New England Journal of Medicine. antigen dose will be critical for pandemic influenza preparedness. Development of new antiviral therapeutics and other, nonpharmaceutical intervention strategies will further supplement pandemic preparedness. This review highlights the current status of egg-dependent and egg-independent strategies against an avian influenza pandemic. The three major influenza pandemics of the 20th (Ref. 1); furthermore, 2009 saw the development century C in 1918 (Spanish Flu), 1957 (Asian Flu) of the Mexican Flu pandemic (Fig. 1). Pandemics and 1968 (Hong Kong Flu) C collectively arise when a novel influenza strain emerges that accounted for millions of deaths worldwide can infect and spread efficiently in immunologically naive human populations. Changes in the influenza viral genome can occur in one of two ways: (1) the accumulation of genetic mutations (antigenic drift), due to host selective pressure and/or a faulty viral RNA polymerase activity; RR6 and (2) the exchange of one or more fragments of its segmented genome (genetic reassortment) with other influenza viruses coinfecting the same cell, leading to the expression of novel surface antigen(s) (antigenic shift). The genetic novelty of the 1957 Asian and 1968 Hong Kong pandemic influenza viruses C classified as H2N2 and H3N2, respectively, according to the subtypes of the surface glycoproteins haemagglutinin (H) and neuraminidase (N) they express C were the result of genetic reassortment between human and avian Cav2.3 influenza viruses, probably due to coinfection in pigs (Refs 2, 3, 4, 5) (Fig. 1). Recent evidence suggested that this genetic novelty of the 1918 Spanish pandemic influenza computer virus (H1N1) was possibly due to direct transmission of an avian RR6 influenza computer virus to humans, although the absolute origin of this computer virus remains unknown (Ref. 6); another study indicated that probably all three pandemic influenza strains of the 20th century may have been generated through a series of multiple reassortment events (Ref. 7). The recent 2009 Mexican (or H1N1) Flu pandemic was also caused by reassortment (of avian, pig and human viruses), to produce a novel H1N1 computer virus that was able to spread rapidly worldwide, but with limited pathogenicity (Ref. 8). Open in a separate window Physique 1 Major influenza pandemics since 1918 and emergence of HPAI H5N1 virusesInformation regarding the computer virus serotype involved in each pandemic, its reassortant features and the estimated number of human deaths is included. The emergence of highly pathogenic avian influenza (HPAI) H5N1 viruses is also presented. Prior to the 2009 Mexican Flu pandemic, the outbreaks over the past ten years of human influenza caused by the highly pathogenic avian influenza (HPAI) H5N1 computer virus caused serious concern because of its high lethality (Fig. 1), although the computer virus does not currently show efficient humanChuman transmission and is considered prepandemic. The 1997 outbreak of H5N1 influenza in Hong Kong was the result of direct transmission of an RR6 entirely avian influenza computer virus to humans (Refs 9, 10, 11, 12, 13, 14, 15), and resulted in 18 documented cases of respiratory disease including six deaths (Refs 2, 15). The amino acid changes in the polymerase proteins, specifically PB2, identified in the 1918 computer virus are also seen in the 1997 H5N1 viruses (Ref. 6). In 2003, H5N1 viruses were again isolated from two human cases in Hong Kong, one of which was fatal (Ref. 16). Since then, human infections with H5N1 viruses have spread to several countries in Asia, Europe and Africa (Ref. 17), accounting for 471 cases, with a RR6 60% case fatality (Fig. 1). H5N1 computer virus transmission within migratory and aquatic birds and its back-and-forth transmission to poultry populations and further spread to humans due to close contacts with the diseased birds are well documented. Furthermore, the H5N1 computer virus causes significant infections in dogs, tigers, cats, stone martens and perhaps other mammals, indicating that it has an expanded host range (Ref. 18). In addition to influenza in humans caused by H5N1, respiratory contamination in humans with other avian influenza subtypes (H9N2 and H7N7) have been documented in Hong Kong, southern China, and the Netherlands (Refs 19, 20, 21, 22). These events spotlight the potential of other avian influenza viruses to cause a pandemic through the emergence of an avianChuman reassortant capable of human transmission (Ref. 23), and have.