The problem with flu vaccinesBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b2065 (Published 21 May 2009) Cite this as: BMJ 2009;338:b2065
As the H1N1 swine flu virus spreads swiftly from Mexico around the world, public health specialists and flu vaccine manufacturers are scrambling to catch up. This week, they are meeting in Geneva, on the margins of the World Health Assembly, to discuss how best to respond.
They face scientific uncertainties and technical problems alike. The first decision is whether to switch to production to a new vaccine tailored to provide protection against the virus. A second question is how to maximise production if they do. A third is how to distribute and make affordable the still scarce stocks likely to result.
At best, the different commercial manufacturers can produce a total of about 480 million doses of trivalent seasonal flu vaccine this year. That figure—a small fraction of the world’s population—reflects a history of modest demand that has kept manufacturing relatively small.
In Europe, vaccination rates remain modest, with wide variations between countries. Where programmes take place, they are concentrated among children, elderly people, and other risk groups with weak immune systems. In the developing world, where most of the estimated annual 500 000 seasonal flu deaths occur, coverage is still more scant.
The scarcity of vaccine even in normal times was highlighted in 2004, when quality problems halted production in Chiron’s Speke factory near Liverpool. The resulting shortage in meeting US orders for seasonal flu vaccine left Americans struggling to find alternative supplies.
Since then, a growing realisation of the burden of seasonal flu and fresh concern over a future pandemic have helped stimulate expanding demand. The rise of more lucrative patented vaccines—led by Wyeth’s Prevnar for pneumococcal disease, the first vaccine to generate more than $1bn in annual sales—has also helped stimulate fresh corporate investment.
Alongside the well established players of GlaxoSmithKline, Merck, and Sanofi-Aventis, other large drug companies have entered the market, with Novartis acquiring Chiron, AstraZeneca taking over MedImmune, and, most recently, Pfizer buying Wyeth.
Yet influenza vaccine is a relatively low priced, commoditised vaccine, which has meant there has been far less innovation in manufacturing than for other vaccines. Most producers still rely on the cumbersome cultivation of antigen in eggs as part of an uncertain process that typically takes six months from identification of each year’s changing seasonal viruses, through production, to final delivery. No manufacturer has yet finalised technology that would overcome the need to make specific vaccines each year in order to tackle the constantly mutating flu viruses, although several biotechnology companies are researching such approaches.
Two important evolutions are currently taking place, however. Firstly, companies such as Baxter have invested in cell based manufacturing techniques, which offer the prospect of trimming a month or more off the current egg dependent production cycle.
Secondly, vaccines are being revolutionised by adjuvants—chemicals that boost the human immune response, offering both the potential to use a smaller volume of antigens in each dose to achieve the same result, and greater “cross protection” against flu viruses other than the one for which a vaccine was specifically developed.
Traditionally limited to aluminium, a new generation of proprietary adjuvants has been developed in recent years that could be added to flu vaccines. Novartis’s MF59 is already included in one relatively expensive flu vaccine it sells in small volumes in Europe for people with weak immune systems. GlaxoSmithKline has also added its own adjuvants to some vaccines, including Cervarix, the human papillomavirus vaccine, and Mosquirix, currently in late stage clinical trials in Africa for malaria.
Rising concern triggered by H5N1 bird flu in 2005 mobilised a number of countries to express interest in stockpiling “pre-pandemic” vaccines. Several companies have already produced supplies based on variants of this strain for distribution in the event that it turns into a pandemic. Although regulators have approved these products in principle, the vaccines still require final authorisation in the event of a pandemic being declared. However, the prospect that the pandemic could come from an H1N1 strain makes production of H5N1 vaccines all but irrelevant, with there being too much genetic difference between the strains to allow cross protection.
WHO experts are trying to understand whether existing H1N1 seasonal flu vaccinations could offer limited protection from the new Mexican H1N1 virus. Novartis says in vitro tests with its adjuvant containing flu vaccine suggest some cross protection may exist. But the consensus from the WHO’s ad hoc advisory working group on A (H1N1) vaccines, published in mid-May, was sceptical of any effect.1
Nevertheless, if the new virus is judged a big public health threat, a new pandemic vaccine will be required. In the coming weeks specialists will need to decide whether to recommend that a vaccine should be produced. That depends on analysing more data on H1N1’s spread and impact on mortality and morbidity, compared with that of the three strains for which the current seasonal vaccine is targeted.
So far, although WHO’s pandemic alert is at its highest ever level (5), it remains one below full pandemic status. However, even this ranking system takes no account of the severity of infection, on which the data remain unclear.
If the scientific advisers consider the new virus presents a greater threat than seasonal flu, which seems increasingly likely given current assessment of its infectivity, they have two choices. One is to incorporate Mexican H1N1 into the seasonal vaccine, either by swapping with one of the current antigens, most likely that for Brisbane H1N1 strain, or by adding a fourth antigen. The alternative is to abandon the next production cycle of trivalent seasonal vaccine entirely and switch all manufacturing to a monovalent H1N1 pandemic strain instead. The advantage of this more radical approach would be higher productivity (as all resources could be concentrated on the one antigen) offering a way to increase total vaccine output. The downside is the loss of the existing seasonal flu vaccines, resulting in an increase in health effects from these infections, which will continue to circulate.
With a pandemic now imminent, much discussion is focused on other ways to boost productivity. Earlier this year the consultancy Oliver Wyman published an analysis of the world’s capability of manufacturing H5N1 vaccine in the event of a pandemic. It concluded that growing interest in flu vaccines has led to a big increase in capacity in the past two years and that in theory, output could rise to between 2.5 billion and 7.7 billion doses a year within 12 months of declaration of a pandemic, and up to 14.5 billion doses within five years.2 WHO’s latest assessment is 4.9 billion doses, with each person likely to require two doses for protection.1
One contribution to this increased output would come from simply cutting out the “down time” between current seasonal flu production cycles, making existing plants work to their current limits. A second contributor would be to adopt widespread “antigen sparing” techniques with broader use of adjuvants, either aluminium or the new patented products. GlaxoSmithKline has indicated that it would be willing to license its adjuvant to others, although it is wary that any such joint manufacturing arrangements could infringe US antitrust rules.
The US itself presents a particular challenge. The country has yet to approve the new generation adjuvants in any vaccine, including Cervarix. The country remains cautious after mass vaccination of Americans against swine flu in 1976 was halted because of claims that the vaccine caused dozens of cases of Guillain-Barré syndrome.
A final way raised by others to make existing vaccine production go further would be to use intradermal injections, although this would require specialist training for those giving vaccinations.
In the longer term, it seems likely that rising global demand for a pandemic vaccine—and perhaps a subsequent willingness to strengthen seasonal vaccination—is likely to expand manufacturing capacity. This may include the opening of new sites in developing countries by both local and multinational companies.
Nearly four fifths of global vaccines are still made within Europe, although the US has encouraged new investment in plants, and some countries in the former Soviet countries as well as India, China, Japan, South Korea, and Australia are expanding local production.
WHO has helped encourage technology transfer to ease this process. Apart from tensions over intellectual property, however, critics respond that it will take several years before any such factories could win good manufacturing practice approval and that opening new factories may prove less efficient and more costly than expanding existing plants.
In any case, the short term prospects for producing large quantities of H1N1 pandemic vaccine are limited. In the next few weeks, most manufacturers will have finished their current production cycle for trivalent seasonal flu doses to supply the southern hemisphere, which is entering its peak flu period.
That will free up capacity to begin to produce a H1N1 vaccine—with deliveries from the end of this year—to developed countries that order it now. That would be in time to help tackle a second and, judging by past pandemics, more dangerous wave of infection during the northern hemisphere’s coming winter.
The problem is very tight production constraints. GlaxoSmithKline last week agreed to produce nearly 130 million H1N1 doses for the UK, France, Belgium, and Finland. Baxter is producing another 30 million for the UK. Yet even these supplies were subject to tough negotiations, suggesting that only modest spare capacity remains during 2009.
With signs that fear of a pandemic has already sent governments rushing to protect their own citizens rather than working cooperatively with others, manufacturers need to keep an eye on ensuring that they can meet the demands of countries where their flu vaccine plants are located. GlaxoSmithKline’s factories are in Canada and Germany, neither of which has yet ordered any H1N1 stocks, for instance, while Sanofi-Aventis has plants in the US and France.
For other countries—such as the EU’s poorer members states and the developing world—that have neither funds nor domestic production capacity, the long term options may look better than ever. But the short term ones look bleak.
Cite this as: BMJ 2009;338:b2065
Competing interests: None declared.
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