ReviewProtective and immunological behavior of chimeric yellow fever dengue vaccine
Introduction
Sanofi Pasteur has conducted an evaluation of clinical responses to dengue vaccine of unparalleled size involving more than 35000 children, ages 2–16, resident in 10 dengue endemic countries [1]. From published reports on this extensive experience it has been established that the CYD live-attenuated tetravalent vaccine was asymmetrically protective and enhancing. The efficacy of vaccine in preventing severe dengue or dengue hemorrhagic fever among children 9 years or older who were hospitalized during year 3 was over 90%. However, in children of all ages severe dengue during hospitalizations occurred more often in vaccinated (18/65) than in placebo groups (6/39) [1]. More pointedly, among 2029 vaccinated children, 5 years or younger (1636 from CYD 14 + 393 from CYD 23/57) subsequent dengue hospitalization rate was significantly higher, 20/2029 (0.99%) than among controls 2/1005 (0.2%), a relative risk of 4.95, p = 0.03. In addition, among vaccinated young children during year 3 of the Thai trial (CYD 23/57), 5 of 22 hospitalized developed plasma leakage and 2 were in shock, while there were no shock cases among 11 controls. The authors explain hospitalized disease in vaccinated young children as a “cluster” immunization effect or an example of vascular or immunological immaturity [1]. A more extensive analysis re-emphasized these hypotheses with the added suggestion that seronegatives are initially protected by vaccination but during year 3 become at risk to enhanced disease [2]. Outside experts suggested that hospitalized disease in vaccinated seronegatives might be only “transient” [3].
Data from the three CYD clinical trials suggest that vaccine related antibody-dependent enhancement (ADE) may have occurred across all age groups during the first two and the third year after vaccination. Because only a small fraction of vaccinated children were bled for serological studies prior to administering vaccine, 8%, 19% and 9.3% for CYD23, 14 and 15, respectively, the pre-illness immunological status in relation to hospitalized dengue illnesses in vaccinated and controls must be inferred [4], [5], [6]. Here we examine and comment on the clinical outcomes among vaccinated children who were naturally challenged by wild-type DENV over a period of 3–4 years.
Section snippets
Clinical responses to DENV infection
Before attempting to interpret the outcome of the CYD clinical trials, it is important to describe the established outcomes of dengue infections of children that occur in differing immunological settings: seronegative (flavivirus susceptible), Japanese encephalitis (JE)-immune, monotypic DENV-immune and polytypic DENV-immune. Unlike most viral infections the clinical presentation and severity of a dengue virus infection is determined by the previous experience with flaviviruses. Infections in
Discussion
The authors of the CYD clinical vaccine trials initially interpreted dengue illnesses observed among vaccinees as instances of primary or secondary vaccine failure. This might be true were vaccine trials against a standard viral immunogen where immune enhancement is not a factor. Had CYD vaccination of susceptibles prevented all or nearly all disease caused by each of the four DENV in susceptibles, classical efficacy calculations might have been appropriate. In actuality the results labeled
Conflict
SBH: Short-term consultant, Sanofipasteur, Takeda, Inviragen.
PKR: Short-term consultant, Inviragen, Takeda.
Acknowledgments
We wish to thank Dr. Ananda Nisalak of the Virology Department, Armed Forces Research Institute of the Health Sciences, Bangkok, Thailand, for supplying data for Fig. 1.
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