Preparing for the first influenza pandemic of the 21st century.

The tsunami tragedy in Asia cruelly exposed the citizens of this area to the mercy of mother nature through lack of planning and scientific investment. In living memory, however, the even greater destructive power of the global outbreak of Spanish influenza overwhelmed a world totally unprepared. In the 7-month period from Oct 1918 to Mar 1919, as many people as died as a result of the tsunami died of virus-triggered pneumonia in every country of the world each and every day, reaching a staggering total of 50 million.2, 3 In 1918, and during the next pandemic in 1957, the scientific infrastructure was still minute and, although influenza vaccines were under serious development, there were no antiviral drugs licensed to combat pandemic influenza. Given the long lead time to reformulate vaccines, it is now acknowledged that antiviral drugs will be our first defence to reduce the mortality—and social and medical disruption—of the first wave of the next influenza pandemic. Influenza pandemics arise and spread as a succession of waves and then settle down to cause yearly epidemics. Given the lack of both antivirals and vaccines, our forebears struggled with the global outbreaks of the past with a mixture of masks, quarantine, and social distancing. There is no evidence that this entirely sensible defence had any effect whatsoever.

As we begin the new century, the WHO in particular has recognised, and broadcast very widely—often to deaf ears—that the key to not being overwhelmed in the first wave of a global infection is to plan very carefully and thoughtfully while there is still time. There is a window of opportunity open now that will gradually close over the coming months.

The WHO and the wider scientific community believe that we are as close to the next pandemic as we have been any time in the past 37 years. Two of the three widely recognised prerequisites for a human pandemic have been met in the avian influenza outbreak in east Asia: first, the emergence of a new influenza virus (avian influenza H5N1), to which the population has little or no immunity, and against which there is—to date—no effective vaccine; and second, its transfer to human beings with virulence. The virus is even battering its way through the final barrier—passage from person to person. The Director General of the WHO, Lee Jong-Wook, discussed the danger of a pandemic of a new infection such as avian influenza with the WHO executive board in January, and highlighted the need to establish emergency systems for an immediate and effective response to an international health crisis. So where are we in terms of planning our response to the threat of an influenza pandemic?

A key part of a pandemic plan is clinical management options. Undoubtedly this is our Achilles' heel. The influenza science base is strong but practical application is frighteningly feeble. Essential stocks of antivirals and vaccines are noteable by their absence. Research shows that the neuraminidase inhibitor (NI) antivirals are very effective against the human and avian H5N1 virus strains, while research into the composition of vaccines against H5N1 has led the USA to order 2 million doses, which will protect the population, at least in a small way, if the next pandemic stems from this strain. But what about the remaining 290 million or so citizens of the USA? How will they be protected? The outbreak of severe acute respiratory syndrome (SARS) in southeast Asia and the deliberate release of anthrax in the USA have shown that modern societies do not take kindly to outbreaks of infectious disease and they are prone to panic very quickly.

The UK, USA, Canada, France, Germany, Japan, and about a dozen other countries, have a pandemic plan in place. However, there is still a long, difficult, and frustrating road ahead to ensure nations are well prepared when the next influenza pandemic strikes. Reassuringly, Australia and France have moved a step forward in planning and will start to stockpile NI drugs for 20–25% of the population.

The great advantage of antivirals is that they can be stockpiled for future use, providing a critical management option in the first months of a pandemic and during the first great wave while a vaccine is in development. There are a number of antiviral attributes that may lend some drugs to being more appropriate than others for stockpiling. For example, the M2 ion channel inhibitors (amantadine and rimantadine) and one of the NIs (oseltamivir) can be taken orally; however, the M2 inhibitors are more likely to be associated with the emergence and spread of drug-resistant influenza than oseltamivir. Thus, the WHO have highlighted the importance of selecting appropriate agent(s) for stockpiling as part of national pandemic plans.

In the two pandemics in 1957 and 1968, the casualties were in excess of 6 million worldwide and the virological community did very little except to observe and record. But the SARS outbreak of 2003 awakened a new aggressive spirit, underpinned with molecular science and rapid diagnostics. We would no longer wish to be the passive audience at a macabre theatre of infection; rather, infectious disease experts, mathematicians, virologists, vaccine specialists, and chemotherapists would be thrown into the fray. The confrontation with SARS was very much like a battle. Indeed, the troops on the ground—epidemiologists, nurses, and doctors—died. The WHO uncovered its new power and used it to the full—nations who failed to act were exposed and had travel restrictions applied. This measure rocked even countries with a firm economy.

The world was lucky with SARS. It turned out to be a slow dachshund of a virus akin to smallpox, and not a speedy greyhound like measles or influenza. These plodder viruses are characterised by a low basic reproductive rate (R0)—in the case of SARS, the R0 was 2, meaning that from a single case only two new cases would be expected. Together with a long incubation period of 10–12 days, the epidemic could be—and was—broken by quarantine. Surprisingly, a retrospective study of the 1918 influenza pandemic has suggested a low R0 of 3–4. But influenza has another vital attribute: a very short incubation period. Thus, we will not be able to rely on quarantine as a defensive measure, except as a second-line strategy. Our first defence must exploit the scientific advances of the past decades: new drugs and vaccines.

The UK has a proud history of intervention and innovation against infectious diseases, from the individual heroism of the people of Eyam during the Black Death, to huge investment in the sewage systems of Victorian Britain, and, in the past century, the scientific discovery of influenza itself as a virus. The UK has more pandemic plans than any country, and a strong, supportive scientific and infectious disease community. But very serious decisions must be made now. The Department of Health has spearheaded discussions about the pandemic plan and supported the purchase of smallpox vaccine stocks in the unlikely event of a bioterrorism attack. But mother nature is more capricious and powerful than any bioterrorist. The coming influenza pandemic will cut huge swathes in the world community, and history would look with a jaundiced eye should governments hesitate and not join in this war, and place monetary priorities elsewhere.