Just a spoonful of sugar

Chemists have developed new vaccine delivery systems that could do away with the need for refrigeration. Henry Nicholls looks at the implications

With just a spoonful of sugar, scientists working on new methods of vaccine delivery are hoping to improve the way their medicines go down. Coating microscopic droplets of vaccine with a cocktail of sugars could change the way that vaccines are delivered, doing away with costly refrigeration and possibly even dispensing with the need for needles.

Most vaccines need to be refrigerated all the way from manufacture to the moment of delivery. This so-called ’cold chain’ costs about $200 million (?105 million) to maintain each year, estimates the World Health Organization (WHO). What’s more, a lot of vaccines have to be thrown away because they pass their expiry date.

But some scientists say these costs could be saved by sealing up droplets of vaccine within a film of glass-like sugars. ’This technology traps the molecules in the glass like an insect trapped in amber,’ says Bruce Roser, chief scientific advisor at UK-based Cambridge Biostability. ’Because the molecules can’t move and therefore can’t react together, they’re completely stable.’ This would remove the need for refrigeration and give the vaccine an effectively indefinite shelf-life, he claims. ’If we can stabilise all vaccines in our form so that you can keep them in the glove box of a Land Rover in the Sahara desert rather than in a refrigerator, then you eliminate the cold chain,’ he says.

The idea is based on a piece of chemical trickery displayed by cryptobionts - a group of organisms that can tolerate complete desiccation by increasing synthesis of the disaccharide trehalose. This sugar is made up of two glucose molecules, but because they are joined by a ?-1-1 glycosidic bond, trehalose has no reducing power and is resistant to hydrolysis. At high concentrations, it is able to preserve the integrity of cell membranes and enzymes, allowing the organism to survive in arid conditions. So, scientists have found, trehalose or one of its derivatives can be used to manufacture chemically inert, completely heat-stable vaccine powders that are activated simply by adding water.

These powder preparations can be made by spraying a mixture of vaccine and sugars into hot air. The water in each droplet evaporates, leaving the vaccine encased in microscopic marble-like spheres. The vaccine is not changed at all and can be made completely stable from around -50?C to +50?C, claims Roser.

The next challenge is how to get these solid microspheres into the patient. ’There is no technology for injecting dry chunks of glass into people,’ he says. The solution is to roll the sugar-glass spheres so that they flow freely over one another and suspend them in an inert liquid ready for injection. ’Once you inject them into the body, the glass spheres dissolve in the body water and release the vaccine.’

Initially, Roser and his colleagues suspended the microspheres in perfluorocarbons. But, he says, these could contribute to global warming. ’The perfluorocarbons we first chose are so stable they stay in the stratosphere for thousands of years and never break down.’ Roser is now suspending vaccine microspheres in hydrofluorpolyethers, which are not as stable as perfluorocarbons. ’They have an oxygen-ether linkage in them and a couple of hydrogen atoms,’ he says. ’That combination enables them to be destroyed in the high ultraviolet flux in the stratosphere.’

Several vaccine powders prepared in this way can be combined without risk of them reacting with each other. This means that it should be possible to immunise against several diseases in one go. With funding from the National Institute of Allergies and Infectious Diseases in the US, Cambridge Biostability is working on a single-shot biodefence vaccine to raise immunity against toxins released by the seven different strains of Clostridium botulinum that cause botulism. It has also received a ?950 000 grant from the UK’s Department for International Development to develop a thermostable pentavalent vaccine with an Indian company, Panacea Biotec, that will immunise children in the developing world against diptheria, tetanus, pertussis, Hib and Hepatitis B. The product should enter clinical trials by the end of 2006, estimates Roser.

It is also possible to tweak the type of coating to alter the way the vaccine is presented to the immune system. ’The glass microspheres that we make don’t have to be immediately soluble,’ says Roser. ’They don’t have to be made of sugar. They can be made of a variety of other materials, some of which dissolve in the body slowly.’ In theory, this slow release should stimulate an immune response over a long period, which might do away with the need for a booster immunisation.

In addition to spray drying, others are experimenting with alternative technologies to manufacture thermostable vaccine powders. By comparison with conventional drying methods, spray-freeze drying is really efficient, says Dexiang Chen of the Program for Appropriate Technology in Health (PATH), the Seattle, US-based NGO intent on improving global health. The droplets of syrupy vaccine are frozen in liquid nitrogen or cold air. These are then freeze dried, a process that removes water by causing it to undergo a phase change from ice to vapour, skipping the liquid phase entirely. It takes just hours instead of days and allows powdered vaccines to be produced in bulk, he says. ’Now we’re coming up with technologies that allow us to produce 100kg of powder at one time.’

However, both spray drying and spray-freeze drying come with a cost, so these thermostable vaccine powders are likely to be more expensive than many established vaccines with long-standing methods of manufacture, says Martin Friede of WHO’s initiative for vaccine research. Chen agrees. Because PATH’s purpose is to come up with affordable vaccines for the developing world, the challenge is to find economic ways of producing these thermostable powders, he says.

Private companies are particularly sensitive to such commercial pressures. Oxford, UK-based PowderMed has developed a gun-like device that blasts solid vaccine through the skin. This delivery system, known as PowderJect, could do away with the need for needles and has been used in a Phase I trial of influenza vaccine spray-freeze dried in a cocktail of trehalose, mannitol and dextran. Pulling the gun’s trigger breaks the valve on a cylinder of pressurised helium, which propels vaccine particles out through a nozzle with sufficient force to penetrate the epidermal layer of the skin. The concentration of antigen-presenting cells in the epidermis can give a better immune response than conventional intramuscular injection, says Clive Dix, chief executive officer of PowderMed.

The sugar-coated influenza vaccine gives an immune response comparable to that produced by intramuscular injection. What’s more, the immunisation is relatively painless and causes only minor symptoms, such as mild and localised bruising. ’These results provide an early indication that epidermal powder immunisation may be a practical and effective vaccination method,’ conclude the PowderMed scientists. However, because many needle-based vaccines can be manufactured at such a low cost, the PowderJect delivery system is only going to be commercially viable for certain vaccines, says Dix. ’We’ve decided to concentrate on DNA vaccines for therapeutic applications,’ he says.

So in spite of the obvious benefits of having vaccines with a virtually indefinite shelf-life, it is unrealistic to think that thermostable vaccine powders can replace cheap, injectable, liquid vaccines overnight, says Friede. This means the refrigeration infrastructure will still be needed for some time to come. Unless all vaccines are manufactured using this or a similar technology, it will not be possible to do away with the cold chain, he says.

Nevertheless, Roser is confident that in the near future thermostable vaccine powders will have a key role to play in saving lives. ’We think it’s within reach now to develop a single-shot vaccination that will protect children in Africa against essentially all of the fatal infectious diseases,’ he says.

Henry Nicholls is a freelance writer based in London, UK