A new study has found a specific immunologic response among people likely to get severe dengue disease. The work could help lead to a screening test for people at risk of getting a serious case of the disease and to targeted vaccines.
February 7, 2017 - By Ruthann Richter
Dengue is a mosquito-borne viral infection that can lead to severe disease and death. Endemic in at least 100 countries, it is carried by the same mosquitoes that transmit Zika, yellow fever and chikungunya infections. The incidence of dengue infection has risen sharply in recent years, with some 50 million to 100 million cases reported each year.
Some infected individuals become ill with flulike symptoms, such as high fever, headache, vomiting, muscle and joint pain and skin rash. But in a small number of cases, it leads to more serious symptoms, including severe abdominal pain, persistent vomiting and severe bleeding. As many as 20,000 people die every year of the disease, which has no specific treatment. A novel vaccine for dengue was introduced in late 2015 and is commercially available in some countries. But large-scale trials of the vaccine have shown it to be only about 60 percent effective in people older than 9, and less than 45 percent effective in children younger than that.
Stanford virologist Taia Wang, MD, PhD, an assistant professor of infectious diseases and geographic medicine, was the lead author of a study published Jan. 27 in Science which found that some people may be more susceptible to severe dengue disease than others. Writer Ruthann Richter recently asked Wang about the disease and the study’s findings.
Q: Why is dengue so difficult to prevent and treat?
Wang: Dengue viruses are an especially challenging target from a vaccine development perspective. Most effective vaccines work by producing antibodies, a subset of which can prevent the virus from entering a cell by “neutralizing” it. Unlike other viruses, antibodies that bind to dengue viruses but fail to neutralize it can actually enhance dengue disease. Making matters worse, there are also four major serotypes of dengue viruses, so an effective and safe vaccine would need to elicit neutralizing antibodies against all four types at once.
The treatment of patients who go on to develop dengue disease poses another set of challenges. Severe cases are most successfully managed when patients are caught early and treated in the hospital, yet we don’t currently have a good way to predict who will develop severe disease. In addition, there are no specific medications that can be used to treat dengue disease; we rely on hydration and blood products for management of severe cases, which is very resource-intensive. This is a serious problem since most dengue infections occur in parts of the world where access to medical care is limited.
Q: Who is at greatest risk for the disease and why?
Wang: The greatest risk factor for progression to severe dengue disease is virus infection in the presence of antibodies that bind to the virus, but do not neutralize it. We typically think of antibodies as protecting us from infection; dengue infections pose a rare example of a situation where some antibodies can enhance disease. This antibody-dependent enhancement most commonly occurs when someone is infected for the second time. When this happens, antibodies that were produced during the first exposure can enhance the severity of subsequent infection. Still, progression to severe disease during second infections is relatively rare, and the reason for progression has not been understood, which limits early clinical intervention. Our study was driven by a desire to understand why some people progress to severe disease during secondary dengue infection while others do not.
Q: Can you tell us about the findings?
Wang: Our previous work showed tremendous variation in the type of antibodies produced by individuals. We were particularly interested in regions of antibodies called Fc domains and their receptors because they have been shown to be directly involved in enhancement of dengue disease. We hypothesized that the variability in Fc domains among people might determine progression to severe dengue. We discovered that people who develop the most severe forms of dengue disease do produce a different repertoire of antibodies — they make antibodies with Fc domains that work through a particular Fc receptor called FcγR3a. We went on to show that the antibodies with higher affinity for FcγR3a are involved in the development of severe dengue disease.
Q: What are the implications for vaccination programs?
Wang: Since people who develop severe dengue disease produce a distinct type of antibody, it may be possible to develop a screening test that identifies patients who are at highest risk for severe disease before they are ever infected. This would be useful for identifying patients who need a higher level of clinical care during dengue infection. Much more work will be required to determine whether such a test is possible.
In addition to the implications for clinical care, our findings may be used to guide vaccine development. Since we found that a specific phenotype of antibody contributes to severe disease, we would want to avoid stimulating production of those antibodies during vaccination. This could potentially be done by using specific vaccine antigens and/or vaccine adjuvants to guide the immune system to produce antibodies that are less likely to enhance disease.
Q: Why not vaccinate everyone in disease-prone areas?
Wang: Vaccinating everyone in areas where dengue is prevalent with a safe, effective vaccine is the surest way to limit dengue disease. However, doing so would be expensive. In areas with limited resources, the next best thing is probably to target vaccination to people at highest risk for severe disease. For this reason, and because it could help guide clinical care of dengue patients, we are investigating inexpensive screening tests that could be used to identify people at highest risk for progression to severe dengue disease.
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