Sanofi recently issued a global statement providing new data on our dengue vaccine that helps to further define the population that would best benefit from its protective value.[i] Currently, the World Health Organization and the National Regulatory Authorities in the countries where the vaccine is approved or under regulatory review today are considering this new information to assess the implications for the continued roll-out of the vaccine.
Dengue is a serious and debilitating disease that is endemic in countries that are home to more than half of the world’s population. The risk of experiencing its disabling symptoms of fever, “bone-breaking” joint pain, nausea and fatigue, or of being hospitalized for several days with dengue without any specific treatment available, looms every year in places where the disease is widespread. The disease can hit particularly hard in bustling city centers where dengue outbreaks have been known to spread rapidly.
The threat is big enough for the World Health Organization (WHO) to rank dengue as “the most important mosquito-borne viral disease in the world”.[ii] Stopping the spread of dengue is a WHO priority and the organization has set clear objectives for endemic countries to “reduce mortality and morbidity from dengue by at least 50% and 25%, respectively, by the Year 2020 (using 2010 as the baseline)”.[iii]
Research and medical teams have been working for decades to develop a vaccine against dengue. It has proven exceptionally difficult because dengue is a complex disease. There are four distinct strains of the virus and a person can become infected with each one – a potential of four dengue infections in a lifetime. At the same time, dengue infections behave in an unusual way as well. While the majority of dengue infections pass without noticeable symptoms, some can be debilitating and, in rare cases, deteriorate to become a serious illness. In most cases, it is the second infection with dengue that is associated with worse disease outcomes requiring hospitalization. An effective vaccine must deal with these highly unusual characteristics of dengue infection.
Because of this complexity, our work to develop a vaccine to reduce the burden of dengue took 20 years of research and scientific evaluation, including a development program with close to 40,000 people from 15 countries over a period of 10 years.
All of these trials were conducted in collaboration with scientific experts and health authorities, and we were transparent with the global health community, including the WHO, each step of the way. Research findings on the vaccine, whether interim or final, were openly shared as soon as they became available. Outcomes from either the trials themselves, or predictive models developed by various internal and external teams using the available epidemiological data and trial results, were published in respected peer-reviewed journals such as The Lancet, New England Journal of Medicine and Nature.[iv],[v],[vi],[vii]
The regulatory approvals required to make this vaccine available to the public followed a long series of technical meetings at both the country and global levels, starting with an unprecedented meeting in Geneva in June 2015 chaired by the WHO and Dengue Vaccines Initiative. This meeting included the European Medicines Agency, the US Food and Drug Administration and regulators from dengue-endemic countries. During open sessions, these regulators were able to ask Sanofi questions about the clinical data on the vaccine before exchanging technical comments on the vaccine’s file amongst themselves and, finally, concluding that the available data were sufficient to allow countries to move ahead with registrations.
The Strategic Advisory Group of Experts (SAGE) on Immunization, an expert body that advises the WHO, conducted an independent review of the clinical trial data available on the vaccine. Based on the SAGE evaluation, the WHO issued a position on the dengue vaccine in July 2016 to guide countries interested in introducing the vaccine into public vaccination programs to reduce their dengue burden
Today this vaccine, after 20 years of development and testing, has been approved in 19 countries. Two of them – the Philippines and Brazil – have initiated targeted public dengue vaccination programs in areas where the dengue burden is heavy.
Periodic safety reports to regulators, ongoing long-term trial results and experience collected from post-marketing surveillance of the vaccine’s impact continue to be shared regularly. All this knowledge about the vaccine is building an understanding of how best to target dengue for vaccination, both within Sanofi and among other research teams working in this field.
Given the complexity of dengue infection, Sanofi continued to work with the scientific community to assess the long-term effectiveness of the vaccine. One hypothesis to be explored was the possibility of diminishing benefit of the vaccine in people without a prior dengue infection before vaccination. The vaccine trials were run mainly in endemic countries so most of the people had a prior dengue infection. So, in order to look back and examine more closely the vaccine’s performance in people who did not have dengue before being vaccinated, Sanofi had to develop a new test that could distinguish antibodies generated in response to vaccination from those due to natural dengue infection.
Development of the test was a complex process and it took close to a year to validate it, conduct supplementary analyses of the long-term clinical trial data and compile the results. In the interim, results from our long-term follow-up continued to show significantly fewer hospitalizations due to dengue in vaccinated individuals nine years and older compared to those who received placebo.[viii] These published findings helped to substantiate the overall public health value of the vaccine in settings where dengue continued to be widespread.
The new analysis that we compiled and released in November 2017 revealed that the dengue vaccine works differently based on prior dengue infection history. Based on this finding, Sanofi is proposing that regulators update the prescribing information requesting that healthcare professionals assess the likelihood of prior dengue infection in individuals before vaccinating. Vaccination should only be recommended when the potential benefits outweigh the potential risks. For individuals who have not been previously infected by the dengue virus should not be recommended. The analysis did, however, confirm that vaccination provides persistent protective benefit against dengue infections in those who have had a prior dengue infection.
We made this new information available first to health authorities and then, shortly thereafter, to the public. Our goal in all of our actions is to ensure proper understanding of this situation by all stakeholders and allow for informed decision making on vaccination between individuals and their healthcare providers.
Together with country health authorities, Sanofi will continue to monitor the long-term impact of vaccination in the ongoing and post-authorization safety and effectiveness studies. We will also invest in efforts to develop and register reliable, rapid and cost-effective diagnostic tests to better support field use of the vaccine.
Sanofi remains committed to the considerable challenge of reducing the threat that dengue presents to four billion people living in tropical and subtropical regions of the world. Together with global and regional health authorities, and the broader scientific community, we continue to work to bring down the burden of this pervasive public health menace.
Head of Global Medical Vaccine
[viii] Limkittikul, Kriengsak, et al. Long-term (6-year) follow-up in Thai children from phase IIb proof of concept efficacy study of cyd-tdv dengue vaccine. Presentation at ACPID, Bangkok, Thailand, 7 – 10 November 2016.