From SARS to Avian Flu: Vaccines on the Scene

When SARS struck more than 8,000 people and killed nearly 800 in the spring of 2003, the world clamored to know when a vaccine against the deadly virus would come to the rescue.

Mar 14, 2005
Jane Parry(jparry@the-scientist.com)
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When SARS struck more than 8,000 people and killed nearly 800 in the spring of 2003, the world clamored to know when a vaccine against the deadly virus would come to the rescue. Vaccine manufacturers and health institutes in Asia, the United States, and Europe rose to the challenge and began to work on vaccine candidates.

Two years later, there are no SARS vaccines on the shelves. None have come to market, nor are they likely to any time soon. Public attention has moved on, and the H5N1 avian flu virus emerging in Vietnam, Thailand, and Cambodia has eclipsed SARS. The threat of SARS has been overshadowed by the possibility that the bird virus, which rarely jumps from human to human, could reassort with a human strain and become highly transmissible, unleashing a worldwide pandemic to rival the deadly Spanish influenza of 1918.

The 2003 SARS outbreak has not repeated, but the threat hasn't disappeared. Last year sporadic cases of SARS were traced to laboratories working on the virus in Beijing, Singapore, and Taipei, and a limited outbreak occurred in the Guangdong province of China, the source of the 2003 epidemic. An effective vaccine is still needed, should the disease reemerge. However, several factors, including the lack of a clear market, have slowed research, but work is ongoing.

"In the early days of the SARS outbreak everyone felt there was going to be a big market for a vaccine," says Gary Nabel, director of the Vaccine Research Center (VRC) at the National Institutes of Health in Bethesda, Md. "When it was relatively well controlled, there was a reticence from companies to dive in. It's not clear how one would license it, and we know from animal coronaviruses that vaccines can be ineffective and even exacerbate the coronavirus infections in cats, for example."

Vaccine producers are keener to tackle H5N1 than SARS. Whereas SARS was a new and unknown disease, influenza is not. Vaccine constituent strains change every year, so regulatory procedures are already established for timely marketing. However, as with SARS, there is a catch-22: A vaccine cannot be fully developed unless an outbreak occurs. And it cannot be predicted in advance whether or not a reassortment will lead to an H5 flu virus strain.

Given that market forces alone are unlikely to spur the production of a mock vaccine, the World Health Organization (WHO) urges governments to make it easier to develop potential pandemic-preventing vaccines by offering tax incentives, financing clinical trials, and waiving fees associated with licensing. But is it enough? "At the end of the day we want vaccine manufacturers with the capability to produce vaccines that can be commercialized to take on challenges such as SARS and H5N1 flu," says Linda Lambert, acting chief of the Influenza, SARS, and Related Viral Respiratory Diseases Section of the National Institute of Allergy and Infectious Diseases (NIAID). "Both H5N1 and SARS have great potential to be needed in large quantities, and the development of vaccines is quite appropriate given the unprecedented outbreaks in Asia."

BIRD FLU, THE BIGGER RISK

Preparing vaccines to combat mutable, global public health threats is, of course, the bread and butter of influenza vaccine researchers and manufacturers. They are on much more familiar ground when it comes to developing a vaccine for the H5N1 avian influenza vaccine than for SARS. Moreover, WHO has a well-established mechanism for the sharing of data about flu strains. "Every year we have to make a new flu vaccine, and the nature of doing that means there is a very integrated process of open exchanges of information between manufacturers, the WHO, and governments. So, for example, when the NIH has clinical data we will be sharing it," says Lambert.

In May 2004 Chiron and Sanofi Pasteur, both suppliers of the annual influenza vaccine, were contracted by NIAID prepare 16,000 doses of an investigational H5N1 avian influenza vaccine. To make the vaccine, virus was taken from a patient who died in February 2004 in Vietnam and altered with reverse genetics to reduce pathogenicity. In March, Sanofi Pasteur had 8,000 doses ready to be shipped to the NIH to begin clinical trials. Chiron's half of the vaccine supply has been delayed due to problems at its Liverpool facility used to produce its commercial flu vaccine (see story on page 40). "We are manufacturing the clinical supply of H5N1 in Liverpool, UK, in the same location that makes our commercial vaccine, Fluvirin, but in a different part of the facility," says a Chiron spokesperson. "Production is now underway." The US and France have each contracted with Sanofi Pasteur to produce 2 million doses of the prototype vaccine.

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"For flu every year we change strains used in the vaccine, and it would be exactly the same for pandemic flu," explains Marie-Jose Quentin-Millet, vice president of research and development at Sanofi Pasteur in France. "The only difference is that when we vaccinate with annual flu, people have one shot because they already have some background immunity. Here, we know the population is totally naïve, so it's difficult to raise a protective immune response." Sanofi Pasteur is the world's largest vaccine supplier, but it is only one of several vaccine manufacturers working on an H5N1 avian influenza vaccine.

In Asia, Beijing-based Sinovac Biotech has signed a deal with the Chinese Center for Disease Control and Prevention to work on a vaccine. The company anticipates completion of preclinical trials by the end of May 2005. The Japanese government has increased funding for influenza research, and pandemic flu vaccines will be allowed to fast-track the licensing process. Clinical trials by Japan's National Institute of Infectious Diseases in collaboration with the country's four influenza vaccine manufacturers are expected to start later this year, according to a WHO report.

<p>SARS Vaccine Developers</p>

ID Biomedical Corporation in Vancouver announced in January that it had begun development of a mock vaccine against H5N1 using the genetically modified rH5N1 reference strain from the UK's National Institute for Biological Standards and Control. "There is a growing consensus among experts supported by the WHO that the development and testing of a mock pandemic vaccine is a critical component of pandemic preparedness, because it will allow manufacturers to shorten production times, thereby providing the general public with a vaccine more quickly," says Anthony Holler, CEO of ID Biomedical.

The only case of human-to-human transmission of the H5N1 virus occurred in Thailand in 2004, but fear is growing that it will become a highly infectious pandemic strain. Since January 2004, about 50 people have died, and the virus has an estimated mortality of 72%. A study by the US Centers for Disease Control and Prevention estimates that 2 million to 7 million people could die in a pandemic if that occurs. Others have higher estimates, but whether 7 million or 100 million people are at risk, the precautions are the same.

SARS VACCINES ON THE WAY

The picture being painted for SARS isn't nearly as scary, which may explain why many vaccine candidates are still in the preclinical stage. NIAID contracted with Sanofi Pasteur and Austrian manufacturer Baxter Healthcare to produce inactivated virus vaccine candidates, which are slated for Phase I clinical trials in 2005. Sanofi Pasteur, which has completed its work for the NIAID, appears to have closed the door on SARS research for the time being. "We've developed the technology, we think we know how to make a SARS vaccine, but there are no plans for us to do anything more on SARS at this stage," says Quentin-Millet.

A number of other vaccines are at a similar stage of development. Researchers at the Hong Kong University-Pasteur Research Center are working on a recombinant protein-based vaccine candidate, and Connecticut-based Protein Sciences is doing the same under contract with NIAID. The VRC is working on a DNA vaccine, and clinical trials began in December. Chiron has also done some early work on an inactivated virus, and a Canadian network of 40 scientists in the SARS Accelerated Vaccine Initiative has developed four vaccine candidates. So far, two have been tested in animal trials.

Only one company, Sinovac, has finished a Phase I trial of a SARS vaccine. A Phase I trial in which an inactivated virus vaccine was given to 24 people will be completed by the end of March 2005. Data from the trial is expected to be compiled by May. Sinovac's research, conducted in collaboration with the Chinese Academy of Medical Sciences, has been funded with $2.2 million in grants from the Chinese government. The State Drug Administration approval process was fast-tracked in order to get work on a vaccine started as soon as possible.

Whether Sinovac's work will progress to Phase II trials depends on approval from the Chinese government. Whether it can conduct Phase III trials may depend on nature: Large-scale, conventional Phase III trials can begin only if another outbreak creates a large pool of infected people. It is theoretically possible to make a vaccine available without going through large-scale efficacy trials if it can be tested successfully on animal models, but none has so far been found.

"As to whether or not there will be a market for it, there is still a question mark, although if we can come up with a vaccine the government will probably stockpile it," says Yang Guang, spokesperson for Sinovac. "The virus is still alive. It won't just disappear for no reason, so for us the job is to do clinical trials. It's not to make money, it's to prove that we have the capability to do world-class research," she says.

Sinovac's getting started on clinical trials so quickly has raised eyebrows in the vaccine research community, not least because none of their data have yet been made available through peer-reviewed scientific publications. Guang cites the difficulties of translating the research into English as one of the obstacles to publication, but she says Sinovac will aim to publish its results in internationally recognized journals this year. Sharing the data collected from its SARS vaccine research will go a long way toward allaying skepticism over their research and fears that they may inadvertently develop a vaccine that exacerbates rather than protects against SARS, says one observer. "It isn't an international competition; there ought to be international collaboration," he says. "If they keep the data to themselves, it won't help them or the world."

POTENTIAL APPLICATIONS

Scientists working on SARS vaccines argue that even taking the research only part of the way is valuable, not least because SARS is one of several examples of human coronaviruses becoming more deadly to humans. Whereas coronaviruses were previously only associated with the common cold, recently they have been linked to pneumonia cases and Kawasa-ki disease, a childhood ailment characterized by high fever, sloughing skin and vascular complications.

"Our decision to pursue a SARS vaccine was part of a larger effort to develop antivirals and therapies. When we decided to do so in 2003 we had no sense of the natural progression of the epidemic. But there are still places where it can break out, and an effective vaccine is a useful insurance policy," Nabel says.

Another outbreak of the disease would change the perspective on the business case for a SARS vaccine, potentially making it a must-have for travelers to the Asian region, healthcare professionals, and those in close contact with animals. "The SARS virus is probably living in such a harmony within an animal reservoir that we still don't understand very well," says Ralf Altmeyer, scientific director of the HKU-Pasteur Research Centre in Hong Kong. "The SARS virus probably became a killer when a mutant accidentally jumped to humans."

Altmeyer notes that SARS could be a potential bioterrorism threat, as the virus, like others, could be synthesized from scratch. The NIAID acknowledges the bioterrorism aspect of SARS. "We did not develop vaccine candidates because of the bioterrorism threat per se, but SARS was added to the NIH list of pathogens for biode-fense research," says Lambert.

The stockpiling of a SARS vaccine would be useless if the SARS virus mutates and an epidemic strain differs from the vaccine strain. Data recently published by Nabel's team at the VRC suggest that the virus samples from early and late 2003 were different. The latter probably represented a fresh jump from animals to humans and was not sensitive to neutralizing antibodies.

This was not a cause for concern for Sinovac. "We collected the virus antigen from different locations in China, both north and south, and found the SARS virus very stable and therefore very good for the development of a vaccine," says Guang. The reality is, no one knows how much SARS may mutate in the future. "We have to observe and test whether candidate vaccines developed are effective against new strains," says Altmeyer.

The chance always exists that viruses such as SARS and H5N1 will mutate and make newly developed vaccines obsolete, but that is one of the challenges of vaccine science. Moreover, popular demand for vaccines will also wax and wane as viruses hit the headlines. For scientists in the field, the research goes on regardless of popular sentiment and which virus seems to be an imminent threat.

"It's shortsighted to say there's no market for a SARS vaccine. I'm not so sure we will be safe from SARS," says Altmeyer. "You have to see a vaccine from a longer perspective. If we acquire enough knowledge of predeveloped vaccine candidates, then the Phase I or even Phase II data [are] there. Developed countries cannot just manage a crisis. The long-term investment is to prevent a crisis."