CLINICAL MATTERS

Last month, the Department of Health warned that dengue had reached outbreak levels. In addition, the number of cases from Jan. to Aug. 2024 exceeded the 2023 levels by 33 percent for the same period, with nearly 400 deaths reported. Dengue remains hyperendemic in the Philippines, which means that transmission occurs the whole year, but there are distinct spikes in cases during the rainy season when the mosquito population rises.

Dengue is so prevalent in the Philippines that nearly 90 percent of the population has had at least one infection by the age of 10. There are four distinct serotypes of dengue and infection with one serotype conferring lifelong immunity to that serotype. This means that someone can get dengue up to four times in their lifetime. The first dengue infection, whatever the serotype, is usually mild. A subsequent infection carries a higher risk of severe dengue. This risk is highest with the second infection and can be fatal due to a phenomenon known as antibody-dependent enhancement (ADE). 

Severe dengue disproportionately affects young people in the Philippines because this specific population is the most likely to have had at least one dengue infection followed by a reinfection with a new serotype. Since all four serotypes occur in the Philippines, the risk of reinfection from a different serotype is higher than in other countries where fewer serotypes circulate. Avoiding that second, potentially fatal, dengue infection is the goal of dengue vaccines. An effective dengue vaccine is not primarily meant to prevent dengue but is instead meant to skip the higher risk of severe disease of a second infection.

This long-term goal of making an effective dengue vaccine was finally achieved in 2015 with the development of CYD-TDV, also known as Dengvaxia. It consisted of a non-replicating chimeric vector which conferred protection against all four serotypes. In efficacy studies, the vaccine conferred over 90 percent efficacy in preventing severe dengue and over 80 percent efficacy in preventing hospitalization among seropositive, those with evidence of at least one dengue infection, subjects greater than nine years old. In a six-year follow-up analysis, protection remained robust among seropositive Dengvaxia recipients, with CYD-TDV decreasing the risk of hospitalization by 81 percent and the risk of severe dengue by 85 percent.

On the basis of the clinical trial efficacy data and one year of follow-up safety monitoring, Dengvaxia was given approval in many countries and was given a favorable recommendation by the World Health Organization Strategic Advisory Group of Experts for Immunization (SAGE) for deployment in dengue-endemic areas. There was initially no requirement to determine whether the recipient was seronegative or seropositive as the early efficacy data showed that even seronegative vaccine recipients were protected from dengue in the first year of follow-up, albeit less than the protection seen in seropositive recipients. 

Longer follow-up of vaccine recipients from the clinical trials eventually showed a worrisome safety signal in the third year of monitoring which seemed to be driven by seronegative individuals and those under nine years old. There was a trend toward increased hospitalization for severe dengue similar to that seen with a second natural dengue infection among the seronegative Dengvaxia recipients. Moreover, protection against infection and hospitalization was no longer apparent after the third year of follow-up among the seronegative patients. Vaccination in some seronegative recipients was behaving like a first infection, while the first natural infection after vaccination acting like a second infection with its attendant higher risk of ADE. 

Dengvaxia itself does not cause dengue or any other viral disease. The incidence of severe dengue for the first natural infection in an unvaccinated seronegative person is two severe cases out of 1000 dengue infections. The increased incidence of severe dengue in a natural second infection in an unvaccinated person is five severe cases out of 1000 dengue infections. The incidence of severe dengue during the first natural infection of a seronegative Dengvaxia recipient was found to be similar to that of a natural second infection in an unvaccinated person, which is five severe cases out of 1000 dengue infections. On the other hand, vaccinating a seropositive person, who has at least one natural dengue infection, with Dengvaxia resulted in a significant reduction in the incidence of severe disease to below one severe case in 1000 dengue infections. There were no reported deaths from severe dengue in the Dengvaxia clinical trials despite the safety signal.

The finding that Dengvaxia lost its vaccine efficacy in seronegative recipients, coupled with the safety signal of increased hospitalization and severe dengue, prompted WHO and Sanofi to change its recommendation on sero testing in 2016. Dengvaxia was now recommended only in persons who were seropositive for dengue or had other evidence of previous dengue infection. Unfortunately, the actual risk (an additional three severe cases out of 1000 dengue infections in seronegative recipients) which is significant but relatively rare, was not communicated well by Sanofi. Based on the initial bulletin released, it only stated that healthcare professionals should not use Dengvaxia among seronegative children, without any meaningful estimate of possible harm.

By this time, the Philippines had already given the Dengvaxia to more than 800,000 school children in a first-of-its-kind mass vaccination drive. Based on the initial WHO recommendation in 2015, the Department of Health decided to initiate mass vaccination in an effort to decrease morbidity and mortality from dengue despite misgivings from experts who wanted longer follow-up data. Dengue season usually meant overcrowded hospitals and many dead children, and the vaccine was meant to alleviate the perennial pressure on the healthcare system since it was projected to decrease hospitalizations from dengue by 80 percent. When the Sanofi bulletin came out without any quantification of the risk, the parents of the children who received Dengvaxia thought their children were going to die. 

What followed was a highly politicized witch hunt where even the clinical trial scientists who had nothing to do with the program were dragged to court. Unscientific autopsies declared that children had died of Dengvaxia-caused complications despite no objective evidence of severe dengue or recovery of the CYD-TDV vector. There was no attempt to isolate the vaccine vector from the supposed victims which would have been essential to support any assertion of vaccine-induced viscerotropism. Whether the Department of Health did anything wrong when it was just following WHO recommendations is still debated among experts, and ultimately lies in whether the vaccination program was pursued in good faith or for other reasons. Nevertheless, immense harm was done in terms of the hysteria generated among the parents of the vaccine recipients, the loss of vaccine confidence resulting in multiple outbreaks of measles and chicken pox, and the persecution of innocent scientists. 

One major casualty was the dengue vaccine itself, which could have protected millions of dengue-seropositive Filipino children from hospitalization and decreased their risk of severe dengue by over 90 percent. Sanofi recently announced that it was discontinuing production of Dengvaxia despite its continued use in other countries due to low demand. In the meantime, two new effective dengue vaccines have been developed and there do not seem to be any safety signals even among seronegative individuals. I just hope that these new dengue vaccines are launched in a more careful and sensitive manner and we can finally make progress in pushing back the scourge of dengue in our country.