Why don't we have a #dengue vaccine yet?

This is taken from a recent special issue of the journal Vaccine from September covering the "state-of-the-art" of dengue virus vaccine research. 

The process of generating - and testing -  a dengue vaccine captures the entire field of vaccinology and highlights it's promises and pit-falls and can be used as a model when thinking of any number of potential vaccine initiatives.

See below for my take and summary of this issue:

So why is Dengue so important? Whitehorn and Simmons (2011) in this issue state:

Dengue is a globally important arboviral infection transmitted by Aedes mosquitoes that endangers an estimated 2.5 billion people and represents a rapidly growing public health problem [1]. There are between 50 and 100 million infections each year, with approximately 500,000 cases admitted to hospital with severe and potentially life-threatening disease [2], [3] and [4]. Dengue is an icosahedral, enveloped virus with a single-stranded positive sense genome; it is a member of the flaviviridae family and has 4 antigenically distinct serotypes (DENV1-4) [3], [5] and [6]. After infection of a susceptible host, an acute, self-limiting febrile systemic syndrome ensues. Resolution of infection occurs within 4–7 days and is associated with a robust innate and adaptive immune response. At present diagnosis is largely clinical, treatment is supportive and disease control is limited to tackling the vector [1]. Development of a vaccine would be a major advance in disease control but efforts have been hampered by the lack of an animal model of the disease and concerns about the role of the immune system in disease pathogenesis [6]. The lack of an animal model further limits our understanding of immunopathogenesis.

See Google news feed for Dengue - there is a pretty serious epidemic going on in Pakistan currently.
See the Dengue vaccine initiative homepage
See an excellent Guardian piece on the production of a vaccine

So why no vaccine yet? Here's some of the problems:

• It's not as simple as with measles and mumps: dengue is actually caused by 4 related but entirely individual viruses (dengue 1 - 4), which differ in their antigenicity, meaning that any vaccine you develop must protect against not 1 virus, but 4. All measles and mumps viruses are considered antigenically the same; one virus = one vaccine.   

• We don't actually know what makes a good dengue vaccine: is it high antibody levels? Cytotoxic T cells? Where must you evoke immunity? How do you know you're successful if you don't know what successful is? 

• Antibody-dependent enhancement of infection is a serious problem with dengue: the most severe form of the disease is caused by your re-infection with another type of dengue than the one you orginally were infected with. It appears that those antibodies you made in the first place cause the virus to replicate more. This means that if the vaccine protected against some of the types more efficiently than others, you could cause serious adverse reactions following natural dengue infection. We need a balanced immunity. And, whats going to happen as your antibody levels decrease as you get older, will that leave you open to the more severe dengue in later life? Will we have to vaccinate continuously? Will antibody-dependent enhancement of infection cause those vaccine viruses to cause more disease? Another case for the need to develop four, long-lived vaccines in one. 

• There is no animal model out there which fully replicates what we see in humans. This further hampers any work we do on how the virus replicates in us and how we can prevent this with vaccinating. 

• Then there's the logistic problems of first producing a vaccine at sufficiently large scales and then going out and distributing it to some of world's most inaccessible populations, in some of world's most harshest conditions (to vaccines anyway). At least maybe we can learn from the lessons from other vaccines in this respect. 

• Clinical trials are not cheap. Period. Nor is any testing and production of any vaccine.

• We don't want any reversion to virulent virus. The use of live-attenuated viruses, especially RNA ones, always holds the risk of a genetic mutation turning your nice and safe vaccine virus back into its deadly counterpart.

Dengue virus particle (http://www.virology.wisc.edu/virusworld)

Well we are in luck in many of these respects, a number of potentially life-saving vaccine candidates are in development:

• A live-attenuated vaccine based on the widely-used yellow fever vaccine (both produced by Sanofi-Pasteur) which is itself a mixture of four viruses, each incorporating the predicted antigenic proteins from each of the four dengue sub-types. This is most likely the most promising candidate to go forward but results from phase 3 trials are not yet in. 

• The U.S team, from the NIH report their development of an alternative live-attenuated vaccine based not on a yellow-fever vaccine virus but on strains of dengue itself. It also aims at protecting against all four types. They document their generation of four seperate vaccine (one for each type) with the plan of combining into a single formulation like above.

• A CDC-backed live-attenuated vaccine based on a safe form of Dengue-2, which will also contain parts of 1, 3 and 4. It is in phase 1 trials. 

• A DNA-based vaccine, consisting of plasmids encoding and results in the synthesis of maybe a nanogram at most of dengue virus antigen - probably within professional antigen presenting cells like langherans dendritic cells in the skin thus kicking off the immune response inside draining lymph nodes. This has successfully completed initial phase 1 trials. 

• A Merck-led, sub-unit based vaccine requiring the large-scale synthesis of correctly folded dengue antigens inside insect cell lines. It is currently in pre-clinical trials. 

• And a number of other pre-clinical candidates: adenovirus-vectored, virus-like particles and whole, inactivated viruses.

There is a serious and timely need to produce and distribute a dengue vaccine to all endemic countries in order to limit the viruses effects on human populations. As you can from above, there is masses of interest - both public and private - in developing and testing candidate vaccines. And a number should be coming into use within the next couple of years. Of course these vaccines may not be perfect but the introduction of those experimental ones in pre-clinical testing should ensure a healthy and diverse pool of potential second - and third - generation pharmaceuticals. But also, there are other strategies that will have to be in place if we are ever to eliminate dengue transmission completely from any one region, as exemplified by TWiV talking about the use of Wolbachia bacteria in dengue eradication.

Guy, B., Barrere, B., Malinowski, C., Saville, M., Teyssou, R., & Lang, J. (2011). From research to phase III: Preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine Vaccine, 29 (42), 7229-7241 DOI: 10.1016/j.vaccine.2011.06.094