The results of the first trial of the effectiveness of a vaccine for dengue, a sometimes fatal disease endemic throughout most tropical countries, have engendered both enthusiasm and disappointment. The vaccine proved safe, and it protected against three of the four dengue virus variants, or serotypes—but surprisingly, it provided no protection against the fourth. Scientists are stumped as to why and pondering what this means for the global fight against a serious public health threat.
"For us, it's encouraging. The vaccine technology clearly has a biological effect that prevents dengue," says Derek Wallace, regional director of clinical development for Sanofi Pasteur, the French pharmaceutical firm developing the vaccine, who reported results online today at The Lancet.
Other scientists are less positive. "True, the vaccine shows protection against three of the strains, but unfortunately—and this is very disappointing—overall it was not effective, showing no protection for the most common dengue strain circulating in Thailand," says Scott O'Neill, a dengue expert at Monash University, Clayton, in Australia.
Public health officials and affected communities are eager to have a dengue vaccine because there is no treatment and the disease burden is growing. Spread by mosquitoes, the four dengue serotypes infect as many as 100 million people, mostly children, worldwide each year. Exposure to one serotype usually causes minor illness, and the patient is immune for life to a second infection of the same serotype. But for poorly understood reasons, subsequent exposure to a second dengue serotype increases the chance of the illness progressing to the severe and sometimes fatal dengue hemorrhagic fever. The World Health Organization estimates that each year about half a million cases of severe dengue require hospitalization, and dengue frequently strikes in outbreaks that suddenly overwhelm hospitals.
Scientists have assumed that a vaccine has to be equally effective against all four serotypes, fearing that incomplete protection against any one could put vaccinees at risk for severe illness. So for several decades, research focused on developing a vaccine for each of the four serotypes and then combining them. But in a case of the whole being less than the sum of its parts, these formulations never worked as well as the individual vaccines. Putting all four vaccines together in humans "encountered some interference effect we don't understand," says Scott Halstead, a senior adviser to the Seoul-based Dengue Vaccine Initiative.
This time, Sanofi Pasteur researchers thought they had solved the combination problem. Early testing indicated that in humans, their vaccine produced a balanced immune response to all four serotypes. In what was the first test of the vaccine's efficacy, more than 4000 children in Thailand's Ratchaburi Province were split into vaccination and control groups. The vaccine proved fairly effective in preventing illness from three serotypes, cutting infection rates by 55.6% for serotype 1, 75.3% for serotype 3, and 100% for serotype 4 after three injections. But it provided near-zero protection against dengue serotype 2, which is the most prevalent one in the region and is most responsible for severe illness throughout the world.
"Of course, our desire would have been to have a vaccine that protects against all four (serotypes)," Wallace says. But he is encouraged that so far at least, there is no evidence that a post-vaccination infection with dengue serotype 2 infection results in severe illness.
Wallace suggests there could be a mismatch between the serotype 2 component of the vaccine and the one circulating in Thailand. In an accompanying comment also appearing online at The Lancet, Halstead says another possibility is the interference problem.
Some understanding of why the serotype 2 component proved ineffective might come from ongoing trials involving 31,000 people in 10 countries. Until those results are available in 2014, Wallace says it would be premature to discuss what comes next with the vaccine. Halstead sees several options. Widespread use of a vaccine that protects against three serotypes might result in fewer cases of dengue hemorrhagic fever and reduce the overall disease burden; modeling could be used to investigate this scenario. Or it might be necessary to reformulate the vaccine to make it effective against dengue serotype 2, which would also require redoing the clinical trials. Halstead says it may be time to reconsider the four-vaccines-in-one strategy. "We might have to think of something dramatic," he says.