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BACKGROUND: Puerto Rico began screening blood donations for Zika virus (ZIKV) RNA using nucleic acid amplification technology (NAT) on April 3, 2016. Follow-up of positive donors was used to assess viral and serologic marker dynamics through the early stages of ZIKV infection and estimate incidence in the Puerto Rico population. METHODS: Individual donations from volunteer blood donors were screened for the presence of ZIKV using cobas(®) Zika nucleic acid testing (NAT). Positive samples were further tested to confirm infection, estimate viral load, and identify ZIKV-specific antibodies by IgM antibody capture ZIKV ELISA. Donations positive in simulated minipools were compared to those detectable only by individual donation NAT with respect to viral load and ZIKV IgM status to evaluate the infection stage. A three step analysis process was used to estimate the mean duration of NAT-reactivity of ZIKV in human plasma and to update the 2016 annual incidence estimate of ZIKV infections. FINDINGS: 52,942 blood donations in Puerto Rico were screened for ZIKV and 339 confirmed NAT positive (NAT+) donations were detected. IgM negative index donations had markedly higher mean viral loads (1·1 × 10(6) vs 8·3 × 10(4) IU/ml) and higher proportions (194 of 209 [93%] IgM negative/Minipool positive versus 29 of 110 [26%] IgM positive/minipool positive) of simulated minipool positive results. The rate of donations detectible only by individual donation NAT and that were IgM+ increased as the epidemic evolved. The mean duration of NAT-detectability was estimated at 11.70 (95% CI 10.06 – 14.36) days. Applying this detection period to the observed rate of NAT+ donations yielded a ZIKV seasonal incidence estimate of 768,101 infections in a population of 3,638,773 in 2016 [21.1% (95% CI 18.1% – 24.1%)]. INTERPRETATION: Characterization of early ZIKV infection is important for blood safety, since infectivity and utility of screening method likely correlate with viral load and serological stages of infection. Our findings also have important implications for diagnostic testing, public health surveillance and epidemiology, including estimating that ~21% of the PR population was infected during the 2016 outbreak. FUNDING: This project has been funded with Federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, under Contract #HHSO100201600010C, and by NHLBI REDS-III Central Lab Contract #HHSN268201100001I. more...

Emerging and re-emerging infectious diseases are an expanding global threat to public health, security, and economies. Increasing populations, urbanization, deforestation, climate change, anti-vaccination movements, war, and international travel are some of the contributing factors to this trend. The recent Ebola, MERS-CoV, and Zika outbreaks demonstrated we are insufficiently prepared to respond with proven safe and effective countermeasures (i.e., vaccines and therapeutics). The State University of New York Upstate Medical University and the Trudeau Institute convened a summit of key opinion and thought leaders in the life sciences and biomedical research and development enterprises to explore global biopreparedness challenges, take an inventory of existing capabilities and capacities related to preparation and response, assess current "gaps," and prospect what could be done to improve our position. Herein we describe the summit proceedings, "Translational Immunology Supporting Biomedical Countermeasure Development for Emerging Vector-borne Viral Diseases," held October 2-3, 2018, at the Trudeau Institute in Saranac Lake, NY. more...

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a “rescue treatment” to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults. more...

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. more...

BACKGROUND: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. METHODS: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. RESULTS: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. CONCLUSION: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue. ispartof: BMC MEDICAL RESEARCH METHODOLOGY vol:18 issue:1 ispartof: location:England status: published more...

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials., Author summary Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective, and early recognition of severe dengue and timely supportive care remain the only means to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding deployment of such vaccines or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers, vaccine developers, and public health specialists to develop endpoints. After two working group meetings and discussions at international meetings, the Delphi methodology was used to clarify and further develop endpoints such that 70% or greater agreement was reached on most endpoint definitions including moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. The process identified areas for further evaluation and standardization within the context of ongoing clinical studies. The endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials. more...

Dengue virus infections are a major cause of febrile illness that significantly affects individual and societal productivity and drives up health care costs principally in the developing world. Two dengue vaccine candidates are in advanced clinical efficacy trials in Latin America and Asia, and another has been licensed in more than fifteen countries but its uptake has been limited. Despite these advances, standardized metrics for comparability of protective efficacy between dengue vaccines remain poorly defined. The Dengue Illness Index (DII) is a tool that we developed thru refinement of previous similar iterations in an attempt to improve and standardize the measurement of vaccine and drug efficacy in reducing moderate dengue illness. The tool is designed to capture an individual’s overall disease experience based on how the totality of their symptoms impacts their general wellness and daily functionality. We applied the DII to a diary card, the Dengue Illness Card (DIC), which was examined and further developed by a working group. The card was then refined with feedback garnered from a Delphi methodology-based query that addressed the adequacy and applicability of the tool in clinical dengue research. There was overall agreement that the tool would generate useful data and provide an alternative perspective to the assessment of drug or vaccine candidates, which in the case of vaccines, are assessed by their reduction in any virologically confirmed dengue of any severity with a focus on the more severe. The DIC needs to be evaluated in the field in the context of vaccine or drug trials, prospective cohort studies, or during experimental human infection studies. Here, we present the final DIC resulting from the Delphi process and offer its further development or use to the dengue research community., Author summary The Dengue Illness Index (DII) is a tool that was developed to improve and standardize the measurement of vaccine and drug efficacy in reducing moderate dengue illness by capturing the overall subjective disease experience of an individual based on how the totality of their symptoms impacts their wellness and daily functionality. The DII was applied to a diary card, the Dengue Illness Card (DIC), which was examined and further developed by a working group. The resulting DIC was then refined with feedback garnered from a Delphi methodology-based query that addressed the adequacy and applicability of the card in dengue research. Here, we report on the Delphi results and present the final DIC. more...

Dengue is the most common arboviral disease of humans. There is an unmet need for a therapeutic intervention that reduces the duration and severity of dengue symptoms and diminishes the likelihood of severe complications. To this end, there are active discovery efforts in industry and academia to develop interventions, with a focus on small molecule inhibitors of dengue virus replication that are suitable for therapy or chemoprophylaxis. Advancements in animal models of dengue virus infection together with the possibility of a dengue human infection model have further enhanced the platform for dengue drug discovery. Whilst drug discovery efforts gestate, there are ongoing clinical research designed to benefit today's patients, including trials of supportive care interventions, and descriptive studies that should improve the ability of clinicians to make an accurate diagnosis early in the illness course and to identify patients most at risk of progression to severe disease. This review provides a state of the art summary of dengue drug discovery, clinical trials, and supportive allied research and reflects discussions at the 2nd International Dengue Therapeutics Workshop held in Ho Chi Minh City, Vietnam, in December 2013. more...

Dengue is an expanding public health problem in tropical and subtropical regions. An estimated 390 million infections occur annually, of which 96 million are clinically overt [1]. Transmission occurs between humans and Aedes vector species in endemic, hyperendemic, and/or epidemic patterns [2]. Multiple dengue virus (DENV) types cocirculate in most endemic regions with seasonal predominance of 1 or 2 DENV types in any given area [3]. The increasing dengue burden is driven by several factors including increased urbanization, world population growth, increased international trade and travel, and changes in human behavior that increase mosquito breeding sites (eg, discarded tires and plastic containers). Vector control has been largely unsuccessful at reducing transmission. There are no anti-DENV therapeutics to protect against or treat dengue infection and disease. Although there are numerous vaccine candidates in preclinical and clinical development, none have been licensed for use. The world needs a dengue vaccine but several development challenges confront the field. First and foremost is the requirement to develop a multivalent vaccine to account for the multiple DENV types (DENV 1–4) capable of causing disease and death. Second are the complex immunologic processes that occur after wild-type infection. These processes are not well understood, making it difficult to predict what a protective immune response may be and to make vaccine development decisions [4, 5]. Third, no validated small animal or nonhuman primate model of dengue disease comprehensively approximates the human in vivo infection and disease experience [6, 7]. For these reasons and others, no immune correlate of protection has been defined. Because of this, vaccine developers are required to make inferences about a candidate's potential for clinical benefit based on its ability to protect a nonhuman primate from viremia after wild-type challenge and by measuring immunogenicity (ie, DENV type-specific neutralizing antibodies) in small to moderate-sized phase 1 and 2 studies. Dengue vaccinologists require development tools, which more accurately predict an immune profile's ability to prevent or significantly attenuate disease after natural infection [8–10]. The limited success of the world's first dengue vaccine efficacy trial underscores this need [11]. For this reason, vaccine and drug developers, immunologists, and entomologists are exploring the idea of a dengue human infection model (DHIM). The concept is to consistently produce, in healthy volunteers, an uncomplicated illness with clinical, biochemical, and immunologic findings consistent with dengue. The concept of a DHIM is not novel. The literature describes the development and use of DHIMs since the early 1900s [12–23]. Hundreds of volunteers have been experimentally infected with DENVs by means of various methods (ie, needle, mosquito) and administration strategies (ie, inoculation into subcutaneous space, mucous membrane exposure). Numerous seminal scientific discoveries and observations have been made using experimental human dengue infection including (but not limited to) the following: (1) identifying the viral etiology of dengue; (2) identifying transmission mechanisms; (3) defining viral incubation periods in mosquitoes and humans; (4) defining the period of infectivity in mosquito and humans; (5) describing the clinical and clinical laboratory features of uncomplicated dengue illness; (6) identifying the existence of multiple DENV types; (7) documenting the development of homotypic immunity after infection; (8) documenting the development of transient, heterotypic, cross-protective, and disease-attenuating immunity against other DENV types after infection with a single type; (9) demonstrating the development of anti-DENV neutralizing antibodies after exposure; and (10) supporting the development of early dengue vaccine candidates. Recent dengue human infection studies have been used to explore serial ultrasonographic findings, characteristics of cellular immune responses, and the clinical and clinical laboratory findings after experimental infection of flavivirus-naive and previously vaccinated (experimental candidate) individuals [24–27]. In 2011, the Walter Reed Army Institute of Research (WRAIR) and the National Institutes of Health cosponsored a workshop designed to reintroduce the DHIM concept. The workshop was attended by dengue vaccine and drug developers, immunologists, entomologists, regulatory affairs personnel, and developers and users of the controlled malaria human infection model. This supplement reviews and documents the proceedings of that meeting, as follows. Ken Eckels and Arthur Lyons of the WRAIR discuss aspects of the dengue human infection experiments executed by the US Army between 1999 and 2001. Eckels reviews the manufacturing and production process of DENV strains, DENV human infection strain candidate pedigree, and the attenuation process. Regulatory requirements and the process of creating and submitting investigational new drug applications to US Food and Drug Administration are also touched on. Lyons provides an overview of the clinical, biochemical, radiologic, virologic, and serologic findings and observations made by the WRAIR group during 2 human infection experiments (1999–2001). In experiment 1, investigators explored potential DENV human infection strains in flavivirus-naive individuals and selected DENV-1 and DENV-3 strains for continued testing based on safety and reactogenicity performance parameters. In experiment 2, investigators called back previous recipients of experimental tetravalent live virus dengue vaccines to receive challenge with either DENV-1 or DENV-3. Volunteers with postvaccination neutralizing antibodies against DENV-1 were assigned to be challenged with the DENV-1 human infection strain, and previous vaccine recipients who demonstrated a DENV-3 neutralizing antibody response were assigned to challenge with the DENV-3 strain. Two flavivirus naive controls were assigned to each group. Four articles describe the results of these experiments [24–27]. Timothy Endy from the State University of New York Upstate Medical University, Syracuse, discusses proposed DHIM performance parameters and reviews influenza human infection model performance and past dengue human infection experiments. He also proposes clinical and biochemical parameters that a DHIM should achieve to adequately support drug and vaccine development and basic science efforts. Alan Rothman from the University of Rhode Island, Providence, reviews aspects of dengue immunology and its complexities. He also discusses potential uses of a DHIM to explore dengue immunology, with a focus on the exploration of immune correlates of protection, and reviews the limitations of a DHIM tool to explore basic immunology concepts. James Whitehorn of the London School of Hygiene and Tropical Medicine, United Kingdom, describes the concepts presented at the meeting by Cameron Simmons, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. Whitehorn also describes the use of a DHIM to support anti-dengue drug development; reviews the case for developing anti-dengue therapeutics, touching on current status; discusses the immunologic mechanism for how a prophylactic or therapeutic may work, and reviews DHIM limitations. Christopher Mores, Louisiana State University, Baton Rouge, expands on the concept presented at the meeting by Jason Richardson, WRAIR that a mosquito-delivered dengue human infection strain could improve a DHIM. He discussed previous experience with mosquito-based human infection models and its immunologic implications and reviews the lessons learned and challenges of using mosquitoes in the context of human infection models and a DHIM specifically. Michelle Spring, Armed Forces Research Institute of Medical Science, Bangkok, Thailand reviews the Controlled Human Malaria Infection Model (CHMI) as presented during the meeting by Mark Polhemus, Veterans Administration Medical Center, Syracuse, New York. The CHMI is now considered one of the most characterized and reproducible human challenge models, and it is commonly used to conduct an initial assessment of the efficacy of malaria vaccines before further evaluation in field studies and/or pediatric populations. Spring reviews how vaccine efficacy demonstrated using the CHMI model paralleled efficacy demonstrated in field studies, validating the utility of the human challenge model as an initial vaccine evaluation tool. The growing global health burden of dengue disease and the ongoing challenges in developing vaccines and drugs against this infection have underscored the need for better models to elucidate the mechanism of dengue pathogenesis and evaluate interventions before large field efficacy trials. If successful, a DHIM could be used to study clinical and immunologic pathogenesis, explore virus-vector-host interactions, and inform vaccine and drug developers as they make development decisions. A DHIM could facilitate vaccine immunogenicity assay development and the optimization, qualification, and validation processes required for these assays to support regulatory strategies and product licensing applications. It could also help define a correlate and surrogate of protection, and once drug or vaccine safety and efficacy was proven in field testing in endemic settings, it could assist the process of bridging these data to nonendemic populations who may benefit from a therapeutic or vaccine (eg, travelers and military personnel). more...

There is an unmet need for a dengue vaccine to further prevent the spread of this disease and contain the growing pandemic. To this end several vaccine companies and academic groups are actively pursuing the development of a tetravalent vaccine to prevent dengue. In the last few years progress has been made in this area, including the first results of a vaccine efficacy trial and improved understanding of the immune responses to the infection. Despite this progress, development of dengue vaccines faces important challenges including the need for a vaccine that induces balanced immune responses against all dengue strains and an incomplete understanding of the mechanism(s) of protection against infection and disease. This is a summary of a Consultation on dengue vaccines held in June 26–28, 2013 by the National Institute of Allergy and Infectious Diseases (part of the US National Institutes of Health) and the Dengue Vaccine Initiative (part of the International Vaccine Institute). The primary goal of this consultation was to review the progress in dengue vaccine development, evaluate the known mechanism of protection of dengue vaccines and discuss avenues for future research. more...

Dengue is a systemic arthropod-borne viral disease of major global public health importance. At least 2.5 billion people who live in areas of the world where dengue occurs are at risk of developing dengue fever (DF) and its severe complications, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Repeated reemergences of dengue in sudden explosive epidemics often cause public alarm and seriously stress healthcare systems. The control of dengue is further challenged by the lack of effective therapies, vaccines, and point-of-care diagnostics. Despite years of study, even its pathogenic mechanisms are poorly understood. This article discusses recent advances in dengue research and identifies challenging gaps in research on dengue clinical evaluation, diagnostics, epidemiology, immunology, therapeutics, vaccinology/clinical trials research, vector biology, and vector ecology. Although dengue is a major global tropical pathogen, epidemiologic and disease control considerations in this article emphasize dengue in the Americas. more...