Paradigm Shift in Vaccines: Our Dengue Vaccine Candidate

Nearly half of the world’s population is at risk of dengue, a mosquito-borne viral infection for which there is no specific treatment. Dengue primarily affects people in Asian and Latin American countries, where it has become a leading cause of serious illness, hospitalization, and death as a consequence of the severe form of the disease: dengue hemorrhagic fever. Given the global burden of dengue disease and the efficacy results from two large-scale Phase III studies of the candidate vaccine, analysts see tremendous value in the impending launch of the world’s first dengue vaccine candidate. The global healthcare costs associated with dengue disease is estimated to be more than € 6 billion today, and its prevalence and indirect impact on tourism and other economic indicators in endemic countries remain underestimated.

The dengue burden underscores the challenge of addressing unmet medical needs in the developing world: resources are mobilized too late to significantly impact neglected diseases and other infectious diseases that are not a top public health priority for the developed world. As a result, the pharmaceutical industry generally resorts to reactive approaches to these global public health issues.

The long-term commitment of Sanofi Pasteur, our vaccines division, to develop an effective dengue vaccine could constitute a milestone for long-term investment in these neglected diseases, which will inspire our industry to take a fresh look at this issue.

A private commitment of $ 1.5 billion towards improving public health in endemic countries

We have spent the last 20 years researching, developing, and now seeking regulatory approval for the world’s most advanced dengue vaccine candidate. Our engagement represents a $ 1.5 billion commitment – with no guarantee of a return. We invested in breakthrough science, a chimeric technology platform, which had never been tried before with vaccines. We began research and development work on the disease in 1994 and faced many hurdles: For instance, the development of a live attenuated vaccine was stopped in 2004 due to the under-attenuation of one of the four serotypes. However, we did not give up and were able to identify a promising recombinant technology that, by 2007, had achieved proof of concept for a new live-attenuated vaccine. In 2010, our candidate received “fast track” status from the US Food and Drug Administration and became the world’s first dengue vaccine to start Phase III trials.

The successful development of the vaccine follows 50 years of research worldwide due to the four-strain complexity of the virus. This development has involved more than a hundred collaborations and is proof of Sanofi Pasteur’s experience, expertise, and extensive public health network around the world. Top talent in science, public health, health economics, and the vaccine business are attracted to the company’s approach and long-term commitment.

An industrial and human bet on the future

Our upfront, at-risk investment included the complete transformation of an existing production site to ensure supply of the vaccine upon approval. This investment epitomizes the public health focus of our approach. Indeed, vaccines are often developed and launched first in developed countries, targeting a limited population such as travelers, thereby allowing for a gradual production and build-up of supplies. However, our dengue vaccine will first be launched in dengue-endemic countries and adequate supplies will be needed upon launch.

This industrial bet has also provided new and unique opportunities for our industrial employees in the Neuvillesur-Saône industrial facility in France. Formerly, the facility produced chemical components for our pharmaceutical business and was due for closure. Today, more than two-thirds of the employees of our new dengue vaccine plant are former employees of the original chemical plant. They have undergone a voluntary training course at our existing vaccine facility in Marcy L’Etoile in order to acquire the necessary skills for vaccines production. At full capacity, the plant is set to produce around 100 million doses per year as early as 2016.

A commitment beyond the vaccine

Currently, the only way to limit the risk of dengue is by avoiding a mosquito bite. Our commitment to dengue is longstanding, and we have been involved in numerous initiatives to increase community engagement by raising awareness and educating local healthcare professionals on dengue prevention. In Malaysia, Sanofi Pasteur launched the Dengue Patrol program with the Ministry of Health and the Ministry of Education in 2011. This is part of Sanofi Pasteur’s commitment to take proactive measures to intensify awareness about dengue and involve public participation, especially from the younger generation. Indeed, the program seeks to recruit students nationwide to form Dengue Patrols in their respective schools, with the aim of organizing activities that encourage dengue prevention and protection against Aedes mosquitoes. Launched as a pilot program, it went nationwide in 2014. Sanofi Pasteur also supports the Break Dengue campaign, whose mission is to build international community engagement around the public health burden of dengue. It also provides a forum for exchanging information, best practices, and news on potential treatments and prevention strategies.

Clinical trials as a vector for capacity-building in local healthcare systems

Our unprecedented clinical study program involved more than 40,000 participants across 15 dengue-endemic countries in Asia, Latin America, and the Caribbean. Sanofi Pasteur’s candidate vaccine was assessed in two major Phase III clinical trials – first, in a cohort of more than 10,000 children, aged 2 to 14, in five Asian countries; followed by a cohort of more than 20,000 children, aged 9 to 16, in five Latin American and Caribbean countries.

These Phase III trials included a number of challenges. The first challenge was recruitment of and follow-up on trial subjects. Vaccines are given to healthy subjects – this is the most fundamental challenge inherent to developing any vaccine. With the awareness that dengue hemorrhagic fever can be fatal, parents were eager for their children to take part in the studies. Nevertheless, children and adolescents are an especially vulnerable population, particularly in developing countries, where healthcare infrastructure is lacking or inadequate. Families had to commit to monitoring their children for acute fevers and report weekly to the trial organizers. Some centers also offered family counseling and organized soccer tournaments with the aim of keeping young people from becoming involved in gangs and drug-related violence. The second challenge was to locate communities where the population would remain stable for at least the two years of the trial: one year during which participants received three doses of vaccine at six-month intervals, followed by 13 months of active surveillance and a further 48 months of passive surveillance. This steered us away from major urban centers, where populations are less stable, even though this is where healthcare expertise and hospitals are concentrated. The third challenge, related to the previous one, was to identify and empower local investigators. It was essential to provide training on regulatory issues and good clinical practices, which, due to the sheer size of our study, represented a daunting task. We needed to locate potential study centers near a hospital, where we could invest in capacity-building and attract qualified investigators and teams.

To prepare for the Phase III efficacy studies and ensure the readiness of investigator sites, we ran practice trials and conducted preparatory studies in some locations, which required a substantial investment of resources and time (€ 1 million for one year). Furthermore, our trials also required the local authorities to set up independent ethics committees to validate the study protocol, which was a new undertaking for some authorities and investigators. For Sanofi, the success of the clinical trial program may be measured by the extremely low dropout rate: 1.5 percent in Asia and 5 percent in Latin America, meaning that nearly all the participants stayed in the trial from start to finish. One of the key benefits for children and teenagers enrolled in the study, as well as their families, was access to state-of-the-art medical facilities and holistic healthcare. Local investigators benefitted from a legacy of expertise, including learning about good clinical practices and logistics (cold chain, proper disposal of unused products, etc.), and gaining long-term health capabilities. This extensive clinical development program led to local capacity-building, skills-transfer, increased standards of care, as well as raised awareness about dengue in the general population and among the healthcare community.

The first findings of the Phase III trial in five Asian countries, published in the Lancet journal in July 2014, showed overall efficacy against symptomatic dengue of 56.5 percent in children aged 2 to 14 years old after a three-dose vaccination schedule. In addition, analyses show an 88.5 percent reduction in dengue hemorrhagic fevers. The study also revealed a clinically important reduction in the risk of hospitalization due to dengue by 67.2 percent during the study period. In November 2014, the New England Journal of Medicine published the results of Sanofi Pasteur’s final landmark Phase III clinicalefficacy study in Latin America and the Caribbean region. Overall efficacy against any symptomatic dengue disease was 60.8 percent in 9- to 16-year-old children and adolescents who received three doses of the vaccine. Analyses show a 95.5 percent protection rate against severe dengue and an 80.3 percent reduction in the risk of hospitalization during the study.

These trials provided pivotal efficacy, safety, and immunogenicity data as well as local insights into the dengue disease. Broad vaccination, including routine and catch-up cohorts, is expected to provide rapid and maximal impact in reducing the incidence of dengue.

The story continues …

The vaccine is currently being registered and set for initial launch in several endemic countries where dengue is a public health priority. These countries have the capacity to initiate wide-scale dengue immunization programs with the appropriate surveillance in order to have the maximum impact on the in-country disease burden from a human and economic standpoint. But the story will not end there. Sanofi Pasteur is committed to being a public health partner in dengueendemic countries. It wants to guarantee that the vaccine is used optimally in comprehensive vaccination programs to ensure its impact on public health and to help these countries attain the WHO objective of reducing mortality from dengue by 50 percent and morbidity by 25 percent by 2020.

Shared value-creation is what drove the dengue story. Both the governments of endemic countries and the communities at risk must take ownership of the dengue vaccine and be able to acknowledge as well as realize the benefits of the vaccine. The dengue vaccine has the potential to galvanize political commitments, healthcare support, and additional private investment in the fight against dengue and to make dengue the next vaccine-prevented disease.