Intended for healthcare professionals


While awaiting the next pandemic of influenza

BMJ 1994; 309 doi: (Published 05 November 1994) Cite this as: BMJ 1994;309:1179
  1. R G Webster

    Largely uncontrolled influenza is a potentially devastating disease of humans and of a limited number of domestic and wild animals. Continued rapid evolution of the influenza A virus is responsible for the annual epidemics and occasional pandemics that have affected humans for centuries.1

    Epidemics can be traced to genetic drift - the accumulation of mutations in the antigenic domains of the haemagglutinin and neuraminidase spike glycoproteins. These changes allow the virus to escape immunological surveillance and spread through human populations. More catastrophic are pandemics. These global outbreaks arise from genetic shift: the emergence of completely new haemagglutinin or neuraminidase molecules to which most people are not immune. The source of these new influenza virus gene segments is wild aquatic birds, which harbour all 14 haemagglutinin subtypes of influenza A viruses.

    Five pandemics of influenza have occurred this century at irregular intervals, including the “Spanish” pandemic, which claimed over 20 million lives in 1918. In two of the three outbreaks for which viruses are available the pandemic strain arose by genetic reassortment between Eurasian avian viruses and those in humans. Only three of the 14 haemagglutinin subtypes (H1, H2, H3) have infected humans this century. Whether the other subtypes (H4 through to H14) could become virulent in the future is unclear, although H7 viruses have caused disease in both horses and seals.

    Curiously, most genetic shifts have occurred in China, as shown by the Asian/57, Hong Kong/68, and Russian/77 pandemic strains, implicating this region as an area of origin of influenza.2 Why this is so is unclear, although several observations provide intriguing clues. All subtypes of influenza A viruses have been found in aquatic birds in China, where current agricultural practices put large numbers of people in close proximity to farm animals, including ducks and pigs. These conditions favour the generation and spread of new viral strains and provide a possible medium - pigs - for the genetic reassortment of human and avian viruses.3

    Several recent events in Europe are noteworthy with regard to the emergence of new influenza viruses. An avian HINI virus infected European pigs in 1979 and has become the dominant virus causing influenza in swine populations. In 1985 reassortant influenza viruses isolated from Italian pigs were found to posses the H3 haemagglutinin and neuraminidase surface glycoproteins from human influenza viruses and the genes encoding the six internal proteins of an avian influenza virus circulating in pigs.4 In 1993 counterparts of these viruses were isolated from two children with mild respiratory symptoms who were living in geographically distinct regions of the Netherlands.5 Each child had had indirect contact with pigs, which supports the idea that such animals may have a pivotal role in the generation and transmission of avian influenza virus genes to humans.

    Although these findings seem to argue against the hypothesis that influenza may originate in China, it must be kept in mind that Europe is adjacent to Asia and that the influenza viruses responsible for the Asian/57 and Hong Kong/68 pandemics originated from the Eurasian lineage of avian influenza viruses. The human-avain ressortant influenza viruses isolated from pigs in Italy and children in the Netherlands are unlikely to spread and produce an epidemic as the human population is immune to their particular heamaggutinin and neuraminidase glycoproteins. On the other hand, these viruses should not be dismissed, for they could be a “Trojan horse” for the introduction of new avian influenza virus gene segments into human influenza viruses. If these human-avian reassortant influenza viruses spread to Asia and acquire envelopes containing new avian influenza virus antigens they may then become the next pandemic strain.

    Historical records suggest that another pandemic of influenza is overdue. It is 26 years since the Hong Kong/68 virus emerged and 17 years since the Russian/77 strain reappeared. We are paying insufficient attention to this probable global event. We have limited understanding of the molecular events that underlie pandemics of influenza: to have any hope of preventing one of these outbreaks we need to identify the specific interplay among people, pigs, and birds that spawns a new pandemic virus. Current preventive strategies involving vaccines and antiviral drugs could be expected to blunt the pandemic in only a few regions of the world. Inactivated and live attenuated vaccines for influenza are about equally efficacious (60-90%) when antigenically matched vaccines are used.6

    Reverse genetics offers a new strategy for improving influenza vaccines - namely, inserting defined mutations into attenuated vaccines or increasing the yields of virus for inactivated vaccines.7 But this strategy could not be expected to overcome the initial lag time in the preparation of a matched vaccine. Although antiviral drugs such as amantadine and its analogue rimantadine would probably be efficacious in the first wave of infection, drug resistance would emerge rapidly, making control of the pandemic unlikely. A new group of antiviral drugs, designed around the structure of the sialic acid binding site on the neuraminidase molecule, have shown promise in animal model studies and are now being tested clinically.8 These first generation antiviral drugs based on structure will probably also have limitations, but they herald future strategies that may provide some control of new pandemics. In the meantime, we need to plan for the next pandemic.


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