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

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

Demonstrating vaccine effectiveness during a waning epidemic: A WHO/NIH meeting report on approaches to development and licensure of Zika vaccine candidates.

Since its peak in early 2016, the incidence of Zika virus (ZIKV) cases has declined to such low levels that Phase 3 field efficacy trials may be infeasible. While great progress was made to rapidly advance several vaccine candidates into Phase 1 and 2 clinical trials, in the absence of sustained viral transmission it may be difficult to evaluate the effectiveness of ZIKV vaccine candidates by conducting traditional clinical disease endpoint efficacy studies. However, ZIKV is still circulating at low levels in some areas and is likely to re-emerge in naïve populations or in sites of prior epidemics once population immunity wanes. Therefore, the public health need for a ZIKV vaccine remains. To facilitate continued ZIKV vaccine development efforts, the World Health Organization's Initiative for Vaccine Research and the National Institutes of Health's National Institute of Allergy and Infectious Diseases co-hosted a meeting of experts in March 2018 to identify strategies to demonstrate vaccine effectiveness in view of waning ZIKV disease incidence. This paper outlines points for consideration for developers, regulators, and other stakeholders working towards a licensed ZIKV vaccine. These deliberations may also be applicable to development of vaccines for other emerging infections where the size, unpredictability, and ephemeral nature of outbreaks makes clinical disease endpoint efficacy trials to demonstrate vaccine effectiveness infeasible

The future of Japanese encephalitis vaccination: expert recommendations for achieving and maintaining optimal JE control

Vaccines against Japanese encephalitis (JE) have been available for decades. Currently, most JE-endemic countries have vaccination programs for their at-risk populations. Even so, JE remains the leading recognized cause of viral encephalitis in Asia. In 2018, the U.S. Centers for Disease Control and Prevention and PATH co-convened a group of independent experts to review JE prevention and control successes, identify remaining scientific and operational issues that need to be addressed, discuss opportunities to further strengthen JE vaccination programs, and identify strategies and solutions to ensure sustainability of JE control during the next decade. This paper summarizes the key discussion points and recommendations to sustain and expand JE control

The long-term safety, public health impact, and cost-effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study

This is the final version of the article. Available from the publisher via the DOI in this record.Background: Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. Methods and Findings: The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%–25% (all simulations: –3%–34%) and in high-transmission settings (SP9 ≥ 70%) by 13%–25% (all simulations: 10%– 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively. The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines. Conclusions: Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccinSF and MJ received funding from WHO and Gavi, the Vaccine Alliance, to conduct this work. LC is a paid employee at Sanofi Pasteur. GM and JK were funded by the University of Western Australia, with computing resources provided by the Pawsey Supercomputing Centre, which is funded by the Australian Government and the Government of Western Australia. MR is funded by a Royal Society University Research Fellowship. NF, ID and DJL received research funding from the UK Medical Research Council, the UK NIHR under the Health Protection Research Unit initiative, NIGMS under the MIDAS initiative, and the Bill and Melinda Gates Foundation. IRB and DATC were funded by MIDAS Center Grant NIH/NIGMS U54-GM088491 and the Bill and Melinda Gates Foundation. DATC was also supported by NIH/NIAID R01-AI114703. TJH, IL, and CABP were funded by a Dengue Vaccine Initiative Grant to IL, NIH/NIAID R37 AI32042. THJ, IL, and KK were funded by MIDAS Center Grant NIH/NIGMS 1135 U54 GM111274. All other authors have received no specific funding to conduct this work. The funders had no role in the study design, data analyses, decision to publish or preparation of the manuscript

Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine.

The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE's working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses

Ninety-eight Percent Too Close for Comfort: The Chimpanzee Challenge to Human Uniqueness and Definition of Self

Genetic data suggests we share approximately 97 percent of our DNA with chimpanzees, so the question of what it means to be human becomes more difficult. Some argue culture, some language, some consciousness. How do we define ourselves with respect to chimpanzees? How is this demonstrated in popular culture? What are the effects of our self-identity on our relationships with animals? To answer these questions, the author observed human behavior toward animals in the San Francisco Zoo for one month. Methodology also includes interviews with Swarthmore College students on their relationships with animals, their knowledge of chimpanzees, and their feeling toward conservation efforts designed at protecting fundamental rights for all apes. Further, research on the early theory regarding the Self and the Other, as well as animal-human relationships, was conducted