Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial

Sabchareon, Arunee; Wallace, Derek; Sirivichayakul, Chukiat; Limkittikul, Kriengsak; Chanthavanich, Pornthep; Suvannadabba, Saravudh; Jiwariyavej, Vithaya; Dulyachai, Wut; Pengsaa, Krisana; Wartel, T. Anh; Moureau, Annick; Saville, Mélanie; Bouckenooghe, Alain; Viviani, Simonetta; Tornieporth, Nadia; Lang, Jean

doi:10.1016/s0140-6736(12)61428-7

Cited by 722 publications

(704 citation statements)

References 24 publications

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“…This finding thus introduces the possibility of developing a universal vaccine protecting against all the viruses from this group. Vaccine design against dengue virus has been hampered by the heterogeneity of DENV particles and the need to use polyvalent formulas to immunize against all four serotypes 19,20 . One feature of DENV is that it undergoes incomplete furin maturation cleavage of prM in many cell types, giving rise to heterogeneous mosaic particles with an immaturelike spiky patch on one side and a smooth mature-like region on the opposite side 21 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

470

540

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Zika virus (ZIKV) is an arthropod-borne enveloped virus belonging to the Flavivirus genus in the family Flaviviridae, which also includes the human pathogenic yellow fever, dengue, West Nile and tick-borne encephalitis viruses 1 . Flaviviruses have two structural glycoproteins, prM and E (for precursor membrane and envelope proteins, respectively), which form a heterodimer in the endoplasmic reticulum (ER) of the infected cell and drive the budding of spiky immature virions into the ER lumen. These particles transit through the cellular secretory pathway, during which the trans-Golgi-resident protease furin cleaves prM. This processing is required for infectivity, and results in the loss of a large fragment of prM and reorganization of E on the virion surface. The mature particles have a smooth aspect, with 90 E dimers organized with icosahedral symmetry in a 'herringbone' pattern 2,3 .Three-dimensional cryo-electron microscopy (cryo-EM) structures of the mature ZIKV particles have recently been reported to near atomic resolution (3.8 Å) 4,5 , showing that the virus has essentially the same organization as the other flaviviruses of known structure, such as dengue virus (DENV) 3 and West Nile virus 6,7 . The E protein is about 500 amino acids long, with the 400 N-terminal residues forming the ectodomain essentially folded as β-sheets with three domains, named I, II and III, aligned in a row with domain I at the centre. The conserved fusion loop is at the distal end of the rod in domain II, buried at the E dimer interface. At the C terminus, the E ectodomain is followed by the 'stem' , featuring two α-helices lying flat on the viral membrane (the stem helices), which link to two C-terminal transmembrane α-helices. The main distinguishing feature of the ZIKV virion is an insertion within a glycosylated loop of E (the '150' loop), which protrudes from the mature virion surface 4,5 .Flaviviruses have been grouped into serocomplexes based on cross-neutralization studies with polyclonal immune sera 8 . The E protein is the main target of neutralizing antibodies, and is also the viral fusogen; cleavage of prM allows E to respond to the endosomal pH by undergoing a large-scale conformational change that catalyses membrane fusion and releases the viral genome into the cyotosol. Loss of the precursor fragment of prM lets the E protein fluctuate from its tight packing at the surface of the virion, transiently exposing otherwise buried surfaces. One surface exposed by this 'breathing' is the fusionloop epitope (FLE), which is a dominant cross-reactive antigenic site 9 . Although antibodies to this site can protect by complement-mediated mechanisms, as shown in a mouse model for West Nile virus 10 , they are poorly neutralizing and lead to antibody-dependent enhancement 11-15 , thereby aggravating Flavivirus pathogenesis and complicating the development of safe and effective vaccines.We recently reported the functional and structural characterization of a panel of antibodies isolated from patients with dengue disease 13,16 . ...

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Section: Discussionmentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

470

540

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“…Although effective vaccines exist for different flaviviruses, no vaccine can prevent ZIKV infection [101,102]. There is an immediate requirement for ZIKV vaccine.…”

Section: Preventionmentioning

confidence: 99%

Zika virus disease: a current review of the literature

et al. 2016

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“…seronegativeAve. FOIIndonesia1870430.2190.2Malaysia1401322.35113.1Philippines3501805.18145.2Thailand2666613.30184.15Thailand1170269.2259.15Vietnam2333537.35188.18Brazil2370782.34266.1Colombia64972144.10214.22Honduras1866616.1592.18Mexico2312763.44336.08Puerto Rico875289.46133.15Totals 7570 18201.71/11 = 0.155aCapeding et al, Thailand component 12 bSabchareon et al 11 …”

Section: Resultsmentioning

confidence: 99%

“…Table 1 shows the numbers of children given vaccine by country 11-13 The numbers of 9 – 11 year-old vaccinated children in cells are estimates from larger age groups assuming that there was an even distribution of enrollees between age groups. The percent contribution of seronegatives to total vaccinated children are calculated using median 9 – 11 year country dengue antibody seroprevalence data from Coudeville et al.…”

Section: Resultsmentioning

confidence: 99%

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

Halstead

2018

Human Vaccines & Immunotherapeutics

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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.

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Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial

Cited by 722 publications

References 24 publications

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Zika virus disease: a current review of the literature

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

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