Lessons (Not) Learned From a Vaccination Campaign Catastrophe

In many places around the world, the leading cause of illness is the mosquito borne viral disease dengue, caused by the dengue virus. In past decades, its frequent outbreaks in many countries triggered tremendous investments and research efforts in the international community to develop vaccines against dengue.

Dengvaxia, which is the first and only vaccine that was approved for mass vaccination, resulted in disastrous outcomes in the Philippines. Yet, the Food and Drug Administration (FDA) still approved Dengvaxia for children aged 9 to 16. Why? Did we learn any lessons from history?

What Is Dengue?

Dengue is a vector-borne disease caused by dengue viruses and predominantly transmitted by the Aedes Aegypti or Aedes Albopictus mosquitoes. Dengue viruses belong to the family flavivirus, which are single-stranded RNA viruses that include the West Nile virus, yellow fever virus, Zika virus, etc.

Dengue is a growing health challenge. Compared to Zika and Chikungunya, both mosquito transmitted diseases, dengue has an impact on many more people around the world, mostly living in Asia, Africa, and the Americas. Estimates show that around more than half of the world’s population, or 4 billion people live in areas that are potentially impacted by dengue. dengue viruses were identified to have four different serotypes, which are denoted DENV-1 through DENV-4. These four serotypes all circulate globally, primarily in South America and Southeast Asia, infecting 400 million people annually.

The dengue virus is transmitted with a mosquito as a vector. The mosquito is infected for life once it bites a human infected with the virus and passes it on when it bites other humans. Once infected, the DENV virus has a number of ways to enter host cells in order to initiate replication. It can enter through a number of cell surface protein receptors and is then ingested through endocytosis, or it can be otherwise taken in through lipid rafts and caveolae on the cell surface and processes like pinocytosis or phagocytosis.

The dengue virus roughly has a spherical structure. It is composed of the viral genome and capsid proteins surrounded by an envelope and a shell of Envelope proteins (E) and Membrane Proteins (M). The genome of the dengue virus is a single-stranded, positive-sense, capped RNA of approximately 10 to 11 kb in length that encodes a single polyprotein that is then cleaved into seven non-structural and three structural proteins.

What a Dengue Infection Looks Like

Infection for dengue is more complicated than a simple bite-and-get-sick matter. The first infection is usually not so bad, as only one in four people who are infected with dengue will get sick, with the symptoms including nausea, vomiting, rashes, aches, and pains. Because the pain in joints can get so bad, dengue is sometimes called the “breakbone disease.”

Primary DENV infection is more often mild and is thought to generate lifelong homotypic immunity (same strain) and temporary heterotypic  immunity, which typically wanes over six months to two years. Subsequent heterotypic secondary infection induces broad cross-protection, and symptomatic tertiary and quaternary cases are rare.

However, a small subset of secondary infections are enhanced by non-neutralizing, cross-reactive antibodies, resulting in severe disease through antibody-dependent enhancement (ADE). In the worst case scenario, secondary symptomatic infection can develop into Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS). Both are severe illnesses that require emergency medical attention as symptoms include severe bleeding, shock, and even death. Warning signs for severe illness tends to appear swiftly after the fever settles and include:

• Severe stomach pain
• Persistent vomiting
• Bleeding from your gums or nose
• Blood in your urine, stools or vomit
• Bleeding under the skin, which might look like bruising
• Difficult or rapid breathing
• Fatigue
• Irritability or restlessness

Therefore, it is vital to monitor someone going through a dengue infection. Since the first one can be asymptomatic, it is clinically important to find out which infection the patient is going through via analysis of the blood serum. For the first infection, the DENV-specific IgM to IgG ratio is rather high in early disease manifestation as IgM is seen as a “first responder” to a new infection while IgG takes some time to establish. For the second infection, the IgM to IgG ratio is not nearly as high in the early infection period.

Dengvaxia Controversy

Few vaccines have been successfully developed against viruses of the family of Flaviviridae, and the only CDC approved vaccine, Dengvaxia, has previously caused quite a stir in the international community. Let’s take a closer look.

Dengvaxia was rather short-lived in the Philippines as vaccinations only continued for about two years before they were halted. Sanofi Pasteur, the company that developed and produced Dengvaxia, first promised the government that their vaccines would reduce dengue by about 10-30 percent in 30 years. But then, it informed the government that their vaccine could increase the severity of illness when administered to patients previously unexposed to dengue. How could this be?

The vaccine is a tetravalent live attenuated vaccine and contains genetic material from all four serotypes of the dengue virus, yet uses the attenuated yellow fever virus genome as the common backbone. Dengvaxia is administered in three separate injections over a 12 month interval.

One potential mechanism that the vaccine causes a worse infection in patients who were previously uninfected is that a Dengvaxia vaccination resembles a first infection and the first real infection is the equivalent of a second infection which conversely brings a higher risk of severe infection. So, when people who did not have prior natural infection obtained the Dengvaxia vaccine, a number of antibodies against the dengue viruses have been established through the vaccines.  This, however, may enable the other DENV serotypes, which are structurally similar, to enter the body through a backdoor mechanism called Antibody Dependent Enhancement (ADE).

In the spring of 2016, Dengvaxia had a high-profile launch in the Philippines, becoming the first country in the world to drive the mass campaign for the live recombinant tetravalent shot. The Philippine Department of Health spent $67 million on Dengvaxia and aimed to vaccinate 1 million students by the end of the year.

Sanofi also had high hopes for Dengvaxia, the development of which had taken 20 years and cost around $1.8 billion. By October 2016, Dengvaxia had received regulatory approval from 10 other countries, including Mexico, Brazil, and Indonesia.

In 2017, after more than 830,000 children had received at least one dose of the vaccine, Sanofi announced that it was changing its label to restrict its use to only those who had already been exposed to dengue virus. Having reanalyzed its trial results, Sanofi said the evidence now suggested those naive to dengue who received the vaccine could be vulnerable to more severe infections. Then, the Philippine DOH quickly suspended the immunization program. In September 2018, DoH Undersecretary Enrique Domingo told reporters that 130 vaccinated children had died, suggesting serious vaccine safety issues; 19 of those had dengue, suggesting that ADE possibly played a role. This quickly resulted in a public fear for the safety of Filipino children as well as an outspoken demand for investigation.

In 2019, the Filipino FDA permanently withdrew the vaccine’s license; the regulator’s director general Nela Charade Puno said the decision had been made because Sanofi failed to comply with its post-marketing commitments. Interestingly, the decision was not correlated to severe adverse effects or protection of Philippine’s children. It was about a pharmaceutical company’s non-compliance issue.

Meanwhile, the Dengvaxia scandal had triggered two related congressional inquiries and a criminal investigation. In March 2019, The Philippine Department of Justice said it had enough evidence to charge staff of Sanofi (including its president) and Filipino health officials, including former Health Minister Janette Garin. The department argued the named defendants had reckless imprudence to ignore “the identified risks and adverse effects of the vaccine” and were responsible for the subsequent deaths resulting in homicide charges.

Until today, there is no report regarding the final outcome of the investigation and the indictment.

While a panel of medical specialists was engaged to examine the alleged link, they concluded that there was no conclusive evidence presented connecting the deaths to Dengvaxia specifically. It is quite obvious that nobody would be able to provide conclusive evidence as the children were not tested for prior dengue infection before vaccination, and no ADE effects would be able to be confirmed postmortem. Does that mean nobody will be held accountable for the death of innocent Filipino children?

Intriguingly, amidst the scandal and unsettled investigations in the Philippines, the European Commission granted marketing approval for the Dengvaxia vaccine in December 2018 to be used in already-exposed individuals aged 9 to 45 years and living in dengue-endemic regions.

Then in May 2019, the U.S. Centers for Disease Control and Prevention (CDC) approved the vaccines. The CDC recommends the three dose vaccine for children ages 9-16 who live in territories where dengue commonly occurs. It also requires a confirmation of previous dengue infection in order for the child to be eligible for the dengue vaccine, which in a sense is its own way of circumventing the ADE fiasco.

So, from WHO, the European Commission, to the United States, all the health authorities took the strategies to require pre-vaccination screening to confirm a prior dengue infection. However, all the health authorities knew that the rapid antibody/antigen tests used to confirm dengue infection are of low sensitivity and limited specificity. How do we avoid false positive results that confuse prior infection from other types of flaviviruses with dengue infection? Are we really in the clear about all the potential severe adverse effects of Dengvaxia and the mechanism of ADE?

What Is ADE, Exactly?

Antibody dependent enhancement, or ADE, is a way for viruses to take advantage of the loopholes in the host’s immune system and exploit it to facilitate a viral infection.

In the case of ADE, the non-neutralizing antibodies generated against the virus from a previous infection bind to the new incoming viruses, forming an antibody-virus complex. The Fc-Gamma Receptor on the host cell surface then binds to these non-neutralizing antibodies which brings the entire complex into the cell. So, in the ADE scenario, the prior infection sets up a Trojan horse mechanism to facilitate the second wave of a viral infection.

In the scientific community, ADE is a serious issue that many vaccine developers, not exclusive to dengue, are trying to avoid. This is why, sometimes, it is worth thinking outside the box when tackling certain issues such as mosquito-borne diseases.

For example, some countries such as Australia and the United States have been releasing Wolbachia-infected mosquitoes as a way to limit the spread of mosquito borne diseases in general. Scientists have discovered that when A. Aegypti mosquitoes carry Wolbachia, the bacteria competes with viruses like dengue, Zika, Chikungunya and Yellow Fever. This makes it harder for viruses to reproduce inside the mosquitoes and reduces the likelihood of transmission.

Sanofi Pasteur claimed it spent 20 years and billions of dollars to develop Dengvaxia.  Imagine if all the funding, expertise, and time was spent on unique methods like the Wolbachia strategy or other mosquito population control methods that tackled the issue at the root, how much success might we have by now in reducing not only dengue, but mosquito borne diseases in general? Since when have vaccines become the go-to method we deal with infectious diseases? Has it become the prime, profit-generating method exploiting healthy people?

Generally speaking, the intelligence of viruses are in no way proportional to their size, and the Dengvaxia story proves just that. This story from the past should have been taken more seriously by vaccine developers and government healthcare agencies as more and more data is emerging on the negative vaccine efficacy the COVID-19 shots have on the latest Omicron variants. It calls the approach we take to tackle pandemics into question since history repeatedly shows that vaccines are not a one-size-fits-all solution to health crises. A more holistic approach to health is not only recommended, it has now become a necessity.

Views expressed in this article are the opinions of the author and do not necessarily reflect the views of The Epoch Times. Epoch Health welcomes professional discussion and friendly debate. To submit an opinion piece, please follow these guidelines and submit through our form here.

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