Chiang Mai Researchers Cure ALL Disease!

At the moment the Thai announcement was made, no less than five other groups already had vaccine candidates in some phase of clinical trials.

By | Wed 27 Apr 2011

At the end of February, the National News Bureau of Thailand (NNT) jubilantly released the following headline: Thailand successfully produced the world’s first vaccine against dengue fever.

This was an announcement deserving of attention. The mosquito-transmitted dengue fever (known as ‘break bone fever’ for the excruciating pain the infected suffer) affects 100 million people worldwide annually, with half of those requiring hospitalisation for life-threatening complications. Each year, twenty five thousand people die from the disease. It is one of the leading causes of death of children in Southeast Asia, and almost 1.5 billion baht is spent on treatment, prevention, and lost productivity in Thailand alone.

So if Thailand, a country that is relatively new to the international medical research game, really beat out the other academic institutions and corporations working to produce a vaccine, that would certainly be an amazing accomplishment. The NNT reports that the new vaccine, “hailed as the world’s first,” has been tested in mice and will be produced by BioNet Asia Company Limited and available for human use in the next three years. The Bangkok Post ran a similar headline: Thai World-First Dengue Vaccine. And yet, testing an attenuated (weakened) virus in mice or monkeys does not make it a human vaccine. If it did, companies in the US and Europe could have announced the creation of a dengue vaccine years ago.

Producing an effective vaccine takes decades, including innumerable years of basic research and three phases of strictly-regulated human trials. In fact, none of the leading researchers have reported the creation of a successful vaccine. As Dr. Nopporn Sittisombut, one of the lead researchers on the Thai vaccine project at Chiang Mai University, has stated, “all the vaccines in the press are just candidates in various phases of development, no one has claimed to have an effective dengue vaccine yet.”

At the moment the Thai announcement was made, no less than five other groups already had vaccine candidates in some phase of clinical trials. Thailand’s vaccine candidates are still in the pre-clinical phase, animal testing in model systems far from the virus’s normal host. The leader in the international efforts at vaccine development is French pharmaceutical giant Sanofi-Pasteur, which has recently started phase III testing (the final phase). Dr. Nopporn was well aware of the corporation’s progress, mentioning that Sanofi-Pasteur “is light years ahead of us,” but maintains he is quite proud of his own lab’s work, saying “our candidates are the only set like this created in the developing world.” Thai researchers are doing important work, but the NNT announcement tells us nothing useful about that work.

Thailand is not alone in its poor scientific press coverage. The disconnection between headlines and the underlying experiments is a problem much-bemoaned by scientists in the US and Europe, who must suffer the translation of their complex projects into attention-grabbing, sometimes horribly misleading headlines. Egregious examples are well-documented. Reexamining Human Origins in Light of Ardipithecus Ramidus becomes the meaningless Did Apes Descend From Us? (The Toronto Star). Beaked Whales Respond to Simulated and Actual Navy Sonar is transformed into the alarmingly false Wind Farms Blamed for Stranding of Whales (The Daily Telegraph). Individual experiments with small sample sizes are often recklessly extrapolated upon, making vaccines the cause of autism, swimming the cause of bladder cancer, and moderate alcohol consumption the cure for all that ails you. Sometimes the ‘scientific discovery’ being touted has yet to be peer reviewed or published, and sometimes it never will be.

It is seldom scientists who write the press releases for their discoveries. As a rule, scientists are stringently precise in their wording, and very few people would be enthusiastic about reading how the Interaction of dengue virus envelope protein with endoplasmic reticulum-resident chaperones facilitates dengue virus production in their local paper. A survey in the US found that 29% of scientists mentioned in a press release thought the importance of their work had been exaggerated (and 30% of news writers relied mostly on the information in a press release for their science stories). But it’s not just scientists who suffer from the embarrassing overstatement and oversimplification of PR departments. Readers also miss out on the interesting process of scientific discovery. They miss out on meaningful information that deserves to be read about.

The real story of dengue fever vaccine development in Thailand is far more nuanced. The modern scientific landscape is complicated, with institutions competing for funding while needing to cooperate to make progress. Pharmacological companies scan the field for promising discoveries that could lead to a lucrative product, and also pour substantial funding into their own research and development teams. Scientific projects span decades and stretch across the globe, including both developed and developing countries.

Dr. Nopporn provided some background for the Thai dengue fever project: In 1964, researchers at Mahidol University in Bangkok isolated the dengue fever virus from Thai patients. To create a live vaccine, the disease-causing potency of the virus had to be reduced (inoculating with the full-strength virus would just give patients the disease). The researchers used prolonged growth in dog kidney cells to gradually reduce the virus’s virulence, producing an attenuated virus.

One of the reasons a dengue vaccine has been so difficult to create is the diversity of viral strains. There are four different serotypes of dengue virus, four types of virus recognised separately by the immune system, each needing its own vaccine. To make matters worse, vaccination against only a single serotype can make infection by one of the other serotypes more severe, leading to the far deadlier dengue hemorrhagic fever. To be effective and safe, it was crucial that the vaccine included all four serotypes.

The four attenuated viruses were known as the ‘Mahidol Set,’ and presented one of the most promising advances towards a dengue vaccine at that time. In the name of scientific collaboration, the first virus from the Mahidol Set was sent to the US Centers for Disease Control (CDC). There, researchers identified the nine mutations that were responsible for its attenuation and altered these genes in the original Thai virus to create a recombinant attenuated virus. Under US patent law, the new virus and its genome were the intellectual property of the US CDC. In 1993 it was licensed to pharmaceutical giant Sanofi-Pasteur (then Pasteur Merieux). As Dr. Nopporn recalled with a laugh, “some Thais were not happy about that.”

The live attenuated vaccine candidate based on the Mahidol Set eventually returned to Thailand for testing under Sanofi-Pasteur. The vaccines for each serotype were successful individually, but when combined into a tetravalent vaccine that covered all four serotypes, one of the four recombinant attenuated viruses dominated the immune response. After decades of work by Thai, CDC, and Sanofi-Pasteur researchers, the Mahidol Set was abandoned in phase II clinical trials. According to a Sanofi-Pasteur spokesperson, this failure was “paving the way for further dengue vaccine development.”

In 2008, Sanofi-Pasteur bought Acambia, also acquiring the full rights to another type of dengue fever vaccine, a chimeric virus created by inserting dengue fever genes into a backbone from its flavivirus cousin, Yellow Fever. This is the vaccine that is now starting phase III clinical trials, and it may be the first vaccine to be approved for public use.

For a company like Sanofi-Pasteur, the race analogy for vaccine development may be appropriate, but for international researchers progress is more piecemeal and always ongoing. One standard by which research efforts are judged (and funding and academic jobs are distributed) is the number of papers published in major peer-reviewed scientific journals.

According to statistics from the Reuter’s-owned Web of Science database (the most inclusive academic indicator available, with over 10,000 majors journals in over forty languages), Thailand has clearly risen to the position of a world leader in dengue fever research. Of the 5,741 papers published on dengue fever in the last ten years, a surprising 498 papers were written by researchers in Thailand. That’s almost 9 percent of all of the published work on the disease in the world, making Thailand the third largest contributor in the world, with only the United States and India publishing more. On a per-capita basis, Thailand publishes more papers on dengue fever than any other country. After the United States, Thai researchers have also published more papers on dengue vaccines than any other country in the world.

The failure of many initial vaccine candidates is to be expected, and each failed attempt is a step towards a working vaccine. Drs. Nopporn and Poonsook at Chiang Mai University have pressed onward, taking the original Thai virus and changing three genes to produce a simpler recombinant attenuated strain. They then added new DNA from the other three serotypes. These genes, taken from Thai patients in 2003 and 2004, are the most recent set in a vaccine candidate. Like HIV and influenza, infamous for their ability to evade immune defences, the dengue fever virus is always changing (although more slowly). The best defence against virus adaption is multiple vaccines. “We can not be happy with only one set of vaccines,” Dr. Nopporn said adamantly, “each one could end up being inadequate in some way. We have to keep up with the virus.”

Although the new vaccine candidates will be significantly different from the others being created around the world, the mutation sites used to create the attenuated backbone are still technically covered by the rights owned by Sanofi-Pasteur. Bionet Asia Company Limited has been licensed to produce the new Thai vaccine, and it will be interesting to see whether Sanofi-Pasteur attempts to shut down the Thai company’s development. Such a move, though perhaps good from a business standpoint, would be harmful to the research project and the thousands of Thai people exposed to dengue fever each year.

The scientific community, including experienced researchers in Thailand and across the world, will have to continue to work on the vaccine regardless of whether the Sanofi-Pasteur candidate makes it through the last clinical trial phase. A vaccine can always be less expensive or more effective. It can always be safer, or work with fewer injections (it is hard for a Thai farmer to travel to the city every couple of days or months for an extended booster schedule). “Vaccine development is a long process, everyone involved has to be patient,” said Dr. Nopporn, “There is a lot more room for development… we can’t look for one magic bullet. We have to keep working hard.” He added that they would keep working to create more sophisticated tools for the fight against dengue fever, “because that’s what science should do, and that’s what it can provide for people.”