Paper of the Month: From kitchen sink to targeted therapy - improving dengue vaccine effectiveness
About the School of Medicine Paper of the Month
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., Associate Dean for Clinical Science Eric Orwoll, M.D., and Assistant Dean for Basic Research Mary Heinricher, Ph.D.
This month's featured paper is from the lab of William Messer, M.D., Ph.D., assistant professor of medicine and molecular microbiology and immunology, and is titled, "Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity." It was published in the Proceedings of the National Academy of Sciences.
February 26, 2014
Suddenly, a headache pounds behind your eyes. Your muscles and bones ache deeply, and after a brief wave of nausea you touch your hand to your forehead to discover it is beyond warm – you have a fever. If you've traveled to any one of over 110 countries across the globe and were bitten by a mosquito, you may have something beyond seasonal influenza: you could have dengue fever.
Dengue fever is caused by a viral infection carried by several species of mosquito, and is endemic in over 40 percent of the global population. Forget West Nile – dengue is the most prevalent mosquito-borne human illness in the world. Although it is rarely lethal, dengue presents a growing public health concern as rates of infection have increased nearly thirty fold since 1960. This year, nearly 50 million to 100 million people will come down with dengue fever. Despite a growing molecular understanding about the virus that causes this illness, an effective vaccine has yet to be developed.
William Messer, M.D., Ph.D, assistant professor of medicine and molecular microbiology and immunology, and colleagues have recently published groundbreaking research in The Proceedings of the National Academy of Science that make enormous strides toward developing an effective vaccine against the virus.
"Dr. Messer’s work not only provides scientists with a molecular understanding of how our bodies mount an immune response to the viral infection, but it opens a new window for vaccine development for not only dengue but very possibly a range of other important viruses,” said Mary Heinricher, Ph.D., assistant dean for basic science and professor of neurological surgery.
So why is it so difficult to develop a vaccine against the dengue virus? Dengue has four different serotypes, DENV-1, -2, -3 and -4. Infection from one serotype will confer immunity to that serotype alone. Therefore, if an infected person has a splitting headache and sudden onset of fever as a result of DENV-1, despite recovering from the illness entirely, the person could still be vulnerable to DENV-2, -3, and -4. "Despite efforts to create vaccines that incorporate viral antigens from all three serotypes in a cocktail approach, results have shown that the mixed vaccine has failed to produce clinically meaningful results," said Dr. Messer. "In order to make an effective dengue vaccine, researchers needed to first clearly understand what confers dengue immunity." Dr. Messer's approach, developed while working as a post-doctoral fellow in Dr. Ralph Baric's lab at UNC, was to first better understand what specific parts of the dengue virus are targeted by our immune systems.
Previous work lead by Dr. Messer's co-author Dr. Aravinda de Silva, found that dengue neutralizing human antibodies, although rare, appeared to target a specific region of the dengue envelop protein known as the envelop domain I/II hinge region (ED I/II hinge). By transplanting a part of the ED I/II hinge region from DENV-4 into DENV-3, they discovered that both human and monkey systems recognized the transplanted virus as serotype number 4. In fact, monkeys that had already developed an immune response to DENV-4 were protected from the recombinant DENV-3/4 hybrid. “This is striking,” said Dr. Messer, “because it indicates that the ED I/II hinge region alone is sufficient to confer a specific, neutralizing immune response.”
The team’s work will help researchers design better vaccines by targeting critically important regions, to maximize vaccine strategies that have the best response rate in the human immune system. Moreover, this study clearly demonstrated a strong correlation between the human and monkey immune response, which validates non-human primates as a highly relevant model for studying human dengue immunity.
So what's next on Dr. Messer's plate? "The current vaccine approach has used the kitchen sink approach, which fails in part because one of the four serotypes generally is more immunogenic than the other, leading to partial or incomplete immunity following vaccination," said Dr. Messer. "Simplifying the vaccine formulation to include fewer viruses that are carefully designed to display the critical regions necessary to illicit a neutralizing immune response will do much to advance the dengue vaccine strategies."
Drs. Messer, de Silva and Baric have designed additional transplant viruses that contain ED I/II hinge regions from DENV-1 and DENV-3. These viruses have been designed such that the transplanted hinge regions are adjacent but not overlap. These viruses are "bivalent" in that they simultaneously look, to antibodies, like both DENV-1 and DENV-3; this virus has the potential to induce immunity to both serotypes in one targeted transplant virus. Dr. Messer is currently testing this in a pilot study. If successful, this will be an incredible advancement in targeted viral therapy, wherein a single infection can induce immunity to two serotypes. If paired with a complementary bivalent DENV-2/DENV-4 virus, a targeted vaccine that produces tetravalent immunity after a single simultaneous infection may become a reality.
Nobody wants to risk vaccination that might still leave you vulnerable to the aches and pains of dengue fever. Dr. Messer's work is taking us one step further to a targeted approach that yields a strong response. Moreover, Dr. Messer's research may pave the way for targeted vaccine development in other areas.