Singapore - Keeping the dengue virus unmasked

Mosquitoes spread four different strains of dengue virus, each of which causes dengue fever. For a vaccine to be effective, it needs to prevent infection by all four strains.

A method that stops the dengue virus from resembling a host’s RNA could yield an effective and affordable vaccine

Cases of dengue fever — a potentially life-threatening disease spread by the Aedesmosquito — are increasing worldwide, thanks to expanding mosquito habitats. According to the World Health Organization, the dengue virus infects 50 to 100 million people annually, with Southeast Asia and South America most affected.

An effective and affordable vaccine has eluded scientists, largely because the dengue virus can be one of four types. Each serotype, or any combination of the types, can prevail in a single location. Thus, an effective inoculation needs to confer protection against all of the serotypes.

Katja Fink and co-workers at the A*STAR Singapore Immunology Network, together with scientists across Singapore, China and the United States, have developed a novel strategy for producing a live dengue fever vaccine¹. The vaccine currently protects against two of the serotypes, and the team is working to expand this to all four strains.

“We used a mutated form of the dengue virus to create the vaccine,” says Fink. “The mutated virus replicates slowly in the body but does no harm, creating an immune memory response, which is triggered if the host encounters the wild-type virus.”

Usually, RNA molecules in the dengue virus are modified by an enzyme called MTase that adds a methyl group to the viral RNA. This methylation makes the viral RNA resemble the host cell’s RNA and consequently, the body’s immune system does not attack it. Fink and co-workers created mutations in MTase so that the RNA remained unmodified by methylation. The mutations led to a form of the dengue virus that cannot spread quickly yet triggers an effective immune response.

“Our virus is the first live dengue vaccine that contains defined mutations to block a viral enzyme,” explains Fink. “These mutations could be equally introduced to all four serotypes, meaning that no serotype would have an advantage over the others — a situation that otherwise creates an imbalanced immunity.”

The new vaccine gave full protection against wild-type virus infection when tested in mice and monkeys. The researchers found that the mutations remained stable over time and did not revert to the wild type, a potential complication in vaccine development. Furthermore, mosquitoes feeding on blood containing the mutant dengue virus did not become infected.

Live vaccines are relatively cheap and easy to produce. “The enzyme mutation can also be introduced into new strains if dengue virus evolves over time,” says Fink. “Our next challenge is to see whether we can achieve full protection against all four serotypes.”

Reference

1. Züst, R., Dong, H., Li, X.-F., Chang, D. C., Zhang, B. et al. Rational design of a live attenuated dengue vaccine: 2’-O-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques. PLoS Pathogens 9, e1003521 (2013). | article

http://www.research.a-star.edu.sg