Dengue Serotype 2 Mutations Create Vaccination Challenges
Dengue virus vaccine development may need a new direction
Researchers from Duke-NUS Medical School (Duke-NUS) have discovered that the dengue virus serotype 2 (DENV2) changes its shape through mutations in Envelope protein to evade vaccines and therapeutics.
“We found that in laboratory-developed DENV2 strains, mutations in the virus’ E protein causes its transformation into bumpy particles. These structural changes can cause vaccines and therapeutics to be ineffective against the virus,” said Ms. Xin-Ni Lim, the study’s lead author who is from Duke-NUS’ Emerging Infectious Diseases (EID) Programme, in a press release.
The new study published on September 20, 2019, in collaboration with the Agency for Science, Technology, and Research (A*STAR)’s Bioinformatics Institute, and the University of Texas Medical Branch, also gives insights on the types of treatment strategies to use at different stages of dengue infection.
The research team also tested four DENV2 strains obtained from patients.
They observed that in contrast to the laboratory-adapted viruses, the majority of these clinical strains maintained a smooth surface structure at 37 degrees Celsius.
However, at 40 degrees Celsius, the temperature of a fever, all virus strains took on a bumpy surface.
This ability to morph helps the dengue virus to evade the immune system of the human host. Hence, understanding the mechanism behind this is important for therapeutics and vaccine development.
“Our study gives a new direction to vaccine development and treatment for dengue disease. For the prevention of disease through vaccines that are administered to the patient before dengue infection, we should use those that are effective against the smooth surface virus,” said Dr. Sheemei Lok, Professor, Duke-NUS’ EID and corresponding author of this study.
“When it comes to patients displaying fever symptoms, treatment strategies effective against the bumpy surface particles should be implemented.”
The study’s findings also show that the lab adapted DENV2 may not be a good model for research, as its structure is different from the clinical strains isolated from patients.
The team is planning to study the other DENV serotypes to find out if there are any other possible structural changes.
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In the USA, as of September 4, 2019, the US Centers for Disease Control and Prevention (CDC) reported 408 dengue cases. Nearly all dengue cases reported in the 48 contiguous US states were in travelers infected elsewhere.
During 2019, Florida (122), and California (69) have reported the most dengue cases.
Worldwide, the Dengue virus (DENV) infects about 400 million people annually. DENV is a flavivirus and is transmitted by the mosquito vectors Aedes aegypti and Aedes albopictus.
DENV comprises of four serotypes (DENV1-4). The sequence variability between the four serotypes is about 25 to 40% and between strains within a serotype is ~3%.
It causes diseases ranging from mild dengue fever to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
The development of vaccines is complicated by the presence of four serotypes.
When an individual is infected with one serotype, subsequent infection with another serotype may result in the development of DHF or DSS.
This antibody-dependent enhancement phenomenon is proposed to be due to antibodies elicited in a primary infection against the first serotype subsequently binding to but not neutralizing the other serotype in the second infection.
Non-neutralizing or sub-neutralizing concentrations of antibodies binding to the virus may help to concentrate the virus onto the Fcγ receptor on the surface of monocytes and macrophage cells, thereby leading to an enhancement of infection.
This suggests that an effective vaccine should simultaneously stimulate equally strong neutralizing antibody responses against all four serotypes.
Currently, several vaccine candidates have been tested in clinical trials. Thus far, CYD-TDV (Dengvaxia) is the only licensed dengue vaccine.
However, this tetravalent dengue vaccine showed poor efficacy towards DENV2 and moderate efficacy to DENV1, DENV3, and DENV4.
Interestingly, we previously observed that the DENV2 mature virus structure can be heterogenous at 37°C, which poses an additional complication when designing vaccines.
On May 1, 2019, Dengvaxia became the first vaccine approved in the USA for the prevention of dengue disease in people ages 9 through 16, who have laboratory-confirmed previous dengue infection, and who live in endemic areas caused by all dengue virus serotypes.
A blood test is the only way to confirm a dengue diagnosis.
The CDC says before being vaccinated with Dengvaxia, inform your healthcare provider if you have dengue symptoms or live in or have recently traveled to an area with risk of dengue.
Pre-travel vaccination counseling sessions can be scheduled at local pharmacies by Vax-Before-Travel.
Note: The CDC says any vaccine can cause side effects, which should be reported to a healthcare provider.
Dengue news published by Precision Vaccinations