Swine flu epidemic has risks for vaccine manufacturers

Pig in a poke

08 October 2009 10:45  [Source: ICB]

The swine flu epidemic provides a huge opportunity for vaccine manufacturers, but many risks as well

Louise Cole/Northallerton, UK

THE CHALLENGES of vaccine development go well beyond the mathematics of mass production.

Rex Features/Chris Eyles

For a relatively mild disease, swine flu, or H1N1, has demonstrated the pharmaceutical industry's limitations when it comes to producing vaccines for the global population.

Until the 1990s, vaccines were not of great interest to large pharmaceutical companies. Most governments had programs to create and produce their own. However, changes in requirements, as well as negative publicity about the side effects of whole-cell ­vaccination, led to more rarefied, complex and value-added production processes. This meant the pharmaceutical industry could once more enjoy significant profit margins.

The World Health Organization (WHO) defines a pandemic as: "A worldwide epidemic of a disease. An influenza pandemic may occur when a new influenza virus appears against which the human population has no immunity." The WHO has predicted that up to one-third of the world's population could be infected with H1N1, with up to 15% of those requiring hospital care.

The huge cost implications, not just in health care, but to the global economy of such widespread illness suggests that prevention is infinitely better than a cure. And while antivirals such as Tamiflu can be mass-produced - indeed many companies are producing generic versions of the oseltamivir phosphate drug - it only reduces the effects of illness by a couple of days.

HUGE TASK
According to research from the University of Washington on the effects of vaccination in the US, 70% of the population would need to be vaccinated in order to reduce infection rates to 15% - or equivalent to a seasonal flu spike. That means vaccinating 214m people with two doses each.

Influenza A has many strains, including H1, H3 and H5. Currently, the WHO isolates strains and chooses the most dangerous and prevalent for inclusion in vaccines for the following season.

The viruses, meanwhile, are incubated in millions of hens' eggs. When the yield is sufficiently high, the virus is killed with heat and formalin and prepared into doses. There are problems with this system, however. Eggs are a dirty environment in which to grow your bugs. This means that the patient is likely to have an immune response to several factors, which have nothing to do with the pathogen.

Some flu viruses have much lower yields than others. H1N1 is particularly difficult to cultivate in eggs and some companies have suggested this will severely limit the speed and amount of vaccine that can be generated. Add to this the fact that H1N1 hits much earlier in the season and it is quite possible that the peak of an epidemic could be over before the bulk of the vaccine is produced. Flu vaccine, responding to a seasonal and global phenomenon, is always produced under great time pressure.

Orders for H1N1 vaccine have been placed by richer countries with Big Pharma firms such as US group Baxter International, UK-headquartered GlaxoSmithKline (GSK), Swiss-based Novartis and France's Sanofi-Aventis and if yields are significantly reduced, as the WHO fear, it will probably be poorer countries that are left wanting.

One company aiming its technology license at those poorer regions under the Emergency Use Authorization - allowing vaccines and medicines to be used ahead of normal licensing rules - is US group Novavax which has developed a vaccine for H1N1, H5N1 and seasonal flus based on virus like particles (VLPs). The proteins taken from the surface of the virus are combined with a core protein, but minus the ribonucleic acid (RNA), which would allow the entire pathogen to reproduce itself.

The technology is proven in the lab with ferrets, but is still preclinical and the company does not expect US licensing until 2012. Jim Robinson, vice president of technical and quality operations at Novavax, says there are several advantages over egg-based growth. These include a cleaner environment, a more precise match between the vaccine and circulating strains and much higher yields.

"We can make 20 times as much HA (vaccine base) per liter of reactor fluid for H5N1 and 10 times as much for other strains. We also use one-use production platforms, so there is no cleaning or validation and this costs about 10-15% of normal plants.

The huge cost implications suggest that prevention is better than a cure

"Our technology should prove cheaper or at least have cost parity with other technologies, because this is important for those countries without access to vaccine," he says.

Baxter Healthcare, the US subsidiary of Baxter International uses Vero cell technology based on green monkey serum to produce its CELVAPAN H1N1 vaccine. Baxter and GSK received an advance purchase agreement from the UK Department of Health in 2007 and Baxter said it took just 12 weeks from receiving the virus seed stock in May 2009 to produce a commercial batch of vaccine. It says the serum process is considerably quicker than eggs because the virus can be used as delivered, without preparation. "We have also boosted our yields in recent weeks with a number of optimization procedures," says a spokeswoman.

US group Opko Health has recently purchased a new protein-based technology from Taiwan, but says it is in "its very early stages." Meanwhile, VaxInnate, in Princeton, New Jersey, US, uses bacterial fermentation, which it says has already taken an H1 strain from seed to animal testing in six weeks. As well as developing its current H1N1 vaccine, it will incorporate swine flu protection into its universal flu vaccine, which targets M2e, a highly stable flu protein.

WHOOPING COUGH BATTLE GOES ON
In the 1950s, a whole cell vaccine was developed against Bordetella pertussis, which along with its sibling pathogen Bordetella parapertussis causes whooping cough, a serious and highly infectious paediatric illness. The vaccine was 95% effective but often had temporary side effects. This shifted parents' focus from fear of contracting disease to fear of vaccine side effects. The unsubstantiated claims that the whole cell vaccine caused neurological damage spurred the industry to develop a product with fewer side effects. An acellular, or protein-based vaccine was created, which contains three to five specific proteins from the bacterium.

Marcel Thalen, scientific officer at Dutch group Synco Bio Partners, has worked on fermenting whooping cough and other pathogenic bacteria for vaccine production, and says: "The immunogenicity [the ability to produce an immune response] of a protein-based product is not comparable to that of giving the entire cell, which contains far more antigens of the pathogen."

But there was a greater problem. Research by Frits Mooij at the Netherlands National Institute for Public Health and the Environment (RIVM) revealed that 40 years after introduction, some of the proteins in the vaccine bore less and less resemblance to those in circulating strains. The proteins were not as immutable as was thought. "This phenomenon is called vaccine-driven evolution. When a vaccine with a certain protein profile is introduced, the corresponding pathogen will evolve to move away from that profile," says Thalen. Since the 1990s, cases of whooping cough have been increasing, even among the vaccinated population. The vaccine is becoming less efficient as the circulating strains move further from the proteins it is based on.

Thalen has tried to define what an improved whooping cough vaccine should look like. Taking into account its necessary attributes, the cost and time to market, he concludes: "The most likely candidates to fulfill all characteristics are oral or intranasal vaccines consisting of inactivated whole B. pertussis cells, which have incorporated the circulating proteins." Oral or nasal vaccines can be given earlier to babies than an injected vaccine, which is important, since whooping cough is most dangerous to this age group.

Eradication of the disease, however, will be difficult, requiring vaccination of adolescents and adults as well, since many babies get whooping cough from parents or grandparents. This means that the vaccine will have to be applied repeatedly - possibly every 10-15 years. With current protein-based vaccines, this is unlikely to happen, given the increasing side effects with each dose, while oral or nasal whole cell vaccines typically show far fewer side effects.

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USEFUL LINKS
UK National Health Service swine flu predictions

World Health Organization, influenza pandemic

Baxter International, CELVAPAN

VaxInnate response to swine flu

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