"Bear in mind that the wonderful things you learn in your schools are the work of many generations, produced by enthusiastic effort and infinite labor in every country of the world. All this is put into your hands as your inheritance in order that you may receive it, honor it, add to it, and one day faithfully hand it to your children. Thus do we mortals achieve immortality in the permanent things which we create in common." - Albert Einstein

Monday, December 4, 2017

Lessons from Dengue: Due Diligence and Expertise Are Necessary for National Programs

When confronting an issue that involves the lives of millions of children as well as billions of cash, we expect leaders to exercise due diligence. It is assumed that our leaders will at least do their homework. The Dengue vaccine fiasco in the Philippines illustrates what is terribly wrong with its leadership. The Philippines has embarked on gigantic national programs on education, and this time, on health, without due diligence. The preliminary data on the efficacy of Dengvaxia have been available even before Aquino met with Sanofi on December 2015 in Paris, France. The data published in the New England Journal of Medicine on September 2015 certainly do not support a large scale vaccination without further studies.

One troubling aspect of the results involves the difference between individuals who have had been infected with Dengue and those who have not been. These are shown in the following tables:

Younger than 9 years

Older than 9 years

CYD14 and CYD15 are the current trials in Asia and Latin America, respectively. The Asia study is smaller but more troublesome is the small number of participants who have not been infected with Dengue (Seronegative). However, even with this sample, the lower and sometimes negative efficacy of the vaccine is an obvious warning sign. From these numbers, serious concerns regarding vaccinating seronegative individuals are already justified.

Scott Halstead of the Uniformed Services in the United States has long been critical of Dengvaxia. He noted earlier that the age profile of the trials looks similar to what has happened in Cuba decades ago, and suspected that the vaccine was sensitizing individuals who have not contracted dengue. In December 2016, Halstead and coworkers wrote, "We believe that the allocation of financial resources implementing the screening, in order to use this “imperfect” vaccine most efficiently and to optimize a beneficial outcome, is justified to avoid an eventual burden of vaccine enhanced disease in vaccinated seronegative individuals." Fast forward, in a paper recently published in Vaccine, Halstead vividly shows what he has been trying to say all this time.

Cuba had a dengue outbreak in 1977. Four years later, another outbreak occurred. Below is the age profile of severe dengue cases in 1981:

Above copied from
Vaccine. 2017 Nov 7;35(47):6355-6358. doi: 10.1016/j.vaccine.2017.09.089. Epub 2017 Oct 10.

The bar chart shown above shows hospitalizations are highest at the youngest age and decreases with age. Focusing on the age 3-14 years, and comparing the cases in these age groups to those of the clinical studies - one sees a very strong resemblance of the Havana data to the results of the Dengvaxia trials:

Top: Havana, 1981, 
Middle: Trial results (Vaccinated), 
Bottom: Trial Results (Placebo, no vaccination)
Above copied from
Vaccine. 2017 Nov 7;35(47):6355-6358. doi: 10.1016/j.vaccine.2017.09.089. Epub 2017 Oct 10.

The age profile for those who have been vaccinated is similar to that of Havana in 1981. In other words, introducing the vaccine has similar effects as the first epidemic. A second infection of dengue is often worse than the first one. The vaccine seems to serve as an initial infection to seronegative individuals such that if these individuals do get infected in the future, it will be more severe. On the other hand, the data on placebo children paint a clearly different age profile.

Thus, it is important that candidates for Dengvaxia are screened. What happened in the Philippines during the Aquino administration clearly did not consider these early warnings. The current administration of Duterte is basically crossing their fingers that the infection rate is about 90% before the vaccine was introduced limiting the number of seronegative 9-year olds to one in ten. Perhaps, this is true for some locations like Cebu where there is indeed a high incidence of dengue. But even in this setting, 15% -40% among 8-10 year olds still appear to be seronegative:

Above copied from
Incidence of Dengue Virus Infection in Adults and Children in a Prospective Longitudinal Cohort in the Philippines
Alera M.T., Srikiatkhachorn A., Velasco J.M., Tac-An I.A., Lago C.B., Clapham H.E., Fernandez S., (...), Yoon I.-K.
(2016) PLoS Neglected Tropical Diseases, 10 (2) , art. no. e0004337

It is true that mistakes happen and in matters of urgency, the potential of making the wrong decision even becomes higher. Sanofi and the previous administration are not necesarily criminally liable for these mistakes unless there are anomalies that occurred during deliberation and procurement of funds. However, there are important lessons to be learned. For programs that are so wide in scope and highly consequential, there is no substitute for due diligence and expertise. Leaders need to be fully informed and it is their responsibility to consult evidence-based research especially on matters that involve health and education. Unfortunately, leaders often go with fads without consulting what is already known. Without learning this important lesson, it is only a matter of time that similar errors are going to happen again and again.

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