As the Philippine Department of Justice (PDOJ) said it found probable cause to indict Sanofi SA and government officials over deaths caused by the Paris-based pharma giant's dengue vaccine, the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) reviewed the BLA for the product in an uneventful session.

Sanofi wants the live, attenuated dengue tetravalent vaccine trade-named Dengvaxia, and intends the product to prevent disease caused by dengue virus serotypes 1, 2, 3 and 4 in people 9 to 45 years of age with laboratory-confirmed prior dengue infection and living in endemic areas. The vote on whether it should be approved for efficacy under such conditions was seven no, six yes and one abstain. Asked about safety under the same conditions, the panel voted seven yes, seven no. On the same question of efficacy but in children 9 to under 17, the vote was 13 yes, one no. On the question of safety in that population, the vote was 10 yes, four no. The FDA doesn't have to follow the recommendation but usually does.

Much of the panelists' questioning of the company involved differences in data between studies submitted to back approval, and testing of would-be receivers of the vaccine who might need to make two doctor visits – one for a blood draw, one for the test results – for confirmation of seronegative people who could be at risk if given the three-shot product. Michael Kurilla from the NIH said he was "struggling with the restriction in the [proposed] label to endemic regions. Calling somebody endemic is a little subjective," he said, calling the definition "squishy."

Cody Meissner from Tufts Medical Center in Boston brought up herd immunity, which he called "an important consideration" – and said there likely wouldn't be any. "This is not going to reduce the circulation of this virus in the population," he said. "It seems to me that on balance this vaccine will reduce the number of severe cases of dengue, but there will be some cases that will probably occur as a result of the vaccine." In vaccinology, "I don't think we've ever gone there before," he said. "I'm uncomfortable about that, I must say."

Sheldon Toubman, staff attorney with the New Haven Legal Assistance Association in New Haven, Conn., conceded that he was less knowledgeable about vaccines than others in the meeting but said he was reluctant to support Dengvaxia. "I have significant concerns," he said, adding that Sanofi, when asked if the vaccine would reduce dengue if no screening was done at all, answered yes. "That's coming from a company that really wants to see this thing approved," Toubman said. And when asked about the results from a trial that were excluded, he said, the company "gave an answer that wasn't accurate." He said the application "should be rejected unless there's really strong testing available." Sanofi should be required to have a fast, on-site assay, in his view. "I just don't trust that this test is going to be done under the current conditions, particularly in Puerto Rico," he said.

Kathryn Edwards from Monroe Carell Jr. Children's Hospital in Nashville proved skeptical, especially about bridging data offered by Sanofi and about the pre-vaccine test. "I don't think we have a test that will allow us to adequately say whether they are seropositive that will be able to be used in the field," she said. Myron Levine from the University of Maryland School of Medicine in Baltimore questioned the age range targeted by the product and said limiting it to a school-age group "is the way to go," rather than depending on bridging data to include older people. Paul Offit from The Children's Hospital of Philadelphia pointed to the suffering caused by dengue. "We have clearly in hand a technology that can prevent that, if used the right way," and said that "instead of backing away because it's difficult to use the right way," the FDA should do all it can to screen for appropriate patients.

At the end, the FDA's Marion Gruber said officials there "had a lot of very similar discussions internally, so we understand this has been a very difficult and complex topic that we've brought before you."

U.S. regulators have granted priority review and fast track designation, and Sanofi Pasteur, the vaccines division of Sanofi, has proposed routine and enhanced pharmacovigilance monitoring to identify risks that could be associated with the compound.

Life-threatening dengue is transmitted by the Aedes mosquito. The disease has spread to most tropical and many subtropical areas and is a leading cause of serious illness and death among children in some Asian and Latin American countries. In the U.S., dengue is endemic in Puerto Rico and the Virgin Islands. The CDC estimates that some 390 million dengue infections occur worldwide, of which approximately 100 million cases are associated with clinical manifestations, 500,000 hospitalizations and 20,000 deaths. According to the World Health Organization, dengue is caused by four closely related serotypes of the virus – those targeted by Sanofi's vaccine.

People may be infected up to four times in a lifetime, with severe disease more likely to occur in people who have already been infected with one serotype when infected by a different one. There is no specific treatment for dengue, and prevention of dengue is limited to vector control measures. Late last year, the European Commission granted marketing authorization for Dengvaxia following the October recommendation by the EMA's Committee for Medicinal Products for Human Use to let the product be used in European endemic areas.

Also in October, as the FDA granted priority review, Sanofi pointed out that Puerto Rico experienced the largest historical outbreak when more than 12,000 cases were confirmed, and incidence remained high in 2012 and 2013. Dengue represents a health and economic burden in Puerto Rico with total annual associated costs reaching an estimated $160.2 million, the company said, adding that the vaccine had been evaluated in studies involving more than 40,000 people from 15 countries around the world with up to six years of follow-up data from large-scale investigations that included Puerto Rico as a study site.

Dengvaxia was first licensed in December 2015 and has been approved by regulatory authorities in 19 countries for use in endemic areas in persons ranging from 9 to 45 years of age. The vaccine was licensed based on the results of two large phase III trials. An experiment called CYD14 was conducted at sites in five countries in Asia, and the CYD15 trial at sites in five countries in Latin America. Together, those studies included more than 30,000 participants ages 2 to 16. The efficacy of the vaccine against laboratory-confirmed dengue, measured for 12 months after the last dose and pooled across both trials, was 59.2 percent in the year following the primary series, and 79.1 percent against severe dengue. Efficacy varied by infecting serotype, age and serostatus. The results were published in 2014 and 2015.

Vaccine confidence drops

VRBPAC's examination took place as reports continued to swirl regarding trouble in the Philippines. In February 2018, the Public Attorney's Office of the Philippines said it was taking legal action against the company over Dengvaxia. The office filed a lawsuit against the firm to demand compensation of up to PHP4.2 million (US$80,332.57) on behalf of the parents of Anjielica Pestilos, a 10-year-old girl the agency claims had died as a result of receiving its dengue vaccine. Word from the PDOJ came late last week. (See BioWorld, Dec. 13, 2017, and Feb. 13, 2018.)

Sanofi responded promptly to the first Philippine claims and has continued to defend Dengvaxia. "The University of the Philippines-Philippine General Hospital expert panel confirmed that there is currently no evidence directly linking the Dengvaxia vaccine to any of the 14 deaths," the company told BioWorld in a statement. "In Dengvaxia clinical trials conducted over more than a decade and more than 1 million doses of the vaccine administered, no deaths causally related to the vaccine have been reported to us."

The company stood by the vaccine's efficacy, too, and declined requests from the Department of Health to refund the government for the used doses of Dengvaxia and financially support an indemnification fund for the more than 800,000 Filipino children ages 9 and older who had been inoculated with Dengvaxia. Sanofi said that agreeing to refund the used doses of Dengvaxia "would imply that the vaccine is ineffective, which is not the case," and gave the same reason for not supporting the indemnification fund.

The Philippine controversy put a serious dent in the public's faith, as measured by the Vaccine Confidence Project, led by the London School of Hygiene and Tropical Medicine. A poll of 1,500 people had 93 percent agreeing strongly that vaccines are important in 2015, dropping to 32 percent last year.