Timeline: the dengue vaccine dilemma
Pharma giant Sanofi has been mired in controversy in the Philippines after allegations that its dengue vaccine Dengvaxia, which had been used in a widespread school vaccination programme, was linked to the deaths of children. Since the vaccine’s ban the Philippines has declared a national dengue epidemic, creating a public health dilemma as infection rates soar. Chris Lo reports.
The Philippines is in the midst of a national epidemic of dengue fever, a mosquito-borne tropical disease that causes flu-like symptoms and can be life-threatening, particularly to children if it develops into the more severe form of the disease. The country has attributed at least 622 deaths to the disease this year, a 98% year-on-year increase, prompting authorities to declare a national epidemic in August.
Immunisation rates for dengue in the Philippines have fallen dramatically just a few years after the world’s first dengue vaccination programme – using Sanofi’s live attenuated vaccine Dengvaxia (CYD-TDV) – was rolled out in the country’s schools. Below are the key dates in the rise and sudden fall of Dengvaxia in the Philippines, and the urgent unmet need that still exists in the response to dengue outbreaks.
Dengvaxia’s launch in the Philippines
In the spring of 2016, Dengvaxia had a high-profile launch in the Philippines, as the country – having been involved in every phase of clinical development – became the first in the world to access the live recombinant tetravalent vaccine. The Department of Health spent $67m on Dengvaxia and kicked off a mass immunisation programme with the aim of vaccinating a million students by the end of the year.
Sanofi also had high hopes for Dengvaxia, the development of which had taken 20 years and cost around $1.8bn. Officials predicted that the vaccine – which helps protect against all four serotypes of dengue – would drive down infection rates by 24% within the next five years, and Sanofi looked well-positioned to reap the benefits of offering the first-ever dengue vaccine to global markets. By October 2016, Dengvaxia had received regulatory approval from ten other countries, including Mexico, Brazil and Indonesia.
safety concerns after relabelling
More than six months later, after more than 830,000 children had received at least one dose of the vaccine (Dengvaxia is administered as three injections, with six-month intervals), Sanofi announced that it was changing its label to restrict its use to only those who had already been exposed to dengue virus. Having reanalysed its trial results, Sanofi said the evidence now suggested that dengue-naïve people who received the vaccine could be vulnerable to more severe infections.
Some dengue researchers, including a team from the University of Minnesota, said they had long predicted this risk due to the dengue-specific phenomenon of antibody-dependent enhancement (ADE) – the same mechanism that often makes repeat infections more serious. Sanofi argued that ADE might not be the full story, but in the meantime the Department of Health immediately suspended the immunisation drive.
a national scandal
Within a few months, the potential implications of the vaccination drive had become a national scandal, and blame was being cast at pharma firms and health department officials alike. Allegations surfaced that the vaccine was linked to the deaths of several children, and in February the Philippines Public Attorney’s Office filed a lawsuit against government officials and executives of Sanofi and distributor Zuellig Pharma. The suit sought damages claiming that a ten-year-old girl died after receiving the vaccine despite the fact that she had a pre-existing condition.
Elsewhere, Sanofi continued seeking regulatory approval for Dengvaxia for use in those who have already been exposed to dengue fever, and in December 2018, the European Commission granted marketing approval for the vaccine to be used in already-exposed individuals aged nine to 45 years and living in dengue-endemic regions.
“In some of the European overseas territories where dengue recurs regularly, people who have had a dengue infection previously are at risk of being infected with the virus again,” said Sanofi Pasteur’s head of global medical affairs Su-Peing Ng. “As the second infection with dengue tends to be more severe than the first, it is important to be able to offer these people a vaccine that could help protect them against subsequent dengue infections,” she said.
licence revoked in the Philippines
While Dengvaxia’s use was suspended after Sanofi’s update in November 2017, its long-term future was still in question until February this year, when the Philippines Food and Drug Administration permanently withdrew the vaccine’s licence; the regulator’s director general Nela Charade Puno said the decision had been made because Sanofi failed to comply with its post-marketing commitments.
Meanwhile, the Dengvaxia scandal had by this time become the subject of two congressional inquiries and a criminal investigation. In March, the Department of Justice said it had enough evidence to charge both staff of Sanofi and Philippine health officials, including former Health Minister Janette Garin. The department argued the named defendants had ignored “the identified risks and adverse effects of the vaccine” and were responsible for the subsequent deaths. While a panel of medical specialists are gathering information about the alleged link, to date no conclusive evidence has been presented that connects the deaths to Dengvaxia specifically.
Dengvaxia was approved by the US Food and Drug Administration in May, having been granted a priority review by the agency. Approved under the same restrictions as its licence in Europe, Dengvaxia is authorised for use in dengue-endemic areas of the US, including Puerto Rico, Guam and American Samoa.
reviewing Dengvaxia amid an epidemic
With dengue cases surging in the first half of 2019 and Dengvaxia the only approved vaccine option, the Philippine government considered reintroducing the vaccine on the condition that all participants are pre-screened to confirm that they have had previous exposure to dengue.
“If Dengvaxia is proven effective to those who already had dengue in the past, then its application to these individuals will surely cause the decline of the overall number of cases,” said presidential spokesman Salvador Panelo in August.
On 22 August, however, the Department of Health rejected Sanofi’s appeal to overturn the FDA’s ban on Dengvaxia, with the department again citing the company’s failure to submit post-marketing data including risk management plans. A statement by health officials noted that re-approving the vaccine “is for the FDA to act upon”, leaving the door open to a reversal of the decision if Sanofi can satisfy the regulator on its post-marketing work.
There is currently nothing to suggest that Dengvaxia is linked in any way to the deaths that have been at the centre of the allegations, and the vaccine’s subsequent approval by European and American authorities validates Sanofi’s statements that it is effective and safe when administered correctly.
Nevertheless, the controversy in the Philippines raises troubling questions around the governance of this immunisation drive, and how, despite years of clinical studies, the vaccine was allowed to be administered to those who may have been harmed by it. Without rock-solid safety data and careful management, a vaccination campaign could easily be seen as an exploitative gamble with public safety.
“When you are the first in class, we’re the ones having to develop and understand the science as we go,” Sanofi’s Ng told Reuters in December 2017.
In the meantime, the race is on for an alternative dengue vaccine that overcomes the exposure issue that held back Dengvaxia. Takeda’s candidate TAK-003 is based on an attenuated version of live dengue 2 virus rather than Dengvaxia’s yellow fever, and late-stage trial results earlier this year have demonstrate effective protection against all four dengue serotypes, regardless of previous exposure to the virus.
Another vaccine candidate based on live dengue virus is being developed by scientists at the US National Institutes of Health and the Butantan Institute in Brazil, and licensed to Merck for commercialisation. TV003/TV005 has seen promising results in antibody response to all dengue serotypes and producing T-cell immunity.