Global challenges in preparedness and response to epidemic infectious diseases
Authors: Piero Olliaro, Els Torreele
Journal: Molecular Therapy (2022)

Lessons drawn from successes and failures with coronavirus disease 2019 (COVID-19) and Ebola virus disease (EVD) should help shaping a robust health innovation system for infectious disease epidemics. Epidemic response research and development (R&D) can be mobilized quickly for public health priorities and yield medicinal products within months. However, to resolve epidemics, technological advances must be equitably accessible and deployed, and these examples expose the limitations of a supply-driven, fragmented R&D ecosystem relying primarily on the private sector to deliver health products. Efficient epidemic response requires a coordinated public health-focused, end-to-end R&D ecosystem for the development, registration, availability, and use of pharmaceutical products. Because pivotal clinical trials can only be conducted during outbreaks, significant preparation must be done beforehand: strengthening clinical research capacity and developing pre-positioned trial protocols and clinical characterization protocols, as well as conducting discovery and pre-clinical research, manufacturing, and early clinical testing of candidate products. This will allow for speedy execution of clinical research early into an outbreak and delivering products within a short time. Effective interventions should be adopted and deployed ensuring equitable access during the ongoing outbreak. Measures to make products available where and when needed must be integrated throughout the R&D value chain. Lessons drawn from successes and failures with coronavirus disease 2019 (COVID-19) and Ebola virus disease (EVD) should help shaping a robust health innovation system for infectious disease epidemics. Epidemic response research and development (R&D) can be mobilized quickly for public health priorities and yield medicinal products within months. However, to resolve epidemics, technological advances must be equitably accessible and deployed, and these examples expose the limitations of a supply-driven, fragmented R&D ecosystem relying primarily on the private sector to deliver health products. Efficient epidemic response requires a coordinated public health-focused, end-to-end R&D ecosystem for the development, registration, availability, and use of pharmaceutical products. Because pivotal clinical trials can only be conducted during outbreaks, significant preparation must be done beforehand: strengthening clinical research capacity and developing pre-positioned trial protocols and clinical characterization protocols, as well as conducting discovery and pre-clinical research, manufacturing, and early clinical testing of candidate products. This will allow for speedy execution of clinical research early into an outbreak and delivering products within a short time. Effective interventions should be adopted and deployed ensuring equitable access during the ongoing outbreak. Measures to make products available where and when needed must be integrated throughout the R&D value chain. An epidemic is "an increase, often sudden, in the number of cases of a disease above what is normally expected in that population in that area."1US Department of Health and Human ServicesPrinciples of Epidemiology in Public Health Practice.3rd edition. 2006https://www.cdc.gov/csels/dsepd/ss1978/SS1978.pdfGoogle Scholar Many conditions would therefore qualify as an epidemic, including both communicable and non-communicable diseases—e.g., the ongoing "obesity epidemic"2González-Muniesa P. Mártinez-González M.A. Hu F. Deprés J.P. Matsuzawa Y. Loos R.J.F. Moreno L.A. Bray G.A. Martinez J.A. Obesity.Nat. Rev. Dis. Primers. 2017; 3: 17034Crossref PubMed Scopus (526) Google Scholar and the "opioid overdose epidemic."3Skolnick P. The opioid epidemic: crisis and solutions.Annu. Rev. Pharmacol. Toxicol. 2018; 58: 143-159Crossref PubMed Scopus (150) Google Scholar Even when focusing on infectious disease epidemics, we still have very different scenarios: seasonal or occasional outbreaks of endemic infections (e.g., dengue and other arboviruses), seasonal spill-overs from animal reservoirs (e.g., Ebola virus disease [EVD], Lassa fever, and other viral hemorrhagic diseases, plague), new diseases (be it a known pathogen introduced in a new geographical area, or a previously unknown pathogen for humans, like sever acute respiratory disease coronavirus 2). Most of these epidemics are geographically and time limited. The spread of an epidemic over several countries and continents may prompt the World Health Organization (WHO) to declare a pandemic. Between the great influenza pandemic of 1918 and the COVID-19 pandemic, many epidemics have occurred, mostly under the radar screen of media and public attention, but also neglected by science and investments in preparedness or response capacity, including tools development. Occasionally, some epidemics overcome this high tolerance threshold and trigger attention and reactions, essentially when they are perceived as a threat to "global health security," i.e., potentially affecting high-income countries.4Heymann D.L. Chen L. Takemi K. Fidler D.P. Tappero J.W. Thomas M.J. Kenyon T.A. Frieden T.R. Yach D. Nishtar S. et al.Global health security: the wider lessons from the west African Ebola virus disease epidemic.Lancet. 2015; 385: 1884-1901Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar Therefore, there is no one-size-fit-all approach to responding to infectious disease epidemics. However, there certainly are cross-cutting elements underpinning a successful prevention, preparedness, and response system. They are the sum of reliable disease surveillance, robust health systems, responsive medical innovation, equitable access to medicine and health care—which means essentially reaching the sustainable development goals 3 (good health and well-being) and 10 (reduced inequalities).5United Nations17 Sustainable Development Goals.2015https://sdgs.un.org/goalsGoogle Scholar Diagnostics, treatments, and vaccines are critical health technologies for public health emergency preparedness and response. Ensuring their timely development and availability is, therefore, a collective public health responsibility. However, even for well-known microbial threats, such technologies are often not (sufficiently) available when needed, or come late during an outbreak, are ill-adapted to the health systems, or are only accessible for few. It is important to understand why and how these health technologies are developed, how they are deployed, and what makes them fail or succeed. At a different scale, both the West African EVD epidemic and the COVID-19 pandemic have shown how dependent the success of public health interventions is on accurate education and science communication and how misinformation can undermine epidemic response. The pandemic has also revealed how collectively unprepared we are to exposing unfiltered scientific debate—which feeds on diversity of opinions—to public scrutiny, often resulting in either naive or malevolent misinterpretations. Scientific journals have also been overwhelmed with submissions, also revealing the limits of the peer review system and its overall capacity to critically absorb a large influx of papers, with sometimes negative consequences on decision-making.6Davey M. Kirchgaesser S. Boseley S. Surgisphere: Governments and WHO changed Covid-19 policy based on suspect data from tiny US Company (2020).The Guardian. 2020; (3 June)https://www.theguardian.com/world/2020/jun/03/covid-19-surgisphere-who-world-health-organization-hydroxychloroquineGoogle Scholar The dearth of available health technologies for epidemic preparedness and response is commonly ascribed to "market failure"—an expression of the current health innovation ecosystem relying largely on the private sector for pharmaceutical product research and development (R&D) and supply. The general lack of commercial attractiveness of infectious diseases (often requiring short-term therapies, as opposed to more lucrative chronic treatments)7Kim T. Goldman Sachs Asks in Biotech Research Report: 'Is Curing Patients a Sustainable Business Model?' CNBC 18 April.2018https://www.cnbc.com/2018/04/11/goldman-asks-is-curing-patients-a-sustainable-business-model.htmlGoogle Scholar is compounded with a weak "business case," given the unpredictable size and timing of "demand" in the case of epidemic outbreaks, and a reluctancy of public health systems and the international community to invest in structural interventions and preventive measures, including stockpiles that might remain unused, expire, and needing replacement. While the COVID-19 pandemic may have temporarily transformed epidemic preparedness and response R&D from an area of market failure to a highly profitable market opportunity, it has still relied on massive public investments and other policy interventions to mobilize and reward the private sector. Despite the successful development of multiple effective vaccines at unprecedented speed, access to these vaccine remains profoundly unequal, which is a likely engine of persistent transmission and mutations in viral genome.8World Health OrganizationVaccine inequity undermining global economic recovery.News Release. 2021; 22https://www.who.int/news/item/22-07-2021-vaccine-inequity-undermining-global-economic-recoveryGoogle Scholar This lack of a globally coordinated end-to-end R&D ecosystem and a public health-oriented governance mechanism when it comes to the availability and use of interventions is hindering our capacity to effectively prevent and curb epidemics—now and in the future—if radical changes are not set in place.9Lurie N. Keusch G.T. Dzau V.J. Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.Lancet. 2021; 27: 1229-1236Abstract Full Text Full Text PDF Scopus (25) Google Scholar,10Torreele E. Kazatchkine M. Mazzucato M. Preparing for the next pandemic requires public health-focused industrial policy.BMJ. 2021; (1 April)https://blogs.bmj.com/bmj/2021/04/01/preparing-for-the-next-pandemic-requires-public-health-focused-industrial-policy/Google Scholar In responding to global health threats, governments and their health authorities are naturally in charge of defining the response strategies and outbreak control measures, from non-pharmaceutical interventions like physical distancing, protective barriers, travel restrictions, and lockdowns, to testing, treatment, and vaccination strategies. Public health authorities would also be expected to (1) define which type of pharmaceutical interventions they need—i.e. determining the target product profile; (2) coordinate a portfolio of R&D projects that covers priority health needs in order to identify and facilitate the development of the most suited products; (3) oversee the research methodology and study designs to ensure they address the most important public health questions in a timely way; and (4) secure the availability, accessibility, and optimal deployment of the health interventions for epidemic preparedness and response. However, this is hardly the case. When infectious disease epidemics arise, and especially when they are not just a public health concern but are also considered a global health security threat, there is a flurry of activities by the global health community to start R&D or revive dormant workstreams, in what is often a very reactive and mostly competitive—uncoordinated, uncollaborative—mode. The R&D ecosystems functions like a conductor-less orchestra, with research groups, public health institutions, funders, and pharmaceutical companies each pursuing their objectives, but not necessarily in harmony toward shared public health goals. For instance, the responsibility to bring investigational products into clinical development and subsequent registration is largely left to commercial product developers that will select which proprietary technologies will be progressed—whether it corresponds or not with the most desirable public health interventions. At the same time, academic and other public researchers—often competing for funding through research financing mechanisms that are ill-adapted to respond to health emergencies—will launch a variety of investigator-driven studies using available products or interventions (e.g., by repurposing or combining drugs). Figure 1 summarizes the critical disruptions at the main steps in product development and use conspiring against mounting an effective epidemic response system. For instance, as of November 2021, 4,299 treatment trials (1,172 recruiting, 1,044 completed, and 760 inactive, suspended, terminated, or withdrawn) and 1,104 vaccine trials (1,104 recruiting, 513 completed, and 242 inactive, suspended, terminated, or withdrawn) are registered just in clinicaltrials.gov.11https://clinicaltrials.govGoogle Scholar It is difficult to know which of these trial results are published where, or when or if they will be published at all.12Jones C.W. Adams A.C. Murphy E. King R.P. Saracco B. Stesis K.R. Cavanaugh S. Roberts B.W. Platts-Mills T.F. Delays in reporting and publishing trial results during pandemics: cross sectional analysis of 2009 H1N1, 2014 Ebola, and 2016 Zika clinical trials.BMC Med. Res. Methodol. 2021; 21: 120Crossref PubMed Scopus (3) Google Scholar Without a mechanism to channel resources to the most promising interventions and ensure global collaboration and coordination rather than fragmented competition, there will be too many ill-designed, underpowered, or otherwise inconclusive or non-comparable trials.13Lowe D. The problem with COVID-19 clinical trials.https://www.science.org/content/blog-post/problem-covid-19-clinical-trialsDate: 2021Google Scholar,14Manoharan L. Olliaro P. Horby P.W. Watson C.H. Chemoprophylaxis trial designs in epidemics: insights from a systematic review of COVID-19 study registrations.Trials. 2021; 22: 370Crossref PubMed Scopus (1) Google Scholar Companies also have no obligation to ensure that products are registered, available, and accessible in countries where outbreaks occur, while research funders typically only finance certain types of activities—for instance, clinical trials—but not necessarily manufacturing, registration, availability, or access. There is no clear division of labor and responsibility across the R&D value chain, nor any agreed plans around ownership and sharing of scientific data, intellectual property (IP) management, strategic use of manufacturing capacity, or allocation of final products in the interest of global public health. Finally, there is currently no collective mechanism to ensure end-to-end financing of epidemic preparedness and response R&D, including equitable global access. Given that the availability of financing is a critical driver of many activities along the value chain, there is an important role for research funders in directing the right kind of studies and coordination, and put conditionalities as needed to the financing to ensure that research efforts are pursued in ways that maximize chances to result in equitable access, including research data sharing. Figure 2 depicts the proposed essential elements of a global research and response architecture for infectious disease epidemics. A specific challenge with medical innovation for epidemic diseases is that interventions can only be tested clinically during an outbreak, often as integral part of response. Since when and where an outbreak will occur is often unpredictable, most of the preparatory work must be done outside (ahead of) epidemics to enable a prompt and coordinated response when an outbreak does occur. This requires strengthening clinical research capacity in "peacetime," as during epidemics health care systems are often stretched dealing with providing medical treatment to patients, which makes it difficult for them to absorb and implement trials, especially in low-resource settings. It also requires a public health-driven priority setting to ensure that the most promising interventions are tested in priority, not just the ones that were able to amass sufficient resources quickly. We have seen various cases where trials did only start past the peak of transmission or where research groups competed for access to patients, thereby fragmenting the effort, with the result that the projected sample size could not be enrolled due to declining number of cases. A case in point are multiple treatment trials set up during the 2016–2018 West Africa EVD epidemic.15Rojek A. Horby P. Dunning J. Insights from clinical research completed during the west Africa Ebola virus disease epidemic.Lancet Infect. Dis. 2017; 17: e280-e292Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,16Olliaro P.L. Initiation and publication time-lags of treatment trials for Ebola virus disease.Lancet Infect. Dis. 2018; 18: 28-29Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Yet, neither the West Africa EVD epidemic nor the COVID-19 pandemic are the archetypal outbreak given their size and duration; most epidemics are short lived, have low caseload, and may be geographically dispersed. For instance, between 2003 and 2021, a total of 862 laboratory-confirmed human cases of avian influenza A (H5N1) have been reported from 16 countries.17World Health OrganizationInfluenza at the human-animal interface. Summary and assessment, from 23 June to 8 August 2021.https://cdn.who.int/media/docs/default-source/influenza/human-animal-interface-risk-assessments/influenza_summary_ira_ha_interface_08_08_2021.pdfDate: 2021Google Scholar Similarly, 1,516 human cases of avian influenza A (H7N9) have been reported between 2013 and 2017, with the largest epidemic being 776 cases occurring in China over 12 months in 2016 and 2017. Under these circumstances, it is particularly challenging to conduct proper clinical trials to test new interventions, despite their high case fatality rates (about one-half and one-third, respectively) and evident epidemic potential.18Centers for Disease Control and Prevention. Asian Lineage Avian Influenza A/H7N)) Virus. https://www.cdc.gov/flu/avianflu/h7n9-virus.htmGoogle Scholar This warrants piloting innovative trial designs that can span multiple outbreaks, in multiple countries, as was intended with the original design of the Ebola PALM trial.19Mulangu S. The PALM Consortium: a multicenter, multi-outbreak randomized controlled trial of Ebola virus disease therapeutics.Open Forum Infect. Dis. 2019; 6: S12-S13Crossref Google Scholar The longer-lasting 2009–2010 influenza A (H1N1)pdm09 pandemic represents instead a failed, belated response, and a hugely missed opportunity to gather timely information essential to setting up an effective response. The US Centers for Disease Control and Prevention estimate that between 151,700 and 575,400 deaths,20Centers for Disease Control and PreventionH1N1 Pandemic (H1N1pdm09 Virus).https://www.cdc.gov/flu/pandemic-resources/2009-h1n1-pandemic.htmlDate: 2009Google Scholar which, contrary to seasonal flu, occurred mostly in a younger population. By the time a specific vaccine became available in large enough quantities, it was already late in the pandemic. Clinical research was of insufficient quality and the results became available mostly well after the pandemic was over.21Rojek A.M. Martin G.E. Horby P.W. Compassionate drug (mis)use during pandemics: lessons for COVID-19 from 2009.BMC Med. 2020; 18: 265Crossref PubMed Scopus (6) Google Scholar Clinical research also requires observational studies to understand clinical presentation and risks of unfavorable outcomes to inform case management practices. This entails the development of pre-positioned and approved clinical record forms for rapid uptake to generate harmonized datasets. These adaptable research tools exist. The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) is a global federation of clinical research networks that work collaboratively to prevent illness and deaths from infectious disease outbreaks. The ISARIC adheres to principles of open-source research22Dunning J.W. Merson L. Rohde G.G.U. Gao Z. Semple M.G. Tran D. Gordon A. Olliaro P.L. Khoo S.H. Bruzzone R. et al.Open source clinical science for emerging infections.Lancet Infect. Dis. 2014; 14: 8-9Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar and collaboration instead of competition.23ISARIC Clinical Characterisation GroupGlobal outbreak research: harmony not hegemony.Lancet Infect. Dis. 2020; 20: 770-772Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar The ISARIC-WHO clinical record form was quickly adopted at the onset of the COVID-19 pandemic,24International Severe Acute Respiratory and emerging Infection Consortium. ISARIC Covid-19 Timeline 2019-2021. https://isaric.org/covid-19-pandemic-response-timeline/.Google Scholar leading to a dataset of more than 700,000 COVID-19 cases at the time of this writing25Baillie J.K. Baruch J. Beane A. Blumberg L. Bozza F.A. Broadley T. Burrell A. Carson G. Citarella B.W. Dunning J. et al.ISARIC Clinical Characterisation GroupISARIC COVID-19 clinical data report Issued: 15 December 2021.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2020.07.17.20155218Crossref Scopus (0) Google Scholar that can be accessed for analyses. This shows that a global collaborative approach, based on research readiness in a peer-to-peer network, is achievable and effective, and can be replicated for future epidemics.26ISARIC Clinical Characterisation GroupThe value of open-source clinical science in pandemic response: lessons from ISARIC.Lancet Infect. Dis. 2021; 21: 1623-1624Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Too often, the battle about access is unsuitably centered on the final product, when in reality it starts much upstream. A key characteristic of market failure is that market demand-and-supply dynamics do not leverage R&D, availability, and access when the purchasing power of those affected is too small to attract commercial interest. Fixing the market failure for R&D—for instance, through public funding or other market incentives—does not guarantee that the resulting interventions will be registered, available, and accessible in countries where outbreaks occur. Outside an ongoing outbreak, there may be little urge for companies to seek product registration, or for countries or public health authorities to purchase (for stockpiling) the new product if registered—unless motivated by reasons like health security. As a result, critical health technologies that have been developed are not necessarily available where and when an outbreak occurs. Since licensure is granted to pharmaceutical companies, even if the research was done by broad consortia of public and private partners, the control over product availability—how much is being manufactured and sold to whom and at what price—is essentially in the hands of the private sector. A company typically holds both IP rights via patents on products and technologies and retains exclusivity on the use of data contained in the regulatory dossier, precluding others to produce and sell the products. Such monopolies compound the fragility of an already precarious supply chain. Reliance on a single source for the supply of critical health technologies is a recipe for scarcity, high prices, or both, with major impact on equitable access. The inequalities in COVID-19 vaccine access in Africa for instance are explained in part to the lack of vaccine manufacturing capacity on the continent (currently importing 99% of all vaccines used).27Irwin A. How COVID spurred Africa to plot a vaccines revolution.https://www.nature.com/articles/d41586-021-01048-1Date: 2021Google Scholar Too often, companies will prioritize licensure in markets of interest, primarily the United States, Europe, and a handful of other countries that may be interested in establishing strategic stockpiles for certain diseases of epidemic potential. For products that are eligible to receive a US Food and Drug Administration (FDA) priority review voucher, an incentive to stimulate the development of drugs or vaccines against neglected tropical diseases, filoviruses (including Ebola), rare pediatric indications, and medical countermeasures for certain global health security threats,28US Food and Drug AdministrationTropical Disease Priority Review Voucher Program.https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-programGoogle Scholar the financial reward is obtained upon registration at the US FDA. Unfortunately, obtention of the reward is not linked to any obligation for availability or access where needed.29Sunyoto T. Potet J. Boelaert M. Why miltefosine, a life-saving drug for leishmaniasis, is unavailable to people who need it the most.BMJ Glob. Health. 2018; 3: e000709Crossref PubMed Scopus (57) Google Scholar As illustrated below, EVD and COVID-19 are two examples of exceptional epidemic R&D efforts where, despite much heralded successes in product development, inadequate public health-focused leadership and governance has resulted in unfinished research agendas, critical availability gaps, and major access inequities. While different in size and health and economic impact, both benefited from massive public investments to support and accelerate the development and availability of medical technologies to help curb the epidemics. Yet, this was not accompanied by commensurate public oversight and end-to-end steering to ensure maximal impact of investments, with major public health, access, and ethics implications. While known since the 1970s, EVD is a typical case of market failure: no treatment, diagnostic, or vaccine was available when a long-expected, major outbreak devastated Guinea, Liberia, and Sierra Leone in 2014–2016, killing more than 11,000 people and creating a global panic.30Torreele E. Olliaro P. Ebola in west africa is a wake-up call. What the Ebola crisis tells us about our failing drug development system.http://www.aljazeera.com/indepth/opinion/2014/11/ebola-west-africa-wake-up-call-2014112125429230915.htmlDate: 2014Google Scholar Yet, thanks to an impressive mobilization of public health institutions, governments, researchers, philanthropic organizations, pharmaceutical companies, and humanitarian actors coming together on an ad hoc basis, a burst of R&D activities ensued, which continued throughout the 2018–2019 outbreaks in the Democratic Republic of Congo (DRC). By early 2021, there were two vaccines and two treatments registered by FDA or European Medicines Agency (EMA), an impressive achievement, yet their availability, affordability, and effective use for current and future EVD outbreaks remain wrought with questions and uncertainties. Of the four new Ebola products that received FDA or EMA marketing authorization, only the rVSV-ZEBOV vaccine (Ervebo) produced by Merck is registered in DRC and in a few other Ebola-prone African countries. It is also WHO prequalified. In January 2021, a GAVI-funded global emergency stockpile of 500,000 doses was created under the auspices of the International Coordinating Group on Vaccine Provision, accessible to all countries.31Gavi The Vaccine AllianceEbola vaccine to be made available to countries for outbreak response.News Release. 2021; 12https://www.gavi.org/news/media-room/500000-doses-ebola-vaccine-be-made-available-countries-outbreak-responseGoogle Scholar While lower income countries can obtain vaccines for free, it is not known how much other countries will be charged, nor the price Merck has charged GAVI. It is also not clear how the supply will be sustained in the future. Johnson & Johnson's (JNJ) prime-boost vaccine (Zabdeno [Ad26.ZEBOV] and Mvabea [MVA-BN-Filo]) was WHO pre-qualified, is being used in further studies but is not yet registered in African countries. The two treatments, Regeneron's Inmazeb (the association of three monoclonal antibodies: atoltivimab, maftivimab, and odesivimab-ebgn) and Ridgeback Biotherapeutics' Ebanga (the monoclonal antibody ansuvimab), are also not registered in any African country. It is thought that the US government has established stockpiles of at least one, if not both, Ebola treatments, but no details of size and price are publicly available. Critically, none of these registered products seems readily available for use in disease-endemic countries, including the DRC, which has been experiencing a series of EVD outbreaks. During the 2018–2020 Kivu EVD outbreak—the second largest recorded outbreak—control efforts made use of remaining clinical supplies of the still-investigational products with little transparency on how to access these stocks, and with often restricted conditions for use because still under restrictive "study conditions." In addition, many outstanding research questions remain around both vaccines and treatments, and there is no pathways or clear responsibilities as to how to address them. The fact that none of these products can be bought through regular procurement channels (there are also no official prices, and secrecy over prices paid for the stockpiles) has hampered operational research to better understand how to best deploy these different tools for epidemic preparedness and response. The pivotal efficacy trial for Merck's rVSV-ZEBOV vaccine in Guinea was designed as a reactive cluster ring vaccination study—whereby contacts and contacts of contacts of cases are randomized to receive vaccine or placebo. The subsequent use of this vaccine in the DRC followed the same approach, and the WHO Strategic Advisory Group of Experts on Immunization (SAGE) continues to recommend it as primary strategy in case of an EVD outbreak, partly because of limited supplies.32World Health OrganizationMeeting of the strategic advisory group of ex