With the onset of the first vaccine preventing the lethal mosquito-borne infection that places third world countries at risk and the current sporadic number of dengue cases for the past five years in Cambodia, Healthwise Digest had the pleasure of interviewing Dr. Philippe Dussart, Head of Virology Unit at the Institut Pasteur du Cambodge (IPC).
We have invited him to share to the public the factors affecting the vaccine and drug treatment development, the country’s present programs that thwart the disease, as well as the role of IPC.
Healthwise Digest (HD): Are the number of dengue cases in the country likely to increase over the next decade, given the current growth from the past years?
Dr. Philippe Dussart (Dr. Dussart):
Dengue virus is an arbovirus, which means it is a virus that is transmitted by an arthropod vector, mainly Aedes mosquitoes. This virus infects approximately 50-100 million people annually in over 100 endemic countries. However, predicting the number of dengue cases over a year in one country remains difficult, given that four dengue serotypes have been described (Dengue-1, -2, -3 and -4). A subject can first get infected by one of the four dengue serotypes: after acquiring the immunity against one serotype, the organism will develop antibodies against this serotype, and will therefore be immunized against this serotype. However, this person would still be at risk of contracting the other dengue serotypes. Dengue circulation is well-described in Cambodia during the rainy season and occurs from May to September with the highest incidence of dengue cases usually observed in July or August. A gradual decrease is then observed from September until the end of the year. Dengue cases are rarely detected from December to April.
Since 2011, we have mainly encountered one same dengue serotype over the Cambodian dengue season, although the three other serotypes are also occasionally detected. Last year, in 2015, we observed an increasing number of dengue cases compared to the previous year, but the outbreak was still lower than in 2013, and variations of dengue cases over the next few years are difficult to estimate.
Dengue-1 serotype has been circulating in Cambodia since 2011 and most of the population is now immunized against this virus which suggests that the next outbreak could be related to another dengue serotype.
Therefore, one cannot easily say that dengue cases are increasing every year, since the occurrence of infections depend on people’s immunity as well as on the types of dengue virus that are circulating in the country during a given period. Bearing all these in mind, predicting the extent and the degree of severity of the next dengue season still remains a difficult task at present.
HD: Given the seasonality and fluctuation in numbers, is it enough to state that the country is ready in battling and preventing this disease in terms of resources and/or facilities?
Dr. Dussart: Dengue has been a major public health challenge in Cambodia, which is why the Ministry of Health has made it a national priority since 1996. As a Franco-Cambodian institute and a research agency placed under the patronage of the Ministry of Health, the Institut Pasteur du Cambodge’s researchers, along with their colleagues from the Ministry of Health from the National Dengue Control Program at the Cambodia National Malaria Center, are dedicating a large part of their research capacity to tackle the disease.
Laboratory testing for dengue was introduced in 2000, whereas active sentinel surveillance of dengue was established in 2001.
From that time, the IPC’s Virology Unit has always collaborated with its CNM colleagues. At the IPC’s Virology Unit, being a reference laboratory for arboviruses diagnosis, we receive samples from different provincial hospitals on a weekly basis, contribute to the detection of the virus and are involved in research such as genotyping and sequencing of the dengue virus.
HD: What is the impact of dengue outbreak on the country’s public health?
Dr. Dussart: This definitely has a huge impact on the country’s public health, since most of the infected patients are young people, mainly children aged between 1 and 15. It has a huge impact because if you are suspected to have contracted a severe form of the disease, you need to be treated in hospital. However, we also have to consider that some patients only present mild-fever or a clinical spectrum of non-severe clinical manifestations, thus not requiring a doctor’s visit.
HD: We have already heard in 2015 that there is an approved dengue vaccine out in the market. Would you care to provide us some insight regarding that vaccine?
Dr. Dussart: Researches on dengue virus started 40 years ago. Dengvaxia, is the first dengue manufactured vaccine. It was developed by the pharmaceutical laboratory Sanofi Pasteur after two decades of research and scientific development. Its commercialization in Mexico, Brazil and the Philippines has recently been approved. The company is now working on obtaining authorizations to distribute it in countries where dengue is endemic. We are entering the era of the dengue vaccine, which makes us hope that we will soon be able to reduce the burden of the disease in Southeast Asia, as well as in all countries where dengue is a major public health priority. This first vaccine is indicated to patients aged from 9 years old up to 45 years old, who are living in endemic areas. The decision to authorize the marketing of this vaccine in Cambodia remains in the hands of the Ministry of Health. Up to now, the vaccine has not been approved in Cambodia yet.
Dengvaxia is a live recombinant tetravalent dengue vaccine, which means it is a chimeric vaccine with a backbone of yellow fever vaccine strain in which genes of envelope and membrane of each dengue serotype have been introduced. Clinical studies have shown that the vaccine was safe to use and designed to protect against all four dengue serotypes. However, its efficacy varies depending on the serotypes. Several vaccine candidates against dengue from other companies, are currently in the development pipeline, with different approaches.
HD: Do you have any idea of why it has taken such a long time to produce a vaccine?
Dr. Dussart: Producing a dengue vaccine took 40 years, it has been a quite long and difficult process. One of the main difficulty faced when developing the vaccine was related to the antibody-dependent enhancement: after being infected by a first dengue serotype (primary infection), a subject develops protective antibodies against this serotype. During a secondary infection (infection by one of the three other serotypes), the presence of antibodies acquired from the first dengue infection (also named heterotypic antibodies) which remains at lows level in some cases, enhances dengue virus infection in cells and can increase the inflammatory response. The consequence of this phenomenon is an increased risk to develop a severe form of dengue disease such as dengue hemorrhagic fever. Developing a monovalent vaccine, active against one dengue serotype would be easier and faster. However, the phenomenon of antibody-dependent enhancement requires pharmaceutical companies to develop an active vaccine against all four dengue serotypes.
HD: What is the immunity duration of the Dengvaxia vaccine?
Dr. Dussart: Dengvaxia has been evaluated as a 3-dose series on a 0, 6 and 12 month schedule in Phase III clinical studies. It has been observed during clinical studies that a set of three vaccinations contributed to increase antibody responses and may also increase the quality of the antibody response and the duration of the protection. The WHO Strategic Advisory Group of Experts on Immunization is currently reviewing the evidence for Dengvaxia and will advise WHO on a policy position for this new vaccine. The elements to be taken in consideration are: vaccine safety, vaccine efficacy, disease burden and cost-effectiveness.
HD: We have seen a few vaccines that have been developed and sold for a higher price, which may not be easy for the general public. Do you have any idea as to how much this vaccine will be priced?
Dr. Dussart: If Sanofi Pasteur wants to sell Dengvaxia to Southeast Asia, the company will have to adapt the price according to the economic level of the country. Of course, I don’t think that their intention is to sell such a vaccine at the same price as in Europe or the U.S., where the targeted population would be people who plan to travel in dengue endemic areas.
HD: If there is a success in delivering a vaccine to prevent dengue, why do we still don’t have a treatment drug?
Dr. Dussart: There are currently several on-going researches on anti-viral drugs that should be able to treat dengue infections, but at this stage I haven’t heard of any component that could be commercialized any time soon. The difficulty to develop anti-viral drugs is explained by several factors: First, components or molecules need to be selected as potential anti-viral drug. Second, we need to target a specific mechanism such as virus entry in targeted cells or virus replication in infected-cells, for example. Designing drug discovery studies and screening natural or synthetized components takes time.
HD: On a final note, what are the basic advices you can share to our readers that they can practice at home to prevent acquiring dengue?
Dr. Dussart: My first advice would be to avoid mosquito bites. We know that the highest rates of mosquito bites occur at sunrise and sunset. You can wear clothes which protect from mosquito bites. You can also use repellents containing an effective product such as DEET, Picardin (Icaridin), Citriodiol (p-menthane-3,8-diol = PMD) or IR3535 (3-[N-Butyl-N-acetyl]-aminopropionic acid, ethyl ester). Babies and young children must sleep under bed-nets during day-time.
My second advice and probably the most important one is to avoid small water collection in and around your house, as this creates larval development sites for mosquito vectors of dengue, Zika and Chikungunya viruses. These water bodies are stagnant water in the garden, jars or tires. If they are not covered or destroyed, mosquito larvae are likely to develop in them.