34 Influenza 2006

Pandemic Management

– See also Reyes-Terán 2006 and WHO 2006c –

Serious influenza pandemics are rare and unpredictable events. Managing unedited situations requires some appreciation of the magnitude of the problems that lie ahead. The impact on human health may be highly variable and is expressed in the number of

•infected individuals

•clinically ill individuals

•hospitalised patients

•deaths.

It is generally assumed that during the first year of the next pandemic 2 billion people will become infected with the new virus and that half of them will have symptoms. Less accurate are the estimates of the number of people that will require hospitalisation and the death toll. During the 1957 and 1968 pandemics, the excess mortality has been estimated at around one million deaths each. In contrast, 50 million individuals are thought to have died from the 1918 influenza pandemic. Excess mortality during the last influenza pandemics varied from 26 to 2,777 per 100,000 population (Table 2). Adjusted for today’s world population, these figures would translate into 1.7 million to 180 million deaths.

Table 2: Death toll in 20th century pandemics and projections for the next pandemic *

According to data from http://www.census.gov/ipc/www/world.html +

http://www.prb.org/Content/NavigationMenu/PRB/Educators/Human_Population/Population_Gr owth/Population_Growth.htm

In countries such as France, Spain and Germany, the yearly mortality from all causes is around 900 deaths per 100,000 population. A devastating pandemic might therefore, in the course of only a few months, cause three times as many deaths as would normally occur in an entire year. Indeed, social and economic disruption would occur in all countries to varying extents. In a world of extensive mass media coverage of catastrophic events, the resulting atmosphere would probably come close to war-time scenarios. In contrast, a mild pandemic similar to the 1968 episode would go nearly unnoticed and without considerable impact on national healthcare systems and on the global economy.

The concern that the world might be in for a revival of the 1918 scenario is based on the observation that the currently spreading H5N1 virus shares disturbing characteristics with the virus of the 1918 pandemic (Taubenberger 2005). However, if

Global Management 35

H5N1 is to be the candidate virus for the next devastating influenza pandemic, why has it not yet acquired the ability to spread easily between humans? Over the past years, H5N1 has had both the time and opportunities to mutate into a pandemic strain. Why hasn’t it? And if it hasn’t in nearly 10 years, why should it do so in the future? It is true that of the 16 influenza H subtypes, only three (H1, H2 and H3) are known to have caused human pandemics (1918, 1957, 1968, and probably 1889 [Dowdle 2006]), and it has even been hypothesised that H5 viruses are inherently incapable of transmitting efficiently from human to human. Shall we one day discover that H5 viruses are not good for human pandemics, because not all possible subtypes can reassort to form functional human pandemic strains? We don’t know.

Apart from stepwise mutations that transform an avian influenza virus into a human influenza virus, reassortment is the second way in which new pandemic viruses are generated. The two pandemics that were triggered by this phenomenon occurred in 1957 and in 1968. Both were relatively mild and fundamentally different from what happened in 1918. There is some preliminary experimental evidence that reassortants of the 1918 virus might be less virulent than the co-ordinated expression of all eight 1918 virus genes (Tumpey 2005). Does that mean that pandemics resulting from reassortment events of a human and an avian virus are milder than pandemics caused by a virus which slowly accumulates mutations in order to “migrate” from water fowl hosts to human hosts? We don’t know.

The revival of the 1918 catastrophe might also never happen. But the 1918 influenza pandemic did occur, and good planning means being prepared for the worst. As it is impossible to predict whether the next pandemic will result in ~20 or ~2,000 deaths per 100,000 people, the international community should prepare for the 2,000 figure. The three defence lines are containment, drugs, and vaccines.

Containment

Containment and elimination of an emergent pandemic influenza strain at the point of origin has been estimated to be possible by a combination of antiviral prophylaxis and social distance measures (Ferguson 2005, Longini 2005). To this purpose, the WHO has recently started creating an international stockpile of 3 million courses of antiviral drugs to be dispatched to the area of an emerging influenza pandemic (WHO 20000824).

If the pandemic cannot be contained early on during an outbreak, rapid intervention might at least delay international spread and gain precious time. Key criteria for the success of this strategy have been developed (Ferguson 2005). However, the optimal strategy for the use of stockpiled antiviral drugs is not known, because stopping a nascent influenza pandemic at its source has never before been attempted.

Drugs

Once a pandemic is under way – and vaccines have not yet become available – national responses depend on the availability of antiviral drugs. As demand for the drug will exceed supply, stockpiling of antiviral drugs, either in the form of capsules or the bulk active pharmaceutical ingredient, has been considered a viable option by some governments.

The debate over which drugs should be stockpiled is not over. Until now, mainly oseltamivir has been used to constitute stockpiles of neuraminidase inhibitors. After the recent isolation of oseltamivir-resistant isolates in serious H5N1 infection, other

36 Influenza 2006

antiviral agents to which oseltamivir-resistant influenza viruses remain susceptible, should be included in treatment arsenals for influenza A (H5N1) virus infections (de Jong 2005) – in other words: zanamivir.

The value of adamantanes for stockpiling is less clear. H5N1 isolates obtained from patients in China in 2003 and in one lineage of avian and human H5N1 viruses in Thailand, Vietnam, and Cambodia were resistant to adamantanes (Hayden 2006). However, isolates tested from strains circulating recently in Indonesia, China, Mongolia, Russia, and Turkey appear to be sensitive to amantadine (Hayden 2005).

With regard to the economical impact, there is some evidence that even stockpiling of the costly neuraminidase inhibitors might be cost-beneficial for treatment of patients and, if backed by adequate stocks, for short-term postexposure prophylaxis of close contacts (Balicer 2005). When comparing strategies for stockpiling these drugs to treat and prevent influenza in Singapore, the treatment-only strategy had optimal economic benefits: stockpiles of antiviral agents for 40 % of the population would save an estimated 418 lives and $414 million, at a cost of $52.6 million per shelf-life cycle of the stockpile. Prophylaxis was economically beneficial in highrisk subpopulations, which account for 78 % of deaths, and in pandemics in which the death rate was > 0.6 %. Prophylaxis for pandemics with a 5 % case-fatality rate would save 50,000 lives and $81 billion (Lee 2006).

Once a pandemic starts, countries without stockpiles of antiviral drugs will probably be unable to buy new stocks. In this context it has been suggested that governments provide compulsory licensing provisions, permitting generic manufacturers to start producing antivirals locally under domestic patent laws or to import them from generic producers at affordable prices (Lokuge 2006). In Europe, some governments are trying to build up stocks of the neuraminidase inhibitor oseltamivir for 25 % of the population. The number of treatment doses required to achieve this degree of “coverage” are based on the daily standard treatment course of 75 mg bid for 5 days. However, if doses twice as high, prescribed over a period twice as long (WHO 2005, WHO 2006d) should turn out to be required in a substantial number of patients, a stockpile planned for 25 % of a population might melt away more rapidly than expected.

For detailed information about drug treatment of influenza, see Hoffmann 2006b.

Vaccines

In an ideal world, we would have 6.5 billion vaccine doses the day after the pandemic starts; in addition, we would have 6.5 billion syringes to inject the vaccine; and finally, we would have an unlimited number of health personnel to administer the vaccine.

We don’t live in an ideal world. At present, the world has a production capacity of about 300 million trivalent influenza vaccines per year, most of which is produced in nine countries (Fedson 2005). 300 million trivalent influenza doses translate into 900 million univalent doses, enough to vaccinate 450 million people with an initial vaccination and a booster dose – if the H5N1 vaccine is sufficiently immunogenic...

Influenza vaccines are currently prepared in fertilised chicken eggs, a process which was developed over 50 years ago (Osterholm 2005). New technologies may one day be able to develop vaccines more (Palese 2006). A dream vaccine would provide broad-spectrum protection against all influenza A subtypes (Neirynck 1999, Fiers