In a Setback, Sanofi’s Dengue Fever Vaccine Falls Short of Its Goal

http://www.nytimes.com/2012/09/11/health/a-dengue-vaccine-falls-short-of-expectations.html

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The leading candidate to become the world’s first vaccine against dengue fever was only 30 percent effective in its first large clinical trial, dealing at least a temporary setback to efforts to control a disease that threatens half the world’s population.

Still, the study marked a milestone in the 70-year quest to develop such a vaccine, demonstrating that a safe and effective inoculation against dengue is feasible, researchers reported in a paper published online Monday in The Lancet, a medical journal.

The results are “the first ever demonstration that dengue vaccine is possible, and that’s huge,” said Dr. Nadia G. Tornieporth, an author of the paper and head of global clinical research and development at Sanofi Pasteur, the company that is developing the vaccine and sponsored the trial.

But in a commentary also published by The Lancet, Dr. Scott B. Halstead, a senior scientific adviser to the Dengue Vaccine Initiative, called the results “a complete surprise.”

“We’re all disappointed,” Dr. Halstead said in an interview. “We built up an enormous expectation.”

A vaccine is considered crucial because there is no specific treatment for dengue, and no way to prevent the disease other than controlling the mosquitoes that transmit it. Infection by dengue virus can cause high fever and intense joint and muscle pain. Severe cases can involve bleeding and shock and can be fatal, particularly for children.

The World Health Organization estimates that 50 million to 100 million infections occur each year, mainly in tropical and subtropical countries. The incidence has increased sharply in the last few decades and the disease now affects more than 100 countries. In 2009, the Florida Keys had its first cases in decades.

Other efforts to develop a vaccine are under way but Sanofi Pasteur, the vaccine division of the French drug company Sanofi, is several years ahead. While previous trials were meant to see if a dengue vaccine was safe or could spur an immune response, the Sanofi trial was the first to test whether a vaccine could actually prevent the disease.

The trial, conducted by Sanofi and Thailand’s Mahidol University, involved 4,000 schoolchildren, ages 4 to 11, in Thailand’s Ratchaburi Province. Two-thirds of the children received three injections of the vaccine over the course of a year, while the other third received three injections either of a rabies vaccine or a placebo.

Among children who got all three doses of either the vaccine or the control, there were 45 cases in the vaccinated group, representing 1.8 percent of that group, and 32 cases, or 2.6 percent, in the control group. The difference was not statistically significant. Using a different calculation the vaccine reduced the risk of getting dengue by 30 percent, well below the study’s goal of 70 percent.

The main problem was that there are four types of dengue virus and the vaccine failed to protect against one of them, known as serotype 2. It turned out that serotype 2 was the prevalent type in that region at the time of the study, accounting for more than half of the infections in the trial. That dragged down the overall results.

It is unclear why the vaccine did not protect against serotype 2, especially since the vaccine did spur an immune response to that serotype. But the trial showed that the vaccine was safe and could help dispel a theoretical concern that a vaccine could actually make the disease worse.

Dr. Tornieporth said the vaccine might be more effective in other regions where serotype 2 is not so prevalent. Sanofi is already testing the vaccine in large Phase 3 trials involving more than 30,000 people in 10 countries, with results expected in 2014.

Duane J. Gubler, a dengue expert at the Duke-NUS Graduate Medical School in Singapore, said a vaccine that protects against only three types of the virus could be sufficient to protect against severe disease. “The fact that it only protects against three of the four viruses doesn’t bother me at all,” he said.

The trial was too small to show whether that was true, since there were only five cases of severe disease — three in the vaccinated group and two in the control group.

Others were more cautious. Orin Levine, professor of international health at Johns Hopkins Bloomberg School of Public Health, said the study provided “some promising but mixed signals.”

Dr. Robert Edelman, a dengue expert at the University of Maryland, called the results “a bit disappointing.”

The results are likely to lead to a delay in the use of the vaccine, according to both Dr. Tornieporth of Sanofi and to Dr. Halstead of the Dengue Vaccine Initiative, which is financed by the Bill and Melinda Gates Foundation.

Given the urgent need, they said, some governments had been considering approving the vaccine based on the results of the Thai trial, even though it was only a Phase 2, or midstage trial. Now the countries are more likely to wait for the Phase 3 results.

The results also raise questions about Sanofi’s communications with investors. The company issued a news release on July 25 proclaiming that the vaccine had “demonstrated proof of efficacy” in the trial, with details to be published in a medical journal.

While the release did mention that the vaccine had not provided protection against one viral type, it did not say that the vaccine had not provided statistically significant protection over all.

“This is certainly not the way I would have described this trial,” Dr. Halstead.

Dr. Tornieporth of Sanofi defended the release, saying that the results were “a huge breakthrough.”

The dengue vaccine, which is made of live, attenuated viruses, is one of the most important products in Sanofi’s pipeline, with some analysts expecting sales to exceed $1 billion a year. Sanofi has spent 350 million euros, or about $450 million, to build a new factory in France to make the product.