In the Time of Dengue Mitigation: RITM’s Contributions to the World’s Fight against the Disease

Published in RITM Update Volume 1 Issue 1 (April – June 2014)

Nelia Dinulos, 51, is a mother of one. A few years ago, she encountered her biggest challenge as a parent. Her nine-year-old daughter developed dengue. At first, Nelia thought it was just an ordinary fever. The fever though, would go on and off for a week. She finally decided to bring her daughter to the hospital. Laboratory tests confirmed that her daughter was suffering from dengue fever. Fortunately, the disease was detected early and proper medical attention led to her daughter’s recovery.

Dinulos shares this nightmare with the rest of 500, 000 parents every year – parents of children hospitalized because of serious cases of dengue. The World Health Organization (WHO) further accounts that around 50 to 100 million people are afflicted by dengue annually, and over 2.5 billion people (over 40% of the world’s population) are at risk to be infected. This makes dengue the world’s fastest-spreading mosquito-borne disease. Of those afflicted by the disease, 22,000 die. Considered by WHO as a ‘neglected disease’, dengue is primarily transmitted to humans by two mosquito species— Aedes aegypti and Aedes albopictus. The virus can be transferred through the bites of infected female mosquitoes. Also, a dengue-afflicted human can indirectly transmit the virus to other persons through the vector mosquitos. Studies suggest that female Aedes aegypti mosquitoes, the most common dengue vector in the world, tend to permanently stay in or around the houses where they emerge as adults. This may imply that people’s mobility could be more responsible in spreading the virus rather than the mosquitos.

In the Time of Dengue MitigationIn the photo: A clinical trial staff of the Dengue Vaccine Study conducts a group orientation to study participants and their guardians.

A lot of preventive actions and control measures are being implemented to avoid the massive burden of the disease. These include early warning systems; vector control; environmental, epidemiological and disease surveillance; laboratory support; clinical case management; environmental controls; and social mobilization. Experts, however, firmly believe that the availability of an effective vaccine is still ‘the holy grail’ of dengue prevention.

CYD-TDV Clinical Trial’s Promising Result

In the Philippines, the clinical development of the world’s first dengue vaccine to complete the initial Phase III efficacy trial is conducted by the Research Institute for Tropical Medicine, with Dr. Rosario Capeding as the principal investigator. This potential vaccine is a live-attenuated tetravalent vaccine developed by the French pharmaceutical company Sanofi Pasteur (CYD-TDV).

The clinical trial included 10,275 children aged 2 to 14 in Indonesia, Malaysia, the Philippines, Thailand, and Vietnam. CYDTDV yielded a promising result as it showed a significant reduction of 56.5% of dengue Disease cases in the five countries combined.

A total of 3,500 children from the Philippines (with San Pablo City, Laguna and Cebu City as study sites) participated in the said clinical study of CYD-TDV. This makes the Philippines the country in Southeast Asian leg of the study with the highest number of enrollees. Capeding added that the Philippines, through RITM, is the only country which has been actively involved in all three phases of clinical development of CYD-TDV.

Asked what will be the implication of the study’s promising results, Capeding stated that it will have a big impact even if the Phase III study only showed moderate efficacy, considering the high burden of the disease not only in the Philippines but also in Asia. The vaccine also showed a clinically important reduction of dengue hemorrhagic fever and the risk of hospitalization. Above all, its safety profile is consistent with the result of the previous clinical studies assessing vaccine’s safety.

The Long Wait for an Effective Vaccine Against the Dengue Virus

It actually took about 70 years to come up with a potentially-effective vaccine against dengue. Capeding cited various reasons on the slow progress of dengue vaccine development. One of the primary problems is the challenge to develop four combined immunogens since dengue is caused by four different serotypes. In other words, the vaccine must be tetravalent to induce a protective immune response against all four viruses.

Dr. Rosario Capeding, principal investigator of the Dengue Vaccine Trial in the Philippines, gives an inspirational talk on the potential impact of the candidate dengue vaccine to the community of San Pablo City, Laguna.

“Another challenge is the absence of suitable animal model for dengue. Monkeys can be susceptible to dengue virus but they can only demonstrate viraemia (presence of virus in the blood) and does not actually present clinical disease. Thus, you really have to test the vaccine in humans,” explained Capeding.

Furthermore, WHO, in their released guidelines for dengue diagnosis and control, inferred that there may have a possibility that a dengue vaccine could potentially cause severe disease (including Dengue Hemorrhagic Fever) in vaccine recipients if solid immunity was not established against all four serotypes. Therefore, vaccine design really requires intensive research to ensure that the dengue vaccine to be developed is safe and efficient.

Also, since there is lack of a validated correlates of protection, clinical efficacy studies are critical to fully understand the mechanism of protective immunity against dengue virus and confirm that the candidate vaccines induce a protective immune response.

CYD-TDV Still a Work in Progress

Despite the positive result of the Phase III clinical trial of CYD-TDV, Capeding clarified that the candidate vaccine is still a work in progress.

“There is a very important component in this clinical trial which is the surveillance phase. Aside from the active surveillance phase, we also have the hospital surveillance phase where we will follow up the hospitalized dengue cases. It will run until 2017,” she explained.

Furthermore, the developer of the vaccine is still waiting for the Latin American leg of the clinical trial which was conducted among 9-16-year-old children in Colombia, Mexico, Honduras, Puerto Rico and Brazil. It is expected to complement the Southeast Asian study.

Continuous monitoring will also be implemented even after the commercial release of the vaccine.

“There will be post-marketing surveillance and this is an SOP for all vaccines and drugs,” added Capeding.

Other RITM Research Activities on Dengue Prevention and Control

Aside from CYD-TDV efficacy study, RITM performs other research projects on dengue control and prevention. Another study headed by Capeding aims to identify protective and pathogenic immune responses against dengue virus (DENV) among infants. Studies show that primary DENV infection during infancy is more likely to lead to Dengue Hemorrhagic Fever and severe illness than during childhood or adulthood.

A study headed by Ms. Edelwisa Mercado and Dr. Fe Espino seeks to understand the genetic factors among humans that may affect the severity of dengue fever among Filipino children. The study focuses on association of dengue infection to the variation of human leukocyte antigens (HLA), a group of genes which are responsible for regulation of the human immune system.

The Department of Medical Entomology is conducting a research to determine the insecticide susceptibility profile of Aedes aegypti and Aedes albopictus and the possible development of resistance in these dengue vectors to ensure that all insecticide-based control strategies remain optimally effective.

A descriptive study, headed by Dr. Nelia Salazar, is also being conducted to describe the implementation of a Department of Interior and Local Government Memorandum which created an interagency cooperation strategy to reduce dengue cases in the country and to assess the outcome of the said dengue control interventions in six highly urbanized cities.

RITM’s Commitment to Combat Dengue

In a tropical country like the Philippines where dengue is endemic, the situation could be worse if no appropriate research initiatives are conducted to complement the present control measures against the virus. Research activities on dengue are expected to inform measures to alleviate, if not immediately eliminate the burden of dengue in the country.

RITM, as the country’s lead agency for research in infectious diseases, is committed to conduct extensive and multidisciplinary research with the hope of contributing to the world’s fight against dengue. As RITM joins the international community in the goal of eliminating the disease, the Institute hopes that the stories like those of Nelia’s would be less likely to be heard in the near future.