How the Dengvaxia Scandal Might Destroy a Good Vaccine
On April 4, 2016, the Philippines became the first country in the world to launch a mass immunization program using the first vaccine against dengue, a disease that afflicts over 200,000 and kills more than 1,000 Filipinos a year.
The data from the efficacy studies was very good: Over 90% decrease in hospitalization due to severe dengue among those vaccinated. With unprecedented efficiency, funds were appropriated and released to fund the vaccine drive. The fact that the mass vaccination program was approved prior to the official release of WHO recommendations was viewed with some suspicion among health experts. In addition, it was an election year, and administration candidates were shown schoolchildren being vaccinated for photo opportunities. Over 830,000 elementary school children in Grade 4 or older were inoculated during the mass vaccination drive.
On November 29, 2017, Sanofi, the maker of the vaccine, announced that it was proposing a label change to reflect that the vaccine could increase the risk of hospitalization for severe disease in those who had not been previously infected by dengue. This announcement triggered mass panic, especially among the parents of the children who were vaccinated. Finally, on Dec 5, 2017, citing safety concerns, the Philippine FDA withdrew the approval of the vaccine.
The Philippine dengue vaccine experience represents a case study in how well-meaning safety and vaccine advocates can be caught up in a political storm and inadvertently harm vaccine programs and expose vulnerable populations to risk.
Meanwhile, accusations flew thick and fast between former Department of Health officials, with reports of improper contact between the former health secretary Dr. Janette Garin and Sanofi officials prior to the inception of the vaccination program, despite denials from the former. Amidst a media firestorm, vaccine advocates and local medical societies raced to release statements in an attempt to salvage an otherwise useful vaccine, which had now become collateral damage in a high-risk game of politics.
Over 3.9 billion people live in countries at risk for dengue, a mosquito-borne virus. Ironically, the first severe dengue outbreak was described in the Philippines in 1953. It is an unusual disease, with four distinct strains, or “serotypes” of the virus. Infection with one serotype confers lifelong immunity to that strain, but paradoxically confers increased risk of severe disease to subsequent infection with another serotype.
Clinical symptoms of dengue include fever, headache, muscle aches, and a rash. Severe dengue can cause uncontrolled bleeding, a drop in blood pressure, and death. Only one out of four persons who are infected with dengue develop symptoms, and not all will need hospitalization. It is difficult to gauge who has been previously infected, and is therefore more likely to develop severe disease. In dengue-endemic countries such as the Philippines, nearly 90% of children at age 9 have been infected with at least one strain of dengue, and are at risk for developing severe disease.
The challenge in developing a vaccine for dengue lies in ensuring immunity to all four serotypes. The current vaccine, Dengvaxia, contains a mixture of all four serotypes. However, not all persons who receive the vaccine develop antibodies against all four serotypes, and some develop immunity to only three or less of the vaccine serotypes. Vaccinating a person who has never had dengue can be harmful if full immunity to all four serotypes is not achieved. This is because it may set up a patient up for severe dengue when they would otherwise not have yet been “primed” for severe infection by an initial dengue infection. On the other hand, a person who has had at least one dengue serotype infection is already at risk for severe disease, and so vaccinating that person will not harm them, and will decrease the risk of severe disease if even just one serotype “takes.”
The breakthrough dengue vaccine does not work like a traditional vaccine, which typically prevents or reduces the risk of the target disease. Instead, it is meant to reduce the risk of severe dengue infection. And it does this very well. In two phase III or clinical efficacy trials involving 30,000 patients, it decreased the risk of hospitalization for severe dengue by more than 90% in children 9 years old and older. Surprisingly, even previously uninfected patients seemed to be protected from severe disease in the first 25 months of the trial. With this in mind, Sanofi did not recommend blood testing for dengue prior to giving the vaccine, since both seropositive (with blood evidence of previous dengue infection) and seronegative (without blood evidence of previous dengue infection) children seemed to be protected.
ILLUSTRATION Jas Serrano
Some safety advocates led by eminent epidemiologist Dr. Antonio Dans and world-renowned dengue researcher Scott Halstead pointed out at that time that there appeared to be an increased risk of hospitalization among those younger than 9 years old, and that a “safety signal” with a possibly increased risk of hospitalization was present in seronegative children. This “safety signal” became the subject of intense debate between vaccine and safety advocates in traditional and social media.
It was one thing on top of another: complexities in understanding how the vaccine worked, highly charged political issues surrounding the vaccination program, the uncertainty. This all resulted in fewer people taking the vaccine, not just through the mass-administration program by the government, but also among private patients.
Safety advocates were vilified for having gone public with their safety concerns over an otherwise effective vaccine, and were accused of undermining the vaccination drive. In the meantime, even vaccine advocates also had misgivings about the propriety of the mass administration program, especially since the mass immunization campaign was approved prior to advice from the World Health Organization (WHO). A few weeks later, WHO (through its Strategic Advisory Group of Experts) released a conditional recommendation that it was appropriate to use the vaccine in countries where the seroprevalence, or proportion of the population with evidence of previous dengue infection, was more than 70%. Since the Philippines falls well within those parameters, the DOH officials took this as a positive sign and continued the program.
A year and a half later, Sanofi, citing new long-term safety data, announced a label change, affirming the vaccine’s efficacy, but recommending that the vaccine not be given to persons who had not had previous dengue infection. It did not release the actual data for scrutiny, and so there was much speculation of harm and even deaths in patients. Safety advocates felt vindicated, and went on a media blitz condemning the undue haste in the implementation of the mass vaccination program, decrying that politics had put the lives of hundreds of thousands of children at risk.
As distraught parents raised a huge outcry demanding answers, former and current health officials started pointing fingers at each other, and partisan legislators and government officials vowed to get to the bottom of the mess. Nearly every death in a child who had previously been given the vaccine was attributed to the inoculation, despite the fact that there were no deaths seen in the initial trial data, some timelines were untenable, and it was it not clear whether a particular child had previously had had dengue infection or not.
As the media and civil society called for blood, Sanofi belatedly organized a press conference to share the findings: there were no deaths at 72 months of follow-up in either seronegative or seropositive patients from the original phase 3 trial; the vaccine continued working well for seropositive patients, but the vaccine lost its efficacy in seronegative patients. The safety signal that was pointed out by safety advocates in seronegative patients persisted. It was not statistically significant, meaning the possibility of harm is not certain, but given the loss of efficacy in seronegatives, the label change was needed to reflect this new finding. It was too little, too late. Explanations from vaccine advocates and professional societies that attempted to calm the panic by stating that the actual children at-risk were only about 10% of the vaccinated population and therefore not the entire cohort were met by the public with suspicion, ridicule and an accusation that they were covering for the previous government and Sanofi. Despite clear benefit when used correctly, the Philippine FDA withdrew approval of the vaccine while the investigations continued.
The breakthrough dengue vaccine does not work like a traditional vaccine...Instead, it is meant to reduce the risk of severe dengue infection. And it does this very well.
Vaccines are still recovering from the damage unleashed by the now-discredited link to autism. In an increasingly connected age, false or misunderstood claims about safety, efficacy, and harm can be magnified and do substantial harm to public health. The Philippine dengue vaccine experience represents a case study in how well-meaning safety and vaccine advocates can be caught up in a political storm and inadvertently harm vaccine programs and expose vulnerable populations to risk. Part of the problem is that the discussions between these groups were highly technical, due to the complicated nature of the dengue vaccine and the disease itself. Both social media and traditional media misinterpreted many of the discussions. Unfounded accusations were hurled on both sides. Nevertheless, the bulk of the blame will likely fall on Sanofi and the politicians and officials from the previous administration who willfully ignored established norms in the conduct of mass vaccination programs. Before going on to mass vaccination programs, most vaccines after approval are typically used in individual patients where risk can be managed on a one-on-one basis, and parents and doctors can discuss the overall benefits of the vaccine with close monitoring. An industry standard Phase 4 post-marketing study is usually sponsored by the manufacturer on these early patients to watch out for any adverse effects that were not detected in the initial trials. Perhaps at best, the health officials who were responsible for implementing the mass vaccination program could claim that given the excellent data and apparent absence of harm, they were anxious to reap the benefits for Filipinos. However, this reasoning falls flat given the undue haste in which the program was implemented especially during an election year.
As for the vaccine itself, its future remains uncertain as health experts continue to debate on how to use it properly with the newly available data. Do children need to be tested for past dengue infection before they are given the vaccine? Or is a reasonably high seroprevalence (proportion of the population with blood evidence of past infection) sufficient? While a past dengue infection can be diagnosed with a blood test, the current tests on the market are used for someone with symptomatic disease, and are not optimized for detecting past infection. A new and highly sensitive test has been developed, but will not be available for wide use until it is cleared by authorities, a process than usually takes one to two years.
From a public health perspective, the decision to use the vaccine is a much easier one. In highly endemic settings such as the Philippines, where nearly 95% of children above 11 years old have evidence of past dengue infection, the risk-to-benefit ratio is clear. Sanofi estimates that for every 1,000 vaccinated seropositive children, the total number of hospitalized children is reduced by 15 cases, and severe dengue cases by 4. For every 1,000 seronegative children who are vaccinated, hospitalizations are increased by 5 cases, and severe dengue cases increase by 2. Therefore, if used in 1,000 Filipino children above 11 years old, about 950 would be seropositive and benefit from the vaccine. while only 50 would be seronegative. The benefit vastly outweighs the harm.
These policy decisions where a subset of patients may be sacrificed for the greater good is unacceptable to safety advocates. Vaccine advocates counter that it is akin to sacrificing 95% of patients who would benefit for the safety of 5%. These policy discussions where life and death are treated as cold numbers used to happen behind closed doors, with a general consensus on how to proceed. In this new age of information, policy makers need to educate the general public on how these decisions are made, and they need think out of the box on how to make these difficult choices palatable. Otherwise a stalemate will occur, we lose vaccines, and we all lose.