Frequently Asked Questions about Dengvaxia® dengue vaccine

Last updated 26th March, 2018

  1. What is the current regulatory status of the Dengvaxia dengue vaccine?
  • The vaccine has been approved in 20 countries in Latin America and Asia where dengue is identified as a public health priority; the license for the vaccine in the Philippines is temporarily suspended for 1 year from January 2018 due to changes in the post marketing study program.
  • As there are overseas European territories where dengue is present, the regulatory dossier for the vaccine has also been submitted to the European Medicines Agency.
  • Sanofi Pasteur is in discussions with US Food and Drug Administration to consider submission of the regulatory dossier on the vaccine for approval and use in the US territory of Puerto Rico, where dengue is endemic.
  1. Are there ongoing public vaccination programs with your vaccine today?
  • Yes, the Parana State health authorities have decided to initiate a fourth wave of their public dengue vaccination program in March 2018 to ensure higher coverage rates for all 3 doses of the vaccine.
  • The national regulatory authority in Brazil, ANVISA, has posted an acknowledgement of Parana’s decision to continue the ongoing program to reduce the dengue burden in high endemic regions of the state on their website.
  1. What is the current indication of the vaccine?
  • The vaccine is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3, and 4 in individuals 9–16/45/60 years of age living in endemic areas.
    age limit differs in various country indications
  • Sanofi Pasteur completed a supplementary analysis of the long-term data on the vaccine that was communicated publicly in November 2017, revealing that the dengue vaccine works differently based on prior dengue infection history. 
  • Based on this new clinical data, Sanofi Pasteur 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, vaccination should not be recommended.
  • The analysis confirmed that vaccination provides persistent protective benefit against hospitalizations due to dengue and severe dengue in those who have had a prior dengue infection for the duration of the five-year follow up period of the ongoing long-term studies.
  1. Did Sanofi Pasteur rush development of this vaccine by initiating large-scale studies in children before you had the Phase II results which turned out to be disappointing?
  • We spent more than 20 years developing and testing the dengue vaccine to address the significant burden that dengue represents in high endemic countries where about half the world’s population lives today.
  • We initiated Phase III studies prior to the close of the Phase IIb study in Thailand based on the fact that we had strong immunogenicity data on the vaccine and no indication of any safety concerns with the vaccine. This decision was supported by the independent data monitoring committee (IDMC) of vaccine experts.
  • The IDMC is responsible for providing an independent and routine review of the benefit/risk profile of the vaccine candidate during the Phase IIb and Phase III studies.
  • While it is true that the Phase IIb results were a surprise from an efficacy point of view; safety of the vaccine was not an issue.
  • Large-scale safety and efficacy studies of new vaccines are required for regulatory approval.
  • The age population for the Phase III studies was based on available epidemiological data about the age groups most affected by dengue at the time that the studies were started the participating countries in Latin America and Asia, respectively.
  1. Did your company launch in the Philippines and other endemic countries before completing the required safety evaluation of the vaccine?
  • No, the 25-month follow up of the clinical efficacy and safety studies for the vaccine that was required for regulatory approval were completed and reported in 2014/15 and provided the basis for the licensing approvals of the vaccine to date, along with the pooled efficacy and integrated safety data on the vaccine observed 3 years after the first dose.[i],[ii],[iii]
  • The recent results were from a supplementary analysis of long-term clinical data for 5 years post first dose.
  •  It is normal practice for manufacturers to continue to assess the safety and impact of new vaccines after approval in long-term phases of clinical studies, as well as in post-marketing surveillance studies and public program evaluations; all of which are being done for our dengue vaccine.
  • In particular, the WHO has issued guidelines for live attenuated dengue vaccines that requires at long-term safety follow-up after the initial clinical efficacy and safety phase required for licensure.
  • All new safety information on approved vaccines is shared periodically with the regulatory authorities in the countries where the vaccine is approved or under review, as well as in countries where studies of the vaccine are being conducted.
  1. Do you have support for the value of dengue vaccination in the Philippines among the medical community there?
  • Yes, about 700 members of the Filipino health care community have posted a public call for a more scientific review of the vaccine benefit/risk assessment, pointing to the potential benefit for the vaccination for a large proportion of the population who have had a prior dengue infection.[iv]
  • People can get dengue up to 4 times in the course of a lifetime since the infection is caused by four different virus serotypes.
  • Severe dengue is rare (about 0.5% of all symptomatic cases) overall; however, severe disease is more common with the second infection compared to the first infection.
  • Sanofi Pasteur’s dengue vaccine shows persistent, long-term protection against severe dengue and hospitalizations due to dengue in 9 years and older who have had a prior dengue infection.
  1. Why are you only now filing with US FDA and EMA while you went ahead to be submit for registration of the vaccine in these low and middle-income countries before conducting this supplementary safety assessment?
  • Sanofi Pasteur set out more than 20 years ago to innovate and first introduce a vaccine against dengue as a priority in endemic countries where dengue is an identified public health priority.
  • Dengue burden in overseas European and US territories tends to be more sporadic and less prevalent so we always intended to file later with EMA and the US FDA.
  • To support earlier access to a needed dengue vaccine in high endemic countries, the WHO and the Dengue Vaccines Initiative convened a meeting of endemic country regulators together with EMA and the US FDA to ensure support in reviewing the technical regulatory dossier on Dengvaxia®.[v]
  1. Did you ignore the potential for antibody dependent enhancement in your development of the vaccine?
  • No, from the beginning of our project to innovate a vaccine against dengue, Sanofi Pasteur, along with the rest of the scientific community, recognized the complex challenge that dengue infection poses to vaccination; namely that people can get dengue four times due to the fact that there are four distinct serotypes of the virus circulating worldwide and that the secondary infection carries a higher risk of severe disease outcomes compared to the first.
  • Due to this unique feature of dengue infections, the WHO established guidelines for development of live, attenuated vaccines against dengue that require additional long-term follow-up in the post approval phase to assess the risk of an increase in severe dengue outcomes in vaccinated individuals.
  • This is also why all live, attenuated dengue vaccine candidates should document efficacy against all four serotypes in large-scale Phase III clinical studies, as was done for our vaccine.
  • Anti-body dependent enhancement or ADE is one hypothesis put forward to explain the unique phenomenon of dengue infections tendency to be more severe upon secondary infection.
  • However, ADE does not explain why some primary infections can also result in severe dengue; rather it is likely that severe dengue is due to a combination of factors related to both the person infected and the virus.
  1. Then why didn’t you stop development of your vaccine when you had evidence of ADE?
  • In fact, our clinical data on the vaccine can neither confirm nor refute ADE since the cases of severe dengue observed in vaccinated individuals in the studies were not more clinically severe than those observed in unvaccinated individuals.
  • At the time of registration, the available evidence pointed to a potential safety issue in 2-5 year old age group that appeared to be mainly linked to age as it was not observed in older age groups.
  • In fact, for the older age group 9 and above, the long-term follow up phases of all the clinical studies continue to show a protective benefit of vaccination against hospitalization due to dengue and severe dengue for up to 5 years.
  1. If you did not doubt the safety of your vaccine, why did you do the supplementary analysis?
  • Sanofi Pasteur is committed to evaluating the long-term impact of all its vaccines.
  • In their position statement on the dengue vaccine issued in 2016, the WHO requested that we further evaluate the vaccine’s long term safety in seronegative individuals.
  • In order to do so, we developed a new assay test and conducted the supplementary analysis reported at the end of 2017.
  1. Now that you have this new proof, will you stop marketing this vaccine until a serotest for prior dengue infection is readily available?
  • No, we have proposed a label update for the vaccine based on the new data which is under consideration by the respective national regulatory authorities.
  • People can get dengue up to four times in a lifetime since the disease is caused by four different virus types.
  • Severe dengue is rare (0.5% of all reported cases) and the majority of dengue infections are symptomless (75%).
  • While a person can get severely ill with dengue at any of the four infections, for reasons not clearly understood by the scientific community, the second infection tends to be worse.
  • The majority of people living in high endemic regions have had at least one dengue infection by the time they reach early adolescence and are, therefore, potentially facing a secondary infection which with dengue is more likely to be severe.
  • For these people, our vaccine can provide up to 93% efficacy against severe dengue and 80% against hospitalizations due to dengue.
  • The potential benefit of dengue vaccination to reduce overall disease burden in high endemic populations has been confirmed and we are committed to working with the health authorities in countries with high dengue transmission to ensure availability of dengue vaccination to individuals who need protection against secondary dengue infections.
  • Secondary infections with dengue are often more debilitating compared to the first infection with the virus and, thus, contribute significantly to dengue’s overall burden on the healthcare system in countries where dengue is endemic.
  1. Your company has stated that it is pursuing development of a rapid dengue test to assist use of your vaccine. What are the timelines for this project and what should physicians do in the meantime?
  • Our proposed label update states that vaccination should only be recommended when the potential benefits outweigh the potential risks.
  • The regulatory authorities in the countries where the vaccine is licensed or under consideration for licensure are currently reviewing the proposed update to the vaccine label.
  • If the label is accepted, vaccinators in that country would be able to use available tools to screen for prior dengue infection which could include a review of medical records and history taking, as well as use of available dengue serotests.
  • Vaccinators need to be aware of the limitations of available dengue test for assessing past dengue infection such as poor accuracy, specificity and the potential for cross reactivity with other flaviviruses like Zika and Yellow Fever.
  • The timeline that we are currently estimating to develop a test that overcomes these limitations is around 2-3 years, including regulatory registration process.
  1. In the Philippine media, we understand that your vaccine is being investigated as the cause of death in several vaccinated children in the Philippines. Can you comment on these cases?
  • In fact, we cannot as everything we know about these cases, we have likewise read in the media. Even though, we have requested the full medical documentation on adverse events from the Philippines Department of Health, according to international standard procedure, we have not been able to gain access to this documentation and, therefore, have not been able to conduct a scientific investigation into the cause of these tragic deaths.
  • However, we would like to point out that illness due to dengue is caused by the virus and not the vaccine.
  • Dengue is not typically fatal with an estimated 2.5% (12,500) of the 500,000 severe cases reported per year leading to death.
  • Furthermore, no deaths have been reported as due to the vaccine in the 11 countries using the vaccine today or during any of the clinical studies of the vaccine which involved over 40,000 people and which includes close monitoring of safety in the large-scale studies by an independent panel of vaccine safety experts.
  • On the contrary, vaccinated individuals 9 years of age and older show a lower incidence of severe dengue and hospitalizations due to dengue compared to unvaccinated people for the 5 year period of the ongoing long-term follow studies.
  1. When do you expect to have an updated WHO position on the vaccine?
  • Probably during May 2018 following the updated SAGE recommendation on the vaccine expected on 18th April.
  • In the interim, the WHO has published an updated Q&A on the dengue vaccine published in December 2017 that recognizes the public health value of vaccination in high endemic settings.[vi]
  1. Did you shut down your dengue vaccine production facility in France?
  • No, we started slowing production down in 2016, just producing enough antigens to rebalance our stocks of the four valences.
  • We now have enough stock to respond to a sudden spike in demand so we have put production of the dengue vaccine on hold since the beginning of this year.
  • However, the site remains open and is currently capable of also producing our new yellow fever vaccine.


[i] “Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease” Jul, 27th 2015 http://www.nejm.org/doi/full/10.1056/NEJMoa1506223

[ii] “Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial” Jul 10, 2014

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61060-6/abstract

[iii] “Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America” Jan, 8th 2015 http://www.nejm.org/doi/full/10.1056/NEJMoa1411037

[iv] Doctor for Truth, “Statement on Dengvaxia Controversy” – January 30, 2018  https://mdpie.com/doctorfortruth

[v] http://dx.doi.org/10.1016/j.vaccine.2017.07.044

Commentary

The value of multi-country joint regulatory reviews: The experience of a WHO joint technical consultation on the CYD-TDV (Dengvaxia) dossier

Kirsten Vannice