What went wrong with the breakthrough dengue vaccine? / by Karen Frances Eng

How a perfect storm of politics, panic and public health misinformation may have once again derailed a vaccine that can save lives.

In April 2016, the Philippines made headlines around the world when its Department of Health vaccinated 830,000 elementary schoolchildren with the world’s first vaccine against dengue, a potentially life-threatening tropical mosquito-borne disease that infects nearly 400 million people per year, with 500,000 severe cases worldwide.

One year later, this ambitious public health initiative had became a “scandal” — causing panic among parents similar to the MMR/autism crisis two decades ago. In December 2017, citing safety concerns, the Philippines FDA withdrew the approval of the vaccine, called Dengvaxia. How was such a promising vaccine abandoned so quickly?

Here, physician Edsel Maurice Salvana, a TED Fellow, explains how and why important vaccines get caught in the crossfire of politics, public policy, and public knowledge — to the detriment of the health of citizens.

Illustration by  Dan Bejar

Illustration by Dan Bejar

What’s the source of the current panic in the Philippines?

A perfect storm of political, policy and communication factors caused the panic. To start, 2016 was an election year, so the vaccination program may have been rushed to be used as prop in political campaigns. The vaccination program was launched shortly after the vaccine’s approval — unusual because such programs typically occur after several years of use in private practice as well as post-marketing studies that collect safety data. Meanwhile, at the time of the vaccination launch in the Philippines, the World Health Organization (WHO) also hadn’t yet approved the vaccine at the time of mass vaccination (though it did several months later).

Mass vaccination also took place without blood testing — and the way dengue works, it’s safer to get the vaccine if you have had the virus at least once and have some immunity in your blood. But according to trial results, this risk was deemed minimal and could be minimized further by using it only in high-burden countries like the Philippines, where most people have had at least one dengue infection. Prior to launch, safety advocates were expressing misgivings about one safety risk: giving the vaccine to children who’d never previously been infected with dengue, also known as seronegative patients.

What was the crisis point?

Sanofi, the vaccine manufacturer, announced on November 29, 2017, that new data showed a loss of efficacy in seronegative patients over time and there was a small but increased risk of severe dengue in these patients, and it would be updating the product labeling to reflect this. Other countries who’d approved the vaccine took this new information in stride — but safety advocates in the Philippines launched a media campaign stating that Sanofi and the DOH had exposed 830,000 children to harm, calling it “the biggest government funded clinical-trial-masked-as-a-public-health-program scam of an experimental drug in the history of the DOH.”

This set off panic among parents of vaccinated children. Politicians and civil society groups accused Sanofi and former DOH officials of “genocide.” On December 5, 2017, with calls for investigation and public outrage mounting, the Philippine FDA suspended Dengvaxia from the market, pending the outcome of investigations. Note, though, that none of the other 18 countries that have approved the vaccine have suspended its use — although they did update their guidelines.

“The most severe damage done so far is the loss of the vaccine due to unnecessary panic.”

I have to agree with the safety advocates that the program seemed rushed for the election. I also think that in the light of the new data, we should avoid vaccinating seronegative patients as much as possible, to reduce harm. But the most severe damage done so far is the loss of the vaccine due to unnecessary panic.

How dangerous is dengue, especially to kids, and why is the vaccine so controversial?

Dengue can cause an unsafe drop in blood pressure and life-threatening bleeding. A little over half of symptomatic cases affect children, but in recent years, an increasing number of adults and adolescents are developing symptoms and dying from dengue.

There are four strains of dengue. If you contract one of the strains, the first dengue infection is usually relatively mild, and then you become immune to that specific strain for life — but if you have a subsequent infection with any of the other three strains, it will likely be severe, possibly life-threatening. Dengvaxia is designed to protect against those severe infections by inoculating the patient with all four strains. Trials showed that in patients 9 years and older, Dengvaxia can reduce instances of severe dengue by 90% and decrease the risk of hospitalization from dengue by 80%.

If you’ve already had dengue at least once, you’re already set up for severe dengue, so there’s no added risk if not all the vaccine’s strains are effective. However, someone who’s seronegative could face the risk of contracting severe dengue if any of the strains don’t take effect and they’re subsequently infected with one of them. This was the safety risk pointed out by advocates: it’s safest to give the vaccine to someone who’s already had at least one episode of dengue. Having said that, the actual risk of severe dengue to a vaccinated seronegative is THE SAME as the risk of an unvaccinated seropositive, or about 5 out of 1000 infected patients.

So why did authorities deem it safe to give the vaccine to so many children who’d not been tested for seronegativity?

The statistics indicated it was safe. Previous studies had shown that nearly 90% of Filipino children in the vaccinated age group had been previously infected with dengue, and the remaining 10% were likely going to get it in the next few years anyway. So from an overall perspective, the potential harm to seronegatives far outweighed the benefit to the seropositives.

Also, the initial 25-month study showed that even seronegatives were protected — so we didn’t think we’d start seeing any increases in severe dengue until 3 years after vaccination. Then, the new data from a 6-year follow-up study found that the efficacy of the vaccine in seronegatives disappeared. Hence the label change.

It’s important to note that whether or not all the vaccine’s strains take effect, Dengvaxia does NOT cause any known disease, including dengue.

There have been reports of vaccinated children dying, fueling the panic. But what percentage of the children who received the vaccinations died, and why? And is there any valid basis for fear that the vaccine may cause deaths?

There’s currently no evidence that the vaccine has caused any deaths. Long term follow-up of 30,000 children for up to 6 years failed to show any deaths in either seronegative or seropositive vaccine recipients.

In the cohort of 830,000 children from the mass vaccination program, about 14 deaths (0.002%) after vaccination are being investigated. Most of them seem to have died from severe dengue, although a few had comorbid conditions such as lupus and appendicitis. No link to the vaccine has been found so far.

The increased risk of severe dengue in seronegative patients translates to an excess risk of 2 severe dengue cases out of 1,000 seronegative patients. From a public health perspective, knowing that only a minority of the vaccinated children are seronegative — the vaccination is overwhelmingly helping children, not making things worse. Meanwhile, banning the vaccine denies the benefit of decreasing severe dengue risk by 90% in those children who have already had dengue.

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Source: https://fellowsblog.ted.com/what-went-wron...