Chinese H5N1 trial points to whole-virus formula as way to stretch vaccine

But the formula used by the Chinese company - vaccine made using whole viruses, rather than viruses broken into particles - is no longer commonly made by western flu vaccine manufacturers. And they appear hesitant to shift gears on their year-to-year vaccine manufacturing processes to improve their output for a pandemic - an extraordinary event the timing and severity of which cannot be predicted. "Companies that have been making split-virus vaccines are reluctant to test whole-virus vaccines because this would require them to get new regulatory approval for their process and this would cost them a great deal of money . . . for a specific product that they may never market," said Dr. David Fedson, a retired academic and flu vaccine industry expert who lives in France.

The Chinese company, Sinovac, announced this week it had achieved protective responses in volunteers who received two 10-microgram doses of their H5N1 vaccine, made with whole virus (also called whole virion) and with a cheap and readily available adjuvant or boosting chemical called alum. Earlier trials have shown that with a regular H5N1 vaccine (split virus, without an adjuvant), protection was only achieved with two doses of 90 mcg each - or 12 times the amount of vaccine needed to protect against regular flu strains. A split-virus vaccine with alum worked at two doses of 30 mcg each. With current production capacity, a dosing regime of two doses of 90 mcg per person would mean only about 75 million people worldwide could be vaccinated in the first year of a pandemic.

At two shots of 30 mcg, that number climbs to 225 million people. If all manufacturers followed the Chinese formula, global supplies could conceivably be stretched to cover 675 million people. Hungary's state flu vaccine manufacturer has also reported good results at low doses with a whole virus vaccine, though the results have not be verified and have been questioned in some quarters. Still, the World Health Organization's special adviser on pandemic vaccine said the evidence is mounting - Hungary, China, and another country with pending results - to support whole-virus pandemic vaccine. "The public health conclusion of this is that whole-virion vaccines have a superior performance to the split and sub-unit vaccines when it comes to low antigen doses," Dr. Klaus Stohr said from Geneva. (Antigen is the virus protein which kicks the immune system into gear.)

"So they are much more likely to fulfil the expectations of the public health authorities, namely that a low dose should be used to protect people from severe disease and from death." Alan Hampson, an Australian flu expert, said the scientific literature shows that in people who are immunologically "naive" to a flu subtype - meaning their immune systems have never been exposed to it or related viruses - whole-virus vaccines provoke a better response. But any change in a manufacturing process would require companies to go through the lengthy and time-consuming licensing process for the revised product. It's not something many will do unless someone else - read: government - picks up the tab. "You're caught in this catch-22 thing where companies are not really going to register a different product for a pandemic than they are for their interpandemic period - that's certainly not their preference," said Alan Hampson, a member of the WHO's pandemic task force, the group that would advise on when the pandemic alert level should be raised or lowered. Likewise, some of the larger companies are more interested in making vaccine with proprietary adjuvants.

These products - Chiron's MF59, GlaxoSmithKline's MPL - are likely to be more effective at boosting the impact of flu vaccine than alum. But they are more costly, are patent-protected, and are unlikely to be used by competitors because of supply limitations and licensing fees. "We're not saying that this research is not important, that one should not look for a better vaccine through better adjuvants," Stohr said. "But the real good news from the recent clinical trials in China and Hungary and perhaps shortly also from other countries is even with non-proprietary adjuvants, low-dose vaccines are achievable and these low dose vaccines may pose fewer issues when it comes to technology transfers and global access to pandemic vaccine than possibly other vaccines would if there is a proprietary adjuvant involved." Still, novel adjuvants may hold a financial appeal for the vaccine makers who own them.

The industry, which until recently was shrinking, is going through an enormous growth spurt. It's projected the global supply of flu vaccine could double by the year 2008, Stohr said. And while every country that can afford to will want to secure vaccine during a pandemic, it's not clear the global market for seasonal flu is expanding at the same rate as production. Some vaccine makers may see branding - using their own more effective adjuvant - as a way to improving and securing market share in the period between pandemics, which is after all their bread and butter, experts suggest.

"Adjuvants can be differentiating features in the market place," said industry consultant David Webster, of Lehigh Valley, Pa. He also noted that vaccine makers may be leery of whole-virus formulations because when they were used there were more reactions to the vaccines - generally painful swelling at the point of injection. A batch that produced newsworthy problems during a pandemic could stain the name of a vaccine maker for years after.