Until the beginning of the last century, infectious diseases were the major cause of mortality of humankind. Around 1900, infectious diseases caused an estimated 50% of all deaths in the industrialised world. In the following decades, this percentage decreased to no more than a few percent. This was largely thanks to the implementation of sanitary and hygiene measures such as the installation of sewage and clean drinking water systems. However, veterinary disease control measures and the development and use of vaccines and antimicrobial compounds have also contributed significantly to this decrease. A major success in the combat of infectious diseases was the formal declaration in 1980 of the worldwide eradication of smallpox, achieved by a global vaccination campaign orchestrated by the World Health Organization (WHO). It is interesting to note, that a second virus - rinderpest virus - was declared eradicated from the globe by the OIE in 2011 after the implementation of major vaccination campaigns: this animal virus had not only devastated cattle herds during the past centuries, but had also caused major problems for the people who depended on them. Stimulated by these successes, certain policymakers and scientists predicted that virtually all infectious diseases of humankind would be brought under control in the foreseeable future.

Paradoxically there seems to be a dramatic increase over recent decades in the emergence or re-emergence of virus threats in humans and animals worldwide. Striking examples in humans were the emergence of the still ongoing AIDS pandemic in the 1980s and the prevented severe acute respiratory syndrome (SARS) pandemic that started in 2002. Viruses that had spilled over from animal reservoirs were at the basis of these two infectious disease outbreaks in humans. Apart from these introductions, which caused major pandemic threats in humans, a large number of other virus infections have spilled over from animal reservoirs to humans or other susceptible species, resulting in considerable morbidity and mortality as 'virgin soil' epidemics. Indeed most of the emerging viruses that threaten humans have their origin in the animal world, highlighting that humankind continues to be part of a global ecosystem. Similarly, recent mass mortalities among wild aquatic and terrestrial mammals caused by previously known and newly discovered morbilliviruses, as well as outbreaks of hog cholera, foot and mouth disease and fowl plague among domestic animals, highlight this trend.

Other examples of virus infections in humans are illustrated by a long list of exotic names of places such as Ebola, Lassa, Rift Valley, Crimea-Congo, Hendra, Nipah and West Nile, associated with the origin of viruses that have crossed the species boundary to humans.

This unexpected increase in infectious disease outbreaks, which started in the second half of the last century, was facilitated by a complex mix of predisposing factors in our globalising world. Major changes in our social environment, technology and the global ecology collectively created opportunities for viruses to infect new hosts. Subsequent adaptation to the newly invaded species then paved the way for an unprecedented spread with often dramatic consequences for public health, animal health, animal welfare, food supply, economies and biodiversity.

The emergence of the last influenza pandemic caused by the new swine H1N1 virus fits this trend of an increasing number of emerging infections from the animal world. It is however important to note that influenza pandemics have also occurred in previous centuries. In the twentieth century alone three influenza pandemics took place, the 'Spanish flu' of 1918–1919, the 'Asian flu' of 1957 and the 'Hong Kong flu' of 1968. These cost the lives of an estimated 50, 2 and 1 million people, respectively.

All pandemic influenza viruses originate from avian influenza A viruses. After crossing the species barrier, an avian influenza virus may become transmissible from mammal to mammal, and from human to human. This process is caused either by the exchange of RNA segments between influenza A viruses ('re-assortment') or by accumulating sequential mutations. In the past 15 years, numerous human zoonotic infections with avian influenza viruses have been reported. Although in some cases leading to a large number of individual human cases of avian influenza, these were all sporadic cases, not leading to sustained human-to-human transmission of the avian influenza virus. Human infections with the highly pathogenic avian influenza virus of the H5N1 subtype (H5N1 HPAI virus) are, however, of particular concern. After we first identified this virus subtype in a deceased child in 1997, H5N1 HPAI viruses have been identified in more than 550 human influenza cases, with a case fatality rate of more than 50%. Most of these were associated with outbreaks of HPAI in poultry, which had spread in an unprecedented way from Asia to the Middle East, Europe and western Africa. In several affected areas, these H5N1 HPAI viruses are still enzootic in wild and domestic birds today. New industrial poultry husbandry systems and virus transmission by migratory birds were probably important factors in the unprecedented spread of H5N1 HPAI viruses. Recently it has been demonstrated by our laboratory and a group in the USA/Japan that only a handful of mutations are necessary for the currently circulating H5N1 HPAI viruses to become transmissible from mammal to mammal, indicating that these viruses do indeed pose a real threat. The pandemic threat posed by these and other avian influenza viruses with zoonotic potential prompted WHO to advise national authorities to develop pandemic preparedness plans, which should allow an adequate response to an emerging influenza pandemic that might cause a huge worldwide burden of disease.

The first twenty-first century pandemic was however not caused by influenza, but by the hitherto unknown respiratory disease, SARS, that rapidly spread from its original geographical source in China. It eventually caused the deaths of about 10% of the estimated 8000 people affected worldwide. A global response coordinated by WHO rapidly identified a coronavirus as the causative agent that had probably emerged from a bat reservoir. This allowed the implementation of societal intervention strategies such as isolation and quarantine measures, which effectively stopped the SARS pandemic. In fact, it was the first pandemic that was interrupted at its start by the implementation of public health measures: the rapidly developed antiviral- and vaccine-based intervention strategies proved eventually not to be necessary to stop this emerging pandemic from spreading further.

Although an emerging influenza pandemic cannot be expected to be as readily contained with similar measures, the successful combat of SARS did spark optimism for the combat of future influenza pandemics. Indeed pandemic preparedness plans were promptly activated when the new H1N1 pandemic virus started spreading beyond its Mexican origin in the spring of 2009. WHO declared the pandemic to be a fact within 2 months of the initial identification of the virus, when it had first crossed the Mexican-USA border. However, the virus had probably already been circulating extensively in Mexico in the preceding months. Surveillance and societal measures, combined with the use of antivirals and at a later stage also preventive vaccines, were the major lines of defence worldwide. The severity of the last H1N1 pandemic eventually proved to be relatively moderate. However, many young people were among the most seriously affected or fatal cases, and about one-quarter of those patients had no pre-existing underlying disease. This H1N1 pandemic virus, which has now continued to circulate as a seasonal influenza virus, did apparently not acquire the mutations that are necessary to develop into a higher pathogenic phenotype. The prudent policy of 'preparing for the worst while hoping for the best', as advocated by Dr Keji Fukuda of WHO, has prompted some critics to accuse health authorities of 'over-reacting' during the last pandemic. Since it is impossible to predict the course of an influenza pandemic as it emerges, the policy of 'better be safe than sorry' is, however, warranted.

Although improved detection and surveillance techniques, as well as increased media attention, may have contributed to our perception of an increase in the incidence of outbreaks of virus infections, it has become clear that the complex mix of major changes in our modern society creates new opportunities for virus infections to emerge. In combating this global threat, we should make optimal use of the new tools provided by the unprecedented advances made in the research areas of molecular biology, epidemiology, genomics and bioinformatics. Early warning systems based on state-of-the-art virus detection and discovery techniques, as well as targeted intervention strategies, have already been shown to be able to make the difference in controlling the SARS pandemic as it emerged.