A Clinical Trial By Any Other Name …

Mosquito borne illnesses pose a significant threat to human health. In the past several years, drug makers have begun developing vaccines for viruses like dengue, Zika, and chikungunya, all of which pose unique risks to billions across the globe. One of them just went terribly, terribly wrong.

Sanofi Pasteur, the vaccine division of the multinational pharmaceutical company Sanofi, has the problem. In a press release distributed last Wednesday, Sanofi reported that new analysis of long-term safety data for its dengue vaccine, Dengvaxia®, revealed that the vaccine may not be safe or effective for individuals who have had no prior dengue infection. The Philippines was the first country in Southeast Asia to approve the vaccine. It has since been administered to more than 600,000 schoolchildren in three highly-endemic regions of the country in the world’s first public dengue immunization program.

The vaccine received regulatory approval in the Philippines in December 2015, and the school program took effect just over three months later. Numerous local public health officials have claimed that the program was initiated too hastily. Susan Pineda Mercado, the former undersecretary of the Philippine’s Department of Health (DOH), has characterized the program in a Facebook post as “the biggest government funded clinical-trial-masked-as-a-public-health-program scam in the history of the DOH.”

Because schoolchildren weren’t screened for prior dengue infection before getting vaccinated, an unknown number of them are at greater risk for developing life-threatening dengue fever. There’s no reliable way to know who these children will be, and they will carry this risk for the rest of their lives. How did this happen, and what can be done to ensure it does not happen again?

The dengue virus manipulates the immune system in a counterintuitive manner called antibody-dependent enhancement. This is very problematic for people who live in areas of the world where the four subtypes of the dengue virus known to cause disease are endemic. Upon a first dengue infection, the body produces neutralizing antibodies which protect against future infection of that particular variant. But in addition to these protective antibodies, the body produces a small amount non-neutralizing antibodies, which are believed to enhance the ability of other subtypes of the virus to invade and infect cells.

A second infection with a different dengue strain is a lot of trouble for anyone who had a first bout of the disease. While a first dengue infection is usually no worse than the flu, secondary dengue infections have been known to cause severe hemorrhaging, dangerously high fevers, heart inflammation and death. Giving a vaccine to someone who’s never had dengue fever before is thought to cause this antibody enhancement phenomenon, rendering vaccination neither safe nor effective.

Indeed, Sanofi’s recent analysis of six years of patient data demonstrates that Dengvaxia® only protects individuals who have been previously sick with dengue fever. In its analysis the vaccine’s clinical trial safety data, the World Health Organization’s Strategic Advisory Group of Experts (WHO SAGE) recommended that the vaccine only be administered to children who live in regions where it’s expected that the majority of people have been sick with dengue fever before. WHO SAGE didn’t recommend that potential vaccine recipients be immunologically screened for prior dengue infection. Even if the DOH relied on the best available epidemiological reports on dengue fever incidence in the country, it is reasonable to expect that some children who had not had dengue were vaccinated. If they get sick with a different strain of dengue fever later in their lives, they could become lethally ill.

WHO’s vaccination strategy put a subset of the Philippine population, that had not been sick with dengue before, at risk for a potentially lethal infection. This raises an important ethical quandary about whether it is permissible for a public health entity to put a portion of the population at risk of serious harm for the greater good of decreasing the burden of disease. Sanofi is proposing that regulatory agencies change their labeling of Dengvaxia® as a result of the worrisome outcome of the pilot program in the Philippines, but many children who already received the vaccine could suffer from severe consequences later.

It is unclear how what epidemiological methods were used to determine where to administer the vaccine. Were the parents of vaccine recipients informed of the potentially life-threatening adverse events? Did Sanofi’s safety data robustly capture the risk to dengue-naïve individuals, and was information about this risk delivered to the appropriate officials? And why did Sanofi market – and the Philippines’ FDA approve – a vaccine about which there are such grave safety concerns?

WHO is completing a detailed review of Sanofi’s safety and efficacy trial data, which may clarify the situation. Vaccination is a public health triumph, and it is encouraging that Dengvaxia® could reduce the burden of dengue fever. Efforts to reduce the global burden of mosquito borne illness ought to continue. But there are a host of ethical questions – about informed consent, adequate oversight of this program, and most crucially the justice of putting some at severe risk in order to protect others from moderate risks – that need to be answered quickly and transparently.

Kelly McBride Folkers, Division of Medical Ethics, NYU School of Medicine

Arthur Caplan, Division of Medical Ethics, NYU School of Medicine


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  1. The phenomena of immune tolerance and its disturbances are very poorly recognized let alone understood, especially during a pregnancy. For instance, there is a continuing, low-level voiced expectation that a universal influenza vaccine is possible. Finally, the original “shingles” vaccine had documented evidence of low level effectiveness for 5 years (as compared to the effectiveness of the Tetanus vaccine). So, does this mean that a certain number of vaccine recipients will eventually have shingles but 10-20 years after the immunization? This outcome would represent potentially lethal consequences. We have no data for shingles vaccine effectiveness for more than 5 years after the original vaccination, but we now have a new vaccine … just to be sure … not!

    The uncertainty principle continues to plague our best efforts.