Taiwan's Centers for Disease Control (CDC) announced in the evening of July 30 that the first death in Taiwan by novel H1N1 had occurred. As they unfolded the next morning's paper, many anxious citizens were wondering when a vaccine would be available.

Five weeks later, on September 8, Adimmune held a press conference to announce the birth of a vaccine for novel H1N1, for which one 20-cc bottle contains 40 doses. As soon as the Department of Health (DOH) gives the green light, human clinical trials on 250 subjects will commence. If all goes well, full-scale inoculations can commence in mid-November at the earliest.

After Adimmune won the CDC's open bid at a vaccine price of NT$199 per dose on July 10 (as compared to the international market price of 10 euros per dose), outsiders' misgivings about the safety of the "homegrown" vaccine ran unabated. With results of human trials not yet available, experts from many fields anxiously raised various criticisms: "It's better to wait and treat people once they're infected," "Let's not put all our eggs in one basket," "Adimmune doesn't have the capability to produce this vaccine on its own," and so forth.

Faced with such media questioning, Adimmune chairman Steve Chan, a former DOH minister, retorts, "If any defects are found during DOH checks, we will discard the entire batch." General manager Ignatius Wei also expresses his dissatisfaction: "Those who disparage us have not personally observed Adimmune in operation."

The most common method for producing influenza vaccines the world over involves cultivating viruses in embryonated chicken eggs. At right, eggs on a conveyor belt are about to be inoculated with the virus. At left and center, ether is used to extract the virus and eliminate living viruses. The ether is then slowly evaporated from the bottled vaccine, and the vaccine's purity confirmed.

A venerable name in vaccines

In the 1960s, Adimmune was a manufacturer of blood serum and animal vaccines located in Shulin Township, Taipei County. At that time, the company was already working jointly with Tokyo's Kitasato Institute, founded by Japanese bacteriologist Shibasaburo Kitasato, the discoverer of antibodies.

In 1982, Taiwan launched the Good Manufacturing Practice (GMP) certification system for pharmaceutical companies. At the same time, Adimmune was considering a major change, deciding to specialize in human vaccine development. Five years later, Adimmune closed down its old plant and moved to its current address in Tanzi Township, Taichung County, and started to produce vaccines for tetanus and Japanese encephalitis using techniques developed at the Kitasato Institute.

In 1997, James Liao, multimillionaire general manager of ADI Corporation, purchased the operating rights for Adimmune in 2001 for NT$200 million with the help of public shares from the National Development Fund. After that, Adimmune became more aggressive in its upgrading efforts, sending employees on an annual basis to the Kitasato Institute to study the vaccine manufacturing process based on fertilized chicken eggs.

In 2002, Adimmune started importing seasonal flu vaccine in bulk from Kitasato Institute, bottling and packaging it at their Taichung plant and selling it domestically. Says Wei, at that time Liao was already thinking about how to produce vaccines in Taiwan.

The Japanese encephalitis vaccine administered to children is 100% made in Taiwan.

The BOO debacle

The annual vaccine purchasing efforts by the DOH for seasonal flu as well as for outbreaks like bird flu and now H1N1 are a true headache. To address this problem, the CDC proposed a BOO (Build, Own, Operate) program for homegrown flu vaccine production in early 2006, calling upon vaccine companies, both foreign and domestic, to build plants in Taiwan with the proviso that they produce at least 16 million doses of flu vaccine per year.

After the name list was published, the first in line for contract negotiation rights was the international pharmaceutical giant GlaxoSmithKline. But since the Legislative Yuan required certain additional conditions including technology transfer, and also because the company was being sought after by other countries, GSK eventually decided not to carry through. Next in line was the Dutch firm Akzo Nobel, which suddenly merged with another pharmaceutical company. Third on the list was Adimmune; however, the company had filed a lawsuit with an administrative court claiming that the CDC had been singling out overseas companies, leading to bad blood between the two sides. As things now stand, this public health BOO project has come to a halt.

Yet this defeat gave Adimmune another opportunity to grow. In March 2007, Crucell, the world's sixth largest vaccine company, noticed Adimmune's OEM potential and its use of the Kitasato Institute's fertilized chicken egg technology, and signed a contract with Adimmune that included technology transfer, OEM, a stake of shares, and support in building a flu vaccine plant. This cooperative framework formed the basis for Adimmune's current H1N1 vaccine production.

The virosome technology provided by Crucell was key. A virosome is a virus shell that contains no viral genes: it has the replication of a virus, but not the virulence. This method of manufacturing vaccines requires no viruses and does not use chicken embryos as carriers, thus preventing allergies caused by ovalbumin and reducing side effects of inoculations.

This collaborative effort enabled Adimmune to upgrade its R&D technology. The CDC issued a press release congratulating Adimmune: "After the failure of the BOO initiative, the ability [of Adimmune] to acknowledge its technical inadequacies and willingness to cooperate with Crucell, which possessed cell culture vaccine manufacturing capacity, is worthy of encouragement. [Adimmune] is indeed a credit to Taiwan's disease control system."

In June, Adimmune invested NT$3 billion to build a new five-story plant that fully conforms to EU PIC/S standards. With the benefit of Crucell's virosome technology added to the fertilized egg and split-virus vaccine technologies gained from the Kitasato Institute, Ignatius Wei proudly states, "This is the only vaccine plant in the world that can simultaneously run these two types of production line!"

Indeed, faced with annual shortages of flu vaccine during the fall and winter flu season, Adimmune's cooperation with Crucell and the Kitasato Institute has broadened the company's opportunities in vaccine production. For one thing, though Adimmune produces virus bulk for Crucell on an OEM basis, the company has also secured rights to package and exclusively sell product in Japan, Macao and Taiwan. Also, the Kitasato Institute fertilized egg process has become Adimmune's mainstay, allowing it to corner a domestic market of around NT$150 million annually.

Currently Adimmune still chiefly sells its vaccines domestically, with 2007 and 2008 sales revenues coming to NT$190 million and NT$240 million respectively. The major chunk of such vaccines-60% to 70%-are for seasonal flu.

The most common method for producing influenza vaccines the world over involves cultivating viruses in embryonated chicken eggs. At right, eggs on a conveyor belt are about to be inoculated with the virus. At left and center, ether is used to extract the virus and eliminate living viruses. The ether is then slowly evaporated from the bottled vaccine, and the vaccine's purity confirmed.

Experimenting with H1N1

Faced with the urgency of the global pandemic of novel H1N1, at least 12 internationally renowned vaccine producers, including Novartis of Switzerland, Sanofi Pasteur of France, CSL of Australia and the Kitasato Institute, are battling the clock. All of them produce injectable vaccines, except for the American firm MedImmune, which manufactures a nasal spray vaccine.

On September 3, mainland China's State Food and Drug Administration approved the Sinovac-produced Panflu 1 vaccine. The World Health Organization predicts that China may become the world's first nation to use an H1N1 vaccine.

On June 1, Adimmune acquired influenza A virus subtype H1N1 vaccine isolated by CSL, and then officially launched its vaccine production program on August 6. Once every two or three days, insulated egg trucks carrying "vaccine eggs," maintained at 28-34°C, enter Adimmune's front gates at six in the morning, and outside the new green factory building, a dozen or so male employees await the order to unload the eggs.

"These are all SPF-like eggs specially produced for making vaccines: breeding eggs that are virtually 'specific pathogen free,'" says Wei, who calls them "clean eggs." To prevent cross-contamination of the virus from different animals, the feed eaten by the breeding hens cannot contain animal products; they cannot test positive for Salmonella enteritidis, Salmonella pullorum or Salmonella typhi, nor for avian flu or avian leukosis viruses; and they must also be free of external hormones and antibiotics.

An Adimmune quality assurance worker tells us that the vaccine eggs must be aged between 10 and 11 days, with a length of 5.5 to 5.8 centimeters, a diameter of 3.6 to 4 cm, and weight of 54 to 67 grams. The hens laying the eggs must be between 28 and 57 weeks old. To get an idea of Adimmune's progress in producing novel H1N1 vaccine, each batch contains between 130,000 and 160,000 eggs, and each egg truck can carry 70,000 eggs.

How many fertilized eggs are needed to manufacture one dose of novel H1N1 vaccine? Wei is unwilling to divulge the trade secret of the Kitasato Institute process used by Adimmune. But roughly speaking it's divided into six steps, requiring seven days: Virus inoculation and culture; virus harvest; sedimentation, filtering and purification of the virus liquid; cracking the virus shells with ether; deactivating the viruses; blending and packaging.

Dawning vaccine industry

Chan took over the chairmanship of Adimmune from Lee Ming-liang in June 2008. Both men have served as DOH ministers, and both have devoted themselves to the development of homegrown vaccines.

During Chan's term as minister, he gave impetus to the inoculation of health workers with the flu vaccine. In August 2007 Lee became chairman of Adimmune, during which time he sought out media reporters to talk about the urgency of homegrown flu vaccines and invited Ho Mei-shang, former epidemiologist for the US Centers for Disease Control and researcher at Academia Sinica's Institute of Biomedical Sciences, to serve as head of R&D at Adimmune.

Ho cites the example of the US National Vaccine Advisory Committee, which is under the authority of the president. Taiwan's corresponding system is managed by the DOH, which places it at too low a level.

With such policy shortcomings, Wei believes that there's a great lack of understanding of vaccines in society as a whole. He targets the media's misunderstandings of Adimmune in particular: "Adimmune is the only domestic human vaccine manufacturer. And with major international firms unable to produce enough on time, how can they participate in open bidding in Taiwan?" he complains: the idea that "only Adimmune benefits" simply doesn't make sense.

Apparently, even though Adimmune has been producing vaccines on its own for over four decades, if the company is to spearhead the drive for domestic development of vaccines, then it can't rely merely on its own efforts; the government, media and general public must also do their parts.