Single dengue vaccine dose shows mixed results: Protection hinges on prior exposure

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In a recent study published in the journal The Lancet Infectious Diseases, researchers conducted a prospective, longitudinal, population-based cohort study in two communities in the Philippines to investigate the effects of the prematurely discontinued CYD-TDV vaccine on children's susceptibility to the dengue virus (DENV). While the first of three required doses of the vaccine was publicly administered in 2016 by the Philippine Department of Health, phase three CYD-TDV outcomes resulted in the vaccination program being discontinued.

The present study reveals that the single administered dose of CYD-TDV was incapable of conferring protection against virologically confirmed dengue among patients without a prior history of DENV infection (zero or one prior infection). In stark contrast, young patients who had been exposed to two or more prior DENV infections were found to have substantially reduced DENV infection risk following the first CYD-TDV vaccine dose. This protection was found to be long-lasting, with the observed risk reduction persisting throughout the first three years and the subsequent follow-up period.

Study: Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study. Image Credit: frank60 / ShutterstockStudy: Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study. Image Credit: frank60 / Shutterstock

The dengue virus and the need for this study

Dengue (DENV) is a mosquito-borne viral disease prevalent worldwide in tropical and subtropical regions, particularly in rural and underdeveloped communities. It can be caused by any of four closely related viruses (serotypes), given that repeat infections are surprisingly common. Disease severity can range from asymptomatic or mild to life-threatening, with common symptoms including high fever, persistent headaches, rashes, and characteristic muscle and joint pain.

Despite years of research, dengue remains without a specific cure, with clinical interventions involving management of the fever and patient discomfort and pharmacotherapy restricted to common anti-viral drugs. Thankfully, numerous dengue vaccines have been developed and proven effective against the disease, saving countless lives, especially in recent decades. One of these vaccines developed in France in 2015 was the CYD-TDV vaccine, targeted at children and adolescents.

"In 2015, a three-dose dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur, Lyon, France) was licensed in several dengue-endemic countries in people aged 9 years and older."

In 2016, the Philippine Department of Health undertook a vaccination drive for children in Calabarzon, Central Luzon, and Metro Manilla using CYD-TDV. Unfortunately, this drive was found to be premature – subsequent clinical trials revealed that DENV underperformed in younger children compared to their older counterparts (DENV seropositivity decreases with age). More importantly, the vaccine was found to be contraindicated in patients without a history of DENV infection. These outcomes resulted in the vaccination program's termination following the administration of only the first CYD-TDV vaccine dose.

Hitherto, however, the effect of that single vaccine dose on children's disease resistance remains unexplored.

About the study

The present study aimed to evaluate the relative DENV infection risk among Cebu children who did or did not receive a single CYD-TVD dose, and the association of these outcomes with the number of previous DENV infections survived by these children. The study was designed as a prospective, longitudinal, population-based cohort study and comprised healthy children between the ages of nine and 14 years from Balamban municipality or Bogo city. The study protocol follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, with data collection carried out via a custom-designed questionnaire (demographic data collection) and 5 mL venous blood sample (for baseline DENV serostatus evaluation).

Anthropometric and sociodemographic region data were additionally acquired from the Rural Health Units, which revealed that out of 285,242 eligible children, 149,023 had received the first CYYD-TVD dose. Enrolled participants were assigned to vaccine or no-vaccine cohorts based on these data sources, with follow-up blood and questionnaire collections 17-28 months following study initiation.

"A participant with virologically confirmed dengue was defined as having acute febrile illness with a positive result by RT-PCR. We interviewed participants or the parent or guardian in hospital or at home in person or via telephone to establish the outcome of the illness. We classified cases of virologically confirmed dengue according to WHO criteria."

The study's outcome of interest was the relative protection confirmed by the single vaccine dose, measured in terms of the number of subsequent infections following vaccination. Inter-cohort comparisons were statistically achieved using two-sample t tests (mean comparisons) and Wilcoxon rank-sum tests (median comparisons).

Study findings

Of the 3,087 children who volunteered for the study, 3,001 were found to meet the study inclusion criteria and were enrolled in the study. Of these, 2,778 provided completed demographic and medical data at both baseline and follow-up evaluations and were included in the final analyses.

Serum sample assays revealed that 241 individuals (10.1%) were DENV naïve, of which 93 were unvaccinated. An overwhelming 1,906 participants (80.3%) were found to be DENV multitypic, indicating multiple infection cycles, potentially by different DENV serotypes.

Analyses of subsequent DENV infection data highlight that the CYD-TDV dose was insufficient to protect naïve and monotypic profile patients from DENV infections, with no statistically discernible difference between individuals who had received the vaccine and those who had not. In contrast, patients with multitype DENV profiles who were then administered the vaccine dose displayed substantial, long-lasting improvements in their infection resistance. These results are surprising, as until recently, DENV monotypic patients were assumed to be at the highest infection risk due to the passive immunity of multitypic profile patients.

"In summary, we found no protection from a single dose of CYD-TDV among children with a naive or monotypic DENV immune profile at baseline. One dose conferred significant protection against hospitalization for virologically confirmed dengue among children with a monotypic DENV immune profile at baseline. Since only one dose of CYD-TDV was given, the study cannot be used to inform public health decisions on vaccination but is relevant for children who receive an incomplete regimen."

Journal reference:
  • Ylade, M., Crisostomo, M. V., Daag, J. V., Agrupis, K. A., Cuachin, A. M., Sy, A. K., Kim, D. R., Ahn, H. S., Escoto, A. C., Katzelnick, L. C., Adams, C., White, L., de Silva, A. M., Deen, J., & Lopez, A. L. (2024). Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study. In The Lancet Infectious Diseases. Elsevier BV, DOI – 10.1016/s1473-3099(24)00099-9, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00099-9/fulltext
Hugo Francisco de Souza

Written by

Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.

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