Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

What Have We Learned From the Typhoid Fever Surveillance in Africa Program?

The Typhoid Fever Surveillance in Africa Program (TSAP) was established in 2009 to fill the data void concerning invasive Salmonella disease in sub-Saharan Africa, and to specifically estimate the burden of bloodstream infections caused by the key pathogen, Salmonella enterica serovar Typhi. TSAP has achieved this ambitious target, finding high incidences of typhoid fever in both rural and urban populations in several countries in sub-Saharan Africa. The results of TSAP will undoubtedly dictate the direction of future typhoid fever research in Africa, and at last provides a key piece of the disease burden jigsaw puzzle. With the dawn of new Vi conjugate vaccines against Salmonella Typhi, the next priority for the typhoid community must be providing the required data on these vaccines so they can be licensed and provided to those in high-risk groups and locations across sub-Saharan Africa

Estimating the proportion of vaccine-induced hospitalized dengue cases among Dengvaxia vaccinees in the Philippines

Background: Dengvaxia was used in the Philippines to vaccinate 9-10-year-old school children, living in areas highly endemic for dengue. After about 830,000 had received at least 1 of 3 recommended doses, risks of enhanced disease in dengue-naïve vaccinees were reported. Methods: We used Phase 3 trial data to derive the proportions of cases of hospitalised and severe dengue that might have been prevented by the Philippines vaccination programme and, among those cases that may occur in vaccinees, what proportions are likely to arise in those who were seropositive or seronegative for dengue at the time of first vaccination and what proportion in the latter group may be enhanced disease attributable to the vaccine. Results: Assuming about 15% of vaccinees were dengue naïve at vaccination and the effects of the vaccine are independent of the number of doses received, we estimate that, in the 5 years following vaccination, the number of cases of severe disease in the vaccinated population will be reduced by about 70%. Among vaccinees who do develop severe disease, about half the cases will be due to vaccine breakthrough in seropositive vaccinees, and about a quarter will be excess cases in seronegative vaccinees that will have occurred as a consequence of vaccination. Conclusions: Overall, the Philippine dengue vaccination programme will likely prevent a substantial number of severe dengue cases and, among those that do occur, the majority are likely to be breakthrough disease in seropositive vaccinees and a minority attributable to the excess risk of enhanced disease in seronegative vaccinees.</ns4:p

Review of data and knowledge gaps regarding yellow fever vaccine-induced immunity and duration of protection

Abstract Yellow fever (YF) virus is a mosquito-borne flavivirus found in Sub-Saharan Africa and tropical South America. The virus causes YF, a viral hemorrhagic fever, which can be prevented by a live-attenuated vaccine, strain 17D. Despite the vaccine being very successful at decreasing disease risk, YF is considered a re-emerging disease due to the increased numbers of cases in the last 30 years. Until 2014, the vaccine was recommended to be administered with boosters every 10 years, but in 2014 the World Health Organization recommended removal of booster doses for all except special populations. This recommendation has been questioned and there have been reports of waning antibody titers in adults over time and more recently in pediatric populations. Clearly, the potential of waning antibody titers is a very important issue that needs to be carefully evaluated. In this Perspective, we review what is known about the correlate of protection for full-dose YF vaccine, current information on waning antibody titers, and gaps in knowledge. Overall, fundamental questions exist on the durability of protective immunity induced by YF vaccine, but interpretation of studies is complicated by the use of different assays and different cut-offs to measure seroprotective immunity, and differing results among certain endemic versus non-endemic populations. Notwithstanding the above, there are few well-characterized reports of vaccine failures, which one would expect to observe potentially more with the re-emergence of a severe disease. Overall, there is a need to improve YF disease surveillance, increase primary vaccination coverage rates in at-risk populations, and expand our understanding of the mechanism of protection of YF vaccine

Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness.

Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle-income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine's effectiveness and safety and, where appropriate and possible, enhance their surveillance systems accordingly. Targeted studies are needed, especially to better understand the effects of vaccinating seronegative individuals

Zika vaccines and therapeutics: landscape analysis and challenges ahead.

BACKGROUND: Various Zika virus (ZIKV) vaccine candidates are currently in development. Nevertheless, unique challenges in clinical development and regulatory pathways may hinder the licensure of high-quality, safe, and effective ZIKV vaccines. DISCUSSION: Implementing phase 3 efficacy trials will be difficult given the challenges of the spatio-temporal heterogeneity of ZIKV transmission, the unpredictability of ZIKV epidemics, the broad spectrum of clinical manifestations making a single definite endpoint difficult, a lack of sensitive and specific diagnostic assays, and the need for inclusion of vulnerable target populations. In addition to a vaccine, drugs for primary prophylaxis, post-exposure prophylaxis, or treatment should also be developed to prevent or mitigate the severity of congenital Zika syndrome. CONCLUSION: Establishing the feasibility of immune correlates and/or surrogates are a priority. Given the challenges in conducting phase 3 trials at a time of waning incidence, human challenge trials should be considered to evaluate efficacy. Continued financial support and engagement of industry partners will be essential to the successful development, licensure, and accessibility of Zika vaccines or therapeutics