Modeling the Worldwide Spread of Pandemic Influenza: Baseline Case and Containment Interventions

Background: The highly pathogenic H5N1 avian influenza virus, which is now widespread in Southeast Asia and which diffused recently in some areas of the Balkans region and Western Europe, has raised a public alert toward the potential occurrence of a new severe influenza pandemic. Here we study the worldwide spread of a pandemic and its possible containment at a global level taking into account all available information on air travel. Methods and Findings: We studied a metapopulation stochastic epidemic model on a global scale that considers airline travel flow data among urban areas. We provided a temporal and spatial evolution of the pandemic with a sensitivity analysis of different levels of infectiousness of the virus and initial outbreak conditions (both geographical and seasonal). For each spreading scenario we provided the timeline and the geographical impact of the pandemic in 3,100 urban areas, located in 220 different countries. We compared the baseline cases with different containment strategies, including travel restrictions and the therapeutic use of antiviral (AV) drugs. We investigated the effect of the use of AV drugs in the event that therapeutic protocols can be carried out with maximal coverage for the populations in all countries. In view of the wide diversity of AV stockpiles in different regions of the world, we also studied scenarios in which only a limited number of countries are prepared (i.e., have considerable AV supplies). In particular, we compared different plans in which, on the one hand, only prepared and wealthy countries benefit from large AV resources, with, on the other hand, cooperative containment scenarios in which countries with large AV stockpiles make a small portion of their supplies available worldwide. Conclusions: We show that the inclusion of air transportation is crucial in the assessment of the occurrence probability of global outbreaks. The large-scale therapeutic usage of AV drugs in all hit countries would be able to mitigate a pandemic effect with a reproductive rate as high as 1.9 during the first year; with AV supply use sufficient to treat approximately 2% to 6% of the population, in conjunction with efficient case detection and timely drug distribution. For highly contagious viruses (i.e., a reproductive rate as high as 2.3), even the unrealistic use of supplies corresponding to the treatment of approximately 20% of the population leaves 30%–50% of the population infected. In the case of limited AV supplies and pandemics with a reproductive rate as high as 1.9, we demonstrate that the more cooperative the strategy, the more effective are the containment results in all regions of the world, including those countries that made part of their resources available for global use. A metapopulation stochastic epidemic model for influenza shows the need to include air transportation when assessing the occurrence probability of global outbreaks. The impact of the use of antiviral drugs is also measured. Background.: Seasonal outbreaks (epidemics) of influenza—a viral infection of the nose, throat, and airways—affect millions of people and kill about 500,000 individuals every year. Regular epidemics occur because flu viruses frequently make small changes in the viral proteins (antigens) recognized by the human immune system. Consequently, a person's immune-system response that combats influenza one year provides incomplete protection the next year. Occasionally, a human influenza virus appears that contains large antigenic changes. People have little immunity to such viruses (which often originate in birds or animals), so they can start a global epidemic (pandemic) that kills millions of people. Experts fear that a human influenza pandemic could be triggered by the avian H5N1 influenza virus, which is present in bird flocks around the world. So far, fewer than 300 people have caught this virus but more than 150 people have died. Why Was This Study Done?: Avian H5N1 influenza has not yet triggered a human pandemic, because it rarely passes between people. If it does acquire this ability, it would take 6–8 months to develop a vaccine to provide protection against this new, potentially pandemic virus. Public health officials therefore need other strategies to protect people during the first few months of a pandemic. These could include international travel restrictions and the use of antiviral drugs. However, to get the most benefit from these interventions, public-health officials need to understand how influenza pandemics spread, both over time and geographically. In this study, the researchers have used detailed information on air travel to model the global spread of an emerging influenza pandemic and its containment. What Did the Researchers Do and Find?: The researchers incorporated data on worldwide air travel and census data from urban centers near airports into a mathematical model of the spread of an influenza pandemic. They then used this model to investigate how the spread and health effects of a pandemic flu virus depend on the season in which it emerges (influenza virus thrives best in winter), where it emerges, and how infectious it is. Their model predicts, for example, that a flu virus originating in Hanoi, Vietnam, with a reproductive number (R0) of 1.1 (a measure of how many people an infectious individual infects on average) poses a very mild global threat. However, epidemics initiated by a virus with an R0 of more than 1.5 would often infect half the population in more than 100 countries. Next, the researchers used their model to show that strict travel restrictions would have little effect on pandemic evolution. More encouragingly, their model predicts that antiviral drugs would mitigate pandemics of a virus with an R0 up to 1.9 if every country had an antiviral drug stockpile sufficient to treat 5% of its population; if the R0 was 2.3 or higher, the pandemic would not be contained even if 20% of the population could be treated. Finally, the researchers considered a realistic scenario in which only a few countries possess antiviral stockpiles. In these circumstances, compared with a “selfish” strategy in which countries only use their antiviral drugs within their borders, limited worldwide sharing of antiviral drugs would slow down the spread of a flu virus with an R0 of 1.9 by more than a year and would benefit both drug donors and recipients. What Do These Findings Mean?: Like all mathematical models, this model for the global spread of an emerging pandemic influenza virus contains many assumptions (for example, about viral behavior) that might affect the accuracy of its predictions. The model also does not consider variations in travel frequency between individuals or viral spread in rural areas. Nevertheless, the model provides the most extensive global simulation of pandemic influenza spread to date. Reassuringly, it suggests that an emerging virus with a low R0 would not pose a major public-health threat, since its attack rate would be limited and would not peak for more than a year, by which time a vaccine could be developed. Most importantly, the model suggests that cooperative sharing of antiviral drugs, which could be organized by the World Health Organization, might be the best way to deal with an emerging influenza pandemic. Additional Information.: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040013.