Developing vaccines against epidemic-prone emerging infectious diseases.
ABSTRACT: Today's world is characterized by increasing population density, human mobility, urbanization, and climate and ecological change. This global dynamic has various effects, including the increased appearance of emerging infectious diseases (EIDs), which pose a growing threat to global health security.Outbreaks of EIDs, like the 2013-2016 Ebola outbreak in West Africa or the current Ebola outbreak in Democratic Republic of the Congo (DRC), have not only put populations in low- and middle-income countries (LMIC) at risk in terms of morbidity and mortality, but they also have had a significant impact on economic growth in affected regions and beyond.The Coalition for Epidemic Preparedness Innovation (CEPI) is an innovative global partnership between public, private, philanthropic, and civil society organizations that was launched as the result of a consensus that a coordinated, international, and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemics.CEPI is focusing on supporting candidate vaccines against the World Health Organization (WHO) Blueprint priority pathogens MERS-CoV, Nipah virus, Lassa fever virus, and Rift Valley fever virus, as well as Chikungunya virus, which is on the WHO watch list. The current vaccine portfolio contains a wide variety of technologies, ranging across recombinant viral vectors, nucleic acids, and recombinant proteins. To support and accelerate vaccine development, CEPI will also support science projects related to the development of biological standards and assays, animal models, epidemiological studies, and diagnostics, as well as build capacities for future clinical trials in risk-prone contexts.
Project description:The filoviruses Ebola virus and Marburg virus are among the most dangerous pathogens in the world. Both viruses cause viral hemorrhagic fever, with case fatality rates of up to 90%. Historically, filovirus outbreaks had been relatively small, with only a few hundred cases reported. However, the recent West African Ebola virus outbreak underscored the threat that filoviruses pose. The three year-long outbreak resulted in 28,646 Ebola virus infections and 11,323 deaths. The lack of Food and Drug Administration (FDA) licensed vaccines and antiviral drugs hindered early efforts to contain the outbreak. In response, the global scientific community has spurred the advanced development of many filovirus vaccine candidates. Novel vaccine platforms, such as viral vectors and DNA vaccines, have emerged, leading to the investigation of candidate vaccines that have demonstrated protective efficacy in small animal and nonhuman primate studies. Here, we will discuss several of these vaccine platforms with a particular focus on approaches that have advanced into clinical development.
Project description:The latest outbreak of Ebola in West Africa overwhelmed the affected countries, with the impact on health extending far beyond Ebola-related deaths that have exceeded 11?000. The need to promptly mobilise resources to control emerging infections is widely recognized. Yet, data on research funding for emerging infections remains inadequately documented.We defined research investment as all funding flows for Ebola and/or Marburg virus from 1997 to April 2015 whose primary purpose was to advance knowledge and new technologies to prevent or cure disease. We sourced data directly from funding organizations and estimated the investment in 2015 US dollars (US$).Funding for Ebola and Marburg virus research in 1997 to 2015 amounted to US$ 1.035 billion, including US$ 435.4 million (42.0%) awarded in 2014 and 2015. Public sources of funding invested US$ 758.8 million (73.1%), philanthropic sources US$ 65.1 million (6.3%), and joint public/private/philanthropic ventures accounted for US$ 213.8 million (20.6%). Prior to the Ebola outbreak in 2014, pre-clinical research dominated research with US$ 443.6 million (73.9%) investment. After the outbreak, however, investment for new product development increased 942.7-fold and that for clinical trials rose 23.5-fold. Investment in new tools to control Ebola and Marburg virus amounted to US$ 399.1 million, with 61.3% awarded for vaccine research, 29.2% for novel therapeutics research such as antivirals and convalescent blood products, and 9.5% for diagnostics research. Research funding and bibliometric output were moderately associated (Spearman's ??=?0.5232, P?=?0.0259), however number of Ebola cases in previous outbreaks and research funding (??=?0.1706, P?=?0.4985) and Ebola cases in previous outbreaks and research output (??=?0.3020, P?=?0.0616) were poorly correlated.Significant public and philanthropic funds have been invested in Ebola and Marburg virus research in 2014 and 2015, following the outbreak in West Africa. Long term, strategic vision and leadership are needed to invest in infections with pandemic potential early, including innovative financing measures and open access investment data to promote the development of new therapies and technologies.
Project description:In 2014 and 2015, the largest Ebola virus disease (EVD) outbreak in history affected large populations across West Africa. The goal of this report is to provide an update on the epidemic and review current progress in the development, evaluation and deployment of prevention and treatment strategies for EVD. Relevant information was identified through a comprehensive literature search using Medline, PubMed and CINAHL Complete and using the search terms Ebola, Ebola virus disease, Ebola hemorrhagic fever, West Africa outbreak, Ebola transmission, Ebola symptoms and signs, Ebola diagnosis, Ebola treatment, vaccines for Ebola and clinical trials on Ebola. Through 22 July 2015, a total of 27,741 EVD cases and 11,284 deaths were reported from all affected countries. Several therapeutic agents and novel vaccines for EVD have been developed and are now undergoing evaluation. Concurrent with active case investigation, contact tracing, surveillance and supportive care to patients and communities, there has been rapid progress in the development of new therapies and vaccines against EVD. Continued focus on strengthening clinical and public health infrastructure will have direct benefits in controlling the spread of EVD and will provide a strong foundation for deployment of new drugs and vaccines to affected countries when they become available. The unprecedented West Africa Ebola outbreak, response measures, and ensuing drug and vaccine development suggest that new tools for Ebola control may be available in the near future.
Project description:Setting: All health centres in Macenta District, rural Guinea. Objective: To compare stock-outs of vaccines, vaccine stock cards and the administration of various childhood vaccines across the pre-Ebola, Ebola and post-Ebola virus disease periods. Design: This was an ecological study. Results: Similar levels of stock-outs were observed for all vaccines (bacille Calmette-Guérin [BCG], pentavalent, polio, measles, yellow fever) in the pre-Ebola and Ebola periods (respectively 2760 and 2706 facility days of stock-outs), with some variation by vaccine. Post-Ebola, there was a 65-fold reduction in stock-outs compared to pre-Ebola. Overall, 24 facility-months of vaccine stock card stock-outs were observed during the pre-Ebola period, which increased to 65 facility-months of stock-outs during the Ebola outbreak period; no such stock-out occurred in the post-Ebola period. Apart from yellow fever and measles, vaccine administration declined universally during the peak outbreak period (August-November 2014). Complete cessation of vaccine administration for BCG and a prominent low for polio (86% decrease) were observed in April 2014, corresponding to vaccine stock-outs. Post-Ebola, overall vaccine administration did not recover to pre-Ebola levels, with the highest gaps seen in polio and pentavalent vaccines, which had shortages of respectively 40% and 38%. Conclusion: These findings highlight the need to sustain vaccination activities in Guinea so that they remain resilient and responsive, irrespective of disease outbreaks.
Project description:There were once again high expectations that a major global health event - the Ebola virus outbreak of 2014-2015 - would trigger meaningfully World Health Organization (WHO) reform and strengthen global health governance (GHG). Rather than a "turning point," however, the global community has gone back to business as usual. This has occurred against a backdrop of worldwide political turmoil, characterised by a growing rejection of existing political leaders and state-centric institutions. Debates about GHG so far have given insufficient attention to the need for institutional innovation. This entails rethinking the traditional bureaucratic model of postwar intergovernmental organizations which is disconnected from the transboundary, fast-paced nature of today's globalizing world.
Project description:Emerging infectious diseases (EIDs) are a significant burden on global economies and public health. Their emergence is thought to be driven largely by socio-economic, environmental and ecological factors, but no comparative study has explicitly analysed these linkages to understand global temporal and spatial patterns of EIDs. Here we analyse a database of 335 EID 'events' (origins of EIDs) between 1940 and 2004, and demonstrate non-random global patterns. EID events have risen significantly over time after controlling for reporting bias, with their peak incidence (in the 1980s) concomitant with the HIV pandemic. EID events are dominated by zoonoses (60.3% of EIDs): the majority of these (71.8%) originate in wildlife (for example, severe acute respiratory virus, Ebola virus), and are increasing significantly over time. We find that 54.3% of EID events are caused by bacteria or rickettsia, reflecting a large number of drug-resistant microbes in our database. Our results confirm that EID origins are significantly correlated with socio-economic, environmental and ecological factors, and provide a basis for identifying regions where new EIDs are most likely to originate (emerging disease 'hotspots'). They also reveal a substantial risk of wildlife zoonotic and vector-borne EIDs originating at lower latitudes where reporting effort is low. We conclude that global resources to counter disease emergence are poorly allocated, with the majority of the scientific and surveillance effort focused on countries from where the next important EID is least likely to originate.
Project description:<h4>Background</h4>Central Africa is a "hotspot" for emerging infectious diseases (EIDs) of global and local importance, and a current outbreak of ebolavirus is affecting multiple countries simultaneously. Ebolavirus is suspected to have caused recent declines in resident great apes. While ebolavirus vaccines have been proposed as an intervention to protect apes, their effectiveness would be improved if we could diagnostically confirm Ebola virus disease (EVD) as the cause of die-offs, establish ebolavirus geographical distribution, identify immunologically naïve populations, and determine whether apes survive virus exposure.<h4>Methodology/principal findings</h4>Here we report the first successful noninvasive detection of antibodies against Ebola virus (EBOV) from wild ape feces. Using this method, we have been able to identify gorillas with antibodies to EBOV with an overall prevalence rate reaching 10% on average, demonstrating that EBOV exposure or infection is not uniformly lethal in this species. Furthermore, evidence of antibodies was identified in gorillas thought previously to be unexposed to EBOV (protected from exposure by rivers as topological barriers of transmission).<h4>Conclusions/significance</h4>Our new approach will contribute to a strategy to protect apes from future EBOV infections by early detection of increased incidence of exposure, by identifying immunologically naïve at-risk populations as potential targets for vaccination, and by providing a means to track vaccine efficacy if such intervention is deemed appropriate. Finally, since human EVD is linked to contact with infected wildlife carcasses, efforts aimed at identifying great ape outbreaks could have a profound impact on public health in local communities, where EBOV causes case-fatality rates of up to 88%.
Project description:Filoviruses (Ebola and Marburg viruses) are among the deadliest viruses known to mankind, with mortality rates nearing 90%. These pathogens are highly infectious through contact with infected body fluids and can be easily aerosolized. Additionally, there are currently no licensed vaccines available to prevent filovirus outbreaks. Their high mortality rates and infectious capabilities when aerosolized and the lack of licensed vaccines available to prevent such infectious make Ebola and Marburg viruses serious bioterrorism threats, placing them both on the category A list of bioterrorism agents. Here we describe a panfilovirus vaccine based on a complex adenovirus (CAdVax) technology that expresses multiple antigens from five different filoviruses de novo. Vaccination of nonhuman primates demonstrated 100% protection against infection by two species of Ebola virus and three Marburg virus subtypes, each administered at 1,000 times the lethal dose. This study indicates the feasibility of vaccination against all current filovirus threats in the event of natural hemorrhagic fever outbreak or biological attack.
Project description:The Ebola virus is a zoonotic pathogen that can cause severe hemorrhagic fever in humans, with up to 90% lethality. The deadly 2014 Ebola outbreak quickly made an unprecedented impact on human lives. While several vaccines and therapeutics are under development, current approaches contain several limitations, such as virus mutational escape, need for formulation or refrigeration, poor scalability, long lead-time, and high cost. To address these challenges, we developed locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) to target critical Ebola viral proteins and the human intracellular host protein Niemann-Pick C1 (NPC1), required for viral entry into infected cells. We generated noninfectious viral luciferase reporter assays to identify LNA ASOs that inhibit translation of Ebola viral proteins in vitro and in human cells. We demonstrated specific inhibition of key Ebola genes VP24 and nucleoprotein, which inhibit a proper immune response and promote Ebola virus replication, respectively. We also identified LNA ASOs targeting human host factor NPC1 and demonstrated reduced infection by chimeric vesicular stomatitis virus harboring the Ebola glycoprotein, which directly binds to NPC1 for viral infection. These results support further in vivo testing of LNA ASOs in infectious Ebola virus disease animal models as potential therapeutic modalities for treatment of Ebola.
Project description:Clinical development of Ebola virus vaccines (EVV) was accelerated by the West African Ebola virus epidemic which remains the deadliest in history. To compare and rank the EVV according to their immunogenicity and safety. A total of 21 randomized controlled trial, evaluating seven different vaccines with different doses, and 5,275 participants were analyzed. The rVSVΔG-ZEBOV-GP (2 × 10 <sup>7</sup>) vaccine was more immunogenic (<i>P</i>-score 0.80). For pain, rVSVΔG-ZEBOV-GP (≤10 <sup>5</sup>) had few events (<i>P</i>-score 0.90). For fatigue and headache, the DNA-EBOV (≤ 4 mg) was the best one with <i>P</i>-scores of 0.94 and 0.87, respectively. For myalgia, the ChAd3 (10 <sup>10</sup>) had a lower risk (<i>P</i>-score 0.94). For fever, the Ad5.ZEBOV (≤ 8 × 10 <sup>10</sup>) was the best one (<i>P</i>-score 0.80). The best vaccine to be used to stop future outbreak of Ebola is the rVSVDG-ZEBOV-GP vaccine at dose of 2 × 10<sup>7</sup> PFU.