快猫短视频

In 1918, a woman boarded a subway train in New York to make a 45-minute trip. She must have felt healthy enough to travel, if perhaps a little achy and shivery. Yet a few minutes into the journey, she started having trouble breathing. Her condition rapidly deteriorated as her lungs filled with fluid. By the time the train reached its destination, she was dead.

Such was the ferocity of the 1918 flu. It killed some 40 million people worldwide. Most of the dead were otherwise healthy adults; not the very young, old or sick that flu usually kills. Disease experts鈥� worst nightmare now is that the bird flu rampaging across Asia will mutate into a similarly deadly strain that could circle the globe in weeks.

If the nightmare does come true, what are our options? The good news is that we have the technology to defeat this killer. The template for mass-producing a vaccine is being made in British and American laboratories right now, something that would not have been technically possible only a year ago.

But it would still be a race against time to produce enough vaccine to immunise millions, and there are tough decisions ahead. Can we afford to take short-cuts with the usual safety tests? Will corporate interests get in the way of public health? And if the virus spreads so fast that there is not enough vaccine, or antiviral drugs, to go round, who will get them?

Every year 10 to 20 per cent of the world鈥檚 population gets the flu. And because the influenza virus鈥檚 two surface proteins are constantly undergoing small mutations, getting vaccinated or catching flu one year does not necessarily stop you catching it the next. Even so, flu is usually a mild disease because, despite its shifting disguises, our immune systems are more or less primed to recognise the main human flu viruses. The 1918 pandemic, and less lethal ones in 1957 and 1968, were triggered by big genetic changes when a flu virus incorporated surface protein genes from a strain that normally infects animals, and which human immune systems did not recognise.

Flu experts have long been warning of a repeat performance (快猫短视频, 14 October 2000, p 29), largely because the huge, crowded chicken farms that have sprung up across Asia in the past decade are potent breeding grounds for a potentially devastating pandemic.

Bird flu normally lives harmlessly in ducks, which Asian farmers keep on paddies to eat pests. If duck flu passes to nearby chickens and is not immediately stamped out, it can readily mutate into a deadly and highly contagious virus that can spread like wildfire in poultry.

That is what has happened in east Asia, where at least eight countries, including China, are battling a particularly lethal strain of the H5N1 flu virus (the name refers to its surface proteins, haemagglutinin and neuraminidase). This was previously thought to infect only birds. But in 1997, six people died in Hong Kong when it somehow jumped to humans (快猫短视频, 14 December 2002, p 36). So far it has done so only with difficulty 鈥� in the present outbreak, despite millions of sick birds, there have been only a few dozen confirmed cases in humans. And while human-to-human transmission has not been ruled out, if it is happening it seems that these infections do not spread any further.

The fear, however, is that H5N1 will change. The genetic material of the influenza virus is RNA, and RNA viruses are known to mutate frequently. A small change that makes it better at binding to human cells could make this flu much nastier.

H5N1 might also hybridise with a human flu virus. The flu virus genome consists of eight strands of RNA, each carrying one or two genes. When the virus infects a host cell, multiple copies of the eight strands are produced and new viruses self-assemble by taking one of each. If two virus strains infect the same cell at the same time, the progeny assemble from strands taken randomly from either of the original kinds. This means hybrids can emerge.

The worst-case scenario is a hybrid with genes from human flu that allow it to replicate and transmit easily in people, but with a gene for the bird flu surface protein, haemagglutinin, which is very different from the surface proteins on existing human flu. No human immune system would be prepared for that.

Right now in Asia conditions are ripe for such a hybrid to emerge. Thousands of workers are culling millions of sick birds, at the height of the region鈥檚 human flu season. Few have protective clothing or masks. If just one worker is infected with bird flu while incubating human flu, he or she could become the breeding ground for a pandemic.

And it could be a monster. 鈥淭o be bad, the virus needs new surface proteins, but it also needs attitude,鈥� says Earl Brown, a flu virologist at the University of Ottawa, Canada. And like many viruses that have recently jumped from animals to humans, H5N1 has attitude in spades. It has killed three quarters of known human cases in this outbreak. Medics believe that the H5N1 strain induces a massive overreaction by the human immune system (快猫短视频, 6 September 2003, p 36). A hybrid version may or may not retain this talent but, ominously, the 1918 strain seems to have killed in the same way.

So what can we do? The World Health Organization is trying to get protective gear, antiviral drugs and vaccines against ordinary flu to people culling sick birds in Asia, to prevent simultaneous infection with human and bird flu. If the pandemic does start, antiviral drugs may minimise the effects and spread of the disease 鈥� provided manufacturers can produce enough in time (see 鈥淧lan B: Antivirals鈥�).

But the best way to stop infectious disease has historically been mass immunisation. Manufacturers make standard flu vaccine by injecting an innocuous strain of flu into chicken embryos in eggs along with the disease-causing strain they want to protect against. The two strains jumble their genes, and some of the progeny get the two surface proteins from the disease strain and the rest of their genes from the harmless virus. This strain is selected and multiplied in millions more chicken eggs, then purified, killed and sold as vaccine.

But this won鈥檛 work with this strain of bird flu. It is lethal to chickens, so injecting the virus into eggs would simply kill the embryos.

If an H5N1 pandemic had emerged back in 1997, we wouldn鈥檛 have had a lot of options at this point. But the sense that 1997 was a near miss galvanised virologists into finding another way of producing a vaccine.

Designer viruses

Less than a year ago, they cracked it. Teams at St Jude Children鈥檚 Research Hospital in Memphis, Tennessee, and the National Institute of Biological Standards and Control in the UK managed to create designer flu viruses without using chicken embryos. The technique they used is called 鈥渞everse genetics鈥�. They inserted genes from the bird and human viruses into plasmids, which are small circles of DNA that can be incorporated into cultured human or monkey cells. The cells then churned out viruses containing the chosen genes. Crucially, the mutation in the surface protein gene that makes it lethal to chickens had been snipped out, so these 鈥渟eed viruses鈥� could be multiplied up in eggs as normal.

The designer virus grows well in eggs, and in initial tests it elicited a strong immune response in ferrets and chickens. A similar vaccine made from another strain of bird flu, H9, got a good response in humans.

Now those labs, and the Centers for Disease Control and Prevention in Atlanta, Georgia, are brewing a similar vaccine virus carrying the H5 and N1 genes from the bird flu strain in Vietnam. The labs will hand the seed virus over to the WHO this month for further safety testing in ferrets and chickens, says Klaus St枚hr, head of the WHO鈥檚 influenza programme. In April or May, vaccine manufacturers and national research agencies will test the killed virus for safety in humans, and will make sure it triggers antibody production.

By July the manufacturers could be ready to start mass-producing the vaccine, using chicken eggs. At that point, their factories will already be occupied making regular human flu vaccine for the northern hemisphere winter of 2004-2005. 鈥淏ut if we see rapid spread of H5N1 among people,鈥� says St枚hr, 鈥淚 will ask them to switch to pandemic vaccine.鈥� It will just be a matter of injecting each new batch of eggs that come in every week or two with the pandemic virus instead of the regular vaccine.

How fast could they make it? The companies are equipped to produce only enough flu vaccine for current demand. Global capacity is some 125 million doses per month of a one-virus vaccine. Production cannot be scaled up quickly, even if the producers commandeered more eggs from the food industry, as the processing capacity can鈥檛 be easily increased. 鈥淵ou can鈥檛 just put more eggs in the front door and get more vaccine out the back,鈥� says Bram Palache of Belgian-based Solvay, a major producer.

The four biggest manufacturers have long been planning to switch to making flu vaccine in cultured cells instead of eggs, a system that could respond better to emergency surges in demand. But no one is quite ready. Solvay鈥檚 new plant needs another year of testing. The biggest manufacturer, Aventis, has only just signed a deal to start developing a human cell-based flu vaccine. Baxter鈥檚 new Czech factory is due to start production next year but could be pressed into service this year in an emergency, says Otfried Kistner, the company鈥檚 head of virology. Chiron鈥檚 new plant in Germany is also nearly ready but still requires regulatory clearance. 鈥淚n an emergency, as the pandemic would be, we could grow a vaccine generated by reverse genetics in the facility,鈥� says Rino Rappuoli of Chiron. If things get bad, governments may have to cut corners to clear plants to operate fast.

There are other potential hitches. Several firms hold patents on technologies involved. The overall patent holder on reverse genetics, a US biotech firm called MedImmune based in Gaithersburg, Maryland, says it will charge only modest fees for using the technology to make pandemic vaccine, as long as no one else profiteers. It is not yet clear whether other patent holders will be so accommodating.

And Chiron can鈥檛 even work with the seed virus in Europe for lack of a laboratory licensed to handle genetically modified organisms under European law. It is trying to build one, quickly. But if people start dying, concerns about patent rights and GMOs may well have to be postponed.

On the bright side, recent research suggests the pandemic vaccine may require less killed virus per dose than ordinary flu vaccines. Pandemic vaccine contains only one strain of flu, while ordinary flu vaccine has three. So it needs only a third as much virus, effectively trebling production capacity. But recent research suggests that if immune-stimulating chemicals called adjuvants are added as well, the amount of virus needed per dose might be further cut to half, or even a sixth as much, says Tony Colgate of Chiron 鈥� although people might need two doses, three weeks apart to be protected.

鈥淚t will be up to the WHO to decide how to distribute the vaccine,鈥� says Colgate, who heads the industry taskforce on pandemic flu. 鈥淲e hope it will be equitable.鈥� If human cases are confined at first to limited areas, it may be possible to contain the virus with some form of local vaccination. But nearly all vaccine is made in Europe and North America. Would those countries be happy to send their limited supplies to Asia? 鈥淲e hope there might be some sort of international registration of this vaccine,鈥� says Colgate. 鈥淥ur big concern as producers is that our governments might nationalise it.鈥�

It wouldn鈥檛 be the first time. In 1976, swine flu was expected to become pandemic, though in the end that never materialised. The American government鈥檚 response was to prohibit export of US-made vaccine until US needs were filled, causing panic in erstwhile importers such as Canada.

We鈥檙e not yet at that desperate stage. 鈥淚t鈥檚 very important we remain calm about worst-case scenarios,鈥� said Mike Ryan, the WHO鈥檚 head of epidemic response, at a bird flu summit in Rome earlier this month. But that does not mean the nightmare can be ruled out. 鈥淭his could be the most serious influenza threat since 1918,鈥� says D. A. Henderson of Johns Hopkins University in Baltimore, who led the smallpox eradication drive.

There are some tough choices ahead. What if we start vaccinating people, only to see the pandemic fizzle out, leaving companies to face lawsuits because regulations were overlooked in the rush? Should authorities bend the rules to get vaccine on the market faster 鈥� even though there will never be enough for all? Should someone start churning out industrial quantities of antiviral drugs, never mind the patents?

Officials like Ryan and St枚hr are doing their best to reassure the public that the pandemic hasn鈥檛 happened yet, and that there are things we can do. If this turns into another near miss, we will, if nothing else, be better prepared when the next flu pandemic does strike. But at meetings and in conversations with scientists, the fear in people鈥檚 eyes and voices is palpable: this could be the big one.