Rev. Med. Virol. 2010; 20: 263–264.Published online in Wiley Online Library

(wileyonlinelibrary.com).DOI: 10.1002/rmv.670

Reviews in Medical Virology

EE DD II T O R II AA L

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Back to the future with influenza

Several recent papers have reported that antibodiesagainst the 2009 pandemic strain of H1N1 influenzacan be induced or boosted with various vaccinesand protect against this and other influenza viruses.How can all of these results be reconciledwithwhatis known about this important pathogen?

When viewed from the perspective of influenzain humans, each circulating influenza strainmutates frequently with selection of a predominantstrain each winter able to escape from accumulatednatural and vaccine-induced immunity. This con-tinuous pressure on the virus from our immunesystems is occasionally removed in dramaticfashion when new haemagglutinin and/or neur-aminidase genes are acquired from animal sources.Thus, there were three major pandemics of the lastcenturywhich gave us our nomenclature for typeAinfluenza: H1N1 in 1918; H2N2 in 1957; H3N2 in1968. Each of these major antigenic shifts allowedeach new virus to gain access to humans who lackedprior protective immunity andwas so successful thatit replaced the previously circulating subtype withina year. Clinically, relative sparing of the elderly wasseen, presumably because of persisting immunityfrom distant infectionwith a related strain. Influenzavaccines from these eras contained two components;one from a strain of type B influenza and anotherfrom a strain of type A influenza (updated annuallyto cope with antigenic drift). In 1977, H1N1 reap-peared, presumably from the frozen state, because itrevealed little evidence of antigenic drift since 1957.Epidemiologically, this infection showed relativesparing of those who were alive prior to 1957,demonstrating that protective immunity had beenretained for over 20 years. This H1N1 subtype didnot replace H3N2 but continued to co-circulatewith it so that seasonal vaccines from that timeuntil the present have had three components (typeB influenza, and both H1N1 and H3N2 strains oftype A influenza).

When viewed from the perspective of influenzain pigs, things look a little different. The porcine

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immune system has not exerted such a strong long-term selective pressure on influenza, presumablybecause of the ready availability of immunologi-cally naive new piglets each year coupled with theshort lifespan of their immune parents, courtesy ofour farming practices and eating habits. Influenzastrains of H1N1 have thus evolved much less inpigs since they were given this virus by humans in1918 and are termed classical swine influenza [1].There was a scare in 1976 when swine influenzainfected military recruits in Fort Dix and co-workers [2]; fearing the start of a new pandemic,a swine influenza vaccine was prepared and givento 45 million Americans, but the virus never spreadbeyond the confines of the military barracks. InApril 2009, a strain which had reassorted its eightsegments of RNA (to include the haemagglutininfrom classical swine influenza) transmitted tohumans and spread around the world [3]. Thismet the definition of a pandemic which WHOdeclared formally on 11 June 2009. Fortunately, the2009 pandemic was less severe than previouspandemics, with only (sic) 18 311 deaths world-wide as of 9 July 2010. Again, there was relativesparing of the elderly, presumably because theyhad residual immunity from prior antigenicexposure to H1N1 strains before they had under-gone extensive selective pressure in humans. Thisimplication has now been tested in detail in amolecular biological tour de force [4].

Influenza haemagglutinin exists as a homotrimerwhose globular membrane-distant componentcontains the receptor binding domain. The anti-genic sites which surround the receptor bindingdomain and mediate neutralisation have beenstudied in pair-wise comparisons of four strainsof influenza type A: the 1918 pandemic virus; strainPR8 from 1934, Brisbane 2007 (a recent vaccinestrain) and the 2009 pandemic virus whoseectodomain was crystallised to 2.6 A resolution[4]. An antibody termed 2D1 from a survivor of the1918 pandemic cross neutralised the 2009 pan-

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demic virus. This antibody bound the Sa antigenicsite and so attention was focused on this part of thehaemagglutinin molecule. Figure 2 in their paperclearly shows progressive acquisition with time ofamino acid changes and glycosylation sites up to2007 yet with conservation of this epitope when the1918 and 2009 pandemic strainswere compared. Theinvestigators next determined the crystal structure ofthe Fab portion of antibody 2D1 when complexedwith haemagglutinin. The footprint of the antibodywas well conserved on the 1918 and 2009 pandemicstrains, but not in the haemagglutinins of the otherstrains examined. For example, compared to the 2009pandemic strain, the 2007 Brisbane strain had threeamino acid differences in the Sa site together withtwoN-glycosylation sites in the central portion of theepitope. These structural features illustrate andexplain why antibody 2D1 cross neutralises the1918 and 2009 pandemic strains but not the viruses ofintermediate pedigree [4,5].

These results explain why an experimental vaccineagainst the 1918 pandemic strain protected miceagainst a lethal challenge with the 2009 pandemicstrain [5] and why mice given a vaccine against the2009 pandemic strain were protected against alethal challenge with 1918 virus [6]. This latterexperiment is most relevant for humans becausethe licensed 2009 vaccine will now be applied toprotect laboratory workers conducting researchwith live 1918 influenza [6]. These results alsoexplain why recipients of the 1976 swine vaccinehave increased neutralising titres to the 2009 strain[7,8] and why only one dose of 2009 vaccine isrequired to protect older people whereas two dosesare required for younger people [9]. However, theresults cannot explain why, in people aged at least60 years, the proportion with antibodies able toneutralise the 2009 pandemic strain increased from33% to 43% after they were given seasonal vaccinein 2007/2008 [8]; an explanation for this requires afurther foray back into the older literature. . .

In 1960, Francis proposed the doctrine of originalantigenic sin for influenza [10]. This posited that theimmune response to antigenically related antigensconsisted of a boost to pre-existing antibodiescoupled with a new response to novel epitopescontained in the latest version of the antigen. Thus,for influenza, the highest titre of antibodies foundagainst a panel of strains indicates which virus thatperson has initially been infected with (in theanalogy, original sin referred to the biblical story of

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Adam and Eve and implied that subsequent sinswere of a lesser magnitude). This doctrine providesthe intellectual basis for conducting sero-archae-ological studies of elderly humans to divine whichstrains of influenza circulated prior to 1918. It alsoexplains why 2007/2008 seasonal vaccine can boostpre-existing antibodies against the 1918 virus inpeople aged greater than 60 years yet is unable toinduce these antibodies in the young. Because these1918 antibodies cross neutralise the 2009 pandemicstrain, administration of the 2007/2008 seasonalvaccine thus probably helped protect some elderlypeople against a virus which did not emerge untilthe following year.

P. D. Griffiths

REFERENCES1. Weingartl HM, Albrecht RA, Lager KM, et al., Exper-

imental infection of pigs with the human 1918pandemic influenza virus. J Virol 2009; 83: 4287–4296.

2. Gaydos JC, Top FH, Jr., Hodder RA, Russell PK.Swine influenza a outbreak, Fort Dix, New Jersey,1976. Emerg Infect Dis 2006; 12: 23–28.

3. Smith GJ, Vijaykrishna D, Bahl J, et al., Origins andevolutionary genomics of the 2009 swine-originH1N1 influenza A epidemic. Nature 2009; 459:1122–1125.

4. Xu R, Ekiert DC, Krause JC, Hai R, Crowe JE, Jr.,Wilson IA. Structural basis of preexisting immunityto the 2009 H1N1 pandemic influenza virus. Science2010; 328: 357–360.

5. Wei CJ, Boyington JC, Dai K, et al., Cross-neutraliz-ation of 1918 and 2009 influenza viruses: role ofglycans in viral evolution and vaccine design. SciTransl Med 2010; 2: 24ra21.

6. Medina RA,Manicassamy B, Stertz S, et al., Pandemic2009 H1N1 vaccine protects against 1918 Spanishinfluenza virus. Nat Commun 2010; 1: 1–15.

7. McCullers JA, van d V, Allison KJ, Branum KC,Webby RJ, Flynn PM. Recipients of vaccine againstthe 1976 ‘‘swine flu’’ have enhanced neutralizationresponses to the 2009 novel H1N1 influenza virus.Clin Infect Dis 2010; 50: 1487–1492.

8. Hancock K, Veguilla V, Lu X, et al., Cross-reactiveantibody responses to the 2009 pandemic H1N1influenza virus. N Engl J Med 2009; 361: 1945–1952.

9. Plennevaux E, Sheldon E, Blatter M, Reeves-HocheMK, Denis M. Immune response after a single vacci-nation against 2009 influenza A H1N1 in USA: apreliminary report of two randomised controlledphase 2 trials. Lancet 2010; 375: 41–48.

10. Francis Tj. On the doctrine of original antigenic sin.Proc Am Philos Soc 2010; 104: 572–578.

Rev. Med. Virol. 2010; 20: 263–264.DOI: 10.1002/rmv