Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine

Abstract

A tetravalent live-attenuated 3-dose vaccine composed of chimeras of yellow fever 17D and the four dengue viruses (CYD, also called Dengvaxia) completed phase 3 clinical testing in over 35,000 children leading to a recommendation that vaccine be administered to >/ = 9 year-olds residing in highly dengue- endemic countries. When clinical trial results were assessed 2 years after the first dose, vaccine efficacy among seropositives was high, but among seronegatives efficacy was marginal. Breakthrough dengue hospitalizations of vaccinated children occurred continuously over a period of 4–5 years post 3rd dose in an age distribution suggesting these children had been vaccinated when seronegative. This surmise was validated recently when the manufacturer reported that dengue NS1 IgG antibodies were absent in sera from hospitalized vaccinated children, an observation consistent with their having received Dengvaxia when seronegative. Based upon published efficacy data and in compliance with initial published recommendations by the manufacturer and WHO the Philippine government undertook to vaccinate 800,000-plus 9 year-olds starting in April 2016. Eighteen months later, dengue hospitalizations and a deaths were reported among vaccinated children. The benefits of administering Dengvaxia predicted by the manufacturer, WHO and others derive from scoring dengue hospitalizations of vaccinated children as vaccine failures rather than as vaccine enhanced dengue disease. Recommended regimens for administration of Dengvaxia should have been structured to warn of and avoid serious adverse events.

Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

“…As the eponymous flavivirus, the study of YFV and its vaccine is of interest to studies of other flaviviruses. Chimeric YF viruses in which prM-E sequences are introduced into the YF vaccine virus backbone are the basis of ongoing vaccine trials against dengue and Japanese encephalitis viruses ( Monath et al, 2015 ), with controversial results in clinical trials ( Vaccine, 2018 ; Halstead, 2018 ). Although still considered a safe and effective vaccine, the uncertainty regarding the causes of YEL-AVD have encouraged attempts to develop an inactivated alternative vaccine ( Monath et al, 2011 ; Monath and Vasconcelos, 2015 ; Pereira et al, 2015 ).…”

Peptide-Based Vaccines: Current Progress and Future Challenges

“…5 Dengue virus is the most globally distributed arbovirus with ∼390 million infections worldwide each year, but the development of a Dengue vaccine has been challenging due to a complex immunopathology in which induction of subneutralizing antibody levels contributes to an enhanced form of the disease. 6 Infectious disease vaccines aim to induce a protective immune response in a naive host by exposing the immune system to epitopes contained on the pathogen prior to exposure to the infectious agent itself. The major challenges that confront infectious disease vaccines stem from the nature of the epitopes against which the immune response is directed; in some cases, immunodominant epitopes arising from natural infection may not be those that are most desirable (e.g., susceptible to neutralization and/or highly conserved).…”

Ethics of a partially effective dengue vaccine: Lessons from the Philippines

“…Fortuitously, prior to initiating phase 3, Sanofi measured DENV antibody prevalence in all 10 participating country vaccine sites. These data provided an estimate of average annual DENV FOI of 0.155 (15.5%) over a period of 14 years [26,27]. We applied the average annual FOI to obtain age-specific primary DENV infection rates for a post-vaccination period of 1 and 4 years.…”