Wednesday, October 30, 2013

Delving into Dengue, Part 2: Current Dengue Research


Today I will give an overview into some of the other areas of dengue research, with a focus on some of the latest vaccine research. As the maps above shows, dengue is distributed throughout the world, particularly around the tropics. While this is a negative from a public health perspective, it encourages research from many different places where dengue directly affects the local population (like Singapore!).

Basic Research

Much of the research concerning dengue examines its pathogenesis, or the mechanism of the cause of the disease. Below is a generalized depiction of dengue pathogenesis, complete with your friendly neighborhood mosquito.

Credit: St. John et al., 
Nature Reviews Microbiology
 
11,
 
420–426
 
 
doi:10.1038/nrmicro3030

Similarly, other research focuses on the human immune response to dengue infection, as generally depicted below.

Credit: Simmons et al, N Engl J Med 2012;366:1423-32DOI: 10.1056/NEJMra1110265

However, the biggest news in the dengue world over the past week or so was the report of a fifth serotype of dengue. Creatively named DENV-5, it was determined to have a significant number of phylogenetic (DNA sequence) differences, while still retaining enough similar characteristics to remain within the dengue family. Nikos Vasilakis of the Univ. of Texas Medical Branch in Gavelston reported the findings in Bangkok last week

There are two current opinions regarding this discovery. The first holds that the new serotype is an anomaly, as it is currently restricted to an isolated region (Malaysia's Sarawak state). Transmission appears to have been limited to macaques until five years ago, and may not be sustainable in human populations. The second position believes that this development inherently complicates vaccine development, such that current progress (see below) will need to re-evaluate its approach. Because any vaccine would need to protect against all dengue serotypes, new consideration would be needed with DENV-5 now in play.

Overall, though, this discovery raises a multitude of questions about the evolution of the virus, and what mutations prompt the emergence of new serotypes. For current researchers, much of the analysis done on DENV-1 through 4 will need to be done on DENV-5.

Vaccine development

The discovery and production of a dengue vaccine has been slow, but recent developments within the past 10 years have reignited hope that a vaccine will be consumer ready in the coming years.

Sanofi Pasteur, the mammoth pharmaceutical company from France, currently leads the push towards an successful, safe, and cost-effective dengue vaccine. Their efforts to eradicate polio are well-documented, so they carry a bit of clout in the vaccine world. The money doesn't lie either, as they have invested hundreds of millions of dollars to scale up for full-blown vaccine production.

Infection from one type of DENV provides long-term immunity from that specific serotype, but only short-term immunity from the others. If one becomes infected with a second type, the body produces antibodies designed to attack the first serotype. Viral entry into host cells is facilitated by this response, making the onset dengue fever far more serious than the initial infection.

This is defined as antibody-dependent enhancement, or ADE which represents one of the largest hurdles that vaccine developers must overcome during vaccine design. For instance, if a vaccine only provides partial immunity, infection from a different type of dengue will be much worse than if the individual had not had any vaccine in the first place. Wikipedia has a nice summary of ADE, with a focus on dengue.

A phase 2b clinical trial was conducted last year, with the results published in the Lancet in Sept. 2012. The results were decidedly mixed, bordering on concerning. The vaccine, designed to be tetravalent (i.e., protecting against DENV 1 through 4), only provided protection against DENV 1, 3, and 4. While promising, this raises some serious concerns. 

Some authors have warned against making hasty conclusions from this stage of the clinical trial, stating that the statistical methods may obscure or mask the actual efficacy of the drug. Because vaccine efficacy against clinically apparent infections differ from efficacy against infection, the vaccine may have in fact protected the participants in the trial.


Singapore scientists are also making progress towards a fully functional vaccine. Led by Dr. Katja Fink from the Singapore Immunology Network (SIgN), they introduce a genetic mutation that deactivates a key enzyme, MTase, that the virus uses to evade detection within the body. This enables the body's immune system to detect and attack the invading viruses. Animal models have shown efficacy against DENV-1 and 2 (the two most common types in Singapore). 

Some researchers have taken the approach of using inactivated virus vaccines, as this results in increased safety and more balanced immune responses for tetravalent vaccines. However, a lack of immunity to the nonstructural proteins in dengue has proven problematic, as a 2005 study showed no sterile immunity from inactivated viruses.

Summary

Research from a multitude of disciplines (biology, computational chemistry, biophysics, etc) are increasingly producing valuable literature that aids the biomedical field's efforts to develop treatments.

Meanwhile, there are many reasons that no effective dengue vaccine or treatment has been produced to date. The disease is quite tricky to attack, as its tetravalency and complex pathology require that the vaccine or drug be both specific (to particular parts of the virus) and global (effective in all serotypes).

Part 3 - Singapore's efforts to fight dengue

The final installment of this little series will take a look at how Singapore is battling dengue from a public health perspective.

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