Elsevier

Vaccine

Volume 34, Issue 14, 29 March 2016, Pages 1643-1647
Vaccine

Review
Protective and immunological behavior of chimeric yellow fever dengue vaccine

https://doi.org/10.1016/j.vaccine.2016.02.004Get rights and content

Highlights

  • Children, ages 5 years and younger, given three doses of CYD vaccine were hospitalized five times more frequently with breakthrough dengue virus infections than were placebo controls.

  • Children who were seronegative at the time of CYD vaccination were poorly protected against symptomatic dengue virus infection.

  • Seronegative children uniformly developed dengue neutralizing antibodies following vaccination.

  • Symptomatic dengue virus infections in individuals circulating non-protective dengue antibodies suggests disease in vaccinated young children is antibody enhanced.

  • CYD vaccination protected seropositives from disease, mild or severe, when challenged by a wild-type dengue virus.

Abstract.

Clinical observations from the third year of the Sanofi Pasteur chimeric yellow fever dengue tetravalent vaccine (CYD) trials document both protection and vaccination-enhanced dengue disease among vaccine recipients. Children who were 5 years-old or younger when vaccinated experienced a DENV disease resulting in hospitalization at 5 times the rate of controls. On closer inspection, hospitalized cases among vaccinated seropositives, those at highest risk to hospitalized disease accompanying a dengue virus (DENV) infection, were greatly reduced by vaccination. But, seronegative individuals of all ages after being vaccinated were only modestly protected from mild to moderate disease throughout the entire observation period despite developing neutralizing antibodies at high rates. Applying a simple epidemiological model to the data, vaccinated seronegative individuals of all ages were at increased risk of developing hospitalized disease during a subsequent wild type DENV infection. The etiology of disease in placebo and vaccinated children resulting in hospitalization during a DENV infection, while clinically similar are of different origin. The implications of the observed mixture of DENV protection and enhanced disease in CYD vaccinees are discussed.

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.

References (32)

  • L. Villar et al.

    Efficacy of a tetravalent dengue vaccine in children in Latin America

    N Engl J Med

    (2014)
  • A. Sabchareon et al.

    Dengue infection in children in Ratchaburi, Thailand: a cohort study I. Epidemiology of symptomatic acute dengue infection in children, 2006–2009

    PLoS Negl Trop Dis

    (2012)
  • N. Sangkawibha et al.

    Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand I. The 1980 outbreak

    Am J Epidemiol

    (1984)
  • T.P. Endy et al.

    Prospective cohort studies of dengue viral transmission and severity of disease

    Curr Top Microbiol Immunol

    (2010)
  • T.P. Endy et al.

    Epidemiology of inapparent and symptomtic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet Thailand

    Am J Epidemiol

    (2002)
  • A. Gordon et al.

    The nicaraguan pediatric dengue cohort study: incidence of inapparent and symptomatic dengue virus infections, 2004–2010

    PLoS Negl Trop Dis

    (2013)
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