I wanted to highlight some recent progress against dengue fever, which is a nasty mosquito-borne disease that has been quite difficult to treat. There really aren't any effective antiviral drugs against it; once you get dengue you pretty much have to ride it out. For the majority of people, that works out fairly well, with fever being the main symptom - at least the first time around. The problem is, the dengue virus exists in at least four serotypes (I think the official count is now five), and infection only gives you long-lasting immunity to that particular variety (you have a short period of immunity to the others, but that disappears). What's worse, dengue is one of the best-known examples of antibody-dependent enhancement (ADE): if you get infected with another dengue serotype after your first round, the chances of a severe infection go up rather than down. The antibodies produced against the original serotype actually make things worse the next time around by enhancing viral entry into immune cells. As I'm sure everyone vividly recalls, ADE was something that everyone was looking out for during the intial period of the coronavirus pandemic, but it has fortunately not been a factor.
Problem is, it's not just infection that can bring on ADE. In viruses that are prone to this effect, vaccination can put you in the same situation. This was the problem with Dengvaxia, the first approved dengue vaccine (from Sanofi Pasteur), which had to be approved only for people who had already been through a round of natural dengue infection. If given to dengue-naive patients, it did indeed worsen the subsequent infection, which is of course exactly what you don't want. And in the same vivid-recall category, readers will remember the (bogus) controversy about whether the coronavirus vaccines led to this effect. They didn't, and they don't - this was looked for very carefully, and there has been no sign, despite what some diehard fear-mongering crackpots are still insisting.
So what the world needs, clearly, is a dengue vaccine that's effective against all the different serotypes and can be given to people who haven't been infected yet. Late last year, Takeda announced clincial results for their vaccine candidate (Qdenga). That one needs two doses, three months apart, but it can be given to children who have never had dengue at all. The efficacy at one year after this protocal was 80%, and follow-up at 4 1/2 years showed 60% efficacy against infection (efficacy against severe infection/hospitalization was 90% and 80% at those two time points). And now comes word from Brazil of another vaccine (Butantan-DV), which shows a two-year efficacy of 80% after a single dose (a real advantage!) The Phase III of that one is still underway, but it certainly looks promising. Neither of these show any signs of the ADE problem.
Interestingly, none of these vaccines are using any of the currently fashionable technologies. They're all live-attenuated ones, using dengue virus that has been passaged under laboratory conditions until it does not cause any real symptoms (but still infects the recipient's cells and sets off an appropriate immune response). This is one of the oldest vaccine techniques, and it's something of an art form. Some viruses can be defanged in this way and some can't, and you always want to make sure that your live virus can't regain its nastier functions through mutation once it's infected your patients. But dengue vaccines are a bit of an art form anyway (as witness the problems with Dengvaxia), and it's very good to see that we have one ready to be deployed and another one on the way. Dengue has been a growing problem for decades now in the tropical regions, and what's worse, its range is spreading as more areas of the world are experiencing warmer and wetter climates. So these vaccines are coming along just in time. Victories over infectious disease are always worth celebrating!
ABOUT THE AUTHOR
Derek Lowe
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He’s worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer’s, diabetes, osteoporosis and other diseases.