The Dengue saga Mythbusters v2 | Revisiting the Dengvaxia Controversy

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Flashback 2017. The Department of Health (DOH) suspended a school-based vaccination program because reports circulated that several children died from various complications allegedly attributed to the dengue vaccine.

The DOH claimed that 729,105 Grade 4 pupils from selected regions have received the first dose of the vaccine.

CYD-TDV, the Dengvaxia Vaccine

A 2014 research on the dengue vaccine, authored by Usa Thisyakorn reported that the vaccine is a live attenuated tetravalent chimeric vaccine made using recombinant DNA technology by replacing the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain vaccine with those from the four dengue serotypes.

Evidence indicates that CYD-TDV is partially effective in preventing infection, but may lead to a higher risk of severe disease in those who have not been previously infected and then do go on to contract the disease. It is not clear why the vaccinated seronegative population have more serious adverse outcomes. A plausible reason is the phenomenon of antibody-dependent enhancement. Read: The Dengue saga Mythbusters 04

Alleged Deaths and Autopsies

Six hundred deaths have been allegedly linked to the vaccine, but based on reports, none of the children were scientifically proven to have died due to the vaccine, since the only investigation done to the autopsies are from the Public Attorney’s Office and not from the Philippine’s own health authorities.

The Public Attorney’s Office investigation noted in the forensic examination conducted on the four children who allegedly died due to severe dengue that all the victims experienced internal bleeding and inflammation of the internal organs.

Health advocate Dr. Susan Mercado attributed it to a term called “viscerotropism” – and not a mention of Antibody-dependent Enhancement, which is supposed to be the main, if not the only concern against the vaccine.

"President Benigno S. Aquino III, together with Interior and Local Government Secretary Mel Senen Sarmiento; and Zambales Governor Hermogenes Ebdane, Jr., witness the ceremonial vaccination of Dengue School-Based Immunization during the launching ceremony and ceremonial distribution of the Tamang Serbisyo Para sa Kalusugan ng Pamilya (TSeKaP) Medical Equipment Package at the People Park in Poblacion, Iba, Zambales on Tuesday (April 05). Also in photo are Health Secretary Janette Garin and Zambales Governor Hermogenes Ebdane, Jr." by Malacañang Photo Bureau is in the Public Domain, CC0
“President Benigno S. Aquino III, together with Interior and Local Government Secretary Mel Senen Sarmiento; and Zambales Governor Hermogenes Ebdane, Jr., witness the ceremonial vaccination of Dengue School-Based Immunization during the launching ceremony and ceremonial distribution of the Tamang Serbisyo Para sa Kalusugan ng Pamilya (TSeKaP) Medical Equipment Package at the People Park in Poblacion, Iba, Zambales on Tuesday (April 05). Also in photo are Health Secretary Janette Garin and Zambales Governor Hermogenes Ebdane, Jr.” by Malacañang Photo Bureau is in the Public Domain, CC0

US Doctor Scott Halstead, who was part of Senate Blue Ribbon Committee who probed the Philippine dengvaxia controversy said that for any child who receives dengvaxia doses and later dies, two things have to be considered before concluding that the two are connected: unequivocal evidence that the infection was caused by dengue virus, which can be done by either virus isolation or identification of NS1; and knowing if the particular individual was given the vaccine when he or she was seronegative or seropositive.

Halstead added that “it is not appropriate to use the terms viscerotropism and neurotropism in relation to Dengvaxia.”

Viscerotropism from the root word viscera, which means organs, is actually a fancier way in medicine to say “it affected the organs” and is rarely used because it’s very broad. In a million people vaccinated by the yellow fever vaccine, there will be some people who are otherwise healthy that will still get yellow fever and these are a few instances where the terms “viscerotropic” are used in which this specific reaction is called.

This must have been the basis of Dr. Susan Mercado when using the term as the Dengue vaccine was indeed created from yellow fever vaccine, but may have failed to understand how the vaccine (and vaccines in general) are created. To put it simply, the yellow fever vaccine was used as a blue print and no trace of the yellow fever vaccine is actually in the finished product – making her statement false, bordering on misinformation and undoubtedly questions the conclusions of the Public Attorney’s Office regarding the autopsies which supported her statements.

As of 2020 no one was scientifically proven or confirmed to have died from the vaccine.

Global Availability of the Vaccine

Dengvaxia became commercially available in 2016, in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore.

In a 2017 statement published in Center for Infectious Disease Research and Policy, the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection (seropositives) as outcomes may be worsened in those who have not been previously infected – which is ultimately a basic precaution, akin to contraindications of vaccines that shouldn’t be taken because of pregnancy or immunodeficiency. But this statement lead to the Philippine Dengvaxia controversy. Surprisingly among the countries where Dengvaxia is available, the vaccine was controversial and got discontinued on in the Philippines.

The World Health Organization (WHO) recommends that countries should consider vaccination with dengvaxia only if the risk of severe dengue in seronegative individuals can be minimized either through pre-vaccination screening or recent documentation of high seroprevalence rates in the area (at least 80% by age nine years).

In December 2018, the European Medicines Agency, of the European Union approved the use of Dengvaxia

Subsequently, in May 2019, the United States Food and Drug Administration approved of the use Dengvaxia.

The FDA conducted its safety and effectiveness study which was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region (areas in the US where Dengue is endemic)

The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals nine through 16 years of age who previously had laboratory-confirmed dengue disease.

All in all, Dengvaxia has already been approved in 19 countries and the European Union.

Why did the controversy happen in the Philippines and not anywhere else in the world?

There are various factors that can be attributed to the descent of infamy of the Dengvaxia vaccine in the Philippines. One, and the most potent factor, is politics. It is common knowledge that dengue is widespread in the country leading the Department of Health and the World Health Organization to consider it an endemic disease in the country by 2019. Back in December 2015, former President Noynoy Aquino met with executives of Sanofi Pasteur in a courtesy call in Paris, making the Philippines the first Asian country to approve of the commercial sale of Dengvaxia.

In April 2016, the Department of Health (DOH), launched the dengue vaccination campaign in regions Central Luzon, Calabarzon and Metro Manila, where about 700,000 individuals received at least one dose of the vaccine. The government paid P3.5-billion for the vaccine.

When Sanofi announced a new recommendation of the vaccine in 2017, what could have been a simple screening issue with quick fixes (ie, catering the seronegatives injected for any untoward reactions care of the government, until they’d recover and essentially enjoy the benefits from being vaccinated) became a full blown national fiasco – these came with waves of media sensationalism and political clout aimed to discredit the previous administration which is commonly labelled as opposing the current one – as is was always the identity and duality in Philippine politics.

People were quick to circulate the words “guinea pigs” or “children killed” and “medical malpractice” and a slew of anti-science, anti-healthcare and anti-vax sentiments garnered attention, some even supported by public figures.

The dengvaxia’s risk which is Antibody Dependent Enhancement, is in itself, still an incomplete science, and honestly, not simple, but it is the burden of the Philippine’s Health authorities to be able to explain it to the public on how the risks and benefits weigh in, and in the case of Dengvaxia, how the benefits significantly outweighs the risks. Instead the Department of Health was also polarized – unable to defend itself from the allegations made by the Public Attorney’s Office. A medical issue the Department of Health can’t defend itself from which is thrown towards it by an office of Law may be attributed as a sign of incompetence. This has effectively lowered the trust in the Philippine’s overall Healthcare system and allegedly decreased the Department of Health’s Vaccination rates the following years leading to the 2019 Measles Outbreak.

Note that in 2019, employees of the Public Attorney’s Office have asked the Office of the Ombudsman to issue a preventive suspension order against their chief Persida Acosta and her forensics chief Dr. Erwin Erfe for alleged corruption in the agency in the time of the Dengvaxia controversy.

Future Implications

As with every health issue on a societal scale, controversy starts with a few drops of misinformation. When this reaches a wide audience, it becomes an infodemic. If Health authorities and people in healthcare themselves fail to answer the questions of the public regarding medicine and science in the context of current health issues, politics will enter and try to pose solutions and the lack of health experts in the latter will more often than not lead to devastating effects like a lowered public trust and an increase of anti-science sentiments like antivax movements.

What‘s alarming in the country besides being the only one with the dengvaxia controversy, is that there is a chance that this will repeat especially in the in the background of the current CoviD-19 crises and the global race toward a CoviD-19 vaccine. Distrust in health authorities and the government in general remain rampant, due to alleged mishandling of the pandemic.

Coronaviruses themselves have risks of having antibody dependent enhancement abilities. While there is yet to be evidence that Antibody dependent enhancement also happens in CoviD-19, it’s still being closely monitored by experts.

Paul-Henri Lambert, an immunologist and vaccinologist retired from the University of Geneva who now advises the university’s center of vaccinology and consults for a multinational collaborative project of researchers on safety evaluations of vaccine candidates, stated that the threat of ADE in CoviD-19 is “a theoretical risk, but people are being extremely careful to make sure that this risk is not becoming a reality,”

The United States, European Union and various Asian countries continue to use the Dengvaxia vaccine unabated and unaffected by the Philippine controversy, as they are well aware of the guidelines and use has been proven safe by their respective FDAs. The Philippines will, however most likely stray away from the vaccine as long as it can due to the damage of the controversy even with the threat of Dengue around the corner.

What could have been an answer to the ever-present Dengue threat became a curse, and in the midst of the ongoing CoviD-19 pandemic, once a vaccine appears, without vigilance from our health authorities, a similar event would make a potential solution turn into a problem.

Meanwhile there are currently at least 4 other Dengue vaccines being developed, the most promising, DENVax or TAK-003 originally developed at Mahidol University in Bangkok is currently on it’s Phase III trials. A 2019 research on its vaccine efficacy by Shibadas Biswal, M.D and co-authors published in the New England Journal of Medicine suggests that its effective in both seronegative and seropositive patients with the goal to avert any form of harm like Dengvaxia’s potential ADE risks on seronegatives.

The other vaccines are TetraVax-DV currently conducting safety tests in Vietnam, and sponsored by the National Institute of Health. TDENV PIV vaccine which is a tetravalent dengue virus purified inactivated vaccine undergoing phase I trials as part of a collaboration between GlaxoSmithKline (GSK) and the Walter Reed Army Institute of Research (WRAIR) and V180 vaccine research headed by Merck Co.

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