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Marie-Paule Kieny

The vaccine research director of the World Health Organization, on swine flu.

The World Health Organization (WHO) is convening its top committee of vaccine experts on 14 May to recommend on whether companies should make a vaccine against the H1N1 swine-associated influenza virus. Declan Butler asked Marie-Paule Kieny, director of the WHO's Initiative for Vaccine Research, about the options and challenges on the table.

What's the likely outcome of this week's meeting? I wouldn't want to second-guess what they will recommend. The meeting will involve the WHO's advisory body, and also manufacturers and regulators. It's this Strategic Advisory Group of Experts on Immunization that makes the recommendations on immunization policies. We have a well-oiled pathway for this.

Marie-Paule Kieny Credit: WHO

We are putting together all the figures for the advisory group on the state of production for the three components of the current seasonal vaccine and for production capacity. We are also starting to get epidemiological data on the outbreaks, especially from the Americas on aspects such as the incubation time and the rate of incidence and severity, and that will feed into discussions.

We are not yet asking the committee whether it would recommend the shift [from seasonal flu vaccine] to a new vaccine; we are asking it at this stage whether there is enough evidence to recommend that manufacturers should start to go to large-scale manufacturing. For the moment, the recommendation from us is only to get under way the preparation needed to be able to start.

Everybody is anxious to have enough seasonal vaccine. I think in a few weeks we will have a better idea of whether we have enough seasonal flu vaccine from the Northern Hemisphere vaccine production that is currently under way for the next flu season.

How are you handling that dilemma of perhaps switching vaccine production away from seasonal flu vaccine?

I think it's less of a dilemma and more about dovetailing the two processes. We are checking where companies are, and we now have details in from most of the multinationals that make most flu vaccine. The vaccine has three components. In the current run for seasonal vaccine for the Northern Hemisphere, most of the manufacturers have already started producing either the H1N1 or the H3N2 components. The third strain, an influenza B strain, seems not to be growing as well as the others.

Production of seasonal flu for the Southern Hemisphere will start in September with the selection of the vaccine strains, with production itself starting around November. So we absolutely must have this at the front of our minds. We need precise estimates of how many doses will be needed, although we know that Southern Hemisphere countries usually request less vaccine than those in the Northern Hemisphere. So we have sent out a survey to all producers, to assess production capabilities and how much they typically produce for the Northern and Southern Hemispheres. We still have weeks, and even months, to get a better understanding of the overall situation.

The new virus will probably come back to the Northern Hemisphere during next winter's flu season. How much vaccine against it might be available by, say, Christmas?

It's difficult to predict. Let's say that we go to full-scale manufacturing of a new vaccine in July. I don't think it will happen before then – some may start before, but it will be July before the main big capacity gets under way. Global capacity is around 700 million to 900 million doses annually, which would translate into between at least one billion to two billion doses of H1N1 pandemic vaccine, if it should be a pandemic. By Christmas we might get half that.

It is difficult to make real projections. We need to see how the vaccine performs in small clinical trials. For the moment it is unknown, for example, whether you need one or two doses. [If the latter, that would effectively cut by two the amount of vaccine available.]

We are having teleconferences every week with all the manufacturers of influenza vaccine - not just the big multinationals but also the smaller companies, the Russian companies, the Chinese, we have invited everybody. The smaller companies are important, as cumulatively their capacity adds up.

Seasonal influenza vaccines use inactivated vaccine. Using a live attenuated influenza vaccine could vastly increase production levels and so make much more vaccine available. Is using live vaccine an option?

There has been a feeling that everything that is live attenuated is maybe not so safe, so everybody has been working towards pure peptide and inactivated vaccines. Live vaccines have fallen out of fashion. For seasonal flu, inactivated virus is by far the largest in terms of volume. The advantage of a live attenuated vaccine is that because it is living, it will reproduce itself in the host. You need much less of it. For inactivated vaccine you get one dose of vaccine per egg; with live vaccine you would get 30 to 50 doses per egg. Also, live attenuated vaccine induces not just an antibody response, but a cellular immune response. It seems to be safe and effective, especially in immune-naive individuals such as children.

Flu vaccines are currently grown in hens' eggs. Might new biotech methods, such as cell culture or growing flu antigens in fields of tobacco plants, be of any practical use in the current situation?

We've had a lot of discussion with regulatory authorities on this. It is very difficult. Most of these technologies are only in early clinical trials and so have been shown to be safe in a few dozen healthy young adults. To go from there to say these technologies are ready to take to mass vaccination would be an enormous leap of faith. None of these new vaccines is ready for large-scale implementation at present.

If the outbreak were to become severe in terms of mortality rate, there is a risk that governments will nationalize or otherwise take control of vaccine plants on their soil to give vaccine first to their own citizens. What is the WHO doing to promote equitable access to any vaccine?

We are discussing with vaccine manufacturers to try to put together a framework where they would offer a certain proportion of the production, either as a donation or at low cost for the WHO and other international agencies to distribute to countries. We are already putting in place deals with manufacturers in emerging and developing countries so that they will give a minimum of 10% of their production to United Nations agencies. We are now investigating whether we can get the same sort of deals from the big multinational vaccine manufacturers. We have not secured any agreements as of now, but they seem open to the idea.

The question of equitable access is really a high-level discussion, at the level of governments, who need to come together to get commitments to make these vaccines available for other countries.

How difficult would distributing any vaccines be in low-income countries with poor health infrastructure?

Carrying out a mass vaccination campaign in developing countries would actually be much easier than you might imagine. These countries have experience with mass vaccination campaigns, such as for measles or meningitis, and there is the infrastructure for this. We've been working on guidelines for deployment of the vaccine, to achieve full distribution down to the district level within one week of the arrival of the vaccine in the country.

The current H1N1 seasonal flu is resistant to Tamiflu. For the moment, the new virus is not. What is the risk that it will reassort with seasonal flu and develop Tamiflu resistance?

It is almost a given that at some point this will reassort with the seasonal flu strain and acquire resistance. Everybody is concerned about that. The question is at what level resistance might appear. For the moment we have two antivirals, Tamiflu and Relenza, that work against the virus.

As not everyone will have access to vaccine or antivirals, should we also be exploring the use of cheap and widely available anti-inflammatory and other drugs that might lessen mortality in the event of a severe pandemic?

Yes, we should be giving attention to looking at new ways of treatment. We must not give people the impression that [in a severe pandemic] if they do not get vaccine or Tamiflu they will die. There are plenty of treatments for symptoms. At present, it seems that most people who have died were referred late for treatment. We are putting together best-practice treatment guidelines for developing countries.

What's your feeling about the potential severity of this virus?

It does seem relatively mild, but we don't know. It came at the end of the seasonal influenza season in the Northern Hemisphere, and we have to watch what it does in the Southern Hemisphere, where the season is just starting, and also in low-income settings and in people with different health conditions. History also tells us that the first wave of the 1918 pandemic was mild, and then it came back in a severe second wave.

For Nature 's ongoing coverage of the H1N1 outbreak, see www.nature.com/swineflu.

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Butler, D. Marie-Paule Kieny. Nature (2009). https://doi.org/10.1038/news.2009.478

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