ReviewArticle Passive Broad-Spectrum Influenza ... · ReviewArticle Passive Broad-Spectrum Influenza Immunoprophylaxis CassandraM.Berry,1 WilliamJ.Penhale,1 andMarkY.Sangster2 1MolecularandBiomedicalSciences

Review ArticlePassive Broad-Spectrum Influenza Immunoprophylaxis

Cassandra M Berry1 William J Penhale1 and Mark Y Sangster2

1 Molecular and Biomedical Sciences School of Veterinary and Life Sciences Murdoch University Perth WA 6150 Australia2 Center for Vaccine Biology and Immunology Department of Microbiology and Immunology University of Rochester Medical CenterRochester NY 14642 USA

Correspondence should be addressed to Cassandra M Berry cberrymurdocheduau

Received 4 July 2014 Accepted 10 September 2014 Published 22 September 2014

Academic Editor John M Nicholls

Copyright copy 2014 Cassandra M Berry et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics Activeprophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals Howeverdisadvantages of this strategy include the impact of antigenic drift necessitating constant updating of vaccine strain compositionand emerging antiviral drug resistanceThe development of other options for influenza prophylaxis particularly with broad actingagents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine is ofgreat interest Exploitation of broad-spectrummediators could provide barricade protection in the early critical phase of influenzavirus outbreaks Passive immunity has the potential to provide immediate antiviral effects inhibiting virus replication reducingvirus shedding and thereby protecting vulnerable populations in the event of an impending influenza pandemic Here we reviewpassive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses including interferons andantibodies

1 Introduction

Seasonal influenza causes serious disease burden particularlyin children and the elderly with the need to develop annualvaccines based on predicted circulating strains due to anti-genic drift of the virus Furthermore newly emerging novelinfluenza A viruses pose a significant threat of a pandemicwith potentially devastating consequences [1] Moreoveras pandemic strain vaccines require time for developmentand deployment virus replication and spread are initiallyunchecked allowing the outbreak to gain momentum Cur-rently vaccines and antivirals are used for control of influenzabut emerging virus resistance to these measures presentslimitations Furthermore as antiviral drugs could not bestockpiled in sufficient amounts for global supply alternativecontrol measures need to be urgently considered A potentialsolution lies in the development of a universal vaccinebased on conserved viral epitopes that induces cross-reactiveantibodies that neutralize variant viruses from within asubtype and protects against heterologous virusesThereforewhilst existing vaccines are inadequate for cross protectionand a universal vaccine may be difficult to achieve it is

both pertinent and timely to consider other possible broad-spectrum options particularly as different virus subtypesnot previously experienced by humans are emerging andhave pandemic potential In this review we discuss broad-spectrum control options with emphasis on harnessing thepower of natural immunity via neutralizing antibodies

2 Influenza

Effective passive broad-spectrum protection during the earlyphase of an epidemic could provide a barricade to virusexposure especially during the interval between virus iden-tification and active vaccine-induced immunity As a con-sequence early intervention with passive prophylaxis mayrevolutionize control options for influenza with potentialimpact on seasonal and pandemic influenza preparednessInfluenza A (H1N1 and H3N2) and influenza B viruses causeseasonal disease in the winter months of both hemisphereswith 250000ndash500000 deaths each year [2] Although the nat-ural animal reservoir for influenza A viruses is aquatic shore-birds high pathogenicity avian influenza (HPAI) viruses

Hindawi Publishing CorporationInfluenza Research and TreatmentVolume 2014 Article ID 267594 9 pageshttpdxdoiorg1011552014267594

2 Influenza Research and Treatment

have recently emerged with high fatality rates in domesticpoultry and species cross over into humans with HA dualbinding affinities for 120572 23-linked and 120572 26-linked sialic acidreceptors predominantly found in avian species and humansrespectively [3] allowing increased infectivity of avian virusesin the human respiratory tract Mortality rates for HPAIH5N1 spreading throughout Eurasia and the newly emergedH7N9 virus in China are around 60 and 30 respec-tively for reported human cases of infection [4 5] At thepresent time human-to-human transmission of these virusesis relatively rare Confounding factors for avian influenzavirus vaccine development include genetic engineering of thevirus for better growth in eggs poorer immunogenicity thanseasonal influenza H1 and H3 subtypes in humans and theneed for use of higher doses andor adjuvants to improveefficacy

Four pandemics have occurred since the start of the20th century the most severe occurring in 1918 due to theSpanish flu pandemicwith an estimated 50million deaths [6]Recently novel H1N1 viruses emerged causing a pandemicin 2009 due to a natural reassortant swine influenza Avirus which was different to the H1N1 virus that had beencocirculating with H3N2 viruses since 1977 [7] Reassortantviruses have been constructed in the laboratory to investigatetheir transmission and virulence with one virus possessingthe H5 HA gene derived from a HPAI H5N1 virus combinedwith the remaining seven gene segments from a 2009 H1N1pandemic virus displaying greater virulence than HPAIH5N1 with potential of increased mammalian transmission[8] Thus we cannot be complacent with the continued threatof a pandemic by such new emerging pathogenic influenzaviruses with increased mammalian transmission

As influenza virus replication also impairs the mucocil-iary clearance there is increased susceptibility to bacterialsuperinfections which can often be fatal (reviewed in [9]) Inaddition immune dysfunction in those prone to respiratorydisease with excessive cytokine stimulation in the airwaysduring influenza virus infection can rapidly progress topneumonia with fatal acute lung injury [10ndash12]Thus effectivestrategies to combat influenza pandemics of catastrophicproportions involve both the generation of broad-spectrumimmunity and protection from immunopathology therebylowering the risk of severe illness-associated complicationsand reducing both morbidity and mortality

3 Vaccines

Current influenza control requires effective vaccinationUpdated vaccines with strain matching are developed onan annual basis requiring seed virus preparation generatedby either reassortment or reverse genetics for propagationin eggs or cultured cells [13] Recombinant DNA plasmid-based and virus-like particle vaccines are alternative options[14] to currently licensed inactivated and live attenuatedvaccines (cold-adapted and temperature-sensitive viruses)[15] and recombinant proteins [16]Heterosubtypic immunityis conferred by a variety of experimental vaccines includingextracellular domain matrix (M2) protein [17] and formalin-inactivatedwhole virus [18] Nonetheless such contemporary

vaccines would have narrow virus specificity delayed avail-ability and restricted capacity to meet the global demandduring a pandemic situation Universal influenza vaccinesthat target invariant regions of the virus and induce effectivebroadly neutralizing immune responses could potentiallyprovide more effective antiviral coverage but finding anappropriate immunogen is a major issue under intense inves-tigation A further limitation is efficacy as vaccine-induced Bcell responses to conserved regions of the HA viral proteinare generally low in frequency and generate poor antibodyresponses [19]

4 Antivirals

Neuraminidase inhibitors although potent at inactivatingvirus replication have been shown to display limited effec-tiveness when used beyond 48 hours after infection due tohigh viral titres and require regular dosing to those at riskof exposure during a virus outbreak Other antivirals besidesNA inhibitors (zanamivir and oseltamivir) that block theM2-ion channel (adamantanes) have been used however prepan-demic stockpiling of such antivirals by governments hasbeen reconsidered as a poor strategy against emerging virusresistance (reviewed in [20]) Antiviral development has tar-geted specific oligosaccharide-comprised sites on envelopedviruses (cyanovirin) [21] viral RNA dependent RNA poly-merase (favipiravir) [22] and their possible combinationtargeting different stages of the virus replication cycle in asynergistic therapeutic approach [23] Innovative drugs mayoffer future clinical benefits including (DAS181) thatmediatescleavage of sialic acid from host glycan receptors [24] 120573-defensins and antiviral peptides that prevent virion entry[25] TLR3 ligand (PIKA) promotion of DCmaturation [26]TLR4 antagonists (eritoran) that block cytokine cascades[27] nucleic acid-based drug (PolyIC CpG) activation ofinnate immunity [28] and siRNA that target conserved viralRNA sequences [29] Furthermore enveloped virus neutral-izing compounds (polyphenols) found in pomegranate juice[30] and green tea [31] and even scorpion venom peptide[32] hold promise in their strain diversity-independence ofantiviral activity

5 Innate Interferons

Innate IFNs are potent pleiotropic cytokines that can stim-ulate cells to induce an antiviral state through signal trans-duction pathways activating transcription of specific genesubsets The IFN molecules comprise multiple subtype pro-teins belonging to the types I II and III families and playimportant roles in early host defense against virus infec-tions through their diverse antiviral and immunomodulatoryproperties (Figure 1) IFN-120572120573 are the best characterized ofthe type I IFN family which is comprised of IFN-120572 (1ndash14 subtypes) beta tau epsilon omega and many moreHowever influenza viruses can evade innate immunity inpart through the nonstructural- (NS-) 1 protein targetinginterferon regulatory factor- (IRF-) 3 blocking IFN promoteractivity and antagonizing endogenous IFN pathways [40]

Influenza Research and Treatment 3

Extracellular

Nucleus

IFNAR1 IFNAR2

Tyk2 JAK1

STAT1

STAT2

ISGF3

Cytoplasm

ISGs

Transcription

IRF9

Phosphorylation

P

P

PP

Type I IFN apoptosis Proliferation Developmentantiviral Survival Activation

Activation Antibody ClassMemory switching

Type II IFN antiviral Activation Antibody classswitching

Type III IFN antiviral

IFN-stimulated gene effects

Virus T cell B cell

OAS PKR Mx RNaseL RIG-I IRF7 CXCL10 SOCS1 IL-6 IL-10 iNOS MDA5

Type I IFN subtypes IFN-120572 IFN-120573 IFN-120576 IFN-120581 IFN-120596

Figure 1 Signal transduction pathway for type I IFNs and a summary of key ISG effects on the virus and mucosal immune response duringinfluenza Type II IFN (IFN-120574) binds IFNGR1 and IFNGR2 heterodimer receptor on the cell surface which leads to activation of JAK1 andJAK2 STAT dimerization and phosphorylation with transcriptional activation of ISGs with the GAS element Type III IFNs (IFN-1205821 -1205822and -1205823) signal via ligand binding to IFNLR1 and IL-10R2 subunits of the cell surface receptor activation of JAK1 and Tyk2 with similardownstream signaling pathways as the type I IFNs ISGs can be either discrete or common sets for the different IFN families Biologicalproperties of type I type II and type III IFNs as identified in T and B cells [33ndash39] do not represent an exhaustive list

IFNs [41] or IFN-inducible proteins (viperin) [42] pro-vide broad-spectrum protection against influenza A virusesThe IFNs have been shown to activate transcription of about2000 IFN-stimulated genes (ISG) [33] with heterogeneousantiviral activity in mammalian cells [34] Major antiviralstates are induced by RNaseL inhibiting viral nucleic acidreplication [35] 2-5OAS blocking virus protein translation[36] and Mx abrogating the formation of viral ribonucleo-proteins [37] IFNs can also affect immune cell proliferationdifferentiation maturation migration and survival IFNsorchestrate the downstream adaptive immune responses byactivating B cells to switch antibody class secretion and bystimulating T cell proliferation and survival to sustain T cellmemoryAlthough each protein of the type I IFN family bindsa single type of cell surface receptor (IFNAR) the bindingaffinities and downstream signaling pathways differ resultingin activation of ISG subsets influenced by virus and cell type[38]

IFNs have been used for clinical therapy of a varietyof infections and diseases Although IFN therapy predomi-nantly utilizes IFN-1205722 other subtypes may be more or lesseffective depending on the virus and cell type [39] Differ-ential efficacies have been found for individual IFN subtypesin mouse models of influenza with IFN-1205725 and IFN-1205726

subtypes being more effective than IFN-1205721 in reducing lungH1N1 influenza virus titers [43] The IFN-120573 subtype has alsobeen shown to protect againstH1N1 driving a pulmonaryTh1type response beyond day 8 which normally switches toTh2with eosinophilianeutrophilia during natural infection [44]

IFN delivery has often been via bolus injections whichcan have adverse side effects including severe influenza-likeillness with fatigue and depression [45] Intranasal instilla-tions of IFN to the respiratorymucosa can protect susceptibletype II alveolar epithelial cells from influenza virus infectionbut is associated with various efficacies in preclinical trials[46] Questions that still need to be adequately addressed arethe timing route and dosage of IFN regimens for effectivecover as a protective measure against influenza Importantlyexogenous IFN cannot be immunogenic otherwise neu-tralizing antibody responses develop rendering treatmentineffective [47] In an attempt to overcome adverse side effectswith current modes of IFN-120572 treatment a recent clinicaltrial investigating administration of low-dose oral IFN-120572prophylaxis was undertaken but was deemed ineffective inprotection against acute respiratory illness during the 2009influenza pandemic [48]

More recently the type III IFN-lambda family was dis-covered (120582-1-3) and found to induce similar antiviral effects to


B cell

Isotype-switchingAffinity maturation and selection

Memory

ProliferationActivation

HA-specific to globular head domain - Block virus entry into cell by inhibiting virus attachment

HA-specific to stalk domain- Block conformational changes in low pH-activation

of endosome preventing virus fusion

Highly functional neutralizing IgM IgA and IgG antibodies

Response to virus

Figure 2 Activities of neutralizing antibodies to influenza virus induced by B cell stimulation Influenza virus stimulates B cell responsesthrough a sequential process of activation proliferation isotype-switching affinity maturation and selection of antibodies and memoryThemajor activities of neutralizing antibody types to viral HA are shown in the inset box [13] HA-specific antibodies are highly functional andprevent virus infection resulting in less cells being infected in vivo

the type I IFNs except for their cell-restriction and signalingmainly in epithelial cells and hepatocytes [49 50] Althoughthese IL-10-like cytokines bind receptors distinct to the typeI IFNs most cells in the body can produce both IFN typeswhich are induced by TLR activation and internal sensorssuch as RIG-I and MDA5 Both IFN-120572120573 and IFN-120582 havebeen shown to be important for control of influenza in exper-imental animal models utilizing double receptor knockoutmice [51] Paradoxically IFNs may either reduce or enhanceinflammatory conditions [52] and as such their repeatedapplications to the respiratory tract need to be addressed inclinical trials Importantly unregulated IFNprotein levels canexacerbate lung inflammation and immunopathology [53]Regulation of IFN pathways is complex mediated by receptordensity binding affinity STAT phosphorylation and multi-merization ISG transcription and regulatory feedback loopsUnless an improved safety regime is utilized clinical studiesusing type I and type III IFN appear to show limited potentialfor influenza prophylaxis and are unsuitable for long-termprotection of the respiratory mucosa Further limitations ofexogenous IFN production capacity and species-specificity ofIFN signaling may be disadvantages in pandemic control

6 Neutralizing Antibodies

Stimulation of polyclonal B cells can generate circulatingantibody pools with multiple epitope reactivity inducedby vaccination or natural infection with influenza virusAntibodies blocking the binding of viral HA proteins to cellsurface receptors directly neutralize the virus and preventvirus entry Once the virus infection cycle has been abrogatedby such humoral immune responses the spread of virusto neighboring cells is inhibited virus shedding is reducedand the infection cleared through a combined antibodyand effector T cell response [54] extensively reviewed else-where [55] Importantly the production of highly functional

neutralizing antibodies against HA epitopes of influenzaviruses even at nominal levels is a relative correlate ofprotection [56] (Figure 2) Cognate signals and secretedfactors from activatedCD4+ Thelper cells also activate B cellsto secrete virus-specific antibody Extrafollicular antibody-secreting cells that mainly produce early IgM are regulatedby type I IFN and IL-12 cytokines whereas inherent innatehost factors influence mature B cells through a process ofclass switching to produce IgG during the course of influenzavirus infection [57] Memory B cells and antibody-secretingcells formed in germinal centers can produce virus-specificantibody in a recall response to secondary virus infec-tion [58] Trivalent inactivated and live attenuated vaccinespredominantly induce humoral responses with neutralizingantibodies directed against the HA globular head domainwhich block specific virus binding thus inhibiting virus entryHowever such antibody specificities can be limited in efficacyagainst variable viral sequences due to the high mutation ratein the HA head domain

7 Passive Antibody-BasedImmunoprophylaxis

Currently there is renewed interest in passive immunitymediated by neutralizing antibodies for protection againstinfluenza [59ndash62] Convalescent sera from survivors of theH1N1 Spanish Flu pandemic were reported to reduce mortal-ity rates [63] and convalescent plasma treatment was deemedeffective for H5N1-infected individuals in China [64] and forthe pandemic H1N1 in Hong Kong [65] It is noteworthy thateven a relatively low titre of anti-HA antibody in convalescentplasma (HAI titer 128) protected 100 ferrets from a fatalHPAI H5N1 virus infection when passively transferred 24hours before virus challenge [66]

Intranasal delivery of bovine IgG obtained fromcolostrum was found to provide passive prophylaxis for


influenza in mice when both specificity of antibodies andchallenge virus were strain-matched [67] Broader efficacyof antibodies with neutralizing capacity may be achievablewith a mixture of polyclonal antibody specificities raisedagainst multivalent HA vaccines Alternatively broadlyneutralizing antibodies to conserved regions of the HAcapable of neutralizing different strains within a subtypeand group or between groups and types of influenzaviruses may be effective as a prophylactic interim therapyIn addition to antihead HA antibodies some antistalkHA antibodies have been shown to block fusion [68]and promote antibody-dependent cellular cytotoxicity ofinfected cells with broad neutralizing capacity [69] Asroutine haemagglutination inhibition assays do not detectantistalk antibodies the discovery and potential of HA-stalk-specific antibodies largely remained unknown for some time[70] An advantage over anti-HA head antibodies that areprone to escape mutations is that certain antistalk antibodiesare less susceptible to mutations as the stalk epitopes in themembrane-proximal region are critical for virus function[71] Rather than attempt to directly induce such broadlyneutralizing antibodies in humans by vaccination which islimited to finding an appropriate immunogen with approvedadjuvants such antibodies may be more practically andeffectively generated in naıve donor animals with optimalvaccination protocols for prophylaxis in humans Howeverknowledge of the protective coverage dosage and route ofadministration of such antibodies needs to be gained fromfurther investigations

Monoclonal neutralizing antibodies cross protectiveagainst H1 H2 H5 H6 and H9 influenza virus strains wererecovered from human IgM+ memory B cells [72] Humanmonoclonal antibodies have also been identified with broad-spectrum prophylactic efficacy against HPAI H5N1 influenzaviruses in mice and ferrets [73 74] Memory from pastexposure to H1N1 influenza virus strains was also apparentin heterovariant immunity of individuals over 30 years of agerather than those younger during theH1N1 pandemic in 2009[75] Variousmonoclonal IgG antibodies against HA epitopeshave been investigated for broad-spectrum prophylaxis inmice and their efficacy compared to the antivirals aman-tadine oseltamivir and zanamivir [76] Use of humanizedand chimeric virus-specific monoclonal antibodies [77] andFab fragments has been explored in recent years to circum-vent immunogenicity issues and address suitability of suchantibodies for broad-spectrum passive prophylaxis howevertheir development and supply may not be practical and costeffective in pandemic control of influenza Furthermore theoptimal dose and mode of delivery of a single monoclonalantibody preparation to the stalk domain are issues withmuch higher titres needed for parenteral delivery as opposedto intranasal delivery [78]

Polyclonal antibodies with high affinity targetingmultipleepitopes of the viral HA protein are under substantial investi-gation for influenza control IgG antibodies have been shownto play a major role in protection of ferrets from homologousand heterologous H5N1 influenza viruses [79] As mentionedbefore select regions of the head and stalk domains of theHA molecule are highly conserved and can induce cross

protective antibody responses albeit suboptimal As theHA head is immunodominant stalk antigens have relativelylow immunogenicity and do not stimulate large amountsof highly reactive antibodies with classical vaccine regimesHowever broadly neutralizing high affinity antibodies couldpotentially be prepared in animals with immune manipu-lation using modified vaccine regimes and better adjuvantsthan those licensed for human use [80] Vaccination of naıveanimals to generate heterologous polyclonal antibodies hasbenefits in targeting responses to potential key epitopessince preexisting memory B cells with specificities for otherimmunodominant epitopes are not present to outcompetethe naıve B cells As an example prime-boost vaccinationstrategies have been found to increase neutralizing antibodytiters 30- to 50-fold and reduce lung virus loads by 2 logs[81ndash83] expanding the number and diversity of activatedHA-specific CD4+ T cell clones

Although universal vaccination in humans is the ultimategoal [84 85] broadly neutralizing antibodies produced in alarge animal donor with strategic vaccination regimes wouldbe useful as an interim therapy for influenza Heterologousantibodies could be passively administered by the intranasalroute to provide immediate protection of the respiratorytract mucosa Intranasal delivery of broadly neutralizingantibodies has been investigated in mice affording protection[86ndash89] and warrants further studies in preclinical modelsVaccination of large ruminant animals such as dairy cowsis currently being considered and has the potential to supplya bulk source of milk-derived neutralizing antibodies forclinical trials Clearly many unanswered questions regardingefficacy of routes of administration dosage timing andimmune memory to reexposure need to be addressed infuture investigations of antistalk HA antibody-based prophy-laxis for influenza

8 Pandemic Control

Despite modern advances in vaccine technology with theavailability of antivirals and antibiotics and improved globalsurveillance of influenza virus a contemporary pandemicmay have a worse case scenario than that which occurredin 1918 [90] Compounding these factors is civil unrest andthe existence of poor medical infrastructure in overcrowdeddeveloping countries likely to be the epicenter of newlyemerging influenza virus outbreaks Clearly interventionneeds to be early effective and robust in the effort tocurtail morbidity and mortality (Figure 3) Antibody-basedpassive immunity is a powerful prophylactic strategy forinfluenza pandemic control reducing the risk of virus spreadin populations Ideally an antibody-based therapy could beself-administered via either an inhaler or intranasal sprayfor protective coverage of the airways during the first waveof a pandemic The dairy industry infrastructure in somecountries (eg Australia) provides an opportunity for bulkantibody production in large ruminants One may speculatethat if a single 50mg dose of potent broadly neutralizingantibodies could be effective over a 7-day duration coveragefor 3 months would require 12 doses that possibly couldbe distributed to families and self-administered Assuming


Pandemic risk

Identification of new virus

Mor

bidi

ty an

d m

orta

lity

Time (months)63

Effective vaccine

Cases

Deaths

Prophylacticprotection

Active immunityPassive immunity

Vaccine development

Figure 3Modeling of the impact of prophylaxis onmortality curvesduring pandemic influenza Prophylaxis could protect against bothmorbidity and mortality rates by lowering the number of casesEffective passive immunity is important to provide coverage duringthe first wave or six-month risk period of the pandemic whilst aneffective vaccine is developed for the identified virus to induce activeimmunity

average annual milk production of 6000 Lcow it is feasiblethat approximately 6 kg of immunoglobulin (10000 doses)could be produced per cow In addition to those susceptibleand at high risk of exposure an immunoprophylaxis optionwould also be particularly important for those who havebeen previously vaccinated with seasonal influenza and maybe unresponsive to pandemic influenza vaccination due toa transient antiviral state recently termed innate imprint-ing [91] Monoclonal antibody-based immunotherapy withbroadly neutralizing capabilities and universal anti-influenzavaccines show promise for influenza prophylaxis affordingprotection of the respiratory tract mucosa (reviewed in [92])Interest in polyclonal antibody-based immunotherapy hasrecently been reignited with a study showing neutralizingefficacy of antistalk antibodies with new modes of action in aferret model [93]

The prospects of producing bulk supplies of antibodies inlarge production animals present a strategic approach likelyto generate a more robust antibody response in the donoranimal which can be passively transferred than that directlyinduced by natural virus infection or currently licensedvaccines and adjuvants for use in humans As an alternativeto animal-based production of antibodies the expression oftherapeutic antibodies in tobacco plants has also recentlybeen of interest for treatment of the current Ebola virusoutbreak in West Africa [94] although scaleup for adequatesupplies may be a limitation In a preclinical model wehave investigated intranasal delivery of ruminant polyclonalantibodies to protect the respiratory mucosa of mice againstinfection with H1N1 influenza virus [95] We found thatexogenous IgG derived from H1N1-immunized sheep asa model ruminant protected mice upon virus challengeProtection was Fc-independent was effective up to 3 daysbefore virus exposure and largely prevented infection in thelungs and preserved normal lung architecture A benefit of

intranasal administration is the direct noninvasive deliveryof antibody to the lumen of the respiratory mucosa whereasin a natural influenza virus infection the presence of IgG inthe airways is derived from circulating antibody by transu-dation with IgM and IgA transported across the epitheliumto the lumen Investigations of antistalk antibody isotypesand subclasses generated in immunized donor animals arerequired to increase knowledge of optimal efficacy and crossprotection against clades spanning H1 H3 H7 and H9 virustypes

9 Conclusion

Antiviral prevention strategies for control of newly emergingor reemerged influenza virus strains of pandemic potentialare of utmost importance Whilst intense efforts are beingmade to meet the urgent need for a universal vaccineeliciting long-term immunity passive immunoprophylaxiswould have benefits of immediate short-term protectionespecially of benefit to the elderly and very young ones whohave poorer antibody responses to vaccination Control ofinfluenzawith antiviral drugs lowers the risk of complications[96] but drug resistance can develop with adamantanesno longer recommended for use [20] Furthermore cost-effective management in low resource settings is problematicin many endemic regions especially in South East AsiaBroad-spectrum immunoprophylaxis holds future promiseas an effective control measure for influenza Preparationof broadly neutralizing antibodies in naıve animal donorsis potentially inexpensive and independent of host immunememory to influenza viruses where dominant responsesfrom HA-specific memory B cells are often induced by vac-cination or natural infection a phenomenon first describedas original antigenic sin [97 98] In conclusion seriousconcerns may be mitigated by passive immunoprophylaxisusing broadly neutralizing antibodies that provide universalcoverage against multiple influenza viruses providing aninterim control option for pandemic influenza

Conflict of Interests

The authors declare that there are no conflict of interests

Acknowledgment

The authors thank Philip Stumbles for insightful discussions

References

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[2] R Salomon and R G Webster ldquoThe influenza virus enigmardquoCell vol 136 no 3 pp 402ndash410 2009

[3] G N Rogers and J C Paulson ldquoReceptor determinants ofhuman and animal influenza virus isolates differences inreceptor specificity of the H3 hemagglutinin based on speciesof originrdquo Virology vol 127 no 2 pp 361ndash373 1983


[4] WHOhttpwwwwhointinfluenzahuman animal interfaceH5N1 cumulative table archivesen

[5] WHO 2014 httpwwwwhointinfluenzahuman animal in-terfaceinfluenza h7n9en

[6] J K Taubenberger and D M Morens ldquo1918 Influenza themother of all pandemicsrdquo Emerging Infectious Diseases vol 12no 1 pp 15ndash22 2006

[7] CDC ldquoSwine influenza A (H1N1) infection in two children-Southern California March-April 2009rdquo Morbidity MortalityWeekly Report vol 58 pp 400ndash402 2009

[8] M Imai TWatanabeM Hatta et al ldquoExperimental adaptationof an influenza H5 HA confers respiratory droplet transmissionto a reassortant H5 HAH1N1 virus in ferretsrdquo Nature vol 486no 7403 pp 420ndash428 2012

[9] J A McCullers ldquoThe co-pathogenesis of influenza viruses withbacteria in the lungrdquo Nature Reviews Microbiology vol 12 no4 pp 252ndash262 2014

[10] C J Sanders P C Doherty and P G Thomas ldquoRespiratoryepithelial cells in innate immunity to influenza virus infectionrdquoCell and Tissue Research vol 343 no 1 pp 13ndash21 2011

[11] K R Short E J Kroeze R A Fouchier and T KuikenldquoPathogenesis of influenza-induced acute respiratory distresssyndromerdquoThe Lancet Infectious Diseases vol 14 no 1 pp 57ndash69 2014

[12] F G Hayden R S Fritz M C Lobo W G Alvord W Stroberand S E Straus ldquoLocal and systemic cytokine responses duringexperimental human influenza A virus infection Relation tosymptom formation and host defenserdquo The Journal of ClinicalInvestigation vol 101 no 3 pp 643ndash649 1998

[13] K Subbarao B R Murphy and A S Fauci ldquoDevelopment ofeffective vaccines against pandemic influenzardquo Immunity vol24 no 1 pp 5ndash9 2006

[14] C-Y Wu Y-C Yeh J-T Chan et al ldquoA VLP vaccine inducesbroad-spectrum cross-protective antibody immunity againstH5N1 and H1N1 subtypes of influenza A virusrdquo PLoS ONE vol7 no 8 Article ID e42363 2012

[15] N Yamane Y Nakamura M Yuki T Odagiri and N IshidaldquoSerological evaluation of an influenza A virus cold-adaptedreassortant live vaccine CR-37 (H1N1) in Japanese adult vol-unteersrdquo Journal of Hygiene vol 92 no 2 pp 231ndash242 1984

[16] R Levi andR Arnon ldquoSynthetic recombinant influenza vaccineinduces efficient long-term immunity and cross-strain protec-tionrdquo Vaccine vol 14 no 1 pp 85ndash92 1996

[17] S Neirynck T Deroo X Saelens P Vanlandschoot W M Jouand W Fiers ldquoA universal influenza A vaccine based on theextracellular domain of the M2 proteinrdquo Nature Medicine vol5 no 10 pp 1157ndash1163 1999

[18] A Takada S Matsushita A Ninomiya Y Kawaoka andH Kida ldquoIntranasal immunization with formalin-inactivatedvirus vaccine induces a broad spectrum of heterosubtypicimmunity against influenza A virus infection in micerdquo Vaccinevol 21 no 23 pp 3212ndash3218 2003

[19] D Corti A L Suguitan Jr D Pinna et al ldquoHeterosubtypicneutralizing antibodies are produced by individuals immunizedwith a seasonal influenza vaccinerdquo The Journal of ClinicalInvestigation vol 120 no 5 pp 1663ndash1673 2010

[20] A C Hurt ldquoThe epidemiology and spread of drug resistanthuman influenza virusesrdquo Current Opinion in Virology vol 8pp 22ndash29 2014

[21] B R OrsquoKeefe D F Smee J A Turpin et al ldquoPotent anti-influenza activity of cyanovirin-N and interactions with viral

hemagglutininrdquo Antimicrobial Agents and Chemotherapy vol47 no 8 pp 2518ndash2525 2003

[22] Y Furuta B B Gowen K Takahashi K Shiraki D F Smeeand D L Barnard ldquoFavipiravir (T-705) a novel viral RNApolymerase inhibitorrdquo Antiviral Research vol 100 no 2 pp446ndash454 2013

[23] K Das ldquoAntivirals targeting influenza a virusrdquo Journal ofMedicinal Chemistry vol 55 no 14 pp 6263ndash6277 2012

[24] R W Y Chan M C W Chan A C N Wong et al ldquoDAS181inhibits H5N1 influenza virus infection of human lung tissuesrdquoAntimicrobial Agents andChemotherapy vol 53 no 9 pp 3935ndash3941 2009

[25] T Gong Y Jiang Y Wang et al ldquoRecombinant mouse beta-defensin 2 inhibits infection by influenza A virus by blockingits entryrdquo Archives of Virology vol 155 no 4 pp 491ndash498 2010

[26] Y-F Lau L-H Tang and E-E Ooi ldquoA TLR3 ligand thatexhibits potent inhibition of influenza virus replication and hasstrong adjuvant activity has the potential for dual applicationsin an influenza pandemicrdquoVaccine vol 27 no 9 pp 1354ndash13642009

[27] K A Shirey W Lai A J Scott et al ldquoThe TLR4 antagonistEritoran protects mice from lethal influenza infectionrdquo Naturevol 497 no 7450 pp 498ndash502 2013

[28] Y Li Y Hu Y Jin et al ldquoProphylactic therapeutic and immuneenhancement effect of liposome-encapsulated PolyICLC onhighly pathogenic H5N1 influenza infectionrdquo The Journal ofGene Medicine vol 13 no 1 pp 60ndash72 2011

[29] L Lin Q Liu N Berube S Detmer and Y Zhou ldquo51015840-Triphosphate-short interfering RNA potent inhibition ofinfluenza a virus infection by gene silencing and RIG-I activa-tionrdquo Journal of Virology vol 86 no 19 pp 10359ndash10369 2012

[30] G J Kotwal ldquoGenetic diversity-independent neutralizationof pandemic viruses (eg HIV) potentially pandemic (egH5N1 strain of influenza) and carcinogenic (eg HBV andHCV) viruses and possible agents of bioterrorism (variola) byenveloped virus neutralizing compounds (EVNCs)rdquo Vaccinevol 26 no 24 pp 3055ndash3058 2008

[31] W-J Shin Y-K Kim K-H Lee and B-L Seong ldquoEvaluationof the antiviral activity of a green tea solution as a hand-washdisinfectantrdquo Bioscience Biotechnology and Biochemistry vol76 no 3 pp 581ndash584 2012

[32] Q Li Z Zhao D Zhou et al ldquoVirucidal activity of a scorpionvenom peptide variant mucroporin-M1 against measles SARS-CoV and influenza H5N1 virusesrdquo Peptides vol 32 no 7 pp1518ndash1525 2011

[33] S A Samarajiwa S Forster K Auchettl and P J HertzogldquoINTERFEROME the database of interferon regulated genesrdquoNucleic Acids Research vol 37 supplement 1 pp D852ndashD8572009

[34] L A Durfee and JMHuibregtse ldquoIdentification and validationof ISG15 target proteinsrdquo Subcellular Biochemistry vol 54 pp228ndash237 2010

[35] R H Silverman and S R Weiss ldquoViral phosphodiesterasesthat antagonize double-stranded RNA signaling to RNase L bydegrading 2-5Ardquo Journal of Interferon and Cytokine Researchvol 34 pp 455ndash463 2014

[36] D Rebouillat and A G Hovanessian ldquoThe human 2101584051015840-oligoadenylate synthetase family interferon-induced proteinswith unique enzymatic propertiesrdquo Journal of Interferon andCytokine Research vol 19 no 4 pp 295ndash308 1999


[37] O Haller G Kochs and F Weber ldquoInterferon Mx and viralcountermeasuresrdquo Cytokine and Growth Factor Reviews vol 18no 5-6 pp 425ndash433 2007

[38] E Baig and E N Fish ldquoDistinct signature type I interferonresponses are determined by the infecting virus and the targetcellrdquo Antiviral Therapy vol 13 no 3 pp 409ndash422 2008

[39] LM Pfeffer C A Dinarello R B Herberman et al ldquoBiologicalproperties of recombinant 120572-interferons 40th anniversary ofthe discovery of interferonsrdquo Cancer Research vol 58 no 12pp 2489ndash2499 1998

[40] G Kochs A Garcıa-Sastre and L Martınez-Sobrido ldquoMultipleanti-interferon actions of the influenza A virus NS1 proteinrdquoJournal of Virology vol 81 no 13 pp 7011ndash7021 2007

[41] Y-F Lau L-H Tang E-E Ooi and K Subbarao ldquoActivation ofthe innate immune system provides broad-spectrum protectionagainst influenza A viruses with pandemic potential in micerdquoVirology vol 406 no 1 pp 80ndash87 2010

[42] K S Tan FOlfatMC Phoon et al ldquoIn vivo and in vitro studieson the antiviral activities of viperin against influenzaH1N1 virusinfectionrdquo Journal of General Virology vol 93 no 6 pp 1269ndash1277 2012

[43] C M James M Y Abdad J P Mansfield et al ldquoDifferentialactivities of alphabeta IFN subtypes against influenza virus invivo and enhancement of specific immune responses in DNAvaccinatedmice expressing haemagglutinin andnucleoproteinrdquoVaccine vol 25 no 10 pp 1856ndash1867 2007

[44] J-K Yoo D P Baker and E N Fish ldquoInterferon-120573 modulatestype 1 immunity during influenza virus infectionrdquo AntiviralResearch vol 88 no 1 pp 64ndash71 2010

[45] U RMalikD FMakower and SWadler ldquoInterferon-mediatedfatiguerdquo Cancer vol 92 no 6 supplement pp 1664ndash1668 2001

[46] R G Thorne L R Hanson T M Ross D Tung and W HFrey II ldquoDelivery of interferon-120573 to themonkey nervous systemfollowing intranasal administrationrdquo Neuroscience vol 152 no3 pp 785ndash797 2008

[47] AD Brideau-Andersen XHuang S-C C Sun et al ldquoDirectedevolution of gene-shuffled IFN-120572 molecules with activity pro-files tailored for treatment of chronic viral diseasesrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 104 no 20 pp 8269ndash8274 2007

[48] A L Bennett D W Smith M J Cummins P A Jacoby JM Cummins and M W Beilharz ldquoLow-dose oral interferonalpha as prophylaxis against viral respiratory illness a double-blind parallel controlled trial during an influenza pandemicyearrdquo Influenza and other Respiratory Viruses vol 7 no 5 pp854ndash862 2013

[49] J Wang R Oberley-Deegan S Wang et al ldquoDifferentiatedhuman alveolar type II cells secrete antiviral IL-29 (IFN-1205821) inresponse to influenza a infectionrdquo The Journal of Immunologyvol 182 no 3 pp 1296ndash1304 2009

[50] M Mordstein E Neugebauer V Ditt et al ldquoLambda interferonrenders epithelial cells of the respiratory and gastrointestinaltracts resistant to viral infectionsrdquo Journal of Virology vol 84no 11 pp 5670ndash5677 2010

[51] R K Durbin S V Kotenko and J E Durbin ldquoInterferoninduction and function at the mucosal surfacerdquo ImmunologicalReviews vol 255 no 1 pp 25ndash39 2013

[52] J S M Peiris C Y Cheung C Y H Leung and J M NichollsldquoInnate immune responses to influenza AH5N1 friend or foerdquoTrends in Immunology vol 30 no 12 pp 574ndash584 2009

[53] J R Teijaro K B Walsh S Cahalan et al ldquoEndothelial cells arecentral orchestrators of cytokine amplification during influenzavirus infectionrdquo Cell vol 146 no 6 pp 980ndash991 2011

[54] A Iwasaki and RMedzhitov ldquoRegulation of adaptive immunityby the innate immune systemrdquo Science vol 327 no 5963 pp291ndash295 2010

[55] E E Waffarn and N Baumgarth ldquoProtective B cell responses toFlu-No flukerdquo Journal of Immunology vol 186 no 7 pp 3823ndash3829 2011

[56] S A Plotkin ldquoCorrelates of vaccine-induced immunityrdquo Clini-cal Infectious Diseases vol 47 no 3 pp 401ndash409 2008

[57] A Sundararajan L Huan K A Richards et al ldquoHost differ-ences in influenza-specific CD4 T cell and B cell responses aremodulated by viral strain and route of immunizationrdquo PLoSONE vol 7 no 3 Article ID e34377 2012

[58] C C Goodnow C G Vinuesa K L Randall F MacKay andR Brink ldquoControl systems and decision making for antibodyproductionrdquo Nature Immunology vol 11 no 8 pp 681ndash6882010

[59] J H Beigel and T C Luke ldquoA study in scarlet-convalescentplasma for severe influenzardquo Critical Care Medicine vol 40 no3 pp 1027ndash1028 2012

[60] J Ye H Shao and D R Perez ldquoPassive immune neutralizationstrategies for prevention and control of influenza A infectionsrdquoImmunotherapy vol 4 no 2 pp 175ndash186 2012

[61] S Akerfeldt S Geijer E Holubars G Fuchs and M BrundinldquoProphylactic and therapeutic antiviral effect of human gammaglobulinrdquo Biochemical Pharmacology vol 21 no 4 pp 503ndash5091972

[62] F Ramisse F-X Deramoudt M Szatanik et al ldquoEffective pro-phylaxis of influenza A virus pneumonia inmice by topical pas-sive immunotherapy with polyvalent human immunoglobulinsor F(abrsquo)

2fragmentsrdquo Clinical and Experimental Immunology

vol 111 no 3 pp 583ndash587 1998[63] T C Luke A Casadevall S J Watowich S L Hoffman J H

Beigel and T H Burgess ldquoHark back passive immunother-apy for influenza and other serious infectionsrdquo Critical CareMedicine vol 38 no 4 pp e66ndashe73 2010

[64] B Zhou N Zhong and Y Guan ldquoTreatment with convalescentplasma for influenza A (H5N1) infectionrdquo The New EnglandJournal of Medicine vol 357 no 14 pp 1450ndash1451 2007

[65] I F N Hung K KW To C-K Lee et al ldquoConvalescent plasmatreatment reduced mortality in patients with severe pandemicinfluenza A (H1N1) 2009 virus infectionrdquo Clinical InfectiousDiseases vol 52 no 4 pp 447ndash456 2011

[66] S Rockman D Maher and D Middleton ldquoThe use of hyper-immune serum for severe influenza infectionsrdquo Critical CareMedicine vol 40 no 3 pp 973ndash975 2012

[67] W C Ng V Wong B Muller G Rawlin and L E BrownldquoPrevention and treatment of influenza with hyperimmunebovine colostrum antibodyrdquo PLoS One vol 5 no 10 Article IDe13622 2010

[68] D C Ekiert G Bhabha M-A Elsliger et al ldquoAntibodyrecognition of a highly conserved influenza virus epitoperdquoScience vol 324 no 5924 pp 246ndash251 2009

[69] D J Dilillo G S Tan P Palese and J V Ravetch ldquoBroadlyneutralizing hemagglutinin stalk-specific antibodies requireFcR interactions for protection against influenza virus in vivordquoNature Medicine vol 20 no 2 pp 143ndash151 2014

[70] N Pica R Hai F Krammer et al ldquoHemagglutinin stalkantibodies elicited by the 2009 pandemic influenza virus as


a mechanism for the extinction of seasonal H1N1 virusesrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 7 pp 2573ndash2578 2012

[71] H Zhang LWang RWCompans andB-ZWang ldquoUniversalinfluenza vaccines a dream to be realized soonrdquo Viruses vol 6no 5 pp 1974ndash1991 2014

[72] N S Laursen and I AWilson ldquoBroadly neutralizing antibodiesagainst influenza virusesrdquo Antiviral Research vol 98 no 3 pp476ndash483 2013

[73] M Throsby E van den Brink M Jongeneelen et al ldquoHetero-subtypic neutralizing monoclonal antibodies cross-protectiveagainst H5N1 and H1N1 recovered from human IgM+ memoryB cellsrdquo PLoS ONE vol 3 no 12 Article ID e3942 2008

[74] R H E Friesen W Koudstaal M H Koldijk et al ldquoNew classofmonoclonal antibodies against severe influenza Prophylacticand therapeutic efficacy in ferretsrdquo PLoS ONE vol 5 no 2Article ID e9106 2010

[75] K Hancock V Veguilla X Lu et al ldquoCross-reactive antibodyresponses to the 2009 pandemicH1N1 influenza virusrdquoTheNewEngland Journal of Medicine vol 361 no 20 pp 1945ndash19522009

[76] W Koudstaal M H Koldijk J P J Brakenhoff et al ldquoPre-and postexposure use of human monoclonal antibody againstH5N1 and H1N1 influenza virus in mice viable alternative tooseltamivirrdquo Journal of Infectious Diseases vol 200 no 12 pp1870ndash1873 2009

[77] Q Zheng L Xia W L Wu et al ldquoProperties and therapeuticefficacy of broadly reactive chimeric and humanized H5-specificmonoclonal antibodies againstH5N1 influenza virusesrdquoAntimicrobial Agents andChemotherapy vol 55 no 4 pp 1349ndash1357 2011

[78] S Sakabe K Iwatsuki-Horimoto T Horimoto et al ldquoA cross-reactive neutralizing monoclonal antibody protects mice fromH5N1 and pandemic (H1N1) 2009 virus infectionrdquo AntiviralResearch vol 88 no 3 pp 249ndash255 2010

[79] J S Shin H S Kim S H Cho and S H Seo ldquoIgG antibodiesmediate protective immunity of inactivated vaccine for highlypathogenic H5N1 influenza viruses in ferretsrdquo Viral Immunol-ogy vol 23 no 3 pp 321ndash327 2010

[80] J Alisky ldquoBovine and human-derived passive immunizationcould help slow a future avian influenza pandemicrdquo MedicalHypotheses vol 72 no 1 pp 74ndash75 2009

[81] Z Zhao F Yan Z Chen et al ldquoCross clade prophylacticand therapeutic efficacy of polyvalent equine immunoglobulinF(ab1015840)2 against highly pathogenic avian influenza H5N1 inmicerdquo International Immunopharmacology vol 11 no 12 pp2000ndash2006 2011

[82] I Margine R Hai R A Albrecht et al ldquoH3N2 influenzavirus infection induces broadly reactive hemagglutinin stalkantibodies in humans and micerdquo Journal of Virology vol 87 no8 pp 4728ndash4737 2013

[83] I Margine F Krammer R Hai et al ldquoHemagglutinin stalk-based universal vaccine constructs protect against group 2influenza A virusesrdquo Journal of Virology vol 87 no 19 pp10435ndash10446 2013

[84] C J Wei J C Boyington P M McTamney et al ldquoInduction ofbroadly neutralizingH1N1 influenza antibodies by vaccinationrdquoScience vol 329 no 5995 pp 1060ndash1064 2010

[85] F Krammer and P Palese ldquoUniversal influenza virus vaccinesneed for clinical trialsrdquo Nature Immunology vol 15 no 1 pp3ndash5 2014

[86] R M Kris R A Yetter R Cogliano R Ramphal and PA Small ldquoPassive serum antibody causes temporary recoveryfrom influenza virus infection of the nose trachea and lung ofnude micerdquo Immunology vol 63 no 3 pp 349ndash353 1988

[87] J P Wong L L Stadnyk and E G Saravolac ldquoEnhancedprotection against respiratory influenza A infection in mice byliposome-encapsulated antibodyrdquo Immunology vol 81 no 2pp 280ndash284 1994

[88] C Dreffier F Ramisse and C Dubernet ldquoPulmonary admin-istration of IgG loaded liposomes for passive immunoprophy-laxyrdquo International Journal of Pharmaceutics vol 254 no 1 pp43ndash47 2003

[89] A I Bot T E Tarara D J Smith S R Bot C MWoods and JGWeers ldquoNovel lipid-based hollow-porous microparticles as aplatform for immunoglobulin delivery to the respiratory tractrdquoPharmaceutical Research vol 17 no 3 pp 275ndash283 2000

[90] G J Milne N Halder and J K Kelso ldquoThe cost effectiveness ofpandemic influenza interventions a pandemic severity basedanalysisrdquo PLoS ONE vol 8 no 4 Article ID e61504 2013

[91] L E Richert A Rynda-Apple A L Harmsen et al ldquoCD11c+cells primed with unrelated antigens facilitate an acceleratedimmune response to influenza virus in micerdquo European Journalof Immunology vol 44 no 2 pp 397ndash408 2014

[92] N Clementi E Criscuolo M Castelli N Mancini MClementi and R Burioni ldquoInfluenza B-cells protective epitopecharacterization a passkey for the rational design of new broad-range anti-influenza vaccinesrdquo Viruses vol 4 no 11 pp 3090ndash3108 2012

[93] F Krammer R Hai M Yondola et al ldquoAssessment of influenzavirus hemagglutinin stalk-based immunity in ferretsrdquo Journalof Virology vol 88 no 6 pp 3432ndash3442 2014

[94] J L Goodman ldquoStudying ldquosecret serumsrdquomdashtoward safe effec-tive Ebola treatmentsrdquo The New England Journal of Medicine2014

[95] C RinaldiW J Penhale P A Stumbles G Tay andCM BerryldquoModulation of innate immune responses by influenza-specificovine polyclonal antibodies used for prophylaxisrdquo PLoS ONEvol 9 no 2 Article ID e89674 2014

[96] T M Uyeki ldquoPreventing and controlling influenza with avail-able interventionsrdquo The New England Journal of Medicine vol370 no 9 pp 789ndash791 2014

[97] R G Webster ldquoOriginal antigenic sin in ferrets the responseto sequential infections with influenza virusesrdquo The Journal ofImmunology vol 97 no 2 pp 177ndash183 1966

[98] J H Kim I Skountzou R Compans and J Jacob ldquoOrig-inal antigenic sin responses to influenza virusesrdquo Journal ofImmunology vol 183 no 5 pp 3294ndash3301 2009

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


have recently emerged with high fatality rates in domesticpoultry and species cross over into humans with HA dualbinding affinities for 120572 23-linked and 120572 26-linked sialic acidreceptors predominantly found in avian species and humansrespectively [3] allowing increased infectivity of avian virusesin the human respiratory tract Mortality rates for HPAIH5N1 spreading throughout Eurasia and the newly emergedH7N9 virus in China are around 60 and 30 respec-tively for reported human cases of infection [4 5] At thepresent time human-to-human transmission of these virusesis relatively rare Confounding factors for avian influenzavirus vaccine development include genetic engineering of thevirus for better growth in eggs poorer immunogenicity thanseasonal influenza H1 and H3 subtypes in humans and theneed for use of higher doses andor adjuvants to improveefficacy

Four pandemics have occurred since the start of the20th century the most severe occurring in 1918 due to theSpanish flu pandemicwith an estimated 50million deaths [6]Recently novel H1N1 viruses emerged causing a pandemicin 2009 due to a natural reassortant swine influenza Avirus which was different to the H1N1 virus that had beencocirculating with H3N2 viruses since 1977 [7] Reassortantviruses have been constructed in the laboratory to investigatetheir transmission and virulence with one virus possessingthe H5 HA gene derived from a HPAI H5N1 virus combinedwith the remaining seven gene segments from a 2009 H1N1pandemic virus displaying greater virulence than HPAIH5N1 with potential of increased mammalian transmission[8] Thus we cannot be complacent with the continued threatof a pandemic by such new emerging pathogenic influenzaviruses with increased mammalian transmission

As influenza virus replication also impairs the mucocil-iary clearance there is increased susceptibility to bacterialsuperinfections which can often be fatal (reviewed in [9]) Inaddition immune dysfunction in those prone to respiratorydisease with excessive cytokine stimulation in the airwaysduring influenza virus infection can rapidly progress topneumonia with fatal acute lung injury [10ndash12]Thus effectivestrategies to combat influenza pandemics of catastrophicproportions involve both the generation of broad-spectrumimmunity and protection from immunopathology therebylowering the risk of severe illness-associated complicationsand reducing both morbidity and mortality

3 Vaccines

Current influenza control requires effective vaccinationUpdated vaccines with strain matching are developed onan annual basis requiring seed virus preparation generatedby either reassortment or reverse genetics for propagationin eggs or cultured cells [13] Recombinant DNA plasmid-based and virus-like particle vaccines are alternative options[14] to currently licensed inactivated and live attenuatedvaccines (cold-adapted and temperature-sensitive viruses)[15] and recombinant proteins [16]Heterosubtypic immunityis conferred by a variety of experimental vaccines includingextracellular domain matrix (M2) protein [17] and formalin-inactivatedwhole virus [18] Nonetheless such contemporary

vaccines would have narrow virus specificity delayed avail-ability and restricted capacity to meet the global demandduring a pandemic situation Universal influenza vaccinesthat target invariant regions of the virus and induce effectivebroadly neutralizing immune responses could potentiallyprovide more effective antiviral coverage but finding anappropriate immunogen is a major issue under intense inves-tigation A further limitation is efficacy as vaccine-induced Bcell responses to conserved regions of the HA viral proteinare generally low in frequency and generate poor antibodyresponses [19]

4 Antivirals

Neuraminidase inhibitors although potent at inactivatingvirus replication have been shown to display limited effec-tiveness when used beyond 48 hours after infection due tohigh viral titres and require regular dosing to those at riskof exposure during a virus outbreak Other antivirals besidesNA inhibitors (zanamivir and oseltamivir) that block theM2-ion channel (adamantanes) have been used however prepan-demic stockpiling of such antivirals by governments hasbeen reconsidered as a poor strategy against emerging virusresistance (reviewed in [20]) Antiviral development has tar-geted specific oligosaccharide-comprised sites on envelopedviruses (cyanovirin) [21] viral RNA dependent RNA poly-merase (favipiravir) [22] and their possible combinationtargeting different stages of the virus replication cycle in asynergistic therapeutic approach [23] Innovative drugs mayoffer future clinical benefits including (DAS181) thatmediatescleavage of sialic acid from host glycan receptors [24] 120573-defensins and antiviral peptides that prevent virion entry[25] TLR3 ligand (PIKA) promotion of DCmaturation [26]TLR4 antagonists (eritoran) that block cytokine cascades[27] nucleic acid-based drug (PolyIC CpG) activation ofinnate immunity [28] and siRNA that target conserved viralRNA sequences [29] Furthermore enveloped virus neutral-izing compounds (polyphenols) found in pomegranate juice[30] and green tea [31] and even scorpion venom peptide[32] hold promise in their strain diversity-independence ofantiviral activity

5 Innate Interferons

Innate IFNs are potent pleiotropic cytokines that can stim-ulate cells to induce an antiviral state through signal trans-duction pathways activating transcription of specific genesubsets The IFN molecules comprise multiple subtype pro-teins belonging to the types I II and III families and playimportant roles in early host defense against virus infec-tions through their diverse antiviral and immunomodulatoryproperties (Figure 1) IFN-120572120573 are the best characterized ofthe type I IFN family which is comprised of IFN-120572 (1ndash14 subtypes) beta tau epsilon omega and many moreHowever influenza viruses can evade innate immunity inpart through the nonstructural- (NS-) 1 protein targetinginterferon regulatory factor- (IRF-) 3 blocking IFN promoteractivity and antagonizing endogenous IFN pathways [40]


Extracellular

Nucleus

IFNAR1 IFNAR2

Tyk2 JAK1

STAT1

STAT2

ISGF3

Cytoplasm

ISGs

Transcription

IRF9

Phosphorylation

P

P

PP






Virus T cell B cell










B cell


Memory






Response to virus















8 Pandemic Control



Pandemic risk


Mor

bidi

ty an

d m

orta

lity

Time (months)63

Effective vaccine

Cases

Deaths



Vaccine development





9 Conclusion




Acknowledgment


References















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Extracellular

Nucleus

IFNAR1 IFNAR2

Tyk2 JAK1

STAT1

STAT2

ISGF3

Cytoplasm

ISGs

Transcription

IRF9

Phosphorylation

P

P

PP






Virus T cell B cell










B cell


Memory






Response to virus















8 Pandemic Control



Pandemic risk


Mor

bidi

ty an

d m

orta

lity

Time (months)63

Effective vaccine

Cases

Deaths



Vaccine development





9 Conclusion




Acknowledgment


References















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















B cell


Memory






Response to virus















8 Pandemic Control



Pandemic risk


Mor

bidi

ty an

d m

orta

lity

Time (months)63

Effective vaccine

Cases

Deaths



Vaccine development





9 Conclusion




Acknowledgment


References















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















8 Pandemic Control



Pandemic risk


Mor

bidi

ty an

d m

orta

lity

Time (months)63

Effective vaccine

Cases

Deaths



Vaccine development





9 Conclusion




Acknowledgment


References















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Pandemic risk


Mor

bidi

ty an

d m

orta

lity

Time (months)63

Effective vaccine

Cases

Deaths



Vaccine development





9 Conclusion




Acknowledgment


References















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

ReviewArticle Passive Broad-Spectrum Influenza ... · ReviewArticle Passive Broad-Spectrum Influenza Immunoprophylaxis CassandraM.Berry,1 WilliamJ.Penhale,1 andMarkY.Sangster2 1MolecularandBiomedicalSciences