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December 2001

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More combination vaccines needed

Faced with a bigger than expected shortfall in supplies of some vaccines, countries must make choices. Phyllida Brown reports

WHEN governments began to set out their immunization plans in their proposals to GAVI last year, most said they wanted to use new combination vaccines – those that immunize a child against four or five diseases in one shot – rather than have two or three separate vaccines. The benefits are obvious – fewer needles, fewer procedures, fewer demands on staff, children and parents. The challenge at the end of 2001 is that the supply of these vaccines is still far short of the demand, and that it will be perhaps three more years before all countries that want them will receive them.

This is frustrating for immunization programme managers and all those they serve – and for the Alliance as a whole. GAVI policy clearly states a preference for combination vaccines where possible(1). At issue are two key combinations: diphtheria, tetanus and pertussis plus hepatitis B (DTPHepB) and a five-antigen (pentavalent) combination that also includes Haemophilus influenzae Type B (DTPHepBHib). Last year, the Alliance had been told that there would be some 30 million doses in total of these two vaccines by 2002. Now the manufacturer, Glaxo SmithKline, has told GAVI that the true figure will be closer to 20 million. "This has created a big challenge for us," says Tore Godal, Executive Secretary of GAVI.

Already, last year, the Alliance had advised countries that there were too few doses of these relatively new vaccines for everyone who wanted them(see 2), and the GAVI Board had agreed a policy to allocate the available vaccines. Countries were allocated vaccine on the basis of need, giving priority to countries with the most fragile immunization systems and the lowest routine coverage. It was argued that the more fragile the immunization system, the greater the difficulties in introducing separate additional antigens. However, in addition, the Board ruled out Pakistan and Bangladesh because the large populations of these two countries alone could have used up the entire supply.

Even though the manufacturer has almost doubled its production in a year, its output has not grown as fast as expected. As a result, the 12 countries that have already received some supplies of these combination vaccines (see Table) will continue to receive them, but no new countries will join the list in 2002 or 2003. GSK says it will be up and running with significantly increased production by early 2004, but it will probably be 2005 before every country gets what it wants.

Table 1: The countries that already get the combination vaccines

Countries receiving DTP+HepB:

Cambodia, Cote d'Ivoire, Eritrea, Laos PDR, Madagascar, Mozambique, Tanzania

Countries receiving DTP+HepB+Hib:

Ghana, Kenya, Malawi, Rwanda, Uganda

Wary producers

So what happened? First, it appears that the manufacturer was wary of putting its full investment into scaling up the production of the vaccines until it had firm evidence of the amounts of vaccine that GAVI would buy. It can take three to five years to scale up production of a vaccine, including adapting the manufacturing plant. But scale-up will only happen when the manufacturer is sure that the buyers are there. The combination vaccines had first been released on the market in 1996, but, says Walter Vandersmissen of GSK, there had been little demand for them until 1999. "The response at first was zero," he says. Surprised, the company sat tight, wondering if there would ever be any customers. Then, in 1999, the Revolving Fund of the Pan American Health Organization (PAHO) started to buy the pentavalent DTPHepBHib combination. "Until then, obviously, we had not stepped up production," says Vandersmissen.

In 2000 and 2001, GSK has been making as much of the two combination vaccines as it can: "We are at the limit of our capacity," says Vandersmissen. The company's estimate that it would have 30 million doses available for GAVI by 2002 was thus vulnerable to any quirk, however small, in production.

Countries needing more time

Vandersmissen points out that GAVI itself has – perhaps inevitably – been slower in approving countries for receiving the vaccines than the ambitious original timetable it originally set itself. Although the GAVI process has been faster than traditional funding mechanisms, its independent review committee has had to request further information from some countries before approving their proposals, and some countries found that they needed more time to gather the information. As a result, says Steve Jarrett of UNICEF, which buys the vaccines on behalf of countries with approvals from GAVI and funding from the Vaccine Fund, "The amount [of vaccine] that we have bought this year is relatively low compared with what we thought we would buy... as there has been a slow uptake by countries." This appears to have made GSK wary of committing itself to immediate full-speed scale-up.

Originally, says Jarrett, UNICEF planned to buy 24 million doses of the two combinations in 2001, but deliveries to most of the approved countries did not start until the autumn. This was due, he says, to combination vaccine not being readily available until the second half of the year, as well as some countries' desire to start deliveries late in the year to allow prior preparation.

Picture: Aventis Pasteur
Join the line:
vaccine production must be planned months or years ahead

GSK's own business decisions may also have played a role. In deciding how to allocate antigens between the manufacture of each of the two combination vaccines, the company appears to have chosen to make relatively more of the DTPHepBHib (pentavalent) vaccine, for which initial demand from countries was more modest, than the DTPHepB (tetravalent) vaccine, for which demand was much greater. Each dose of pentavalent vaccine is priced at above $3, compared with around $1 for the tetravalent vaccine. "It is difficult to understand why there was this huge offer of pentavalent vaccine when both the UNICEF tender and the [GAVI] forecasting group projections of demand were much lower," says Julie Milstien in the WHO Department of Vaccines and Biologicals.

Vandersmissen at GSK admits that the higher-priced pentavalent vaccine is more attractive for the company to make. "There is a difference in price and clearly that makes it more interesting to us to have the newer product added to our output," he says. But he stresses that the prices of the two products are not directly comparable because the tetravalent vaccine is packed in 10-dose vials whereas the pentavalent vaccine is in two-dose vials.

Nor is profit the sole consideration, he says. First, the company had been told that demand for the pentavalent vaccine was likely to rise further in future, he says. Second, the Hib component of the pentavalent vaccine must be freeze-dried, and competition for freeze-drying capacity in the plant creates a "severe bottle neck," says Vandersmissen. Having committed a significant part of that capacity to Hib, the company was not about to waste it. "If you have a scarce resource you must put it to the best use," he says.

While the shortfall continues, there are alternatives. There are plentiful supplies of hepatitis B vaccine available in monovalent form, and, given the delay until the combined vaccine will be fully available, most countries may choose to use it alongside DTP. So far, countries have been "very pragmatic" about the shortfall between demand and supply, says Godal, and he is optimistic that the impact of the delays will be small.

In the medium term, an alternative combination vaccine could become available from 2002. A liquid-form tetravalent vaccine combining DTP and Hib, made by Chiron Vaccines, is expected to be prequalified by WHO shortly and a freeze-dried combination of the same four antigens has been put forward to WHO for approval. Some countries might choose to use one of these together with monovalent hepatitis B vaccine, although the available quantities are not yet known.

Despite the new money available for vaccine purchase, the overall system is still in need of improvement, says Klaus Friederich, head of government and international institutional policy for Chiron Vaccines in Marburg. Industry needs earlier decisions from the public sector on the number of doses of each vaccine it needs, and firmer commitment to buy, he says. He has been told to wait for a final decision on the amount of the liquid DTPHib that UNICEF will buy from Chiron for delivery from September 2002 onwards. "But the lead time to produce the product is more than 50 weeks," he says. "What do I tell the production guys?"

But Milstien at WHO points out that the vaccine is still not prequalified, with WHO awaiting "minor" information from Chiron. "It's a bit of a catch-22." Everyone, it seems, is waiting for someone else. "We are asking countries to consider what substitute they want," says Godal. "We will be seeking to make decisions in early February."

All players can suggest ways to improve the process. Friederich is puzzled that the public sector purchasers cannot commit themselves earlier to buy vaccines whose shelf life is more than a year. Public-sector representatives point out, in turn, that since the formation of GAVI there have been forecasting meetings at which the industry has always been present, giving them knowledge of further demand.

Ultimately, the small number of players in the vaccine industry creates a seller's market for certain products, which some observers feel is inappropriate. For example, says Friederich, PAHO is shortly to tell Chiron how much of the DTPHib vaccine it wants, effectively coming forward as a customer before UNICEF. With a limited amount of vaccine available, Friederich does not believe it should be left to a company to decide which public-sector buyers should get the vaccine.

"Everyone is trying very hard, and this is a mutual challenge," he says. "But the system really has to be fine-tuned."


(1) Immunize Every Child, GAVI policy document, February 2000, p 10 (Word – 366k)

(2) GAVI Board Policy on Vaccines of Limited Supply.


Phyllida Brown


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