Untangling the Fate of the Dengue Vaccine

It can't be emphasized enough the dengue fever is a deadly viral infection that exacts a considerable burden on the world. Any tool to diminish this impact would be welcomed by the world. This mosquito-borne virus has a unique aspect about its pathophysiology that makes it especially intriguing and difficult to develop a vaccine against. There are 4 types or strains of dengue virus (maybe five) that circulate and it has been shown that antibody-based immunity to one strain enhances the severity of subsequent infections with the other strains. This phenomenon is known as antibody-dependent enhancement and is what accounts for severe dengue. 

Because of this capacity of dengue, it is essential that any vaccine not induce antibodies that lead to enhancement of infection. The only dengue vaccine on the market to seemingly clear this hurdle was Sanofi Pasteur's Dengvaxia which has been licensed in several countries (but not the US). This vaccine, based on a yellow fever vaccine platform, is protective against 4 strains of dengue.

Dengvaxia has been in the news because of new longer term data showing that in those with no prior immunity to dengue, the vaccine increases the chances that infection will lead to severe disease. Perhaps vaccine induced antibodies -- in the absence of any naturally formed antibodies -- are enhancing. Interestingly, in the clinical trials of this vaccine an increased rate of hospitalization and severe dengue was noted in children less than 9 years of age which restricted its use to those above 9.  I wonder if this is because those younger than 9 are more likely to have escaped natural dengue infection and be liable to develop severe dengue due to vaccine-induced antibodies. Of course, some people may reach 9 years of age and escape natural infection and have a similar risk as those below age 9.

It may be that restriction of the vaccine to those with laboratory confirmed dengue -- irrespective of age -- will be the best way to salvage this vaccine as a tool to prevent severe dengue. However, adding a lab test will considerably increase the costs and logistical difficulty of deployment. This finding also makes it very difficult to market the vaccine to travelers, most of whom will not have any natural dengue antibodies.

While this negative finding is clearly a setback for Sanofi, the dengue vaccine field, and for the countries using the vaccine it should be seen as a validation for the rigor of post-licensure vaccine safety testing in which this signal was uncovered and openly publicized. This finding should not be misinterpreted as some way to bolster the veracity of the anti-vaccine movement (which I am sure is inevitable) and be used to smear other vaccines to which this finding is wholly inapplicable.

Chikungunya Gets Its Green Card

It comes as no surprise that autochthonous chikungunya has occurred in Florida. The simple maxim that must be kept in mind with respect to vector borne diseases is: if a competent vector exists in areas in which imported cases are occurring, it is only a matter of time before local vector populations contract the pathogen.

Florida is an area hospitable to Aedes mosquito and has been plagued with locally-transmitted dengue for several years. As chikungunya shares many of the same characteristics of dengue, it is no surprise that it has found welcome in Florida. 

Intensified efforts to control the vector, which is already ongoing for dengue, will likely occur. However, it may be exceedingly difficult to eradicate chikungunya if it has thoroughly settled in local Aedes population.

For a great overview of these issues see this recent NEJM piece by Fauci and Morens. 

GMO Mosquitoes: The 21st Century Bug Zapper

There are several mosquito-borne diseases that merit a lot of attention in the US. These include dengue, chikungunya, and West Nile Fever. The key to the control of these infections--none of which  are vaccine-preventable--is controlling the mosquito which serves as the vector for human infection. 

Vector-control is a challenging task. Prior to the sermons of fellow Pittsburgher Rachel Carson, which led to bans on DDT use and the collapse of the malaria eradication efforts in the 1960s, mosquito control was achieved using this highly efficacious insecticide. Current vector-control activities employ other compounds targeting mosquito larvae as well as adults. Often, simple efforts such as removing standing water from tires and other household items are highly effective measures. 

A new 21st century approach to vector control that I find very promising is the use of genetically modified mosquitoes. In this approach, pioneered by Oxitec, male mosquitoes are genetically engineered to produce offspring that cannot live outside the laboratory because they require the presence of the antibiotic tetracycline to live. In the wild, when a female mosquito mates with one of these engineered male mosquitoes, the offspring produced will die. Such an activity can substantially reduce vector populations and, therefore, render infection with mosquito-borne viruses less likely. Thus far this approach has been used against Aedes mosquitoes (the vector for chikungunya, dengue, and yellow fever).

Already, this approach has been employed in Malaysia, Brazil, and Panama with great success. Even Florida, recently plagued with dengue, has used this approach.

What I can't seem to fathom is why this measure, which could literally change the landscape in the realm of vector control, is met with derision and fear over tampering with the "fragile ecosystem." Such a reaction completely drops the context. All types of vector control, from bug zappers to DDT to a fly swatter, represent attempts to "tamper" with the ecosystem and are laudable attempts to tame mosquito-borne diseases. Mosquito lives aren't as important as human lives, unless one holds a wickedly egalitarian and nihilistic standard. 

I wonder if these individuals would have counseled against smallpox eradication because of the ecological niche once played by the virus. 

A favorite quote of mine, from Francis Bacon, is applicable here: "Nature, to be commanded, must be obeyed." Viewing nature as a realm able to be shaped and reconfigured by man's mind, while respecting the rules of reality, is what is sorely missing in the minds of those who reflexively oppose the use of these mosquitoes. It is reminiscent of Mary Shelley's panic over the progress of science, which inspired her Frankenstein.

Dengue Fever: Back in the USA?

There has recently been an uptick in media reports focused on the threat of the mosquito-borne dengue virus in the US. The latest is an article, in which I am quoted, that details the mosquito control efforts of California, a state where no cases have been detected. 

Until this year, local spread of dengue was know to have occurred in Texas (chiefly along the border with Mexico), Florida, and Hawaii, the details of which can be found in a paper my colleagues and I wrote on the topic. This year, however, in addition to the uncovering of evidence of local spread in Houston, a locally-acquired case was detected in New York.

The key thing to remember with respect to dengue is that since the Aedes mosquito is present over a large swath of the US and there are a continual stream of potentially infected travelers--who may be asymptomatic--it is not surprising to find instances of local spread of dengue occurring in the US. In fact, serosurveys along the Texas-Mexico border have shown up to 40% of individuals exhibit evidence of exposure to dengue. 

Clinicians and public health officials should keep these facts in mind when investigating or treating unexplained febrile illnesses.