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August 25, 2020

The Dengue Vaccine: A Cautionary Tale

 

 

As we anticipate the arrival of a fast-tracked and liability-free SARS-Cov-2 vaccine candidate, vaccine proponents and developers like Paul Offit and Peter Hotez have been notably reticent. It would be wise to consider why.

Both doctors have acknowledged previous failures in attempted coronavirus vaccines and have alluded to the issue of “antibody-dependent enhancement,” also called “pathogenic priming.” Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID), has also addressed this potential problem. Let’s examine how carefully these problems were examined in the past and how those lessons were or were not applied.

… causing this antibody-dependent enhancement which could potentially worsen the problem if you then were exposed to wild-type or natural virus.

Pathogenic priming

According to a 2009 article published in Expert Review of Vaccines, “The greatest fear among vaccinologists is the creation of a vaccine that is not only ineffective, but which exacerbates disease. Unfortunately, CoV vaccines have a history of enhancing disease, notably with feline CoVs.”

Dr. Paul Offit is Director of the Vaccine Education Center at Children’s Hospital of Philadelphia. In April, Offit reiterated the concerns about a SARS-CoV-2 vaccine in an interview with Dr. Zubin Damania (better known as ZDogg). In the interview (timestamp 11:53), Offit addressed problems that surfaced with the dengue vaccine, Dengvaxia:

So you have the neutralizing antibodies and you have the binding antibodies. You want to make sure that the quantity of the neutralizing antibodies that you have, and the persistence of those antibodies, is much greater than the binding antibodies. Because the binding antibodies could be dangerous and cause something called antibody-dependent enhancement. 

And we’ve seen that. We saw that with the dengue vaccine…. The dengue vaccine, in children who’ve never been exposed to dengue before, actually made them worse when they were then exposed to the natural virus. Much worse. Causing something called dengue hemorrhagic shock syndrome. Children died because, vaccinated children who were less than 9 years of age who had never been exposed to dengue before were more likely to die if they’d been vaccinated than if they hadn’t been vaccinated…. And that was because of antibody-dependent enhancement. 

Because what happens is, those binding antibodies, they don’t neutralize the virus, they just bind to it. Now we have on our cells something called an Fc receptor, which then can allow the antibody, will bind the antibody and bring the virus into the cell. It’s actually a more efficient way for the virus to enter the cell than otherwise. So what you’re doing by creating all these antibodies is potentially causing this antibody-dependent enhancement which could potentially worsen the problem if you then were exposed to wild-type or natural virus.

But in the end, estimates are that more than 100,000 Philippine children received a vaccine that health officials say increased their risk of a severe and sometimes deadly condition.

Gatekeeper failures

If we are to learn from past vaccine failures, it seems important to examine what went wrong with the introduction of the dengue vaccine. This NPR article from May 2019 lays it out in a nutshell:

The goal was to save thousands of kids’ lives and prevent an estimated 10,000 hospitalizations over a five-year period. But in the end, estimates are that more than 100,000 Philippine children received a vaccine that health officials say increased their risk of a severe and sometimes deadly condition. In addition, other children who received the vaccine may have been endangered because, their parents alleged, they were not in good health. The French pharmaceutical company Sanofi Pasteur spent 20 years — and about $2 billion — to develop Dengvaxia. The company tested it in several large trials with more than 30,000 kids globally and published the results in the prestigious New England Journal of Medicine.

Despite 20 years of research and multiple clinical trials, Dengvaxia caused injury and death among the very population it was designed to serve. How did this vaccine make its way past all of the gatekeepers who were put in place to ensure a “safe and effective” candidate? Why, in 2016, did a panel at the World Health Organization (WHO) go ahead and declare Dengvaxia safe and recommend it for children aged 9 and older? Was the scientific community unaware of potential risks and shortcomings? Did the deaths of children in the Philippines come as a complete surprise?

They shouldn’t have.

Dengue virus (DENV), which is transmitted by mosquitoes, infects an estimated 100 million people annually. The virus has four serotypes. Exposure to one serotype generally causes mild illness and provides lifetime immunity from infections of the same serotype. However, subsequent exposure to a second dengue serotype can result in more severe presentations that can lead to hemorrhagic fever, shock and even death.

Early signs of a problem with the dengue vaccine surfaced back in 2012 when researchers observed that it protected against three of the four dengue virus serotypes but failed to provide protection against the fourth—serotype 2—then the most prevalent. In July 2014, an article published in Science (entitled “Dengue vaccine trial poses public health quandary”) described the emerging dilemma:

The first large efficacy trial of a vaccine for the tropical disease dengue has returned puzzling results. The vaccine, developed by Sanofi Pasteur, proved safe, had an overall efficacy rate of 56.5%, and reduced cases of severe disease by 88.5%. But it had limited efficacy against dengue 2, one of four dengue virus serotypes in circulation [emphasis added]…. In considering the vaccine for national immunization programs, public health officials will have to carefully weigh the benefits of reducing that burden against the yet-to-be-determined cost of the vaccine and its limited efficacy against dengue 2. The results also pose quandaries for scientists. The trial showed that a standard in vitro assay used to predict the level of immunity in vaccines correlated poorly with actual protection from disease.

Retired dengue expert, Scott Halstead, asserted that the Dengvaxia vaccine should not be given to children who had never had a dengue infection, as it might mimic the effect of an initial infection and, therefore, make children vulnerable to a more severe presentation later. In fact, a 2011 paper had already issued a clear warning about the need to avoid antibody-dependent enhancement:

Serious disease can be seen during primary infection but is more frequent following second infection with a serotype different from that of a previous infection…. The high level of virus replication seen during both secondary infection with a heterotypic virus and during primary DENV infection in late infancy is a direct consequence of antibody-dependent enhancement of replication. This enhanced virus replication is mediated primarily by preexisting, nonneutralizing, or subneutralizing antibodies to the virion surface antigens that enhance access of the virion-antibody complex to FcγR-bearing cells. Vaccines will need to provide long-term protection against each of the four DENV serotypes by inducing neutralizing antibodies, and live, attenuated and various nonliving virus vaccines are in development.

In all, vaccine manufacturer Sanofi Pasteur conducted three clinical trials “involving more than 35,000 children between the ages of 2 and 16 years in Asian–Pacific and Latin American countries.” One of the trials, called CYD14, took place in five Asian-Pacific countries and focused on 2- to 14-year-olds. Here is some of what Sanofi learned from that trial, reported in 2015 in the New England Journal of Medicine:

In the CYD14 trial, among participants younger than 9 years of age who were hospitalized for dengue, severe disease (according to the criteria of the independent data monitoring committee) occurred in 8 of 19 participants in the vaccine group and in none of 6 participants in the placebo group (relative risk could not be calculated) [emphasis added].

By April 2019, the deaths of 600 children were under investigation in the Philippines in connection with Dengvaxia.

Fallout from the Philippines

Singapore’s environment minister Vivian Balakrishnan was less than impressed by the clinical trial results in Southeast Asia. The vaccine’s limited protection against dengue serotype 2 (as well as serotype 1) prompted him to declare that Dengvaxia was “not good enough” to be added to his country’s national vaccination program.

The nation of the Philippines was not so lucky. By December 2017, when the Philippines Department of Health belatedly suspended Dengvaxia’s use, nearly 734,000 children aged 9 and over had received one dose of the vaccine as part of a program that cost nearly $70 million. By April 2019, the deaths of 600 children were under investigation in the Philippines in connection with Dengvaxia.

When, that same month, the U.S. Food and Drug Administration (FDA) approved the use of Dengvaxia, the U.S. press immediately got to work on a new narrative, illustrated in NPR’s reporting. Describing lessons learned from the tragedy in the Philippines, NPR flagged the issue of waning confidence in vaccines (so-called “vaccine hesitancy”):

Since the Dengvaxia controversy, the confidence in vaccines among Philippine parents has plummeted from 82% in 2015 to only 21% in 2018, a recent study found. Over that same time span, the proportion of parents who strongly believe vaccines are important has fallen from 93% to 32%. As result, vaccine coverage for childhood diseases in the Philippines, such as the measles, has dropped, WHO says. And the Philippines is now facing a large measles outbreak, with more than 26,000 cases and more than 355 deaths during 2019. Here in the U.S., the approval of the vaccine — to be used in Puerto Rico, the U.S. and British Virgin Islands and Guam — comes with an important restriction: Doctors must have proof of a prior dengue infection to ensure the vaccine will not pose any risks to the child. That’s a safeguard Philippine families never had.

Observe how the NPR article tries to override healthy skepticism with fear about measles. In the Philippines, people were reassured that Dengvaxia was safe for their children, and then children died. Understandably, they became wary not only of this vaccine but began to question others. Now, their growing skepticism is being blamed for a measles outbreak and other deaths. We will likely start to see new stories about dengue outbreaks, coinciding with attempts to restore confidence in Dengvaxia and other dengue vaccine candidates.

SARS-CoV-2 and lessons learned (or not learned)

Did the scientific community ever revisit whether Dengvaxia made sense, or did corporate interests just apply another band-aid to their profitable solution? Most of us have never considered the broader potential repercussions of a live, attenuated dengue vaccine, but the WHO has:

The primary environmental risks of live dengue vaccines relate to their capacity to be spread from human to human by vector mosquitoes, and the risk that prolonged or repeated cycles of replication in mosquitoes could permit reversion to virulence.

The WHO hastens to add that “live vaccines currently under development have been shown to replicate poorly both in vaccinees and in mosquitoes, such that the risk for transmission by the mosquito vector is very low,” but we’ve heard similar reassurances before, with often troubling results.

Consider where we are with regard to mosquito-borne illness—despite decades of research—and compare it to the lessons we continue to learn. For example, a March 2019 article in Nature reached disturbing conclusions when discussing the “effects of dengue immunity on Zika virus [ZIKV] infection.” Scientists introduced large dengue vaccine clinical trials in Brazil, and only THEN pondered the possibility that “the unexpected appearance of congenital disease following the introduction of ZIKV into the Americas raised the possibility that cross-reactive antibodies produced during a prior exposure to DENV worsen the severity of Zika through similar mechanisms to those that increase the severity of dengue after a second DENV infection.”

Now, we are at a pivotal point with SARS CoV-2 vaccines. Clinical trial data are coming in, and concerns are being raised. The Oxford-AstraZeneca vaccine candidate demonstrated some troubling results in animal models, as all of the vaccinated monkeys became infected upon viral challenge and some became clinically ill. Based on these initial findings, Oxford’s vaccine would not stop disease transmission and would not, therefore, provide a public health benefit. Since all the animals were euthanized seven days post-challenge, we don’t know what other issues may have developed.

Meanwhile, Moderna is working hard to downplay safety concerns about its mRNA vaccine, claiming “No serious adverse events were noted, and no prespecified trial halting rules were met.” However, a WIRED article, entitled “Covid-19 vaccines with ‘minor side effects’ could still be pretty bad,” furnished a more candid picture: 

According to the press release from May, there were no serious adverse events for the people in that particular dosage group. But last week’s paper shows the full results: By the time they’d had two doses, every single one was showing signs of headaches, chills, or fatigue, and for at least 80 percent, this could have been enough to interfere with their normal activities. A participant who had a severe reaction to a particularly high dose has talked in detail about how bad it was.

History clearly demonstrates that trusting the experts does not always pan out, as seen with the “profit now, apologize later” approach that Big Pharma and governmental agencies often use for product approval. Where Dengvaxia is concerned, time will tell whether new restrictions on who can receive it will make a difference in terms of either consumer reassurance or product safety. With SARS-Cov-2 vaccines, THIS is our opportunity to carefully review the evidence and make sure the cure is not worse than the disease.

 

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