By Dr. Ira Longini
As part of the DVI program, a team has been working to develop and advance a model for the impact of dengue vaccine immunization on infection and disease, one that allows the simulation of a wide range of scenarios, including the impact of vector control. The team has been analyzing dengue transmission and control with vaccines using statistical and mathematical models.
The work includes the eventual statistical analysis of Phase 1-4 vaccine trial data to better understand how dengue vaccines protect against infection, disease and transmission. Additionally, dengue cohort data from Thailand, Colombia and Nicaragua are being analyzed to better understand the infection and immune process of the four dengue serotypes.
Based on this information and a good deal of epidemiological and demographic data, an individual-level (including both humans and mosquitoes), stochastic simulation model for dengue transmission and control in a semi-rural area in Thailand has been developed. The model is calibrated to dengue serotype-specific infection, illness and hospitalization data from Thailand. Simulations show that a realistic roll-out plan, starting with young children then covering progressively older individuals in following seasons, could reduce local transmission of dengue to low levels. They also indicate that this strategy could avert about 7,700 uncomplicated dengue fever cases and 220 dengue hospitalizations per 100,000 people at risk over a ten-year period. In the model, potential dengue vaccines that may not be efficacious against all four dengue serotypes are also evaluated. The model shows that such a vaccine could still be effective, but is conditional on the mix of dengue serotypes circulating. This work was published in the journal PLoS Neglected Tropical Diseases in October 2012.
The team has also developed statistical and modeling approaches to evaluate dengue vaccine effectiveness in coming community trials and during the large scale rollout of dengue vaccines in the future. This includes work with field sites in the State of the Yucatan, Mexico, where the team is helping to develop dengue cohort and community-wide epidemiological studies. The ultimate goal of this work will be to estimate the community level effectiveness of the large-scale introduction of dengue vaccines in the Yucatan. This work should serve as a template for developing similar efforts in other countries and regions.
This statistical and mathematical work has shown that dengue vaccination will have an important role in controlling dengue. According to modeling results, small children should be prioritized to receive vaccine first, but vaccination catch-up campaigns in older children and sometimes adults will be needed to control dengue. The precise rate and inclusion of vaccination of older age groups will depend on the epidemiology, age structure, and dengue immune structure in the target population.
Dr. Ira Longini is a professor of biostatistics at the University of Florida and co-director of the Center for Statistics and Quantitative Infectious Diseases (CSQUID) at the Emerging Pathogens Institute at the University of Florida.
DENVax, a live, attenuated, tetravalent dengue vaccine has been rapidly progressing through Phase 1 and 2 clinical trials. DENVax was originally developed by researchers at the Division of Vector-Borne Diseases of the CDC (U.S.) and Mahidol University (Thailand). DENVax is based on an attenuated DEN-2 virus that generates long-lasting antibody and cellular immune responses to DEN-2. This clinically tested, weakened DEN-2 virus then was engineered to express the structural proteins of DEN-1, DEN-3 or DEN-4 viruses. DENVax is a four-way mixture of the three engineered viruses and the original DEN-2 strain.
Inviragen completed a successful Phase 1 clinical trial at high altitude in Rio Negro, Colombia in collaboration with Universidad de Antioquia. The study demonstrated that the two doses of DENVax are safe and well-tolerated in healthy adults who had not been exposed to dengue. The Phase 1 study also showed that DENVax induced antibodies that were capable of neutralizing each of the four dengue viruses. A Phase 1 study in the U.S. has been completed and follow-on Phase 1 studies evaluating alternative formulations and dosing schedules are ongoing.
An ongoing Phase 2 study is testing the safety and immune response of DENVax in multiple age groups in dengue endemic countries including Colombia, Puerto Rico, Singapore and Thailand. In the first stage of the trial, individuals were enrolled in four age groups between 1.5 and 45 years. This stage was completed in 2012 and an independent safety monitoring board determined that the vaccine was safe in all ages in these settings. Inviragen has now advanced DENVax into the second stage of the Phase 2 study, in which hundreds of children from 1.5 to 11 years of age are being enrolled.
“DENVax has demonstrated safety in multiple age groups and in dengue endemic and non-endemic settings in three continents” commented Dr. Dan Stinchcomb, CEO of Inviragen. “The next stage of our Phase 2 study will expand our safety database to support future efficacy studies.”
DENVax is now the most advanced tetravalent dengue vaccine that utilizes an attenuated dengue backbone. The dengue backbone may be the key to inducing potent antibody and cellular immune responses that can protect against dengue fever. To test this hypothesis, Inviragen intends to begin Phase 2b/3 efficacy studies in late 2013 or early 2014.
In addition to its dengue vaccine efforts, Inviragen is clinically testing a vaccine against hand, foot and mouth disease (HFMD). Vaccines to protect against chikungunya and Japanese encephalitis, which affect millions of individuals in Asia, are in earlier stages of manufacturing and development. Inviragen was founded in 2005 and has offices in Colorado, Wisconsin and Singapore. Inviragen’s investors include Charter Life Sciences (Palo Alto, CA), Venture Investors (Madison, WI), Bio*One Capital Pte. Ltd. (Singapore) and Phillip Private Equity (Singapore). The dengue vaccine research also has been funded by grants and contracts from the NIH, DVI, and the Singapore Economic Development Board. Please see www.inviragen.com for more details.
Dr. Jorge Osorio DMV, MS, PhD, is an Associate Professor at the University of Wisconsin (USA) and the Universidad de Antioquia (Medellin, Colombia). Dr. Osorio is also a co-founder and Chief Scientific Officer of Inviragen, a biotechnology company that is developing DENVax, a very promising novel chimeric tetravalent dengue vaccine based on the dengue 2 PDK-53 attenuated virus. The safety and immunogenicity of this vaccine has been evaluated in preclinical animal models and human Phase I clinical trials. DENVax is currently in Phase 2 clinical trials in Puerto Rico, Colombia, Singapore and Thailand.
Dr. Osorio has been studying dengue and other vector borne diseases in the endemic area of Medellin, Colombia. This research is sponsored by DVI and includes the development of a field site to study the disease and transmission factors. This work is providing important information on the natural history of dengue, such as evolution of circulating viruses, clinical characterization of the disease and the economic burden of the disease.
“Growing up in Colombia, I experienced first-hand the devastating effect of hemorrhagic dengue. I will never forget the faces of dying children and their parents affected by this devastating disease,” says Dr. Osorio. “I was working in public health, but I felt I should do more to save lives and improve human well-being. These experiences heavily influenced me to dedicate my professional research career to the study of neglected tropical diseases such as dengue and the application of novel molecular approaches for vaccine development and disease control. I am extremely fortunate and thankful for all support received from DVI and the dengue scientific community”.
On April 9-11, DVI, in collaboration with the Brazil Ministry of Health, will convene a meeting in Brasilia, Brazil to bring together several developing countries likely to be among the first-to-introduce dengue vaccines. Major attention will be accorded to identifying introduction strategies and to regulatory issues.
Introducing a dengue vaccine will require being able to undertake surveillance, catch-up immunization (immunization of older groups to maximize the population protection in addition to on-going infant immunization), mobilization of required financing, cost effectiveness analyses, modeling, demonstrations projects and Phase 4 trials, and many other functions. The meeting will address each of these.
Regulatory oversight of clinical trials and review of registration dossiers for novel vaccines is a great challenge even for strong National Regulatory Authorities (NRAs). Experience shows that collaboration among regulatory authorities enhances the quality of the reviews, allows for more time-efficient use of resources and strengthens regulatory capacity of the participating countries. DVI is committed to provide support to the NRAs of countries that are targets for clinical trials and countries that will be first to license and introduce dengue vaccines. For this purpose, there will be a closed session for regulators where regulatory support needs and a plan of action can be discussed in confidence.
As the prominence of dengue grows, the need for an up-to-date and comprehensive understanding of the burden of disease becomes more and more important. For dengue, this means not just mortality but also morbidity; the true cost of the disease lies not just in the lives lost, but in the burden placed on health systems, the days of work missed, and other harder to calculate figures. DVI is not the only one working on determining the disease burden of dengue.
“Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus” from Professor Simon Hay’s group at the University of Oxford presents the results of an exhaustive search of the literature to identify verifiable dengue case reports. The investigators present their findings in the form of maps that display the geographic spread of dengue over the last decades. The results identify three dozen countries that were not included in the WHO and/or U.S. Center for Disease Control list of countries with dengue and highlight the lack of good dengue data from many countries.
“Mapping by evidence consensus not only encourages greater data inclusion, but it also better illustrates the current global distribution of dengue”, summarize the authors. “Consensus mapping is thus ideal for a range of neglected tropical diseases where the evidence base is incomplete or less diagnostically reliable.” This paper is the first of a five year research project aiming to develop comprehensive, peer-reviewed and up-to-date data on the burden of dengue.
“Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010” provides a welcome update to earlier studies. Dengue is included in this analysis, and it concludes there has been a two-fold increase in YLDs due to dengue between 1990 and 2000.
The authors of the study argue that, “quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Measuring the impact of dengue beyond mortality figures is an important part of quantifying the burden of the disease, and moving forward with a vaccine and continued control measures.”
These studies are two promising examples of the ongoing work to better define the impact of dengue, information which will be crucial in determining how to combat its growing spread.
On December 11 – 12, 2012, the DVI Consortium Management Committee and senior staff met in Geneva, Switzerland. The committee is composed of the heads of the dengue programs in the four Consortium partners: Dr. Luiz da Silva from the International Vaccine Institute (IVI), Dr. Joachim Hombach from the World Health Organization (WHO), Dr. Ciro de Quadros from the Sabin Vaccine Institute, and Dr. Dagna Constenla from the Johns Hopkins University International Vaccine Access Center (IVAC). Most of the two-day meeting was taken up with a detailed strategic planning exercise, motivated in part by the changing nature of the dengue vaccine field following the publication of the results from the Sanofi Pasteur Phase 2b study in Thailand.
In addition to examining the continuing priority and importance of existing DVI programs, the meeting identified three important areas for potential involvement by DVI in the future. First, there is a renewed importance of facilitating the development of a range of dengue vaccines. Private pharmaceutical firms are investing in the development of some candidates. In addition, public-sector vaccine producers in Brazil and Vietnam are seeking to develop the U.S. National Institutes of Health (NIH) vaccine candidate. These public-sector efforts deserve increased support based on the promising results obtained with the US NIH vaccine in Phase 1 trials. As has been shown with several other vaccines, developing country suppliers can play a critical role in ensuring adequate and affordable supplies.
Second, it is clear that there is a need to identify surrogates of protection of dengue vaccines and to further assess diagnostics and assays for dengue research. The Thai results indicated the vaccine generated antibodies against all four dengue viruses and these measurements were thought to indicate protection against infection, i.e. the antibodies were thought to be “surrogates” of protection. But the results indicate a need to reassess this view and identify real surrogates. Third, the Sanofi Pasteur results again emphasize the complexity of dengue epidemiology and reinforce the need for standardizing surveillance methodologies on both global and national bases. Not only are there four dengue viruses, but there are genetic subtypes of each. The Thai results may suggest that a vaccine’s efficacy will vary depending on the circulating subtype. Surveillance will help us understand this issue.
In general, DVI will continue to serve as a focal mechanism to identify needs and seek solutions in a dynamic field of dengue vaccine development. For example, DVI, in collaboration with the Brazil Ministry of Health, will convene a meeting in Brasilia in April among several developing countries that are likely to be among the first-to-introduce dengue vaccines.
The International Vaccine Institute (IVI) is leading a number of DVI studies looking at how to better define and understand the impact of dengue. Here we provide brief updates on the range of research ongoing.
The dengue disease burden studies in Colombia and Thailand are well underway. The full studies in both countries include healthcare utilization surveys to complement the ongoing fever surveillance, and data collection for these healthcare utilization surveys has been completed.
In Brazil, the cost of outbreak control study in three cities, Terezina, Goiania, and Belo Horizonte, is ongoing. The data collection from the records in Goiania and Terezina is complete and the study team has now moved to collect data in Belo Horizonte. The results from these three cities will be used to make a national extrapolation.
The cost of illness (COI) surveys in three focal countries (Vietnam, Thailand, and Colombia) aim to estimate the economic burden of confirmed dengue patients based on an analysis of hospital patient records, including both direct expenditure (treatment, diagnostics, medicine, transportation, etc.) and the opportunity cost of time lost by dengue patients and their caretakers. In Vietnam, the study team has collected data from the desired sample size of 150 patients and preliminary data have been analyzed and reports are currently being prepared. In Thailand and Colombia, the study team is still identifying NS-1 rapid test confirmed patients in the surveillance to be further enrolled into the COI survey. The caseloads in 2011-12 were low in both Thailand and Colombia, which is causing delay in fulfilling the desired sample size of 150 NS-1 rapid test confirmed dengue patients.
Data collection for the private demand studies (Willingness to Pay (WTP)) is complete in Vietnam, Thailand and Colombia. The household surveys estimate private household demand and the ex ante (before illness) perceived benefits of dengue vaccines. They also provide evidence on how vaccines are prioritized by families given a limited budget. The studies will be used to develop dengue vaccine demand models with statistically significant determinants (e.g., income, education, severity, etc). The preliminary data have been analyzed and reports are being prepared.
We look forward to keeping you up to date on the progress of these studies and sharing reports as they become available.
In response to the growing need to analyze dengue vaccine related costs to determine the benefits of future introduction of dengue vaccines, the International Vaccine Access Center at Johns Hopkins University (a member of DVI) convened an expert panel in March 2012 to discuss and develop a standardized methodology for estimating costs of dengue in the Americas.
The resulting Guidelines aim to ensure robust assessment of the economic burden of dengue infections and to make the results of future dengue cost studies more comparable among Latin-American countries. To date, only a handful of economic studies have been published in the region, and there is great variation in methodology which makes it difficult to compare findings. The Guidelines provide an overview of the state of the field and identifies appropriate methodologies for costing dengue.
There are many considerations that need to be taken in to account when doing such analyses including understanding the health care system , and using uniform definitions of outbreaks. The expert panel concludes that, while there is no single theoretically correct approach for costing dengue, there are certain generally accepted principles including the adoption of a societal perspective, the inclusion of all relevant costs and effects, the use of an adequate sample size, and the use of uniform methods for collection and valuation of unit cost data in multi-country studies and comparisons.
Last month, the WHO released its Second Report on NTDs: Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases. The report includes updates on NTDS, including dengue. In a statement, the WHO says that “in 2012, dengue ranked as the fastest spreading vector-borne viral disease, with an epidemic potential in the world, registering a 30-fold increase in disease incidence over the past 50 years." It goes on to add that, “the world needs to change its reactive approach and implement sustainable preventive measures.”
The report was released in coordination with the one-year anniversary of the London Declaration—an unprecedented pledge by a group of public and private partners to control or eliminate 10 NTDs by 2020. This includes an uptick in drug donations, research and development and bilateral support for NTD programs around the world. This month marks the anniversary, and several reports and updates were released yesterday to showcase the progress since 2012, as well as the goals and challenges for 2013 and beyond.
The report also notes that support from countries endemic for NTDs and partners have helped fast-track actions and initiatives that are now having a measurable impact.
It has long been known that dengue is the world's most prevalent vector-borne viral disease and the WHO report emphasizes that it is also rapidly spreading. In addition, over the last decade, dengue has spread more rapidly than other major infectious diseases. There is no doubt that it is becoming one of the most prevalent diseases in the world, and DVI welcomes this report by WHO.
The 13th edition of the Dengue International Course will be held at the “Pedro Kouri” Tropical Medicine Institute of Havana, Cuba from 12-23 August 2013. Find out more at the course website.
We would like to issue two corrections to our 2012 Year in Review email from last month. That email omitted an update on the dengue vaccine under development by Inviragen. Inviragen’s live attenuated vaccine has entered Phase 2 clinical trials in Puerto Rico, Colombia, Singapore and Thailand. It also misstated that the results of the Sanofi Phase 2b trial support the continuation of Phase 2b studies to obtain pivotal efficacy data. This should be corrected to “continuation of Phase 3 studies to obtain pivotal efficacy data”.
The correct version of the 2012 Year in Review can be found here.