Diving into Dengue with Dr. Thomas Monath, Developer of One of the First Dengue Vaccines

Masuma uses insecticide spray to try to prevent mosquitoes from entering her home in Mirpur, Dhaka. Her child is suffering from dengue. The locality is badly affected, with many households with someone who has contracted the disease.
©WHO/Fabeha Monir

Dr. Thomas Monath, winner of the Albert B. Sabin Gold Medal in 2023, developed one of the few existing vaccines against dengue during his extensive research and development of vaccines. With dengue infections surging globally – the U.S. Centers for Disease Control and Prevention issued a health alert in June – we connected with Dr. Monath at Quigley BioPharma for his thoughts on why this mosquito-borne illness is a growing menace and what lies ahead.

 

Why are there suddenly so many cases of dengue?

I don’t think there is only one factor involved. Everybody talks about climate change, and I think that is an important element because the rising temperature not only increases the human population at risk, but also accelerates transmission of dengue by shortening the time between when the mosquito feeds on blood containing dengue virus and its ability to transmit the infection. Mosquitos transmitting the virus are now found at higher altitudes and latitudes, putting more people at risk for the disease.

Higher temperatures also expand the human population living within an area where dengue transmission occurs, both geographically and in terms of elevation. So, climate change is certainly a factor.

What else is behind the rising numbers?

Improved surveillance and reporting play a role – there’s a tendency to recognize more cases and report them, especially when there’s an outbreak. Travel and movement of people carrying dengue virus in their blood is another factor contributing to global spread of dengue viruses. Then, as with any epidemic, disease spread is exponential, with an increasing reproductive rate of the outbreak as more and more people become infected. Since the year 2000, we have seen at least a 10- or 15-fold increase in reported dengue cases worldwide. So, the rising incidence of this disease has been a longstanding trend, and it is only partly due to climate change.

Why is it so difficult to develop a vaccine for dengue?

There are four dengue serotypes. You can get infected by each serotype – simply put, you can get dengue four times. Infection with one dengue serotype does not confer immunity against the others. In fact, infection from one of the four serotypes can sensitize and make a second infection much more serious, in the form of dengue hemorrhagic fever and shock syndrome. Cousins of dengue such as yellow fever and West Nile occur in only one serotype. So, you only have to make one vaccine that protects against all strains of the virus. With dengue, we need a vaccine that immunizes and protects against four dengue serotypes.

We have other vaccines that are composed of multiple serotypes. For instance, there are three types of polio in the polio vaccine and five types of rotaviruses in the rotavirus vaccines. So, multivalent vaccines have been successfully developed. What’s interesting and problematic about dengue, however, is that immunity is a double-edged sword. A low level of immunity to one serotype induced by a vaccine can sensitize rather than protect and may lead to more severe disease, such as dengue hemorrhagic fever, during a subsequent infection. So, a dengue vaccine must solidly protect but not sensitize. The goal is for a vaccine to generate sufficient protective antibodies against all four dengue serotypes (the so-called tetravalent dengue vaccine) so we don’t have incomplete immunity, which may cause sensitization instead of immunization. Since adverse events associated with sensitization may be rare, very large clinical trials are required to demonstrate safety of a dengue vaccine, especially for very young children and travelers who may have no prior exposure or immunity to dengue viruses.

You developed a dengue vaccine – does it work against all four serotypes?

The vaccine we developed back in the early 2000s, Dengvaxia, is still out there. It’s approved in some countries, including the US, but its use is restricted to persons who have had prior infection with a dengue virus. During testing it was found that a small proportion of people who had never had dengue were sensitized by the vaccine to develop severe symptoms when they experienced dengue infection. While the vaccine prevented about 60% or so of severe dengue cases, its use is restricted to people with antibodies from a prior natural infection. Obviously, this restricts use of the vaccine in some populations, such as travelers. So, Dengvaxia was not the optimal solution.

Are there new vaccines on the horizon?

There is a very promising vaccine called QDenga being developed by Takeda, a large Japanese pharmaceutical company. It is a live attenuated vaccine, which usually stimulates strong memory and persisting immunity. The vaccine is similar to Dengvaxia in its construction, utilizing molecular methods to insert dengue genes into a live virus vector backbone. All the genes in the multivalent vaccine are from dengue viruses and this is the vaccine that Takeda is now advancing in development. They have done a number of large clinical trials demonstrating prevention of severe dengue in up to 80% of people and protection of up to five years. There have been none of the safety concerns that were seen with Dengvaxia. These are very promising results and QDenga is now approved by the World Health Organization for use in Europe and some other countries including Brazil and Argentina. It appears to be also safe for travelers who have no prior exposure to dengue, which will be different from the older vaccine.

So now that vaccine needs country-level regulatory approval…

The regulatory challenges aren’t the biggest issue. It’s how do you get vaccine out there and how do you deliver it to the populations in need? The number of people that require immunization is huge. There are hundreds of millions of cases of dengue each year. So, while there is a very large opportunity to prevent disease, the implementation at an operational level is daunting. Moreover, while large clinical trials were done, we can’t take our eyes off of vaccine safety as the vaccine is rolled out at a population level and rare adverse events could be revealed.

Are there other solutions as well?

There’s novel work targeting the vector mosquito. The main transmitter of dengue is a type of mosquito called Aedes aegypti, which is more a domesticated animal in that it lives and breeds around human habitations. With the growth of human populations and urban environments, mosquito control has become much more difficult. So what people are doing now is trying more sophisticated ways to reduce Aedes mosquito populations. One way is to sterilize male mosquitoes with radiation and because once released, they obviously can’t inseminate female mosquitoes, the mosquito population declines. Another approach is to release mosquitoes infected with a bacteria that blocks viruses like dengue from growing in the bodies of Aedes aegypti mosquitoes.

These are promising approaches in addition to vaccines. I think both vaccination and vector control can play important roles in disease prevention.

Since COVID-19, people seem more focused on a vaccine solution for an outbreak…

COVID-19 was an amazing story of rapid response for development, regulatory approval, production, and implementation of vaccination. But it was addressed by multiple companies. On the manufacturing side alone, there are challenges to producing the large number of vaccine doses that will be required for dengue control. COVID-19 was also a contagious disease, spread from person to person, and nearly 20% of COVID-19 patients who were admitted to hospital died. Dengue is not directly contagious. The percentage of those who develop severe dengue is small, and of those cases, a small subset succumbs to the disease. So, while dengue is a major public health problem and is associated with high costs to the health care system, it is not like COVID-19 in terms of the imperative to find a vaccine or therapy. Nevertheless, dengue incidence and its geographic footprint are increasing dramatically. Now that a highly promising new preventive measure is in sight, I hope we can add dengue to the list of vaccine-preventable diseases.