Author response: Efficacy profile of the CYD-TDV dengue vaccine revealed by Bayesian survival analysis of individual-level phase III data

Abstract

Background: Sanofi-Pasteur’s CYD-TDV is the only licensed dengue vaccine. Two phase three trials showed higher efficacy in seropositive than seronegative recipients. Hospital follow-up revealed increased hospitalisation in 2–5year-old vaccinees, where serostatus and age effects were unresolved. Methods: We fit a survival model to individual-level data from both trials, including year 1 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 against 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 & Melinda Gates Foundation, National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Royal Society. Clinical trial number: NCT01373281 and NCT01374516. Introduction Over 40% of the world population is at risk of dengue infection. An estimated 105 million infections and approximately 50 million symptomatic cases occur each year (Stanaway et al., 2016; Cattarino et al., 2020). Dengue disease is caused by four distinct viruses, termed serotypes (DENV1–4). Infection confers lifelong immunity to a homologous serotype, but against a heterologous serotype protective immunity is only temporary (St John and Rathore, 2019). Furthermore, secondary infection with a heterologous serotype drastically increases the likelihood of disease (St John and Rathore, 2019). Traditional vector control interventions have had little impact on dengue disease burden (Guzman et al., 2010) and no antiviral treatments yet exist. Several vaccine candidates are in development, but the only licensed vaccine is Sanofi-Pasteur’s CYD-TDV (marketed as Dengvaxia). CYDTDV is a live attenuated tetravalent chimeric vaccine, where genes for the structural proteins (E and prM) are taken from the four DENV serotypes, while the other proteins are based on the yellow fever Laydon et al. eLife 2021;10:e65131. DOI: https://doi.org/10.7554/eLife.65131 1 of 26 RESEARCH ARTICLE 17D vaccine strain. The vaccine has now been licensed in 21 countries and the EU. A phase two trial in 2012 (ClinicalTrials.gov number NCT00842530) (Sabchareon et al., 2012) reported moderate efficacy of 30.2% ( 13.4% to 56.6%) and showed the vaccine to be well tolerated and largely safe. Two large scale phase three trials followed: the CYD14 trial (ClinicalTrials.gov number NCT01373281) in South East Asia of 10,275 children aged 2–14 (Capeding et al., 2014), and the CYD15 trial (ClinicalTrials.gov number NCT01374516) in Latin America of 20,869 children aged 9–16 (Villar et al., 2015). After stratifying by age, participants were randomly assigned to vaccine or control arms in a 2:1 ratio, and vaccine doses were given at baseline then 6 and 12 months later. For a subset of participants (approximately 20% for CYD14% and 10% for CYD15), immunogenicity and prior dengue exposure was determined using baseline sera. Participants were actively surveilled by weekly phone calls for 25 months post-first dose (where any symptomatic disease was detected), after which surveillance was passive using routine hospital surveillance, (where only hospitalisations were detected). See (Capeding et al., 2014; Villar et al., 2015; Hadinegoro et al., 2015) for further details of the trial design. The CYD14 and CYD15 trials showed overall vaccine efficacies of 56.5% (43.8%–66.4%) and 60.8% (52.0%–68.0%) respectively, with efficacy varying significantly by serotype and prior exposure. However, in 2015, results from the first year of long-term follow up (Hadinegoro et al., 2015) showed that while the vaccine remained beneficial overall, the number of hospitalisations among 2– 5 year olds was significantly greater in vaccinees than in controls. A potential explanation for these results considered age as a proxy for serostatus (Aguiar and Stollenwerk, 2018), and that the vaccine may act as a ‘silent’ disease-free infection that primes host immunity (Ferguson et al., 2016; Flasche et al., 2016). Therefore, a seronegative child, who would ordinarily experience their first and relatively low-risk natural infection, would after vaccination instead experience a ‘secondary-like’ infection that is more predisposed to clinically apparent disease. Conversely, a child with a single prior natural infection would have a lower risk of disease when exposed to dengue post-vaccination, normally associated with tertiary and quaternary infection [Figure 1]. The immunogenicity subset was only a small fraction of the entire trial, and the estimated efficacy in seronegatives had wide confidence intervals indicating neither benefit nor harm, and so it was not possible to determine conclusively whether age or lack of prior exposure was the dominant factor in the increased hospitalisation of 2–5 year-old vaccinees. Further, it was not possible to retroactively expand the immunogenicity subset to determine prior dengue exposure, as Dengvaxia can elicit Figure 1. Model Schematic 1: vaccine as silent infection. Top row: unvaccinated individuals are naive, or infected with either: their first dengue infection with moderate disease risk; their second higher risk infection; or their third or fourth lower risk infection. Middle row: vaccinating seropositive individuals with a single prior infection lowers the disease risk associated with secondary infection to that associated with tertiary and quaternary infection. Bottom row: vaccinating naive (seronegative) individuals increases disease risk upon their first natural infection. Figure adapted from Ferguson et al., 2016 with permission. Laydon et al. eLife 2021;10:e65131. DOI: https://doi.org/10.7554/eLife.65131 2 of 26 Research article Epidemiology and Global Health