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The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.).

CYD-TDV protected against severe VCD and hospitalization for VCD for 5 years in persons who had exposure to dengue before vaccination, and there was evidence of a higher risk of these outcomes in vaccinated persons who had not been exposed to dengue. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 .).

Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2-14 y (CYD14) and 9-16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence features of dengue viruses (DENVs). DENV premembrane/envelope amino acid sequences from VCD endpoint cases were aligned with the vaccine insert sequences, and extensions of the proportional hazards model were applied to assess variation in VE with amino acid mismatch proportion distances from vaccine strains, individual amino acid residues, and phylogenetic genotypes. In CYD14, VE against VCD of any serotype (DENV-Any) decreased significantly with increasing amino acid distance from the vaccine, whereas in CYD15, VE against DENV-Any was distance-invariant. Restricting to the common age range and amino acid distance range between the trials and accounting for differential VE by serotype, however, showed no evidence of VE variation with distance in either trial. In serotype-specific analyses, VE against DENV4 decreased significantly with increasing amino acid distance from the DENV4 vaccine insert and was significantly greater against residue-matched DENV4 at eight signature positions. These effects were restricted to 2- to 8-y-olds, potentially because greater seropositivity of older children at baseline might facilitate a broader protective immune response. The relevance of an antigenic match between vaccine strains and circulating DENVs was also supported by greater estimated VE against serotypes and genotypes for which the circulating DENVs had shorter amino acid sequence distances from the vaccine.

This study defined the genetic epidemiology of dengue viruses (DENV) in two pivotal phase III trials of the tetravalent dengue vaccine, CYD-TDV, and thereby enabled virus genotype-specific estimates of vaccine efficacy (VE). Envelope gene sequences (n = 661) from 11 DENV genotypes in 10 endemic countries provided a contemporaneous global snapshot of DENV population genetics and revealed high amino acid identity between the E genes of vaccine strains and wild-type viruses from trial participants, including at epitope sites targeted by virus neutralising human monoclonal antibodies. Post-hoc analysis of all CYD14/15 trial participants revealed a statistically significant genotype-level VE association within DENV-4, where efficacy was lowest against genotype I. In subgroup analysis of trial participants age 9–16 years, VE estimates appeared more balanced within each serotype, suggesting that genotype-level heterogeneity may be limited in older children. Post-licensure surveillance is needed to monitor vaccine performance against the backdrop of DENV sequence diversity and evolution.

The overall benefit-risk remained positive in those aged ≥9 years up to year 4, although the protective effect was lower in years 3 and 4 than in years 1 and 2.

Background Invasive meningococcal disease (IMD) causes high fatality in untreated patients alongside long-term sequelae in 20% survivors. For a comprehensive assessment of epidemiology, an analysis of these sequelae is required. This study aims to investigate the epidemiology of disease between 2008 and 2017 including a description of the sequelae, through the analysis of data collected from the UK Clinical Practice Research Datalink (CPRD) linked with data from the Hospital Episode Statistics (HES), and Office for National Statistics (ONS) mortality registry data. Methods This was a 10-year retrospective observational cohort study designed to describe the incidence, case-fatality rate (CFR) and occurrence of sequelae due to meningococcal disease, in the UK between 2007 and 2017 using data from the UK CPRD-HES-ONS. Cases were identified and matched on age, gender, date of diagnosis of IMD and followed-up-time with a control group without IMD. Demographics, clinical characteristics, mortality, and IMD-related sequelae were examined for IMD cases and compared with matched controls for a more comprehensive assessment. Results The study analysed 640 IMD patients with majority of the cases diagnosed (76.9%) in a hospital setting. Age-group analysis showed a decrease in the incidence rate of IMD in patients aged <1 year (30.4 – 7.5%) and an increase in those >50 years (10.4 – 27.8%). CFR was slightly higher among females, toddlers, and adults >50 years. No significant change in CFR was observed over study period. Case-control study showed a higher number of IMD sequelae among cases compared to age- and gender-matched controls, especially in those ≥ 50 years. Conclusion The study showed that, despite a relatively low incidence rate, IMD is responsible for a high CFR, namely in older age groups and by a high number of IMD sequelae. The study showed that leveraging data from existing databases can be used to complement surveillance data in truly assessing the epidemiology of IMD. Despite the availability of routine vaccination programs, IMD still poses a significant burden in the healthcare system of the UK. Optimization of vaccination programs may be required to reduce the disease burden.

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