Detection of dengue cases by serological testing in a dengue vaccine efficacy trial: Utility for efficacy evaluation and impact of future vaccine introduction.
Dengue diagnosis confirmation and surveillance are widely based on serological assays to detect anti-dengue IgM or IgG antibodies since such tests are affordable/user-friendly. The World Health Organization identified serological based diagnosis as a potential tool to define probable dengue cases in the context of vaccine trials, while acknowledging that this may have to be interpreted with caution.



In a phase IIb randomized, placebo-controlled trial assessing the efficacy of a tetravalent dengue vaccine (CYD-TDV) in Thai schoolchildren, case definition was based on virological confirmation by either serotype-specific RT-PCRs or by NS1-antigen ELISA (Clinicaltrials.gov NCT00842530). Here, we characterized suspected dengue cases using IgM and IgG ELISA to assess their utility in evaluating probable dengue cases in the context of vaccine efficacy trials, comparing virologically-confirmed and serologically diagnosed dengue in the vaccine and placebo groups. Serologically probable cases were defined as: (1) IgM positive acute- or convalescent-phase samples, or (2) IgG positive acute-phase sample and ≥4-fold IgG increase between acute and convalescent-phase samples.



Serological diagnosis had good sensitivity (97.1%), but low specificity (85.1%) compared to virological confirmation. A high level of false positivity through serology diagnosis particularly in the 2 months post-vaccination was observed, and is most likely related to detection of the immune response to the dengue vaccine. This lack of specificity and bias with vaccination demonstrates the limitation of using IgM and IgG antibody responses to explore vaccine efficacy.



Reliance on serological assessments would lead to a significant number of false positives during routine clinical practice and surveillance following the introduction of the dengue vaccine.
Chief Medical Office, Sanofi Pasteur, Marcy l'Etoile, Lyon, France. Electronic address: Eric.Plennevaux@sanofipasteur.com.
Eric
E
Plennevaux
Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Arunee
A
Sabchareon
Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Kriengsak
K
Limkittikul
Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Pornthep
P
Chanthavanich
Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Chukiat
C
Sirivichayakul
Chief Medical Office, Sanofi Pasteur, Marcy l'Etoile, Lyon, France.
Annick
A
Moureau
Global Clinical Immunology, Sanofi Pasteur, Swiftwater, PA, United States.
Mark
M
Boaz
Clinical Sciences and Medical Affairs Asia, Sanofi Pasteur, Singapore.
T Anh
TA
Wartel
Chief Medical Office, Sanofi Pasteur, Marcy l'Etoile, Lyon, France.
Melanie
M
Saville
Clinical Sciences and Medical Affairs Asia, Sanofi Pasteur, Singapore.
Alain
A
Bouckenooghe
D000914:Antibodies, Viral / Q000097:blood*; D015982:Bias; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000175:diagnosis* / Q000517:prevention & control; D053059:Dengue Vaccines / Q000276:immunology / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005189:False Positive Reactions; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D012680:Sensitivity and Specificity; D012698:Serologic Tests; D013785:Thailand; D017361:Viral Nonstructural Proteins / Q000097:blood
D000914:Antibodies, Viral; D053059:Dengue Vaccines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C082515:NS1 protein, dengue-1 virus; D017361:Viral Nonstructural Proteins
Dengue; Flavivirus; Serology; Vaccine