Rev. Med. Virol. 2008; 18: 1–3.Published online in Wiley InterScience

(www.interscience.wiley.com)Reviews in Medical Virology DOI: 10.1002/rmv.567

Whatever happened to bird flu?

If the dire predictions in the newspapers had beencorrect, many of you should have suffered fromH5N1 influenza by now. In fact, the WHOreports a worldwide total of only 335 cases up to12 November 2007, albeit with 206 (61%) deaths.Why have we not had a pandemic?

Epidemiological investigations report close con-tact with birds as a risk factor for H5N1 influenzawith minimal evidence of human to human trans-mission. This poor onward transmissibility mayreflect the well known receptor specificity foravian and human strains in terms of their sialicacid linkages; avians prefer an �(2-3) linkagewhereas humans prefer �(2-6). Furthermore,those cells with �(2-3) linkages are found lower inthe human respiratory tract so that productiveinfections may have difficulty leaving the hostand transmitting to others [1]. The severity of theinfection when it is transmitted from bird tohuman on rare occasions may reflect ‘unnatural’binding to the human receptors triggering innateimmune responses and so producing a cytokinestorm [2]. Although there has not been a pandemicyet this century, there were three last century (orfour if you include the return of H1N1 in 1977),so another pandemic is inevitable. However, it isnot inevitable that H5 will be the responsible hae-magglutinin, with H7 and H9 (or indeed any of thetotal of 16 haemagglutinins known to infectavians) also potentially responsible.

We have never before been able to study themolecular evolution of an influenza virus in realtime, so it is possible that several viruses mayspread widely in avians without being able toacquire the mutations required to transmit tohumans. H5N1 infections are normally mild inaquatic avians, despite having high mortalitywhen transmitted to poultry, but some strainscan also cause disease in mallard ducks [3]. Muta-tions in H5N1 strains which have high mortalityfor mallard ducks map to the PA and PB1 compo-nents (acidic and basic respectively) of the poly-

merase but are not associated with enhancedviral replication and had increased mortality onlywhen they were administered intravenously,implying a contribution from host as well as viralgenes [3].A key set of 32 polymorphisms has been

described in multiple proteins from the viruseswhich adapted to humans following the 1918,1957 and 1968 pandemics [4]. To date, H5N1viruses have acquired only four of these mutationswith no single isolate possessing more than two ofthem. Whether this slow adaptation towards gro-wth in humans represents transition towards themilder phenotype seen in seasonal infections is amatter for conjecture. It should also be noted thatno unusual patterns of avian mortality weredescribed before the 1918 pandemic [5], so thatthis is not a prerequisite for human disease. Never-theless, it is also possible that such evolution inavians presages a future human pandemic, so itis both prudent and justifiable for health authori-ties around the globe to make plans to mitigate apandemic caused by H5N1. This is being led bythe WHO, with individual countries conductingtheir own implementation of how antiviral drugsand vaccines could be developed into specificdefences [6]. A general assumption is to plan foran outbreak of the severity of the 1918 pandemic(25% case attack rate, 0.35% case fatality, basicreproductive number (R0) of 1.8) while hopingthat a virus of lower severity and/or transmissibil-ity evolves in practice.The antiviral drugs oseltamivir and zanamivir

inhibit the neuraminidase of H5N1 in addition tothat of the current strains of H3N2 and H1N1type A as well as type B influenza, against whichthey are licensed. There are differences bet-ween the drugs in that, unlike zanamivir, oseltami-vir requires an induced fit in the enzyme activesite, so making it easier for a resistant virus to beselected [7]. Oseltamivir has the advantage ofbeing orally bioavailable. At the onset of a

EE D I T OO R I A L

Copyright # 2007 John Wiley & Sons, Ltd.

pandemic, these antiviral drugs could be used inthree ways which would all need rapid deliveryof medication, so producing logistical difficultiesif health care staff were decimated by a pandemic.First, the drugs could be used to treat infectedindividuals with the aim of moderating diseaseseverity. Second, the drugs could be given tofamily members of an index case to interrupttransmission. Such household prophylaxis hasbeen shown in randomised controlled trials to beeffective, even when combined with the treatmentof the index case [8,9]. This contrasts with rimanta-dine or amantadine which, when used for bothtreatment and household prophylaxis, rapidlyselected for resistant strains in the index casewhich were fully pathogenic and transmitted tofamily members, so abolishing the benefits ofhousehold prophylaxis [10,11]. Third, the drugscould be given to the whole population in anarea surrounding an index case (ring prophylaxis).Mathematical models suggest that effectivedeployment of drugs in this way could alter thetrajectory of the epidemic, and even abort a pan-demic, if delivered rapidly enough to a populationexposed to a virus with a moderate R0 eg 1.8[12,13]. Social factors are also important in thesemodels, showing that household quarantine couldbe combined with household prophylaxis toimprove the control of transmission [12,13].Vaccines can be produced against viruses con-

taining H5, but the human immune system willalmost certainly require two doses for primingagainst this novel immunogen (reviewed in Refer-ence [14]). While there is little evidence that mod-ern adjuvants can induce priming with a singledose, their inclusion has been shown to reducethe dose of immunogen below the 15 mg normallyrequired for seasonal influenza [15–17]. Thisshould greatly expand the number of peoplewho could be protected by a given quantity of vac-cine. Whole virus vaccines also require lowerimmunising doses than do subunit vaccines fornon-H1-H3 influenza [18]. Apparently, there issufficient manufacturing capacity to make H5N1vaccine because, while the plants are fullyengaged in making trivalent vaccine for eachnorthern hemisphere influenza season, there isspare capacity in the rest of the year because thepopulation of the southern hemisphere is somuch smaller [19, 20]. Accordingly, many coun-tries have placed sleeping contracts with manufac-

turers for H5N1 vaccines to be activated once apandemic appears imminent. Prototype batcheshave also been supplied. Normally, influenza vac-cines are labelled with only a short shelf lifebecause they will be rapidly supplanted by thenext season’s vaccine. However, for H5N1, a long-er shelf life would be desirable for stockpiling, solong term stability studies are underway [20].What should governments do with these stock-piles if they approach the end of their shelf liveswithout a pandemic appearing? As a taxpayer, Iwould not like to see such material discarded.One possibility would be to offer the vaccine tohealthcare workers to define the immunogenicity,reactogenicity and persistence of neutralising anti-bodies, as well as their cross protection againstother H5N1 strains as they evolve. The data sofar from animal experiments are rather encoura-ging, in that some cross-protection has been seenbetween different viruses containing H5 [21–23].Cross-protection against virus challenge was notpredicted by HI or neutralisation results, was pas-sively transferred by serum and included a com-ponent from the neuraminidase [22,23]. It wouldbe unrealistic to expect such cross protection toprevent infection, but it might be sufficient tomoderate pathogenesis so that pandemic influenzacould be made to resemble seasonal influenza i.e.the objective would be to reduce deaths and severedisease not necessarily influenza itself [12, 13]. Themathematical models predict that even a poorlymatched pre-pandemic vaccine could help to miti-gate the extent of the pandemic. Importantly, thisbenefit is predicted to be offset by closing schoolswhich would have the adverse effect of alteringsocial mixing, thereby allowing potentially infec-tious children to contact other carers, includinggrandparents, who may be in the age group likelyto experience severe disease. Thus, vaccination ofchildren with pre-pandemic vaccine should beseen as a way of keeping schools open [12, 13].If immunogenicity and cross-protection studies

continue to produce encouraging results, onecould even propose that humans should beprimed against all 16 HAs as a strategic policyobjective. If this suggestion seems an outlandish,unjustifiable panic reaction to the current bird fluthreat, reflect that it was first recommended [24] bya WHO committee back in 1969.

PD Griffiths

2 EditorialEditorial

Copyright # 2007 John Wiley & Sons, Ltd. Rev. Med. Virol. 2008; 18: 1–3.DOI: 10.1002/rmv

REFERENCE1. Yao L, Korteweg C, Hsueh W, Gu J. Avian influenza

receptor expression in H5N1-infected and nonin-fected human tissues. FASEB J 2007; 22.

2. Peiris JS, Yu WC, Leung CW, et al. Re-emergence offatal human influenza A subtype H5N1 disease. Lan-cet 2004; 363: 617–619.

3. Hulse-Post DJ, Franks J, Boyd K, et al. Molecularchanges in the polymerase genes (PA and PB1)associated with high pathogenicity of H5N1 influ-enza virus in mallard ducks. J Virol 2007; 81: 8515–8524.

4. Finkelstein DB, Mukatira S, Mehta PK, et al. Persis-tent host markers in pandemic and H5N1 influenzaviruses. J Virol 2007; 81: 10292–10299.

5. Morens DM, Fauci AS. The 1918 influenza pandemic:insights for the 21st century. J Infect Dis 2007; 195:1018–1028.

6. Department of Health. Pre-pandemic and pandemicinfluenza vaccines: scientific evidence base. April 1.www.dh.gov.uk/en/publicatoinsandstatistics/publications/publicationspolicyandguidance/DH_077276 [June 2007].

7. Moscona A. Oseltamivir resistance—disabling ourinfluenza defenses. N Engl J Med 2005; 353: 2633–2636.

8. Hayden FG, Gubareva LV, Monto AS, et al. Inhaledzanamivir for the prevention of influenza in families.Zanamivir Family Study Group. N Engl J Med 2000;343: 1282–1289.

9. Hayden FG, Belshe R, Villanueva C, et al. Manage-ment of influenza in households: a prospective, ran-domized comparison of oseltamivir treatment withor without postexposure prophylaxis. J Infect Dis2004; 189: 440–449.

10. Galbraith AW, Oxford JS, Schild GC,Watson GI. Pro-tective effect of 1-adamantanamine hydrochloride oninfluenza A2 infections in the family environment: acontrolled double-blind study. Lancet 1969; 2: 1026–1028.

11. Hayden FG, Belshe RB, Clover RD, Hay AJ, OakesMG, Soo W. Emergence and apparent transmissionof rimantadine-resistant influenza A virus infamilies. N Engl J Med 1989; 321: 1696–1702.

12. Ferguson NM, Cummings DA, Fraser C, Cajka JC,Cooley PC, Burke DS. Strategies for mitigating aninfluenza pandemic. Nature 2006; 442: 448–452.

13. Germann TC, Kadau K, Longini IM Jr, Macken CA.Mitigation strategies for pandemic influenza in the

United States. Proc Natl Acad Sci USA 2006; 103:5935–5940.

14. European Centre for Disease Prevention and Con-trol. Expert Advisory Groups on Human H5N1Vaccines. vol 1. www.ecdc.eu.int/health_topics/pandemic_influenza/guidance/html [August 2007].

15. Lin J, Zhang J, Dong X, et al. Safety and immunogeni-city of an inactivated adjuvanted whole-virion influ-enza A (H5N1) vaccine: a phase I randomisedcontrolled trial. Lancet 2006; 368: 991–997.

16. Nicholson KG, Colegate AE, Podda A, et al. Safetyand antigenicity of non-adjuvanted and MF59-adju-vanted influenza A/Duck/Singapore/97 (H5N3)vaccine: a randomised trial of two potential vaccinesagainst H5N1 influenza. Lancet 2001; 357: 1937–1943.

17. Stephenson I, Bugarini R, Nicholson KG, et al. Cross-reactivity to highly pathogenic avian influenzaH5N1 viruses after vaccination with nonadjuvantedand MF59-adjuvanted influenza A/Duck/Singa-pore/97 (H5N3) vaccine: a potential priming strat-egy. J Infect Dis 2005; 191: 1210–1215.

18. Stephenson I, Nicholson KG, Gluck R, et al. Safetyand antigenicity of whole virus and subunit influ-enza A/Hong Kong/1073/99 (H9N2) vaccine inhealthy adults: phase I randomised trial. Lancet2003; 362: 1959–1966.

19. Gerdil C. The annual production cycle for influenzavaccine. Vaccine 2003; 21: 1776–1779.

20. Wyman O. Influenza Vaccine Strategies for BroadGlobal Access. 1 October 2007 www.path.org/publi-cations/pub.php?id=1538.

21. Govorkova EA, Webby RJ, Humberd J, Seiler JP,Webster RG. Immunization with reverse-genetics-produced H5N1 influenza vaccine protects ferretsagainst homologous and heterologous challenge. JInfect Dis 2006; 194: 159–167.

22. Lipatov AS, Hoffmann E, Salomon R, Yen HL, Web-ster RG. Cross-protectiveness and immunogenicityof influenza A/Duck/Singapore/3/97(H5) vaccinesagainst infection with A/Vietnam/1203/04(H5N1)virus in ferrets. J Infect Dis 2006; 194: 1040–1043.

23. Sandbulte MR, Jimenez GS, Boon AC, Smith LR,Treanor JJ, Webby RJ. Cross-reactive neuraminidaseantibodies afford partial protection against H5N1 inmice and are present in unexposed humans. PLoSMed 2007; 4: e59.

24. Kilbourne ED. Future influenza vaccines and the useof genetic recombinants. Bull World Health Organ1969; 41: 643–645.

EditorialEditorial 3

Copyright # 2007 John Wiley & Sons, Ltd. Rev. Med. Virol. 2008; 18: 1–3.DOI: 10.1002/rmv