“Dengue has been a road on which there have been many obstacles,” Scott B. Halstead, MD, founder of the Pediatric Dengue Vaccine Initiative, said during a presentation.
According to Halstead, approximately 4 billion people across 128 countries are at risk for infection with dengue virus, with 393 million infections and 96 million overt cases of dengue illness occurring in 2010. More severe forms of the disease carry a 5% mortality rate.
Primary infection with a single dengue virus will provide lifetime homotypic immunity, but subsequent infection from the other three virus types are possible. Antibody responses to a primary infection are known to enhance disease caused by secondary infections.
Halstead, somewhat tongue-in-cheek, characterized the severity of the disease in adults: “For 3 days you’re afraid you’re going to die, and for the next 2 days you’re afraid you’re not going to die.”
Since the 1970s, the burden of dengue has increased significantly. Efforts to control the disease have focused on a two-pronged strategy: mosquito control and vaccination. However, in the past 40 years, there has been “a systemic global failure of vector control,” according to Halstead.
“I don’t know whether those in charge of mosquito control retired or went to sleep,” he said.
The focus has since shifted to vaccine development. The challenge for drug developers is to produce a single-dose vaccine that can protect against all four dengue virus types. Naturally, infection from two different viruses results in lifelong protection against severe disease, and researchers were tempted to replicate this effect by developing separate vaccines and immunizing patients with one at a time. However, a live dengue virus induces cross-protective immunity, delaying the administration of sequential vaccinations for up to 6 months. Those living in endemic regions who receive only the first dose of a monovalent vaccine would be sensitized to severe disease occurring during a secondary infection. Developers instead opted for the simultaneous administration of the four virus types, according to Halstead.
However, interference from the live viruses prevented a balanced immune response. Despite adjustments made to the dosages of serotypes — a successful strategy applied to polio vaccines — quadrivalent dengue vaccines have failed to demonstrate robust immunogenicity across all four viral types. Changing the injection site also showed no improvement.
Currently, three of five vaccine candidates are live-attenuated. The first, developed by Sanofi-Pasteur, is a chimeric quadrivalent dengue vaccine. A 2012 study published in The Lancet indicated that vaccine efficacy was 61.2% against dengue virus type 1, 81.9% against type 3 and 90% against type 4. However, there was virtually no protection against serotype 2. More recent results from a phase 3 trial of 10,000 children demonstrated a 56% reduction of dengue cases, according to the drug company.
A vaccine from Takeda — also a chimera — is now approaching phase 3 development. It, too, showed inconsistent protection against the four serotypes. The NIH also is testing a live-attenuated dengue vaccine, licensed to drug companies in Brazil, India and Vietnam. In a randomized trial conducted in 2010 and 2011, the NIH vaccine demonstrated greater protection against types 1, 3 and 4 in flavivirus-naive adults, but type 2 remained elusive.
Although current dengue vaccines do not offer complete protection against all four virus types, there have been reductions in severe dengue cases in clinical trials.
“We’re left with the possibility that maybe we have a dengue vaccine that doesn’t offer complete protective immunity, but it might take the edge off the immune response and therefore dampen down disease,” Halstead said. “Now, is that true? I don’t know. I guess we’ll have to wait and see.”
Halstead said future research should examine how viral interference can be mitigated, which may result in increased protection against infection and severe disease.
“Stay tuned,” he concluded.