We continue to monitor developments associated with Dengvaxia. We did not identify any new press releases or statements on the Sanofi website.
Sanofi agrees to pay for proven Dengvaxia adverse events in the Philippines
by Eric Sagonowsky | Fierce Pharma
Jan 23, 2018 11:41am
Sanofi had already agreed to refund the Philippines for unused Dengvaxia shots as part of an ongoing safety controversy there. Now an executive has told legislators the company will “shoulder the cost” of any adverse events that are scientifically linked to vaccination.
Speaking at a Senate hearing on Monday, Sanofi Pasteur Asia-Pacific head Thomas Triomphe said that “should there be any case related to vaccination, death or any other case, we will shoulder the cost, if there is a causality that has been demonstrated through scientific evidence,” according to The Inquirer.
The testimony came as a safety controversy for the vaccine intensified over the last week, with reports that preliminary autopsy results showed a common cause of death among children who died after vaccination, though experts said no causal link was found. At the same hearing, an expert panel from the Philippine General Hospital reported that there was “no evidence linking Dengvaxia to any deaths,” a Sanofi spokesperson told FiercePharma on Monday.
“This finding is consistent with the fact that Sanofi Pasteur has not had any reports of deaths due to vaccination in any of the clinical studies of the vaccine involving over 40,000 people nor in the public or private use of Dengvaxia where over 1 million dose of the vaccine have been administered in several endemic countries,” the spokesperson added…
The Lancet Infectious Diseases
The dengue vaccine dilemma
Dengue is the most common mosquito-transmitted viral infectious disease. A 2016 study estimated nearly 60 million symptomatic dengue cases worldwide every year (estimates including asymptomatic cases are at least six times higher), resulting in about 10,000 deaths. 4 billion people are at-risk in 128 countries where aedes mosquito vectors are present. Efforts to develop a vaccine against dengue have been ongoing for decades. The first such vaccine to be used routinely is CYD-TDV (marketed as Dengvaxia), a live, attenuated tetravalent product developed by Sanofi Pasteur. Following two phase 3 clinical trials published in 2014, Dengvaxia was licenced in December, 2015, and approved in 19 countries. Subsequently, regional mass vaccination programmes were launched in the Philippines and Brazil, targeting 1 million people.
However, after reassessment of data from the clinical trials, Sanofi warned on Nov 29, 2017, that the vaccine can increase the risk of severe dengue in particular circumstances. The vaccination programme in the Philippines has been suspended, with information released to WHO by Sanofi raising questions about future use of Dengvaxia.
How any vaccine against dengue is used is complicated by the fact that virus occurs in four serotypes, and immunity against any one serotype does not generate lasting immunity against the other three, hence the need for a tetravalent vaccine. Furthermore, being infected with—and developing immunity to—one viral serotype seems to be the trigger that can lead to a patient having more severe disease manifestations when subsequently infected with a different serotype, a phenomenon known as antibody-dependent enhancement. Infections with the third and fourth serotypes, if they occur, usually result in milder disease.
Expert opinion and a position paper on Dengvaxia were issued by WHO in 2016. When licenced, the vaccine was approved for people aged 9–45 years, in which group the phase 3 trials at 2 years of follow-up showed a reduction in severe dengue of 93% and of hospital admissions due to dengue of 82%. The vaccine was not approved in younger children because of less favourable efficacy and safety; in particular, an increase in hospital admissions due to dengue among those aged 2–5 years. This finding, which might have been an effect of age or because of more dengue-unexposed (ie, seronegative) individuals in the younger age group, could not then be explained since serostatus before immunisation was unknown for most trial participants. However, some experts warned in 2016 that the increased risk of hospital admission was a serious safety concern, including Maíra Aguiar and colleagues in this journal, a point emphasised by Aguiar and Nico Stollenwerk in their Correspondence published online on Dec 21, 2017.
Sanofi’s statement in November came about because—prompted by WHO—the company developed an assay to estimate dengue serostatus before vaccination in trial participants. A supplemental statement from WHO on Dec 22, 2017, verifies that overall Dengvaxia reduces the risk of confirmed severe dengue and hospital admissions. Vaccine recipients presumed to be seropositive at immunisation had sustained protection during 5 years’ follow-up. However, among recipients seronegative before immunisation—and regardless of age at vaccination—there was a higher risk of severe dengue disease and hospital admission compared with unvaccinated controls. Thus, in seronegative individuals, the vaccine seems to enhance the severity of subsequent dengue infection.
Where then do these findings leave the status of Dengvaxia and other candidate vaccines against dengue? The Dec 22 WHO statement notes that in settings of high dengue seroprevalence, the vaccine is likely still beneficial at a population level. However, Aguiar and Stollenwerk state that “ethically no one should have been put under risk by receiving this vaccine”. Age was clearly used as a proxy for seropositive status in the original recommendations, a position that is no longer tenable. Indeed, the new WHO recommendation is for vaccination only in individuals with proven past dengue infection. But no point-of-care test for dengue serostatus exists. In a phase 2 trial of the Takeda TDV tetravalent dengue vaccine published in this issue, serostatus at the time of vaccination was measured, but follow-up is too short to detect risks associated with being seronegative. Phase 3 trials of the Takeda vaccine and another from the Instituto Butantan, Brazil, whose primary completion dates are later this year, might provide more answers. A new position paper from WHO is also expected later this year. In the meantime, a rapid assay of dengue serostatus is surely a priority.