What Now, Dengvaxia?

Close to a million children in the Philippines have been vaccinated with Dengvaxia, the world’s first vaccine against dengue. However, what seemed to be a  breakthrough in curbing the deadly disease has turned into a threat of a serious illness in a subset of patients vaccinated

By Gelyka Ruth R. Dumaraos

French pharmaceutical company Sanofi Pasteur, makers of Dengvaxia, revealed last November that new analysis of long-term clinical trial data showed some differences in the effect of vaccine depending on prior dengue infection.

The new analysis was based on up to six years of clinical data, evaluating long-term safety and efficacy of Dengvaxia in people who had been infected with dengue prior to vaccination and those with no previous infection or exposure.

In those with previous infection, the new analysis confirmed the vaccine’s protective benefit against dengue fever; but for those not previously infected by dengue virus, the vaccine could do more harm than good. More cases of severe disease could occur following vaccination, as what seems to be suggested in newspaper reports of a few reported deaths of children vaccinated with Dengvaxia within six months previously.

“These findings highlight the complex nature of dengue infection. We are working with health authorities to ensure that prescribers, vaccinators and patients are fully informed of the new findings, with the goal of enhancing the impact of Dengvaxia in dengue-endemic countries,” said Dr. Su-Peing Ng, Global Medical Head of Sanofi Pasteur.

With this new analysis and the recent deaths of a few vaccinated children, the Department of Health (DOH), which started administering the vaccine a year ago to about 830,000 children, placed the dengue vaccination program on hold while the consultation between health experts are ongoing.

It can be recalled that in 2016, DOH launched the dengue vaccination initiative in three highly endemic regions (Regions III, IV-A and NCR) with over 730,000 individuals receiving at least one dose of the vaccine. Most of these came from public schools after DOH tied up with the Department of Education (DepEd) to expedite the implementation of the dengue vaccination program.

Warned by health experts

Amidst the abrupt implementation was the call made by health experts to halt the execution of the program due to inconsistencies of the available data to support the vaccine’s efficiency to curb dengue.

In November 2016, health experts voiced out the impending risk of DOH’s goal to vaccinate over one million children. The warning, expressed during hearings of the Congress Committee on Health, came amidst questions about cost-effectiveness, safety and ethics. Health experts reiterated that the vaccine has a “lingering uncertainty.”

The joint statement were made by  Antonio L. Dans, MD, MSc academician of the National Academy of Science and Technology; Leonila F. Dans, MD, MSc professor at the University of the Philippines College of Medicine; Anthony Leachon, MD, independent director, Philhealth (Representative of the Monetary Board); Ana Maria R. Nemenzo of Woman Health; and Mercedes Fabros, chairperson, Alternative Budget Initiative.

They pointed out that the evidence from the manufacturer’s trial reveals that there may be a paradoxical increase in the incidence of severe dengue for the rest of their lives, which may start a few years after they get vaccinated.

“This danger especially applies to children who have never had dengue fever before,” they said.

They cited one study involving Asian children aged 2-14 years; vaccination increased the incidence of severe dengue by 400 percent on the 3rd year after vaccination.

“Until these trials are completed, we recommend, as many other groups have, that children should be tested for past dengue infection before vaccination,” the statement reads.

The group noted that a cost-effectiveness study was done but was funded by pharmaceutical company and not an independent body. This suggests that the study was done with bias and with strategies to minimize the expenses.

Aside from this, the program cost is also a thing to consider. It highlighted that the whole program cost the Philippine government PhP 3.5 billion, for just one million children in only three regions—a mere 1 percent of the population.

Health workers and communities also had inadequate preparation, which is far from the regulation of 12-18 months preparation.

“Health workers need to be trained to give the vaccine and answer questions from parents and children,” the group adds. “Referral systems for adverse events need to be activated and tested, a research protocol for monitoring on adverse events should be in place. These could not have been done in 26 days.”

The statements note that parents, teachers, and health workers were not fully informed about the vaccine.

WHO’s recommendation

Amidst all the warnings, then DOH Secretary Janette Loreto-Garin said that this immunization program was in line with the recommendation of WHO for mass vaccination in highly endemic countries.

WHO’s recommendation was that the vaccine, which is to be given in three doses, must only be used in areas where at least 70 percent of the community had already been exposed to the virus and must be given to children 9 years of age and older.

However, on December 5, 2017, WHO stressed that DOH decided on the implementation even before they issued the advisory. It clarified that WHO did not recommend the dengue vaccine to the country’s immunization program.

“Rather, WHO outlined a series of considerations national governments should take into account in deciding whether to introduce the vaccine, based on a review of available data at the time, along with possible risks,” the organization said.

Children’s death

As of January 11, Dengvaxia has been linked to the deaths of five children; all of them were inoculated with the vaccine.

One of them is an 11-year-old boy from Bataan, who was said to have died 12 hours after experiencing headache and fever, according to a report from Inquirer.net.

Parents and guardians of the children have also sought help from the Public Attorney’s Office (PAO) for legal action against the authorities who ordered the vaccination. According to forensic experts from PAO, there is a pattern in the death of the five children, characterized by massive bleeding in their organs.

What now?

In another statement, Sanofi Pasteur still underscored the benefit of Dengvaxia for individuals with record of previous infection which can protect them up to six years since their first injection.

“In individuals who have not been previously infected by dengue virus, there is an increased risk of hospitalization for dengue and severe dengue, predominantly the Grade I or II Dengue Hemorraghic Fever (DHF),” Ruby Dizon, Sanofi Pasteur medical director said.

As Sanofi’s latest advisory about Dengvaxia create scare among parents and the Filipino public, DOH has also conducted a Task Force for the management of concerns related to the school-based immunization initiative using the tetravalent dengue vaccine.

The Task Force is composed of top management officials of the DOH Central Office, officials of affected regions, the Food and Drug Administration, PhilHealth, and the National Children’s Hospital.

“This Task Force will conduct a thorough review of the dengue vaccination initiative which started in March 2016 and the new evidence on safety provided by Sanofi,” current Health Secretary Francisco Duque III declared. “This shall guide the Department of Health in responding to the safety concerns relevant to the use of this vaccine and how to proceed with the dengue program to ensure safeguards and prevent similar incidents in the future.”

DOH also reiterated its commitment to monitor all children who were vaccinated by Dengvaxia, as they hired thirty officers to lead the surveillance to regions where the vaccine was administered. This will be done in five years.

DOH also said that PhilHealth is ready to cover the expenses of any child who may be hospitalized for severe dengue after vaccination. PhilHealth’s dengue case rate can cover up to PhP 16,000 for severe dengue which includes hospital and physician fees.

Demand for refund

Early this year, the Food and Drug Administration (FDA) imposed an administrative fine of PhP100, 000 on the French pharmaceutical giant due to failure of complying with post-marketing authorization requirements for Dengvaxia. They also suspended the sale of Dengvaxia for a year.

The FDA, a regulatory agency under the Department of Health (DOH), also imposed a P100,000-administrative fine on Sanofi for failing to comply with post-marketing authorization requirements for the vaccine.

In response to a demand later coming from the DOH, Sanofi has agreed to refund the DOH its payment made for more than PhP 1 billion-worth of unused Dengvaxia. However, Sec. Duque said that the DOH will demand a full refund of the PhP 3.5 billion budget allotted for purchasing Dengvaxia. He will also ask Sanofi to set up a fund to cover the children’s hospitalization and medical treatment should they acquire severe dengue.

“The DOH assures the public that it is serious in carrying out its mandate to always guard the health and well-being of its constituents. Thus, it shall ensure that vaccines are always safe and effective to optimize its health benefits,” Sec. Duque said.

“Referral systems for adverse events need to be activated and tested, a research protocol for monitoring on adverse events should be in place”

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