Dengvaxia: Knowns and unknowns

In 2018, together with colleagues, I agreed that “vaccine confidence has suffered following the [dengue] vaccine scare, and that trust needs to be rebuilt before the next pandemic.”* As a Jan. 24 South China Morning Post article put it, the “ghost of Dengvaxia controversy lingers.”

The COVID-19 pandemic tells us that vaccination is vital to achieve herd immunity. Dengvaxia problems were not made in the Philippines. Revised recommendations for safe use of this vaccine have been made. To restore confidence in vaccines, it is important to understand the Dengvaxia story in the Philippines, past, present, and future. This is written to support all those whose lives have been impacted by Dengvaxia.

We may benefit from a step-wise review of events and observations in the public domain or published in peer-reviewed scientific journals:

2012: In a Thailand vaccine trial, Dengvaxia showed poor protection against dengue 2 virus.

2015: Dengvaxia completed a phase 3 trial in 35,000 Asian and American children. Two-thirds received the vaccine, one-third, placebo control. Young vaccinated children were hospitalized at a higher rate than controls. Using statistical analyses, Sanofi concluded Dengvaxia was moderately effective in preventing dengue illnesses in children, ages nine to 16.

2015:  Dengvaxia was licensed in the Philippines.

2016: World Health Organization (WHO) expert groups, relying on mathematical models, endorsed Dengvaxia for use in nine to 16 year olds.

2016: Philippines initiated a ₱3.5 billion, school-based dengue immunization program.

2016: Independent expert review of phase 3 data concluded that Dengvaxia protected children who were partially dengue-immune when vaccinated, but sensitized seronegative children (those who had never had dengue before) to breakthrough dengue disease.

2017: Sanofi re-analyzed phase 3 data, finding Dengvaxia protected seropositives, but sensitized some seronegatives to severe breakthrough dengue infections.

2017: The Dengvaxia campaign in the Philippines halted.

2019-20: Sanofi Phase 3 data predicted there would be dengue among Dengvaxia sensitized seronegative Philippine children vaccinated in 2016-17. Dengue experts called for an international effort to assist the Philippines to identify “at risk” vaccinated children.

Beginning with smallpox vaccine in the 18^th century, the world entered an age of “vaccine miracles”: live attenuated yellow fever, measles, mumps, rubella, polio, chickenpox and Japanese encephalitis vaccines. These are weakened viruses. We know they protect, but do not fully understand why. Not all vaccines have happy outcomes. A killed measles vaccine, licensed in the 1960s, sensitized children to a more severe form of measles. This vaccine was quickly taken off the market. Fortunately, it was replaced by an excellent vaccine.

After 1954, when “H fever” was discovered in the Philippines, it became known that sequential infection with two different dengue viruses was the cause of severe dengue. This information put vaccine makers “on guard” to the possibility that a dengue vaccine itself could act like a first dengue infection, sensitizing to severe disease during a second infection. Vaccine-enhanced dengue may be exactly like H fever.

The immune status of children given Dengvaxia was not known during the phase 3 trial. Breakthrough cases were thought to be “vaccine failures.” The vaccine was declared safe and effective. Public health authorities in the Philippines, acutely aware of dengue’s yearly toll, made the brave decision to obtain Dengvaxia.

The revised phase 3 data were only available after vaccinations had begun. The full story was known only then.

The world is making an effort to share the burden of preventing COVID-19. In this same spirit, help should be offered to the Philippines to lessen the impact of this historically unique vaccine failure.

*Antonio L. Dans, Leonila F. Dans, Maria Asuncion A. Silvestre, Scott B. Halstead & Gordon H. Guyatt, “Cause and consequence of loss in vaccine trust,” Human Vaccines & Immunotherapeutics, Volume 15, Issue 3, 2019

Scott B. Halstead, M.D., a 1955 graduate of Columbia University School of Medicine, was assigned in 1961 on active duty in the US Army to open a research laboratory in Bangkok studying Philippine and Thai hemorrhagic fevers. It was there that severe dengue was discovered to be an outcome of a second infection but also accompanied first infections in infants born to dengue-immune mothers. His laboratory studies at Yale and the University of Hawaii resulted in the discovery of the pathogenic mechanism, antibody dependent enhancement. He has been active in vaccine research and promotion. At the Rockefeller Foundation in 1990, he founded the Children’s Vaccine Initiative and in 2003, the Pediatric Dengue Vaccine Initiative, funded by the Gates Foundation.