The full results of a clinical trial testing a potential dengue vaccine were published Tuesday in the Lancet, in a study that both disappointed and encouraged researchers.
The vaccine developed by Sanofi Pasteur was only about 30 percent effective in preventing dengue fever during a randomized, controlled trial in Thailand – well below the 70 percent researchers had been expecting. While disappointing, the results were not totally deflating.
Roughly 4,000 schoolchildren ages 4 to 11 were included in the study in the Muang district, about 100 kilometers (62 miles) west of Bangkok. Of those, 2,452 of them received three doses of the vaccine. Researchers followed students for two years, and took blood samples any time the children fell ill with a fever. The samples were tested to confirm dengue and to identify the dengue virus serotype.
The results were compared against a control group, and researchers found that the overall efficacy of the vaccine was lower than expected (around 30 percent) and not significant.
But when researchers examined the effectiveness of the vaccine against each serotype individually, a different story emerged. Against three of the four serotypes (1, 3 and 4) the vaccine actually showed an efficacy of about 70 percent – much closer to what researchers had been expecting.
The vaccine failed, however, to protect against the serotype that was most prevalent in the area during the study. Thirty-one of the 45 cases in those who received the vaccine were infected with dengue virus type 2. The predominance of this one serotype was the biggest limitation of the study, researchers said.
The dengue virus belongs to a genus of other viruses known as flaviviruses, which are transmitted through the bites of arthropods, like mosquitoes or ticks. Others in the genus, such as yellow fever and Japanese encephalitis, have had effective vaccines available to the public for decades.
But the complex nature of the dengue virus serotypes and their interactions is a major hurdle in developing an effective vaccine.
“Serious deficits remain in our understanding of the mechanism or mechanisms by which human beings are protected against … the four DENV [dengue viruses],” wrote Scott Halstead, a senior scientific adviser for the Dengue Vaccine Initiative, in a commentary about the study.
When exposed to a virus, the body typically responds by creating antibodies to fight off the pathogen. The next time the person is exposed, the body is ready to attack, and usually fights off the virus before it can cause symptoms – thus providing a sort of immunity.
But the dengue virus works differently. Exposure to one serotype provides lifelong immunity against that one type, but not for the other three. In fact, through a phenomenon known as “immune enhancement,” being exposed to one type of dengue virus can actually make symptoms more severe if exposed to a second type. This can increase the risk of developing the more serious dengue hemorrhagic fever or dengue shock syndrome.
The vaccine attempted to protect against all four serotypes simultaneously, but it appeared to have uneven results.
“This trial is a cautionary tale for investigators designing future dengue vaccine efficacy trials,” wrote Halstead. The study was done in an area when many of the children might have already been exposed to the different dengue virus serotypes, he added, making it difficult to establish the true effectiveness of the vaccine.
Despite the low efficacy, the vaccine did not produce any major negative side effects during the two years of follow-up. While results were not as researchers hoped, “this study represents a major milestone,” wrote study authors. “These data show for the first time that a safe vaccine against dengue is possible.”
There is no specific treatment or cure for dengue fever. Successful development of a vaccine would be a giant step in the global fight against a disease that affects between 50 and 100 million people each year.
Sanofi is conducting Phase III trials with over 30,000 patients in Asia and Latin America, where researchers hope to answer some of the questions raised by this study.