PANDEMIC

A/H1N1, uncovering a new type of influenza

Policeman protecting himself against the A/H1N1 epidemic, Mexico, April 2009.© Shutterstock
Policeman protecting himself against the A/H1N1 epidemic, Mexico, April 2009.
© Shutterstock
A test for the new A/H1N1 virus developed by the Centers for Disease Control and Prevention (CDC – Atlanta, US).© Greg Sykes/ ATCC
A test for the new A/H1N1 virus developed by the Centers for Disease Control and Prevention (CDC – Atlanta, US).
© Greg Sykes/ ATCC
A/H1N1 influenza virus.© CDC
A/H1N1 influenza virus
© CDC
Culture of the influenza virus on embryonated hens’ eggs. © Institut Pasteur
Culture of the influenza virus on embryonated hens’ eggs.
© Institut Pasteur
Model of the influenza virus produced for the centenary exhibition of the Institut Pasteur. Prominent spicules are visible on the outside of the viral coat and the segments of RNA associated with the inside of the nucleocapsid. © Institut Pasteur
Model of the influenza virus produced for the centenary exhibition of the Institut Pasteur. Prominent spicules are visible on the outside of the viral coat and the segments of RNA associated with the inside of the nucleocapsid.
© Institut Pasteur
In the streets of Kobe (Japan), passersby wearing masks to protect against the A/H1N1 flu epidemic, May 2009. © Shutterstock/Hinochika
In the streets of Kobe (Japan), passersby wearing masks to protect against the A/H1N1 flu epidemic, May 2009.
© Shutterstock/Hinochika

Even if the latest influenza virus fails to spread panic, it will, all the same, have managed to disrupt health authorities worldwide. As it spreads across the world at the speed of light without proving to be particularly lethal, the new public enemy number one is not what we expected.

‘Let’s hope that the threat will come from a predicted direction for once’ mused one of our journalists recently in an article on the potential sources of viral epidemics(1). Even just a few months ago, the famous H5N1 virus, responsible for the avian influenza that raged since 2003, was considered the most threatening. But today things seem to have advanced somewhat, towards a viral epidemic or, more precisely, an influenza pandemic. A new subcategory of the influenza virus, the A/H1N1, has emerged without warning, compelling the World Health Organization (WHO) to raise its level of alert to the maximum phase 6 in only a few weeks, declaring a global pandemic last 11 June.

Just as this edition was going to print, WHO counted at least 622 482 confirmed cases, nearly 8 768 of which were fatal. If we compare these figures to those of the dreaded H5N1, which, in six years, infected about 450 people and killed just over half of them, these figures seem alarming. Yet, the transition from alert phase 5 (imminent pandemic) to phase 6 (full-blown pandemic) was marked by clearly discernable doubt as to the severity of the situation. Of course, the new virus spreads from person to person and has colonised the planet in eight months, but the strength of the illness seems relatively limited. It is difficult to know how to respond to this invader!

A/H1N1 versus H5N1

How did A/H1N1 get the upper hand over H5N1? While H5N1 aroused fears of pandemic from the moment that its transmission from poultry to man was observed, no humanto- human transmission has been registered to date. ‘H5N1 is a very frightening virus because the death rate, that is to say the number of deaths reported in relation to the number of cases, is 60 %. But until now, it has not humanised, although it spreads with great intensity,’ explains Antoine Flahault, a doctor and biostatistician, developer of FluNet, the Global Influenza Surveillance Network with WHO, and current director of the EHESP School of Public Health in Rennes (FR). According to the school, the new A/H1N1 virus strain has acquired the much-dreaded capacity to be easily transmitted from one human to another. It also contains genetic fragments of the swine, bird and human influenza viruses. Even so, does this make A/H1N1 a particularly formidable virus?

‘It is difficult to assess the strength of a virus other than by the death rate it provokes. The death rate due to seasonal flu is quite stable, amounting to one death per 1 000 cases in developed countries,’ points out Antoine Flahault. ‘It seems to have the same type of strength as the A/H1N1 virus. Although the death rate is a little higher, four deaths per 1 000 cases, it is close to that of the seasonal influenza and far from that of the influenza pandemic of 1918,’ he continues. Simply speaking, even if it is very contagious, A/H1N1 is not a source of infection that we can qualify as ‘serious’ for the time being. Even if the risk of the virus mutating in order to resist the antiviral drugs used to treat those infected is in fact real, treatments with oseltamivir and zanamivir will have allowed us to limit the damage while we await a vaccine.

One of the fears elicited by the appearance of the new virus is a genetic recombination with the H5N1 virus, which would enable the latter to cross the barrier between the species. The product of this recombination could simultaneously inherit the contagious character of the A/H1N1 virus and the highly lethal character of H5N1. Even if no one can predict the behaviour of H5N1 under pressure from a A/H1N1 pandemic, this scenario is nevertheless unlikely, according to Antoine Flahault. ‘Since H5N1 first appeared in 2003, there have been seasonal influenza viruses which have spread widely each year, including in Asia, and there has never been a recombination with H5N1 to produce a more virulent virus.’

Great Danger in the South?

Based on recent virological history, three big probable scenarios emerge. First, a scenario comparable to that of Severe Acute Respiratory Syndrome (SARS), provoked by a very powerful coronavirus. This virus, which appeared in Asia in 2002, was at the root of a global level epidemic in 2003, but oddly, it did not emerge again the following winter. In the case of A/H1N1, this scenario would translate into a non-resurgence of the virus in the autumn. Second, A/H1N1 could provoke a fairly moderate global epidemic, as observed in the case of the so-called Hong Kong influenza of 1968. Possibly, there could be fresh outbreak of A/H1N1 influenza cases in the northern hemisphere in the autumn, but without the illness becoming more serious. Finally, there is the most catastrophic scenario, like in 1918, whereby A/H1N1 would become extremely virulent after mutating and would provoke a pandemic, causing devastating numbers of deaths.

‘I would not be surprised if the scenario in the northern hemisphere proves to be moderate but of the 1918 variety in the southern hemisphere,’ says Antoine Flahault. According to WHO, the impact of a pandemic on a population depends on three characteristics: the characteristics of the virus with its epidemiological and clinical manifestations, the vulnerability of the population and, finally, its capacity for action. Now, we know that these last points are far from being uniform the world over. As Louis Cruvellier wrote in the annals of the Institut Pasteur in 1919, ‘If influenza condemns, it is the secondary infections which execute’. The influenza virus is, in fact, rarely the direct cause of death. It is the complications linked to secondary bacterial infections which make influenza infections fatal. We can thus assume that in countries where, on the one hand, the population includes a large number of people already afflicted by other illnesses and where, on the other, access to treatment is limited, death rates are likely to be high.

The consequences of a global pandemic of A/H1N1 could thus differ considerably depending on location. ‘In Europe, we can expect a pandemic wave on a greater scale than a seasonal epidemic, with 30 % to 40 % of the population infected by the virus, but its severity would be very similar to seasonal influenza. The best equipped countries are those with the most robust health infrastructure,’ explains Antoine Flahault. As for the countries that are least well equipped, there are major uncertainties regarding how they will overcome the pandemic wave. ‘At the time of the chikungunya fever, 75 % of the populations of Mombassa and Lamou in Kenya were infected by this virus which caused thousands of deaths. But this generated much less attention than in developed countries which have media coverage and surveillance and information systems in place,’ continued the biostatistician. Africa may thus experience a pandemic wave in silence…

Qualify the alert levels

Between 29 April, when the WHO pandemic alert level rose to five, and 11 June, the day it was declared a global pandemic, the UN agency appeared undecided as to the attitude it should adopt in the face of a new public enemy number one. Since the end of May, however, all the criteria corresponding to phase 6 of the alert plan coalesced. The difficulty stems from the definition of the different phases of the plan, which was established, for the most part, following the experience of the Spanish influenza of 1918, revised in 2005 to cope with a potential H5N1 pandemic and then adapted when a far more powerful, deadly influenza virus than the A/H1N1 strain emerged. ‘The system envisaged by WHO is out of proportion for the current pandemic. It is as if soldiers had prepared for battle with classic arms, only to then realise that the measures taken did not really apply to the urban warfare they faced. The consequences of level 6, as envisaged in the WHO plans, are too great, at this stage, in relation to the measures appropriate to adopt,’ indicates Antoine Flahault.

As the WHO alert system is solely based on the geographic reach of the epidemic and not on its level of severity, the measures suggested to the States should have been adapted to the situation. When the transition to level 6 of the alert operation took place, WHO qualified the pandemic as ‘moderate’, recommending that the governments of affected regions classify their countries as in a ‘state of emergency’ and encouraging countries that were not yet affected to finalise their preparatory plans for an ‘imminent pandemic’.

From the egg to the vaccine

By May, WHO had delivered the virus strains with which to produce the vaccines to pharmaceutical laboratories. These strains were perfected, as they are each year for the seasonal influenza, by four reference laboratories in Atlanta (US), London, Melbourne (AU), and Tokyo. ‘The process for a vaccine against A/H1N1 is the same as for the seasonal flu,’ says Albert Garcia, doctor and epidemiologist at Sanofi Pasteur in Lyon (FR). The pharmaceutical companies prepare working seed viruses using WHO virus strains, by taking progressive steps which enable them to adapt the virus for large-scale vaccine production. ‘This takes about two weeks and, once the quality controls have been carried out, the working seeds are placed in culture in fertile hen eggs. This technology can be used to obtain billions of viral particles to produce a maximum number of vaccine doses with which to confront a pandemic,’ explains Albert Garcia.

The influenza viruses multiply very effectively in the embryonated hen’s eggs. For decades, these have been used by pharmaceutical laboratories to produce millions of doses of the seasonal influenza vaccine each year. ‘But the fierce avian influenza virus, H5N1, does not develop in the eggs since it kills them,’ explains Albert Garcia. And what if the A/H1N1 virus, which contains components of the avian influenza virus, adopted this type of behaviour? ‘In principle, the virus strains selected by WHO develop very well in the eggs. We have received different strain types, of which the strains, or the parts most affected by the avian flu virus, have been removed using genetic manipulation techniques. We will use those which grow best in the eggs,’ continues Albert Garcia.

After an incubation period of three days, the viral particles are collected, treated and purified to ensure that they come back completely harmless. The final dose kept for the new A/H1N1 vaccine has been determined on the basis of the results of clinical trials launched in August. After these tests, the experts have also established whether or not there is a need to insert additives, either pharmacological or immunological agents that stimulate immunity and thereby strengthen the effectiveness of the vaccines. As Albert Garcia explains, the choice of these substances is vital in terms of the capacity to produce vaccines to combat A/H1N1. ‘We estimate that there is global capacity to produce between 400 and 500 million doses of the influenza vaccine. Yet, in the case of a pandemic, much more must be produced. To increase this capacity, it is important to test the strategies that will produce a vaccine which provokes a sharp immune system response given a reduced number of micrograms of influenza antigen.’

Towards a universal vaccine?

Since the threat of an H5N1 avian influenza pandemic increased, research to develop a universal vaccine to protect against all types and sub-types of influenza has intensified. Though we may still have to wait a few years for such a vaccine to emerge, some research leads do seem promising. Amongst these is the development of a vaccine based on the external part (M2e) of the M2 surface protein in influenza viruses, which is taking place in the context of the Universal Influenza Vaccine project, which was funded by the European Commission from 2005 to 2007. ‘Unlike hemagglutinin, the protein on which current influenza vaccines are based, the M2 protein is highly conserved by all strains of the influenza virus,’ explains Walter Fiers, molecular biologist at the University of Ghent (BE), who discovered the potential of this protein segment. The hemagglutinin, which is also located in the viral coat, is the viral molecule recognised by the immune system. Upon contact with it, immune cells produce masses of antibodies, which will protect the organism should it be attacked by the virus again.

‘The greatest task for the Universal Influenza Vaccine project was to make the M2e protein segment immunogenic, that is, to ensure that it provokes an immune reaction and stimulates the organism to produce antibodies,’ indicates Walter Fiers. At this stage, the effectiveness of the new vaccine has been demonstrated on mice and ferrets, and phase 1 clinical trials were successfully completed last year. ‘We are currently testing whether the M2e segment of the A/H1N1 virus is recognised by the immune system. But, given that this segment is very similar to other M2e segments recognised by the organism, there is a strong chance that it would be too,’ claims Walter Fiers.

With the emergence of H5N1 and now of A/H1N1, the arms race between man and the influenza virus has well and truly shifted into top gear. Up until now, viruses always had the upper hand. Will mankind soon be able to make his all-time enemy surrender? As we wait for researchers to perfect the ultimate vaccine, coordinated surveillance systems and international solidarity should enable us to cope with the first pandemic of the 21st century.

Audrey Binet

  1. research*eu n° 59 ‘Should we be afraid?’.
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The masks: do they protect us?

In addition to hygiene and vaccinations, masks are another way of limiting the spread of the virus. Indeed, the virus is transmitted by dispersal of particles into the air such as droplets or aerosols. There are two types of masks: anti-projection masks and respirators. As a preventive measure, the first are reserved for the sick and their family circle. They prevent the spread of the droplets produced when a person coughs or sneezes. These masks are intended for one-off use and are effective for eight hours.

As for the respirators, these are reserved for health professionals who have to work in close contact with people who have contracted the A/H1N1 virus. Being far more ‘selective’, these masks prevent droplets from going out, or liquid particles from coming in, when patients speak or breathe.

It acts as a proper filter that protects the wearer from inhaling infectious agents in a contaminated atmosphere. Effective as these masks may be, they are intended for single usage and must be replaced every 4 hours.

Become actors in the fight

Since the influenza virus does not tolerate the heat well, the A/H1N1 has provided a relative respite to countries in the northern hemisphere this summer, but a second wave of contaminations started this autumn and its peak could be reached in January and February.

As a result, it is important that the populations of the northern hemisphere continue to rally round until then. ‘It is through altruistic behaviour and gestures, such as washing our hands, getting ourselves vaccinated, confining ourselves if we are infected, that people protect both themselves and others,’ Antoine Flahault, Director of the EHESP School of Public Health in Rennes (FR), reminds us.

While the media has widely monitored the progression from epidemic to pandemic over the spring and summer of 2009, citizens who watch the news as spectators risk getting tired of repeat alerts. ‘There is a delay between the release of the alert and the moment at which citizens should become actors in the fight against the A/H1N1 virus, but this should not stop people from rallying round,’ warns Antoine Flahault.


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