John M. Barry – This month, the World Health Organization finally declared that the new H1N1 virus has become pandemic. This week it reported a big jump in cases and fatalities since last Friday. How many people this virus will sicken and kill depends, ultimately, on three things: the virus itself; the impact of what are known as ‘non-pharmaceutical interventions’; and the availability and effectiveness of a vaccine. The virus will be the most important factor. Influenza is one of the fastest-mutating organisms in existence, which makes it unpredictable, and a virus newly infecting the human population is likely to be even more unpredictable as it adapts to a new environment. There have been four pandemics that we know about in some detail: 1889-92, 1918-20, 1957-60 and 1968-70. All four followed similar patterns: initial sporadic activity with local instances of high attack rates – just as H1N1 has behaved so far – followed four to eight months later by waves of widespread illness with 20 to 40 per cent of the population sickened. (In a normal influenza season about 10 per cent of the population gets sick.) Subsequent waves followed as well.

In all four pandemics, lethality changed from wave to wave – sometimes increasing, sometimes decreasing. It’s impossible to know what will happen this time, but in 1999 the Centres for Disease Control and Prevention modelled a moderate pandemic in the United States, including a vaccine in its calculations, and concluded that the death toll would probably be 89,000 to 207,000. If the virulence of this virus does not significantly increase – and right now there is no reason to think it will – something close to the lower number looks probable. What could help bring about such a best case? Again, the virus is the most important factor, and we have no control over it. But we do have non-pharmaceutical interventions and the possibility of a vaccine. Such interventions would come into play primarily in a moderate or severe pandemic. For a mild one, we may not need to take steps beyond washing hands, exercising ‘cough etiquette’ and keeping the sick at home. But if the virus increases its virulence, other measures, such as closing schools, urging people to telecommute and even banning public meetings, could mitigate the impact.

The most important human intervention is, of course, a vaccine. There are many unknowns: Because influenza mutates so rapidly, a new vaccine has to be made each year just for seasonal flu. Vaccines for most diseases approach 100 per cent effectiveness, but a good flu vaccine is 70 per cent effective; a great one is 90 per cent effective. The vaccine in the 2007-08 flu season was only 44 per cent effective. Hitting the ‘good’ mark for a new virus that may be changing even more rapidly than seasonal flu will be difficult. Supply is another problem. In a best case, enough vaccine could be available by October as long as an adjuvant is used to simultaneously stimulate the immune system, which lessens the need for antigen from the virus itself. However, if the virus used to make vaccine grows slowly, or if a dose requires more antigen than seasonal flu, or if two doses are required to provide protection, producing that much vaccine could easily stretch deep into 2010. The more virulent the virus, the more likely it is that foreign governments will refuse to allow export of the vaccine until their own populations are fully protected.

The bottom line? Little can be done in the short term beyond exerting diplomatic pressure to guarantee that foreign governments allow manufacturers to honor contracts to export vaccine. In the medium term, sustained investment in vaccine production technologies – especially recombinant ones – could make it possible to produce massive amounts of vaccine in a few weeks. In the long term, we need a vaccine that works against all influenza viruses. Enough work has been done to suggest that this Holy Grail is achievable. Had influenza been taken seriously for the past 30 years, we would probably have one by now. No matter what happens over the next year or two, that’s one history lesson we need to learn.