Efficacy profile of the CYD-TDV dengue vaccine revealed by Bayesian survival analysis of individual-level Phase III data

  1. Daniel J Laydon  Is a corresponding author
  2. Ilaria Dorigatti
  3. Wes R Hinsley
  4. Gemma L Nedjati-Gilani
  5. Laurent Coudeville
  6. Neil M Ferguson
  1. Imperial College London, United Kingdom
  2. Sanofi-Pasteur, France

Abstract

Background: Sanofi-Pasteur’s CYD-TDV is the only licensed dengue vaccine. Two phase III trials showed higher efficacy in seropositive than seronegative recipients. Hospital follow-up revealed increased hospitalisation in 2-5-year-old vaccinees, where serostatus and age effects were unresolved.

Methods: We fit a survival model to individual-level data from both trials, including year one of hospital follow-up. We determine efficacy by age, serostatus, serotype and severity, and examine efficacy duration and vaccine action mechanism.

Results: Our modelling indicates that vaccine-induced immunity is long-lived in seropositive recipients, and therefore that vaccinating seropositives gives higher protection than two natural infections. Long-term increased hospitalisation risk outweighs short-lived immunity in seronegatives. Independently of serostatus, transient immunity increases with age, and is highest against serotype 4. Benefit is higher in seropositives, and risk enhancement is greater in seronegatives, against hospitalised disease than febrile disease.

Conclusions: Our results support vaccinating seropositives only. Rapid diagnostic tests would enable viable “screen-then-vaccinate” programs. Since CYD-TDV acts as a silent infection, long-term safety of other vaccine candidates must be closely monitored.

Funding: Bill and Melinda Gates Foundation, National Institute for Health Research, UK Medical Research Council, Wellcome Trust.

Data availability

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com. Additional details of the trial designs and data can be found in Sridhar et al (NEJM 2018).All model code is available at https://github.com/dlaydon/DengVaxSurvival, which is linked to in the manuscript. This repository also contains simulated data, generated to closely match the trial data, giving comparable case numbers across strata. When our model is fitted to the simulated data, the resulting parameter estimates closely approximate the results presented in this analysis.

Article and author information

Author details

  1. Daniel J Laydon

    Department of Infectious Disease Epidemiology, MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom
    For correspondence
    d.laydon@imperial.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4270-3321
  2. Ilaria Dorigatti

    Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9959-0706
  3. Wes R Hinsley

    Department of Infectious Disease Epidemiology, MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Gemma L Nedjati-Gilani

    Department of Infectious Disease Epidemiology, MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Laurent Coudeville

    Sanofi-Pasteur, Sanofi-Pasteur, Lyon, France
    Competing interests
    Laurent Coudeville, Laurent Coudeville is employed by Sanofi-Pasteur.
  6. Neil M Ferguson

    MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.

Funding

Bill and Melinda Gates Foundation

  • Daniel J Laydon
  • Gemma L Nedjati-Gilani
  • Neil M Ferguson

National Institute for Health Research (NIHR: PR-OD-1017-20002)

  • Daniel J Laydon
  • Gemma L Nedjati-Gilani
  • Neil M Ferguson

Medical Research Council (MR/R015600/1)

  • Daniel J Laydon
  • Ilaria Dorigatti
  • Wes R Hinsley
  • Gemma L Nedjati-Gilani
  • Neil M Ferguson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ben S Cooper, Mahidol University, Thailand

Version history

  1. Received: November 24, 2020
  2. Accepted: June 29, 2021
  3. Accepted Manuscript published: July 2, 2021 (version 1)
  4. Version of Record published: July 29, 2021 (version 2)
  5. Version of Record updated: August 4, 2021 (version 3)

Copyright

© 2021, Laydon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Daniel J Laydon
  2. Ilaria Dorigatti
  3. Wes R Hinsley
  4. Gemma L Nedjati-Gilani
  5. Laurent Coudeville
  6. Neil M Ferguson
(2021)
Efficacy profile of the CYD-TDV dengue vaccine revealed by Bayesian survival analysis of individual-level Phase III data
eLife 10:e65131.
https://doi.org/10.7554/eLife.65131

Further reading

    1. Epidemiology and Global Health
    Victoria P Mak, Kami White ... Loic Le Marchand
    Research Article Updated

    Background:

    The Coronavirus Disease of 2019 (COVID-19) has impacted the health and day-to-day life of individuals, especially the elderly and people with certain pre-existing medical conditions, including cancer. The purpose of this study was to investigate how COVID-19 impacted access to cancer screenings and treatment, by studying the participants in the Multiethnic Cohort (MEC) study.

    Methods:

    The MEC has been following over 215,000 residents of Hawai‘i and Los Angeles for the development of cancer and other chronic diseases since 1993–1996. It includes men and women of five racial and ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and White. In 2020, surviving participants were sent an invitation to complete an online survey on the impact of COVID-19 on their daily life activities, including adherence to cancer screening and treatment. Approximately 7,000 MEC participants responded. A cross-sectional analysis was performed to investigate the relationships between the postponement of regular health care visits and cancer screening procedures or treatment with race and ethnicity, age, education, and comorbidity.

    Results:

    Women with more education, women with lung disease, COPD, or asthma, and women and men diagnosed with cancer in the past 5 years were more likely to postpone any cancer screening test/procedure due to the COVID-19 pandemic. Groups less likely to postpone cancer screening included older women compared to younger women and Japanese American men and women compared to White men and women.

    Conclusions:

    This study revealed specific associations of race/ethnicity, age, education level, and comorbidities with the cancer-related screening and healthcare of MEC participants during the COVID-19 pandemic. Increased monitoring of patients in high-risk groups for cancer and other diseases is of the utmost importance as the chance of undiagnosed cases or poor prognosis is increased as a result of delayed screening and treatment.

    Funding:

    This research was partially supported by the Omidyar 'Ohana Foundation and grant U01 CA164973 from the National Cancer Institute.

    1. Epidemiology and Global Health
    Gayathri Nagaraj, Shaveta Vinayak ... Dimpy P Shah
    Research Article Updated

    Background:

    Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.

    Methods:

    This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.

    Results:

    1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.

    Conclusions:

    Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.

    Funding:

    This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.

    Clinical trial number:

    CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.