKline PH I
H6N1-Teal-HK 97/AA Nat. Inst. Allergy & Infectious Dis. H6 avian influenza live attenuated vaccine consisting of a recombinant virus with HA and NA genes from A/teal/HK/W312/97 (H6N1) virus and the internal protein genes derived from cold - adapted (ca) influenza A vaccine donor strain, A/AA/6/60 (H2N2) virus
PH I
M2e-HBc sanofi-aventis/ Acambis Influenza A vaccine consisting of virus - like particles based on hepatitis B core protein fused to extracellular domain of the ion channel protein M2 (M2e)
PH I
NB-1008 NanoBio Fluzone vaccine formulated with nanoemulsions (W805EC) as mucosal adjuvant
PH I
SCH-900795 BioDiem/ Nobilon Live attenuated influenza virus vaccine composed of three attenuated influenza virus
PH I
V-512 Merck & Co. Bivalent influenza peptide conjugate vaccine formulated with aluminium and ISCOMATRIX(TM)
PH I
VRC-FLUDDNA056-00VP Nat. Inst. Allergy & Infectious Dis. DNA Influenza vaccine that encodes H1, H3, and influenza B hemagglutinin (HA) proteins
PH I
VRC-FLUDNA047-00-VP Nat. Inst. Allergy & Infectious Dis. DNA trivalent seasonal influenza vaccine
PH I
655089 University of Bergen Virosomal Avian influenza vaccine based on A/Vietnam/2004 H5N1 (NIBRG - 14) strain formulated with ISCOM adjuvant
PH I
468374 US Department of Health & Human Services Pandemic influenza vaccine consisting of a formalin - inactivated reassortant virus H7N7/PR8, containing the Mal12 (H7N3) virus HA gene, the Mal2 (H10N7) virus NA gene and the remaining six genes from Joh/PR8 virus
PH I
AP205-M2 Cytos Biotechnology Influenza A vaccine consisting of bacteriophage AP205 virus like particles displaying the highly conserved extracellular domain of influenza A M2 protein
Pre-
clinical
EP-1400 Affitech Pre-
clinical
FLU-v PepTcell Synthetic influenza vaccine containing multiple T cell peptides epitopes that are present on all influenza viruses
Pre-
clinical
FP-01 Immune Targeting Systems (ITS) Synthetic universal Flu vaccine using Immune Targeting System's (ITS) T - cell vaccine platform
Pre-
clinical
GI-8000 GlobeImmune Pre-
clinical
L-M2eA Molecular Express Influenza vaccine consisting of matrix 2 protein ectodomain segment of influenza A strains coupled to a soluble hydrophobic domain (HD) and formulated in liposomes using VesiVax technology
Pre-
clinical
LG-611 Lentigen Influenza virus - like particle vaccine containing core protein (M) and surface antigens (HA and NA) using LentiMax technology
Pre-
clinical
M2e/NP-ISS Dynavax Influenza vaccine consisting of a fusion protein containing 8 tandem repeats of extracellular domain of M2 (M2E) protein followed by nucleoprotein (NP); produced in E.coli and it is conjugated to an immunostimulatory ODN (ISS)
Pre-
clinical
NB-006 NanoBio Pre-
clinical
NP-ISS/M2e-ISS Dynavax Influenza vaccine consisting of influenza nucleoprotein NP and influenza extracellular domain of matrix protein (M2e) both linked to immunostimulatory DNA (ISS)
Pre-
clinical
VLI-03A VectorLogics Influenza vaccine
Pre-
clinical
639397 iBioPharma Subunit influenza vaccine based on hemagglutinin(HA) from the A/Wyoming/3/03 (H3N2) strain using a plant - based technology
Pre-
clinical
452409 LigoCyte Influenza vaccine consisting of influenza - pseudotyped virus - like particles produced via the expression of influenza A/PR/8/34 (H1N1) hemagglutinin (HA) and neuraminidase (NA) and the murine leukemia virus Gag protein in the baculovirus - insect cell expression system
Pre-
clinical
648869 Vivaldi Live attenuated influenza vaccine by altering the NS1(nonstructural protein) gene
Pre-
clinical
681702 NanoBio Avian influenza vaccine consisting of recombinant H5N1 antigen (HBsAg) formulated with nanoemulsions (NEs) as adjuvant
Pre-
clinical
649740 iBioPharma Subunit Avian influenza vaccine based on hemagglutinin(HA) from H5N1 strains and produced using iBioPharma's proprietary plant - based platform
Pre-
clinical
654231 LigoCyte Influenza vaccine consisting of influenza - pseudotyped virus - like particles produced via the expression of influenza A/Hong Kong/68 (H3N2) hemagglutinin (HA) and neuraminidase (NA) and the murine leukemia virus Gag protein in the baculovirus - insect cell expression system
Pre-
clinical
665334 Pevion Influenza vaccine based on an optimized synthetic M2e peptide combined with the Pevion's virosome technology
Pre-
clinical

Copyright 2009 Prous Science. All rights reserved.

 

Bibliography

Arvin, A.M. and Greenberg, H.B. 1 Record(s) Retrieved
New viral vaccines
Virology 2006, 344(1): 240
Kemble, G. and Greenberg, H. 1 Record(s) Retrieved
Novel generations of influenza vaccines
Vaccine 2003, 21(16): 1789
Nichol, K.L. et al. 1 Record(s) Retrieved
Effectiveness of influenza vaccine in the community-dwelling elderly
New Engl J Med 2007, 357(14): 1373
Osterholm, M.T. 1 Record(s) Retrieved
Preparing for the next pandemic
New Engl J Med 2005, 352(18): 1839
Treanor, J.D. 1 Record(s) Retrieved
Influenza-the goal of control
New Engl J Med 2007, 357(14): 1439
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