DVI Dengue Champion Spotlight: Dr. Luis Ángel Villar Centeno
Every three months, the Dengue Vaccine Initiative (DVI) highlights a “Dengue Champion,” calling attention to that person’s contribution to the dengue vaccine research field and their commitment to the fight against dengue fever. Dr. Luis Villar, the lead investigator in the second Phase III trial ever completed for a dengue vaccine candidate, is DVI’s first 2015 Dengue Champion. The results of this trial were published on November 3rd in the New England Journal of Medicine under the title “Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America.”
Here we share the exclusive interview, originally published by DVI, on Dr. Villar’s thoughts about dengue, dengue vaccines and the Phase III trial in Latin America. The results of this trial and progress of other dengue vaccines candidates will continue to be further analyzed and discussed in DVI’s work, including the upcoming Americas Dengue Prevention Board Meeting in Bogotá, Colombia on February 16-17.
Tell us about yourself: how did you start your career in epidemiology and clinical studies? Why and how did you become interested in dengue?
Twenty years ago, after completing my training in infectious diseases I returned to my city Bucaramanga, Colombia. A national dengue outbreak was unfolding and Bucaramanga was one of the hot spots. For the first time in the country, severe dengue cases started to emerge, raising medical uncertainty and several questions by my university research group. Some of these questions focused on defining dengue diagnostics using clinical skills in febrile cases and on predicting early complications of the disease. It was in this context that I came to understand the importance of developing studies on the clinical epidemiology of dengue.
From your experience, how do people (the general public) perceive and deal with dengue in Latin America?
People in Latin America perceive dengue as a highly serious disease, knowing that it can be mortal and fearing its effects. Generally people deal with the disease by visiting healthcare centers. Dengue is one of the most important public health issues in Colombia. To offer the best attention possible we need to improve our health system and give timely responses to avoid further complications.
How would you describe the global burden of dengue? How is it a global public health threat, when, as some argue, it has a relatively low mortality rate?
Dengue is a threat to nearly half of the world’s population. It is a healthcare priority in many Latin American and Asian countries where epidemics occur regularly. The WHO estimates up to 100 million infections per year, but the overall number of people infected with dengue globally is not fully known. Each year, 500,000 people, including children, are affected with dengue hemorrhagic fever (DHF), the severe form of the disease.
Dengue is underreported because the disease is often misdiagnosed due to a large spectrum of clinical symptoms from mild non-specific illness to life threatening complications and because of the limitations of the surveillance systems. The mortality rate is also underreported due to the same limitations mentioned. Timely access to appropriate health care is critical to reduce the risk of mortality in case of severe dengue.
Why invest in a dengue vaccine? Why is it important?
There is a significant and continually growing public health need for effective interventions against dengue. A safe, effective and affordable dengue vaccine would represent a major advance for the control of the disease.
Currently, there is no specific treatment available for dengue. DHF is a leading cause of hospitalization, placing tremendous pressure on health systems and straining medical resources resulting in significant economic and social impact. Undoubtedly, a vaccine against dengue will be a key part of the overall strategy for dengue control.
What are the major challenges for the R&D of a dengue vaccine? Why has it taken so many decades to develop dengue vaccines? Why has the process accelerated in recent years?
The following have generally been identified as the main challenges for the research and development of dengue vaccines:
- Lack of animal model for the disease, requiring clinical studies.
- Four different viral serotypes, requiring a vaccine that must protect against all four.
- Theoretical risk of immunopotentiation after sequential infections, tetravalent vaccine is needed.
- Live attenuated vaccine technology to optimize protection.
- No known correlate of protection, large efficacy studies are needed.
I would add that, since dengue is such a complex disease, it requires testing the vaccine in geographically different populations, with different epidemiological environments, varying prevalence of the 4 serotypes, and diverse age groups. As progress has been made in the development of dengue vaccines, and, according to the results of the studies, additional questions and challenges have emerged. These include the differential efficacy among serotypes; the efficacy between naive and pre-immune population; efficacy against overall disease versus severe disease; the role of the immune cellular response, genetic determinants, among other.
The Sanofi Pasteur dengue vaccine has been characterized by more than a decade at preclinical and Phase I/II clinical levels, in which satisfactory reactogenicity and immunogenicity were demonstrated. In recent years, research has accelerated the process of vaccine development, as they have completed the phase II studies and in 2014, the large scale Phase III efficacy trials that were conducted in 10 endemic countries of Asia and Latin America, demonstrated safety, satisfactory reactogenicity and efficacy over the 25-month period of the active surveillance phase and a 4-year long term follow up is ongoing.
What are the main conclusions of the trial? What are the implications of this trial for the dengue research community? Of its results?
The data from the overall clinical program, Phase I, II and III and especially from this efficacy trial support the fact that this dengue vaccine has the potential to provide an important public health benefit as part of the comprehensive strategy for dengue control, in dengue endemic countries. The results of the first efficacy study in Latin America, are particularly relevant for the scientific community, the sample size allowed with robust data demonstrate the efficacy of the vaccine against the 4 serotypes and confirmed the favorable safety profile.
How would you explain the variability in protection by serotype and serostatus? What implications can the heterogeneity of vaccine efficacy by serotype and serostatus at baseline have from a programmatic perspective?
This subject is being studied. There are many hypotheses regarding this question. We still don’t have a specific answer.
What are your thoughts on the Asian and Latin American trials, when viewed together? Are they comparable, being in such different regions? If so, how are they comparable?
The two efficacy Phase III trials are comparable considering that they have the same design, the same objectives, and the same primary endpoint. Their surveillance systems were similar. The main differences were the age group (the trial in Asia included younger children between the ages of 2 -14 and in Latin America it included children and adolescents of between ages 9 – 16) and the sample size (10,275 participants in Asia and 20,869 in Latin America). Both Asia and Latin America had all 4 serotypes during the phase of active surveillance, in which efficacy was determined.
What questions do you think health specialists and ministries of health should ask themselves if they seek to introduce this vaccine, if licensed?
The first considerations of a safe vaccine with moderate overall efficacy should be age group in which to introduce the vaccine, the groups for the catch up, and the preparation of the pharmacovigilance system. Post vaccine licensure and introduction, more investigations will be required on the impact on dengue burden, dengue related health care utilization, vaccine performance, vaccine safety and effectiveness, and the implementation of the vaccine pharmacovigilance system.
What are the main lessons that you learned from leading this trial? What has excited you the most, personally, about leading this trial?
While conducting this trial, I appreciated the necessity of multi-centric studies to respond to clinical epidemiology research questions. The participation of researchers in 22 centers in 5 countries made possible the number of cases to evaluate the efficacy of this vaccine. Another major lesson was the application of a rigorous protocol in all the involved research centers to obtain valid results was a valuable lesson.
Personally I found pleasing the active, responsible and altruistic participation of the volunteers in the study. This is evidence that research can be empowered by people’s generosity and welfare.