Impact of Dengue Vaccination on Serological Diagnosis: Insights From Phase III Dengue Vaccine Efficacy Trials.

Background: We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments. Methods: We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2-16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples. Results: There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 17673 other febrile episodes (11668 and 6005, respectively). Compared with VCD, the sensitivity and specificity of probable dengue definition were 93.1% and 77.2%, respectively. Overall positive and negative predictive values were 22.9% and 99.5%, respectively, reflecting the much lower probability of correctly confirming probable dengue in a population including a vaccinated cohort. Vaccination-induced bias toward false-positive diagnosis was more pronounced among individuals seronegative at baseline. Conclusions: Caution will be required when interpreting IgM and IgG data obtained during routine surveillance in those vaccinated with CYD-TDV. There is an urgent need for new practical, dengue-specific diagnostic algorithms now that CYD-TDV is approved in a number of dengue-endemic countries. Clinical Trials Registration: NCT01373281 and NCT01374516.

Detection of vaccine-derived polioviruses in Mexico using environmental surveillance.

BACKGROUND: Early detection and control of vaccine-derived poliovirus (VDPV) emergences are essential to secure the gains of polio eradication. METHODS: Serial sewage samples were collected in 4 towns of Mexico before, throughout, and after the May 2010 oral poliovirus vaccine (OPV) mass immunization campaign. Isolation and molecular analysis of polioviruses from sewage specimens monitored the duration of vaccine-related strains in the environment and emergence of vaccine-derived polioviruses in a population partially immunized with inactivated poliovirus vaccine (IPV). RESULTS: Sabin strains were identified up to 5-8 weeks after the campaign in all towns; in Aguascalientes, 1 Sabin 3 was isolated 16 weeks after the campaign, following 7 weeks with no Sabin strains detected. In Tuxtla Gutiérrez, type 2 VDPV was isolated from 4 samples collected before and during the campaign, and type 1 VDPV from 1 sample collected 19 weeks afterward. During 2009-2010, coverage in 4 OPV campaigns conducted averaged only 57% and surveillance for acute flaccid paralysis (AFP) was suboptimal (AFP rate<1 per 100,000 population<15 years of age) in Tuxtla Gutierrez. CONCLUSIONS: VDPVs may emerge and spread in settings with inadequate coverage with IPV/OPV vaccination. Environmental surveillance can facilitate early detection in these settings.

Immunobridging efficacy of a tetravalent dengue vaccine against dengue and against hospitalized dengue from children/adolescents to adults in highly endemic countries.

BACKGROUND: The recombinant tetravalent live-attenuated dengue vaccine based on the YF 17D vaccine virus backbone (CYD-TDV) demonstrated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype from month 13 to month 25 (VCD-DENV-AnyM13→M25) in the CYD14 (2-14-y-olds) and CYD15 (9-16-y-olds) phase 3 trials. Fifty percent plaque reduction neutralization test (PRNT50) titers are a potential surrogate for immunobridging VE to adults. METHODS: Using PRNT50 calibration datasets, we applied immunobridging approaches using baseline and/or M13 PRNT50 titers to estimate VE against VCD-DENV-AnyM0→M25 and against hospitalized VCD (HVCD)-DENV-AnyM0→M72 in hypothetical 18-45-y-old and 46-50-y-old CYD14 and CYD15 cohorts. RESULTS: Baseline and M13 geometric mean PRNT50 titers were greater in 18-45-y-olds and in 46-50-y-olds vs 9-16-y-olds for most comparisons. Estimated VE (95% CIs against VCD-DENV-AnyM0→M25 ranged from 75.3% to 90.9% (52.5% to 100%) for 18-45-y-olds and 74.8% to 92.0% (53.4% to 100%) for 46-50-y-olds. Estimated VE (95% CIs) against HVCD-DENV-AnyM0→M72 ranged from 58.8% to 78.1% (40.9 to 98.9%) for 18-45-y-olds and 57.2% to 78.4% (40.5 to 97.6%) for 46-50-y-olds. Corresponding predictions among baseline-seropositive individuals yielded comparable or higher VE estimates. CONCLUSIONS: VE M0→M25 against DENV-Any and VE against HVCD-DENV-AnyM0→M72 are both expected to be higher in 18-45 and 46-50-y-olds vs CYD14 and CYD15 9-16-y-olds.